WO2008083442A1

WO2008083442A1 - Method for formulating combination medications for adhd

Info

Publication number: WO2008083442A1
Application number: PCT/AU2008/000022
Authority: WO
Inventors: Evian Gordon
Original assignee: Brc Operations Pty Limited
Priority date: 2007-01-10
Filing date: 2008-01-10
Publication date: 2008-07-17

Abstract

The present application relates to a method of determining a treatment regime for ADHD for a single patient comprising providing a series of tests to an ADHD group and a normative group to determine a series of brain markers determining the expected effect of a series of candidate drugs on the markers, providing the series of tests to the single patient, determining the likely effect of a combination of candidate drugs on the single patient, and selecting and administering a combination of candidate drugs to the single patient. The present application also relates to methods o treating ADHD comprising administering at least one dopaminergic agent and at least one cholinesterase agent, and optionally one or more agents selected from the group consisting of NMDA receptor antagonists, mGluR agonists, antagonists, and positive modulators of AMPA receptors, and more preferably administering a Dl receptor agonist an a nicotinic agonist and/or an anti-cholinesterase.

Description

Method for Formulating Combination Medications for ADHD FIELD OF THE INVENTION

[0001] The present invention belongs to the fields of pharmacology, medicine and medicinal chemistry, and provides methods and compositions for treating ADHD symptoms and or cognition within the same individual.

BACKGROUND OF THE INVENTION

[0002] The present invention relates providing exploratory personalized treatment regimes for utilizing compositions and methods for supplementing or complementing natural central nervous system neurotransmitter activity to optimize brain function, particularly in disorders that result in ADHD and or conditions that are associated with ADHD.

[0003] Attention-deficit hyperactivity disorder (ADHD) is a prevalent psychiatric disability in children and adults, affecting 8%-12% of the population worldwide. The cardinal features of ADHD are hyperactivity, impulsivity and inattention. Neuro-cognitive studies have indicated that these behavioural abnormalities in children with ADHD may occur as a result of executive control dysfunction. This disorder of executive control results in poor behavioural self-regulation, preventing the devising of approaches to performing and carrying out new tasks. Typically these cognitive deficits manifest due to abnormalities within distinct neurotransmitter systems.

[0004] Patients usually take psycho-stimulants as the major form of treating ADHD and improving symptoms and or cognition. However, although most patients rapidly respond to acute dosages, there remains 25% of patients that do not respond and an overall greater proportion where the effects are sub-optimal or there are significant side effects.

[0005] For example, patients taking psycho-stimulants, while associated with an acute response to treatment in the morning or immediately after consumption, by afternoon or a few hours later there is associated loss of effectiveness, yet if a further afternoon dosage is taken then, frequently this results in insomnia. Thus, symptoms return in the evening but cannot be treated with psycho-stimulants. It appears that other neurotransmitter systems may be required to be modulated in order to obtain a great treatment benefit to the patient. Patients finally withdrawn from medication later in life usually return to baseline, with up to 70% going on into adulthood with attentional problems unmodified by years of medication. [0006] Other therapeutic non-dopaminergic medications, such as the tricyclic antidepressants and SSRIs have generally not been useful in adults with ADHD in the absence of depression or dysthymia, while it is noted that they continue to respond to stimulants that influence dopaminergic transmission within the brain. Although combinational therapy using both SSRI's and dopaminergic medications have been lacking.

[0007] There is a need to explore how dopaminergic modulation can be improved in children and adults with ADHD. Furthermore there is a need to improve cognitive performance and treatment outcomes in individual patients with ADHD and other associated disorders such as persistent irritability, aggression, maladaptive behaviors and problems with learning in general or within specific domains such as performing and executing mathematical problems. All these cognitive systems are in need of pharmacological manipulation for a positive benefit to the patient.

BRIEF SUMMARY OF THE INVENTION [0008] As a result of research conducted into mapping of the brain, it has been discovered a concept of further therapy to combat the negative side effects for psycho-stimulants in form of additive compounds to psycho-stimulants and or combinational therapy that does not involve psychostimulant treatment and treats many aspects of ADHD accordingly. [0009] In accordance with a first aspect of the present invention, there is provided a method of determining a treatment regime for a single patient for the treatment of ADHD symptoms, the method comprising the steps of: (a) providing a series of ADHD brain tests to a group of ADHD sufferers and a group of normative patients to determine a series of brain markers for each with the ADHD suffers having, on average, a distinguishing set of brain markers from the normative patient group; (b) determining an expected effect of a series of candidate drugs on the brain markers; (c) for the single patient, providing a series of ADHD brain tests to determine a likely value of at least some of the brain markers for the single patient; (d) determining the likely effect of a combination of the series of candidate drugs on the brain markers for the single patient, (e) selecting a likely combination of candidate drugs for the single patient that are likely to draw the markers of the single patient closer to the markers of the normative group; and (f) administering the likely combination of candidate drugs to the single patient. The method can also include the step of: (g) monitoring the difference of the value of at least some of the brain markers from the markers of the normative group for the single patient upon utilisation of the selected drugs to determine if the expected change can be operative.

[0010] The likely combination of candidate drugs preferably can include comprising the administration to a subject requiring such treatment of a therapeutically effective amount of at least one dopaminergic agent and at least one cholinesterase agent.

[0011] In accordance with an aspect of the present invention a novel pharmaceutical composition is provided for treating ADHD. More specifically, the composition combines at least one drug that influences dopaminergic function or related neurotransmitters and functions, and at least one compound that influences cholinergic function or related neurotransmitters and functions. [0012] A first embodiment of the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more psycho-stimulants or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more anti-cholinesterase agents or a pharmaceutically effective salt thereof. This combination is effective in modulating working memory and or improving symptoms and or signs of ADHD and or improving brain electrical function and or improving cognition.

[0013] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more psycho-stimulants or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more muscarinic agonists or a pharmaceutically effective salt thereof. This combination is effective in modulating working memory and or improving symptoms and or signs of ADHD and or improving brain electrical function and or improving cognition.

[0014] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more psycho-stimulants or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more nicotinic agonists or a pharmaceutically effective salt thereof. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function and or improving cognition.

[0015] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more psycho-stimulants or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more nicotinic antagonists or a pharmaceutically effective salt thereof. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function as is measurable and or improving cognition. [0016] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more psycho-stimulants or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of a nicotinic antagonist and a nicotinic agonist. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function and or improving cognition. [0017] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more of Dl agonists or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more cholinergic modulators selected from nicotinic antagonist and or nicotinic agonist and or muscarinic agonists and or a cholinesterase inhibitor or pharmaceutically effective salts thereof. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function and or improving cognition.

[0018] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more of anti-psychotic compounds or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more cholinergic modulators selected from nicotinic antagonist and or nicotinic agonist and or muscarinic agonists and or a cholinesterase inhibitor or pharmaceutically effective salts thereof. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function and or improving cognition. [0019] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more serotonin active compounds that may include an SSRI or a selective 5HT agonist or 5HT antagonist and or combinations thereof or pharmaceutically effective salts thereof; and (b) a pharmaceutically effective amount of one or more cholinergic modulