WO2011143721A1 - Compositions et procédés pour le traitement de troubles neurodégénératifs - Google Patents

Compositions et procédés pour le traitement de troubles neurodégénératifs Download PDF

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WO2011143721A1
WO2011143721A1 PCT/AU2011/000610 AU2011000610W WO2011143721A1 WO 2011143721 A1 WO2011143721 A1 WO 2011143721A1 AU 2011000610 W AU2011000610 W AU 2011000610W WO 2011143721 A1 WO2011143721 A1 WO 2011143721A1
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disease
pharmaceutical composition
agents
disorder
kit
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PCT/AU2011/000610
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English (en)
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Philip Bird
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Gosforth Centre (Holdings) Pty Ltd
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Publication of WO2011143721A1 publication Critical patent/WO2011143721A1/fr

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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
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • NEURODEGENERATIVE DISORDERS FIELD OF THE INVENTION relates to combination therapy of neurodegenerative disorders such as dementia and Parkinson's disease. More particularly, this invention relates to combination therapy of neurodegenerative disorders using anti-epileptic agents, in combination with one or more agents useful in treating neurodegenerative diseases, conditions or disorders.
  • Neurodegeneration is the progressive loss of structure or function of neurons, including the death or functional disablement of neurons in the brain and/or central nervous system.
  • Neurodegenerative diseases include Parkinson's, dementia, Alzheimer's disease and Huntington's disease.
  • Parkinson's disease is characterised by tremor, rigidity, akinesia or bradykinesia, and loss of postural reflexes, associated with reduced dopamine activity in the brain. It may be classified as follows:
  • Parkinson's disease formerly paralysis agitans
  • parkinsOnism is a feature of other degenerative diseases of the CNS, such as progressive supranuclear palsy and multiple system atrophy.
  • Parkinson's disease is often used for the idiopathic form, that is, Parkinson's disease.
  • Parkinson's disease and postencephalitic parkinsonism have been attributed primarily to depletion of striatal dopamine in the basal ganglia as a result of the loss of neurones in the substantia nigra.
  • Striatal dopamine deficiency results in loss of the normal functional balance between dopaminergic and cholinergic activity and the aim of treatment is to increase the former and/or decrease the latter.
  • MPTP l -methyl-4-phenyl- l ,2,3,6- tetrahydropyridine
  • MPPP l -methyl-4-phenyl-4-propionoxypiperidine
  • Drug-induced parkinsonism can arise from depletion of presynaptic dopamine, as with reserpine and tetrabenazine, or from blockade of postsynaptic dopamine receptors in the striatum, as by antipsychotics and some antiemetics such as metoclopramide. It is generally reversible on drug withdrawal or dose reduction and may sometimes disappear gradually despite continuous drug therapy. Although the use of levodopa to overcome antipsychotic-induced blockade of dopamine receptors might appear rational, it has generally been reported to be ineffective or to increase psychiatric symptoms. Antimuscarinics may provide relief from the extrapyramidal symptoms that occur as adverse effects of antipsychotic therapy; however, they do not relieve the symptoms of tardive dyskinesia and should be withdrawn if it develops.
  • Parkinson's disease Although the possibility of using drug therapy to slow neurodegeneration is being investigated, no drug so far has a proven neuroprotective effect.
  • Treatment is palliative and symptomatic and consists mainly of drug therapy supplemented when necessary with physical treatment such as physiotherapy and speech therapy. Surgery is occasionally used and there is growing interest in the use of transplantation and in electrical devices for the control of tremor.
  • L-dopa (or levodopa) in various forms.
  • L-dopa is transformed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa- decarboxylase).
  • L-aromatic amino acid decarboxylase (often known by its former name dopa- decarboxylase).
  • dopa- decarboxylase of L-dopa enters the dopaminergic neurons.
  • the remaining L-dopa is often metabolised to dopamine elsewhere, causing a wide variety of side effects.
  • Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive.
  • Carbidopa and benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations of carbidopa/levodopa (co- careldopa; e.g. Sinemet, Parcopa) and benserazide/levodopa (co-beneldopa) (e.g. Madopar). There are also controlled release versions of Sinemet and adopar that spread out the effect of the L-dopa.
  • Duodopa is a combination of levodopa and carbidopa, dispersed as a viscous gel.
  • the drug is continuously delivered via a tube directly into the upper small intestine, where it is rapidly absorbed.
  • Another drug Stalevo (carbidopa, levodopa and entacapone), is also available for treatment.
  • Catechol-O-methyltransferase (CO T) inhibitors such as entacapone and tolcapone, are selective and reversible inhibitors of COMT, with mainly peripheral actions. They are given as adjunctive therapy to patients experiencing fluctuations in disability related to levodopa and dopa-decarboxylase inhibitor combinations; because of the risk of serious hepatotoxicity, tolcapone should be restricted to when other adjunctive therapy is ineffective or contra-indicated.
  • levodopa When levodopa is used with a peripheral dopa-decarboxylase inhibitor, O- methylation becomes the predominant form of metabolism of levodopa; adding a peripheral COMT inhibitor can thus extend the duration and effect of levodopa in the brain, and allow lower and less frequent doses of levodopa. They therefore can help to stabilise patients, especially those experiencing 'end-of-dose' deterioration.
  • Dopamine agonists such as bromocriptine, cabergoline, lisuride, pergolide, pramipexole, and ropinirole act by direct stimulation of remaining postsynaptic dopamine receptors.
  • Dopamine agonists are increasingly used in the early treatment of younger patients with parkinsonism in an attempt to delay therapy with levodopa (younger patients are at an increased risk of motor complications with levodopa).
  • their efficacy often decreases after a few years. In older patients they may be reserved for adjunctive use when levodopa is no longer effective alone or cannot be tolerated. They are sometimes useful in reducing 'off periods with levodopa and in ameliorating fluctuations in mobility in the later stages of the disease.
  • Apomorphine is a potent dopamine agonist, but must be given parenterally and with an antiemetic. Although this restricts its use, it has a role in stabilising patients who suffer unpredictable ⁇ -off effects. It is also used in the differential diagnosis of parkinsonism. Transdermal patches containing rotigotine, another dopamine agonist, are available for use as monotherapy in the treatment of early- stage Parkinson's disease in some countries.
  • Antimuscarinics are considered to have a weak antiparkinsonian effect compared with levodopa. They may reduce tremor but have little effect on bradykinesia. They may be of use alone or with other drugs in the initial treatment of patients with mild symptoms, especially when tremor is pronounced, or later as an adjunct to levodopa, such as in patients with refractory tremor or dystonias. Antimuscarinic adverse effects, particularly cognitive impairment, occur frequently and can limit their use. However, some antimuscarinic effects can ameliorate complications associated with Parkinson's disease; dry mouth may be an advantage in patients with sialorrhoea.
  • Parkinson's disease There appear to be no important differences in the efficacy of antimuscarinics for Parkinson's disease but some patients may tolerate one drug better than another. Those commonly used for Parkinson's disease include benzatropine, orphenadrine, procyclidine, and trihexyphenidyl.
  • Amantadine is a weak dopamine agonist with some antimuscarinic activity although its activity as an antagonist of N-methyl-D-aspartate may also have a beneficial effect in Parkinson's disease. It has mild antiparkinsonian effects compared with levodopa but is relatively free from adverse effects. It can improve bradykinesia as well as tremor and rigidity but only a small proportion of patients derive much benefit. It is used similarly to antimuscarinics in early disease when symptoms are mild, but tolerance to its effects can occur rapidly.
  • Prarnipexole was proposed in late 2009 as an early-stage treatment alternative to Levodopa.
  • Selegiline and rasagiline reduce the symptoms of Parkinson's disease by inhibiting monoamine oxidase-B (MAO-B).
  • MAO-B breaks down dopamine secreted by the dopaminergic neurons, so inhibiting it will result in inhibition of the breakdown of dopamine.
  • Metabolites of selegiline include L-amphetamine and L-methampheiamine (not to be confused with the more notorious and potent dextrorotary isomers). This might result in side effects such as insomnia.
  • Use of L-dopa in conjunction with selegiline has increased mortality rates that have not been effectively explained. Another side effect of the combination can be stomatitis.
  • Dementia is another neurodegenerative condition that is characterized by a progressive decline in cognitive function which may be due to damage or disease in the brain beyond what might be expected from normal aging. Areas particularly affected include memory, attention, judgement, language and problem solving. Dementia typically begins gradually and worsens progressively over several years due to nueronal degeneration of the brain and causing gradual but irreversible loss of function. The causes of dementia depend on the age at which symptoms begin. In the elderly population (usually defined in this context as over 65 years of age), a large majority of cases of dementia are caused by Alzheimer's disease, vascular dementia or both. Dementia with Lewy bodies is another fairly common cause, which again may occur alongside either or both of the other causes
  • Acetylcholinesteraseinhibitors Tacrine (Cognex), donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon) are approved by the United States Food and Drug Administration (FDA) for treatment of dementia induced by Alzheimer's disease. They may be useful for other similar diseases causing dementia such as Parkinsons or vascular dementia.
  • FDA United States Food and Drug Administration
  • Memantine ( amenda) is a drug representative of this class. It can be used in combination with acetylcholinesterase inhibitors.
  • Amyloid deposit inhibitors Minocycline and Ciioquinoiine, antibiotics, may help reduce amyloid deposits in the brains of persons with Alzheimer's disease.
  • Antidepressant drugs Depression is frequently associated with dementia and generally worsens the degree of cognitive and behavioral impairment. Antidepressants effectively treat the cognitive and behavioral symptoms of depression in patients with Alzheimer's disease, but evidence for their use in other forms of dementia is weak.
  • Anxiolytic drugs Many patients with dementia experience anxiety symptoms. Although benzodiazepines like diazepam (e.g. Valium) have been used for treating anxiety in other situations, they are often avoided because they may increase agitation in persons with dementia and are likely to worsen cognitive problems or are too sedating. Buspirone (Buspar) is often initially tried for mild-to-moderate anxiety. There is little evidence for the effectiveness of benzodiazepines in dementia, whereas there is evidence for the effectives of antipsychotics (at low doses).
  • diazepam e.g. Valium
  • Buspirone Buspirone
  • Selegiline a drug used primarily in the treatment of Parkinson's disease, appears to slow the development of dementia. Selegiline is thought to act as an antioxidant, preventing free radical damage. However, it also acts as a stimulant, making it difficult to determine whether the delay in onset of dementia symptoms is due to protection from free radicals or to the general elevation of brain activity from the stimulant effect.
  • Subjective Cognitive Impairment is a mild and variable condition with an identified nonspecific cognitive impairment.
  • Mild Cognitive Impairment is a diagnosis given to individuals who have cognitive impairments beyond that expected for their age and education, but which do not interfere significantly with their daily activities. It is considered to be the boundary or transitional stage between normal aging and dementia and is seen as a risk factor for Alzheimer's disease.
  • the third is Alzheimer's Type Dementia (ATD) and associated dementias which represent the most severe and end-stage presentation of cognitive impairment in the elderly.
  • ATD Alzheimer's Type Dementia
  • the medications introduced for the treatment of dementia were the cholinesterase inhibitors (ChEI) in 1997. Since this time most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.
  • the individual drugs have slightly different pharmacological profiles, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease.
  • Mild cognitive impairment also known as incipient dementia, or isolated memory impairment
  • MCI Mild cognitive impairment
  • incipient dementia is a diagnosis given to individuals who have cognitive impairments beyond that expected for their age and education, but that do not interfere significantly with their daily activities. It is considered to be the boundary or transitional stage between normal aging and dementia.
  • MCI can present with a variety of symptoms, but when memory loss is the predominant symptom it is termed "amnesic MCI" and is frequently seen as a risk factor for Alzheimer's disease. Studies suggest that these individuals tend to progress towards probable Alzheimer's disease at a rate of approximately 10% to 15% per year.
  • MCI may represent a prodromal state to clinical Alzheimer's disease
  • treatments proposed for Alzheimer's disease such as antioxidants and cholinesterase " inhibitors, may be useful.
  • two drugs used to treat Alzheimer's disease have been explored in particular, for their ability to effectively treat MCI or prevent/slow down the progress towards full Alzheimer's disease.
  • Rivastigmine failed to stop or slow progression to Alzheimer's disease or improve cognitive function for individuals with MCI, and Donepezil showed only minor, short-term benefits and was associated with significant side effects.
  • Colostrinin which confirm the drug offers a viable treatment for MCI.
  • the present invention addresses one or more of the deficiencies of the prior art by providing combination therapy of neurodegenerative diseases using anti-epileptic agents in combination with one or more agents typically used to treat neurodegenerative diseases such as dementia and or Parkinson's disease.
  • the anti-epileptic agent is used at a dosage lower than that used to treat epilepsy or mood disorders, which dosage may be as low as 0.1 or ' 0.2% of that used to treat epilepsy or mood disorders.
  • co-administration of the anti -epileptic agent and the one or more agents typically used to treat neurodegenerative diseases enables the dosage of the one or more agents to be reduced. In particular, this may be relevant to co-administration of the anti- epileptic agent and the one or more agents typically used to treat Parkinson's disease.
  • the invention provides a method of treating a neurodegenerative disease, condition or disorder in a subject, including the step of administering to the subject one or more anti-epileptic agents and one or more agents effective in the treatment of the neurodegenerative condition or disorder, to thereby treat the neurodegenerative disease, disorder or condition.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in combination: one or more anti-epileptic agents and one or more agents effective in the treatment of the neurodegenerative condition or disorder; together with a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the invention provides a pharmaceutical kit comprising a first pharmaceutical composition comprising (i) one or more anti- epileptic agents together with a pharmaceutically acceptable carrier, diluent and/or excipient; and (ii) a second pharmaceutical composition comprising one or more agents effective in the treatment of the neurodegenerative disease, condition or disorder; together with a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the invention provides one or more anti-epileptic agents and one or more agents effective in the treatment of a neurodegenerative disease, condition or disorder, for use in treating a neurodegenerative disease condition or disorder.
  • an anti-epileptic agent or an agent for treating a neurodegenerative disease, disorder or condition may be in the form of a pharmaceutically effective or acceptable salt.
  • the neurodegenerative disease, condition or disorder is dementia, inclusive of mild-cognitive impairment (MCI), subjective cognitive impairment (SCI) and Alzheimer's Type Dementia (ATD), and/or Parkinson's disease.
  • MCI mild-cognitive impairment
  • SCI subjective cognitive impairment
  • ATD Alzheimer's Type Dementia
  • Parkinson's disease the subject may have more than one neurodegenerative disease, condition or disorder ⁇ e.g. Parkinson's disease and dementia).
  • the one or more agents effective in the treatment of the neurodegenerative disease, condition or disorder include L-dopamine or levodopa, a dopamine agonist and/or a cholinesterase inhibitor.
  • combination therapy of dementia comprises administration of one or more anti-epileptic agents and one or more cholinesterase inhibitors.
  • therapy of Parkinson's disease comprises administration of one or more anti-epileptic agents and one or more of L-dopamine and a dopamine agonist. In some embodiments, therapy of Parkinson's disease comprises administration of one or more anti-epileptic agents, L-dopamine and a dopamine agonist.
  • the method or composition may be used to treat Parkinson's disease and dementia in a subject.
  • the combination therapy comprises administration of (i) one or more anti-epileptic agents; (ii) one or more of L-dopamine and a dopamine agonist or other agent useful in treating Parkinson's disease; and (iii) one or more cholinesterase inhibitors.
  • the amount of anti-epileptic agent is less than 40%, 30%, 20%, 10%, 5% or less than 1 % of the daily dose of anti-epileptic agent typically effective in mood stabilization or in treating epilepsy or epileptic symptoms.
  • a minimum dose applicable to the above upper dosages may be 0.1 %, 0.2%,0.5%, 1 %, 2.5% or 5% of the daily dose of anti-epileptic agent typically effective in mood stabilization or in treating epilepsy or epileptic symptoms.
  • the reduction in daily dose of the one ore more agents for treating Parkinson's disease may be in the range 15-30%, for example 1 5%, 20%, 25% or 30%.
  • One particular embodiment of the combination therapy of the invention includes, prior to administration of the anti-epileptic agent with the one or more agents effective in the treatment of the neurodegenerative disease, condition or disorder, a step of determining whether said subject is, or may be, in need of prophylactic or therapeutic treatment for said neurodegenerative disease, condition or disorder. This step may be performed by clinical assessment, genetic testing or genetic counseling, alone or in combination.
  • subject or “individual” or “patient” refers to any subject for whom or which therapy is desired, and generally refers to the recipient of the therapy to be practiced according to the invention.
  • the subject can be any vertebrate, but will preferably be a mammal. If a mammal, the subject will preferably be a human, but may also be a domestic livestock, laboratory subject or pet animal. The subject is most preferably a human adult, child or infant, who is or has been the object of treatment, observation or experiment.
  • treat means to counteract a medical condition (e.g., a neurodegenerative disease, condition or disorder) to the extent that the medical condition is improved according to clinically acceptable standard(s).
  • a medical condition e.g., a neurodegenerative disease, condition or disorder
  • to treat a neurodegenerative disorder means to improve the disorder or relieve symptoms of the particular disorder in a patient, wherein the improvement and relief are evaluated with a clinically acceptable standardized test (e.g., a patient self-assessment scale) and/or an empirical test.
  • a clinically acceptable standardized test e.g., a patient self-assessment scale
  • Treatment as used herein also includes prophylactic treatment unless the context requires otherwise.
  • active agent or “agent” means any substance which can affect any physical or biochemical properties of a biological system, pathway, molecule, or interaction relating to an organism, including but not limited to animals and humans.
  • agents include but are not limited to any substance intended for diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental well-being of humans or animals.
  • biologically active molecules include, but are not limited to, peptides, proteins, enzymes and small molecule drugs.
  • Classes of active agents that are suitable for use with the methods and compositions described herein include, but are not limited to, drugs, prodrugs, radionuclides, imaging agents, polymers, antibiotics, fungicides, anti-viral agents, anti-inflammatory agents, anti-rumor agents, cardiovascular agents, anti-anxiety agents, hormones, growth factors, steroidal agents, microbially derived toxins, and the like.
  • agents, biologically-active molecules and other active compounds according to this invention may exist as enantiomers. Where they possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the agents or compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the agents or compounds may form solvates with water (i. e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • agent whether in the context of an anti-epileptic agent or an agent for treating a neurodegenerative disease, disorder or condition, may be in the form of a pharmaceutically effective or acceptable salt, as are well known in the art.
  • the pharmaceutical composition and method of treatment provide combination therapy or co-therapy of neurodegenerative disease, disorder or condition.
  • co-therapy and “combination therapy” shall mean treatment of a subject in need thereof by administering one or more anti-epileptic agent(s) and one or more agents for treating a neurodegenerative, disease, disorder or condition by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation or combination.
  • the number of dosages administered per day for each compound may be the same or different.
  • the anti-epileptic agent(s) and one or more agents for treating a neurodegenerative disease, disorder or condition may be administered via the same or different routes of administration.
  • an effective amount or “therapeutically effective amount” means that amount of active compound that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated; reduction of the severity of one or more of the symptoms of the disease or disorder being treated; or otherwise provides the desired effect.
  • the precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, medical history, etc.), the disorder or condition, and the treatment being affected.
  • therapeutically effective amount means that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response.
  • therapeutically effective amount of co- therapy comprising administration of a anti-epileptic agent(s) and one or more agents for treating a neurodegenerative, disease, disorder or condition would be the amount each agent that, when taken together or sequentially, have a combined effect that is therapeutically effective.
  • the amount of anti-epileptic agent(s) and one or more agents for treating a neurodegenerative, disease, disorder or condition individually may or may not be therapeutically effective.
  • administering typically these will be expressed as mg/day", “mg/kg” or “mg/kg/day” and may be standardized to a 70kg individual. That is, doses may be expressed both independently of patient weight and based on patient weight since minimum and maximum doses can apply. Typically, mg/kg/day is more commonly applied in relation to children whereas the total mg/day may be more appropriate for adults
  • the invention provides a method of treating a neurodegenerative disease, condition or disorder in a subject, including the step of administering to the subject one or more anti-epileptic agents and one or more agents effective in the treatment of the neurodegenerative condition or disorder, to thereby treat the neurodegenerative disease, disorder or condition.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in combination: one or more anti-epileptic agents and one or more agents effective in the treatment of the neurodegenerative condition or disorder; together with a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the invention provides a pharmaceutical kit comprising a first pharmaceutical composition comprising (i) one or more anti- epileptic agents together with a pharmaceutically acceptable carrier, diluent and/or excipient; and (ii) a second pharmaceutical composition comprising one or more agents effective in the treatment of the neurodegenerative disease, condition or disorder; together with a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the invention provides a method or pharmaceutical composition for combination therapy of a neurodegenerative disease, disorder or condition, wherein a combination of one or a plurality of anti- epileptic agents and one or a plurality of agents therapeutically effective in the treatment of neurodegenerative disease disorders or conditions are administered to a subject to thereby treat the neurodegenerative disease, disorder or condition.
  • Non-limiting examples of neurodegenerative disease disorders or conditions include dementia, inclusive of mild-cognitive impairment (MCI), subjective cognitive impairment (SCI) and Alzheimer's Type Dementia (ATD) and/or Parkinson's disease.
  • the combination therapy may be used to treat a subject with both Parkinson's disease and dementia.
  • antiepileptic agent or “anti -epileptic drug” (abbreviated as “AED") will be used interchangeably with the terms “anti-convulsant agent”, “anticonvulsant” “antiepileptic mood stabilizer”, “mood stabilizer”, and “antiepileptic” and as used herein, refer to an agent capable of treating, inhibiting or preventing seizure activity or ictogenesis when the agent is administered to a subject or patient.
  • AED is not determinative of the utility of any specific AED in the compositions and methods of the invention. Rather, it is the efficacy of AEDs in treatment of epileptic, pre-epileptic, or ictogenic events, convulsions, mood stabilization that identifies the relevant compounds or agents useful within the invention.
  • AEDs of diverse chemical classes are useful and relevant (with suitable adjustments of dose) according to the invention.
  • the AED is suitable administered at a sub-therapeutic dose. This means that the dose administered is below the dose range that would be administered to epileptics and/or individuals with bipolar disorders to achieve mood stabilization, control of seizures or control of mania, as appropriate. As mentioned above, the use of such sub-therapeutic dosages is advantageous for the treatments described herein.
  • the amount of anti-epileptic agent(s) is less than 50% of the daily dose of anti-epileptic agent typically effective in mood stabilization or in treating epilepsy or epileptic symptoms.
  • the amount of anti-epileptic agent is less than 40%, 30%, 20%, 10%, 5% or less than 1 % .of the daily dose of anti-epileptic agent typically effective in mood stabilization or in treating epilepsy or epileptic symptoms.
  • a minimum dose applicable to the above upper dosages may be at least 0.1 %, 0.2%, 0.5% or 1 % of the daily dose of anti-epileptic agent typically effective in mood stabilization or in treating epilepsy or epileptic symptoms.
  • AEDs include sodium valproate (sodium di-n- propylacetic acid) and derivatives thereof (valproic acid, valproate pivoxil, semi- sodium valproate, divalproex, valproyl amides such as valpromide, Depakene, Depakote, Depakote ER), tiagabine, ethosuximide, zonisamide, carbamazepine, oxcarbazepine, lamotrigine, gabapentin, pregabalin, phenytoin, primidone, phenobarbitone, phenobarital, topiramate, diazepam and related compounds, levetiracetam, brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, lacosamide, retigabine, rufinamide, safinamide, seletracetam, tal
  • the AED is other than sodium valproate
  • Particularly preferred AEDs are tiagabine, topiramate, carbamazepine, oxcarbazepine, ethotoin, phenytoin, gabapentin, pregabalin, and rufinamide.
  • the AED is a hydantoin such as phenytoin or ethotoin.
  • examples of AEDs include, but are not limited to, the following, described non-exclusively by either mode of action or chemical class:
  • AMPA antagonists such as AMP-397, E-2007, NS- 1209, talampanel, perampanel, and the like;
  • Benzodiazepines such as diazepam, lorazepam, clonazepam, clobazam, clorazepate, midazolam, nimetazepam, nitrazepam, temasepam, and the like;
  • Barbiturates such as phenobarbital, amobarbital, methylphenobarbital, primidone, Barbexaclone sodium, metharbital, pentobarbital, and the like;
  • Valproates including fatty acid derivatives
  • valproic acid such as valproic acid, valproate semisodium, valpromide, divalproex, valnoctamide, and the like;
  • GABA related agents such as gabapentin (2-[l - (aminomethyl)cyclohexyl]acetic acid), pregabalin ((S)-3-(aminomethyl)-5- methylhexanoic acid), vigabatrin, and the like;
  • AEDs such as losigamone, retigabine, rufinamide (l -[(2,6-difluorophenyl)methyl]triazole-4-carboxamide), SPD-421 (DP-VP A), T- 2000, XP- 13512, and the like;
  • Iminostilbenes such as carbamazepine, oxcarbazepine, and the like;
  • Hydantoins such as phenytoin sodium, phenytoin, mephenytoin, fosphenytoin sodium, ethotoin, and the like;
  • NMDA antagonists such as harkoseride, and the like
  • Sodium channel blockers such as BIA-2093, CO- 102862, lamotrigine, and the like;
  • AEDS such as acetazolamide, clomthiazole edisilate, zonisamide, felbamate, topiramate, tiagabine, levetiracetam, briveracetam, GS -3621 15, GSK-406725, ICA-69673, CBD cannabis derivative, isovaleramide (NPS- 1776), RWJ-333369 (carisbamate), safinamide, seletracetam, soretolide, stiripentol, valrocemide, and the like; (m) oxazolidinediones such as trimethadione, paramethadione, ethadione and the like;
  • succinimides such as ethosuximide, phensuximide, mesuximide, and the like;
  • sulphonamides such as acetazolamide, methazolamide, zonisamide, sultiame, and the like;
  • aromatic allylic alcohols such as stiripentol, and the like
  • ureas such as phenacemide, pheneturide, and the like
  • (x) pyrrolidines such as brivaracetam, levetriacetame, nefiracetam, selectracetam, and the like;
  • AEDs have been described in the art and useful as anti-epileptics and mood stabilizers.
  • one or more agents effective in the treatment of the neurodegenerative disease, condition or disorder includes any agent useful in the treatment of neurodegenerative disorders, including Parkinson's disease and dementia.
  • co-administration of the AED and the one or more agents typically used to treat neurodegenerative diseases allows the therapeutically effective dose the one or more agents to be reduced.
  • the reduction in daily dose of the one or more agents for treating Parkinson's disease may be in the range 15-30%, for example 15%, 20%, 25% or 30%.
  • Non-limiting examples of agents useful in treating neurodegenerative disease, condition or disorders such as Parkinson's disease include apomorphine, benserazide, benzatropine, bromocriptine, cabergoline, carbidopa, clozapine, domperidone, entacapone, L-dopa or levodopa, lisuride, orphenadrine, pergolide, piribedil, pramipexole, procyclidine, quetiapine, rasagiline, rivastigmine, ropinirole, rotigotine, selegiline, tolcapone and trihexyphenidyl,
  • the agent is L-dopa or levodopa.
  • the agent is a dopamine agonist.
  • dopamine agonist examples include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, apomorphine, cabergoline, lisuride and pramipexole.
  • the agent is a dopamine decarboxylase inhibitor.
  • dopamine decarboxylase inhibitor examples include carbidopa and benserazide
  • the agent inhibits the catechol O methyl transferase (COMT) enzyme.
  • CCT catechol O methyl transferase
  • Non-limiting examples include tolcapone and entacapone.
  • the agent is a monoamine oxidase-B inhibitor.
  • Non-limiting examples include selegiline and rasagiline.
  • the agent is preferably an acetylcholinesterase inhibitor.
  • acetylcholinesterase inhibitor include tacrine, donepezil, galantamine and rivastigmine.
  • the pharmaceutical composition and/or method of the treatment may be used to treat both Parkinson's disease and dementia in a subject.
  • the method of treatment comprises administration of (i) one or more AEDs; (ii) one or more of levodopa and a dopamine agonist; and (iii) one or more cholinesterase inhibitors, as hereinbefore described.
  • the pharmaceutical composition comprises (i) one or more AEDs; (ii) one or more of levodopa and a dopamine agonist; and (iii) one or more cholinesterase inhibitors, as hereinbefore described.
  • a combination of one or more AEDs, one or more of a cholinesterase inhibitor, levodopa or a dopamine agonist effective provide enhanced treatment of one or more neurodegenerative diseases, conditions or disorders, or symptoms or another underlying cause of the symptom(s), in comparison with either agent alone.
  • the therapeutically effective amount or dosage of one or more of a cholinesterase inhibitor or levodopa or a dopamine agonist and one or more AEDs would include an amount of cholinesterase inhibitor or levodopa or dopamine agonists agent(s) and AED(s) that, when taken together or sequentially, have a combined effect that is therapeutically effective.
  • the amount of each agent per unit dosage of combination may encompass currently therapeutically effective amounts of each agent (other than AEDs, which are administered at sub-therapeutic doses, as hereinbefore described) when administered separately.
  • the pharmaceutical compositions herein will contain, per unit dosage unit, (e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like) of from about 0. 1 -3000 mg of each active agent independently or any range therein.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the agents being employed. The use of either daily administration or post-periodic dosing may be employed.
  • Therapeutically effective dosage levels and dosage regimens for the anti-epileptic agents disclosed herein may be readily determined by one of ordinary skill in the art.
  • therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example as listed on packaging labels, in standard dosage guidelines, in standard dosage references such as the Physician's Desk Reference (Medical Economics Company or online at http://www.pdrel.com) and other sources.
  • a typical dose for treating epileptic seizures is in the range of from 400 to 800 mg/day.
  • the target dose for controlling epileptic seizures is between 100 to 500 mg day.
  • a preferred sub-therapeutic dose is in the range of from 25 to 200 mg day, such as more than 50, 75 or 100 mg/day but less than 250, 200 or 150 mg/day.
  • a preferred sub-therapeutic dose is in the range of from 6.25 to 75 mg day, such as at least 10, 15, 20, 30 or 40 mg/day but less than 80, 75 or 60 mg day.
  • a preferred sub-therapeutic dose is in the range of from 0.2 mg- 13 mg/day, such as at least 0.2, 0.5, 1 , 2, 5, 8 or 10 mg day but less than 30 or 40 mg/day.
  • a preferred sub-therapeutic dose is in the range of from 30 to 80 mg/day, such as more than 30 or 40 mg/day but less than 80 or 70 mg/day.
  • a preferred sub-therapeutic dose is in the range of from 5 to 200 mg/day, such as more than 10 or 20 mg/day but less than 150 or 1 5 mg/day.
  • the sub-therapeutic dose is less than 50%, such as less than 40%, 30%) or 20%, of the minimum dose that would be administered to epileptics and individuals with bipolar disorders to achieve mood stabilization, control of seizures or control of mania, as appropriate.
  • AED e.g. phenytoin
  • the inventor has found that 5- 10% of the normal minimum dose of AED (e.g. phenytoin) that would be administered to epileptics and individuals with bipolar disorders to achieve mood stabilization, control of seizures or control of mania, as appropriate, works well for the particular compounds tested in human subjects.
  • the sub-therapeutic dose may be as little as 0.1 %, 0.2 %, 1 %, 2.5%, 5% or 10% of the minimum dose that would be administered to epileptics and individuals with bipolar disorders to achieve mood stabilisation, control of seizures or control of mania, as appropriate,
  • a sub-therapeutic dose for mood stabilization in the context of the present invention is therefore preferably (though not exclusively) less than 50%, such as less than 40% or 30% of the minimum dosages listed below for each particular agent (e.g. for ethotoin), a sub-therapeutic dose is less than 500 mg/day, such as less than 4 ⁇ 0 or 300 mg day.
  • the minimum dose to be administered in the context of the present invention is preferably at least 0.1%,
  • a preferred dose within the subtherapeutic range for antiepileptic therapy or ' mood stabilization would be less than 50% of the minimum therapeutic dose for mood stabilization listed below,
  • the dosage administered of AED is sub-therapeutic for mood stabilization for the entire, or at least substantially the entire, treatment period. In other words, it is preferred that the dosage of AED administered does not exceed the maximum stated sub-therapeutic dosages described above throughout the treatment.
  • Particularly preferred combinations of AEDs and cholinesterase inhibitors or levodopa or dopamine agonists are: (i) one or more of topiramate, carbamazepine, oxcarbazepine, phenytoin, gabapentin or pregabalin; together with (ii) one or more cholinesterase inhibitors for treating dementia and/or (iii) one or more of levodopa and dopamine agonists.
  • the intended daily dose of AED may range from 0.5 mg d to less than 10% of the minimum dosages for treatment of epilepsy or mood disorder for each particular AED, while the normal, recommended amount of cholinesterase inhibitors or levodopa or diamine agonists is used.
  • a suitable Parkinson's treatment may be levodopa (50-750 mg), benserazide ( 12.5- 150 mg) with a dosage of phenytoin (0.2- 18 mg) daily.
  • a suitable dementia treatment may be donepezil
  • Particular doses for particular combinations may be created using a matrix formed by rows of AED doses with columns of cholinesterase inhibitors or levodopa or dopamine agonist doses.
  • a matrix formed by rows of AED doses with columns of cholinesterase inhibitors or levodopa or dopamine agonist doses For example, an entry of (20 mg of AED, 30 mg of cholinesterase inhibitors or levodopa or dopamine agonist) in a matrix denotes 20 mg of AED and 30 mg of cholinesterase inhibitors or levodopa or dopamine agonists compounded as, for example, a single tablet or unit dose.
  • Such a dose may be formulated or effective as a single, daily dose, or may be repeated a number of times in a day to result in a total daily dose of 80 mg of AED and 120 mg of cholinesterase inhibitor or levodopa or dopamine agonist.
  • the units of measure of each agent may be divided as convenient into steps of 0.01 , 0.5, 1 .0, 2.0, 5.0 mg and the like.
  • the units are not constrained by any particular step value and all possible values between the minimum and maximum doses for each agent are contemplated.
  • the dimensions of the matrix row relevant to any particular AED are formed by its minimum and maximum contemplated doses along with the desired step values.
  • the matrix column dimensions are formed by the minimum and maximum contemplated doses of cholinesterase inhibitors or levodopa or dopamine agonists along with the desired step values.
  • the matrix dimensions are increased by the addition of a dimension corresponding to the further agent.
  • a 3 dimensional matrix would list all contemplated combination of three active agents. All combination unit doses and pharmaceutical compositions so described are within the scope of the invention.
  • AEDs alone or in combination with cholinesterase inhibitors or levodopa or dopamine agonists, may be administered in the form of a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in combination, one or a plurality of anti-epileptic agents, one or a plurality of cholinesterase inhibitors and/or one or a plurality of levodopa and/or dopamine agonists, or pharmaceutically acceptable salts thereof.
  • the invention provides a pharmaceutical kit comprising a first pharmaceutical composition comprising (i) one or a plurality of anti-epileptic agents or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent and (ii) a second pharmaceutical composition comprising one or a plurality of cholinesterase inhibitors or levodopa or dopamine agonists together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition is suitable for administration to a human.
  • routes of administration applicable to the pharmaceutical composition and/or the method of the invention include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), trans-dermal, and rectal.
  • Compositions may also be administered directly to the nervous system including, but not limited to, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal or peri-spinal routes of administration by delivery via intracranial or intravertebral needles or catheters with or without pump devices.
  • cholinesterase inhibitors or levodopa or dopamine agonists(s) and the anticonvulsant or anti-epileptic agent(s) may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
  • compositions containing one or more of the agents described herein can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier, diluent and/or excipient according to conventional pharmaceutical compounding techniques.
  • pharmaceutically acceptable carrier includes any material which, when combined with an active ingredient of a composition, allows the ingredient to retain biological activity and without causing disruptive reactions in the subject.
  • examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil and water emulsion, and various types of wetting agents.
  • Preferred diluents for aerosol or parenteral administration are phosphate buffered saline or normal (0.9%) saline.
  • Compositions comprising such carriers are formulated by well known conventional methods (see, for example, Remington's Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Col, Easton Pa. 18042, USA).
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric- coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • the salts of the agents of this invention refer to non- toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycoHylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy naphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, oleate,
  • acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-( l S)- camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glu
  • the oral solid dosage form includes a sustained release carrier that effectuates the sustained release of the AED, or both the AED and the cholinesterase inhibitors or levodopa or dopamine agonists when the dosage form contacts gastrointestinal fluid
  • the sustained release dosage form may comprise a multiplicity of substrates and carriers that include the agents.
  • the substrates may comprise matrix spheroids or may comprise inert pharmaceutically acceptable beads that are coated with the agents.
  • the coated beads are then preferably overcoated with a sustained release coating comprising the sustained release carrier.
  • the matrix spheroid may include the sustained release carrier in the matrix itself, or the matrix may comprise a simple disintegrating or prompt release matrix containing the drugs, the matrix having a coating applied thereon which comprises the sustained release carrier.
  • the oral solid dosage form comprises a tablet core containing the agents within a normal or prompt release matrix with the tablet core being coated with a sustained release coating comprising the sustained release carrier.
  • the tablet contains the agents within a sustained release matrix comprising the sustained release carrier.
  • the tablet contains the AED within a sustained release matrix, and the chohnesterase inhibitors or levodopa or dopamine agonists coated into the tablet as an immediate release layer.
  • the pharmaceutical compositions containing the cholinesterase inhibitors or levodopa or dopamine agonists and AED agents set forth herein are administered orally.
  • Such oral dosage forms may contain one or all of the agents in immediate or sustained release form.
  • the oral dosage forms may be in the form of tablets, troches, lozenges, aqueous, solid or semi-solid solutions or mixtures, or oily suspensions or solutions, dispersible powders or granules, emulsions, multiparticulate formulations, syrups, elixirs, and the like.
  • a pharmaceutical composition containing the AED(s) and cholinesterase inhibitors or levodopa or lopamine agonists(s) can be administered in dosage form as a topical preparation, a solid state and or depot type transdermal delivery device(s), a suppository, a buccal tablet, sub-lingual preparation, or an inhalation formulation such as a controlled release particle formulation or spray, mist or other topical vehicle, intended to be inhaled or instilled into the sinuses.
  • compositions containing the agents set forth herein may alternatively be in the form of microparticles such as microcapsules, microspheres and the like, which may be injected or implanted into a human patient, or other implantable dosage forms known to those skilled in the art of pharmaceutical formulation.
  • the compounds may be formulated individually or in combination as sustained release preparations. If formulated individually, different release times or bioavailability may be afforded each active agent though they may ultimately be compounded or mixed together into one unit dose. Numerous examples of techniques for formulating sustained release preparations are described in the following references: U.S. Pat. Nos.
  • compositions of this invention are prepared, one or more of aof the choiinesterase inhibitors or levodopa or dopamine agonists and one or more of of the AEDs are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredients necessary to deliver an effective dose as described herein.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate
  • a pharmaceutical composition comprising the active agents may be formulated with distinct halves or further subdivisions, each half or subdivision comprising primarily one agent. Scoring or pre-division of the halves or subdivisions thereby allow easy modulation of dose of each active agent.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • one or more of the cholinesterase inhibitors or levodopa or dopamine agonists agents may be separately formulated or compounded, then coated or embedded in one or more of aof the anticonvulsant or anti-epileptic agents or formulations thereof.
  • the anticonvulsant or anti-epileptic agents or formulations thereof may be embedded in or otherwise bound to cholinesterase inhibitors or levodopa or dopamine agonists agents or their formulations.
  • the two or more active agents may be compounded separately but ultimately provided together in one unit dose as a combination.
  • Each, separately compounded agent may thus be provided in timed release, slow release, or other suitable formulation specifically advantageous to that agent, though ultimately provided as a single unit dose.
  • one or a plurality of AEDs in combination with cholinesterase inhibitors or levodopa or dopamine agonists may be administered in the form of a pharmaceutical composition, including but not limited to the particular pharmaceutical compositions hereinbefore described.
  • optimal dosages and schedules to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition.
  • factors associated with the particular patient being treated including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • doses can be appropriately adjusted, or alternative choice of agent(s) made within the teaching of the invention.
  • a therapeutically effective dosage of the combinations of the present invention can include repeated doses within a prolonged treatment regimen that will yield clinically significant results.
  • combinations of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the combinations may be administered through a single transdermal patch, or via subdivided transdermal patches or even separate transdermal patches, as may be desired.
  • Determination of effective dosages is typically based on animal model studies followed up by human clinical trials and is guided by determining effective dosages and administration protocols that significantly reduce the occurrence or severity of targeted exposure symptoms or conditions in the subject.
  • Suitable models in this regard include, for example, murine, rat, porcine, feline, non-human primate, and other accepted animal model subjects known in the art.
  • effective dosages can be determined using in vitro models. Using such models, only ordinary calculations and adjustments are typically required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the biologically active agent(s) (e.g., amounts that are intranasally effective, transdermally effective, intravenously effective, or intramuscularly effective to elicit a desired response).
  • a 70yr old man has a 10 year history Parkinson's symptoms. Early- symptoms included becoming excessively tired and some impairment in the marshalling and organisation of his thinking. He also noted that his voice became weaker. These symptoms resulted in more a negative outlook and mood, although not sufficient to warrant a diagnosis of depression. He was assessed by a specialist and diagnosed with Parkinson's disease. He has been treated with a number of different formulations of L-dopa and a dopamine agonist together with a stimulant. He always remained compliant with his medication and carefully titrated his dose to the maximal efficiency. He does notice that the improving cognitive symptoms often come at a disadvantage with increasing physical immobility.
  • pre-and post usually 30 to 60 minutes
  • a significant improvement in the processing speed as measured by this test In situations where the dose has been too high there has been a reduction or no alteration in the speed of naming pre-and post dose.
  • Other measures have included the Alzheimer's quick test and serial mini mental state examinations. These data are currently involved in a retrospective study using computational analysis. This will attempt to determine whether there are structural changes in the conversation and non-verbal communication which are associated with clinical improvement.
  • Stroop test undertaken one month prior to treatment, prior, to initiation dose 15 minutes post 1 mg sub-lingual troche phenytoin.

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Abstract

L'invention porte sur un procédé de traitement d'une maladie, d'un état ou d'un trouble neurodégénératif, tel que la démence ou la maladie de Parkinson. Ce procédé comprend l'étape d'administration d'un ou plusieurs agents anti-épileptiques dans une quantité inférieure à la dose quotidienne d'agent anti-épileptique typiquement efficace dans la stabilisation de l'humeur ou dans le traitement de l'épilepsie ou de symptômes épileptiques, et d'un ou plusieurs agents efficaces dans le traitement de l'état ou du trouble neurodégénératif. L'invention porte en outre sur une composition pharmaceutique, ou une trousse pour celle-ci, pour le traitement de la maladie, de l'état ou du trouble neurodégénératif, comprenant, en combinaison : un ou plusieurs agents anti-épileptiques dans une quantité inférieure à la dose quotidienne d'agent anti-épileptique typiquement efficace dans la stabilisation de l'humeur ou dans le traitement de l'épilepsie ou de symptômes épileptiques, et un ou plusieurs agents efficaces dans le traitement de l'état ou du trouble neurodégénératif. Le ou les agents efficaces pour le traitement de l'état ou du trouble neurodégénératif peuvent comprendre de la lévodopa ou un agoniste de la dopamine pour le traitement de la maladie de Parkinson et/ou un inhibiteur de l'acétylcholinestérase pour le traitement de la démence.
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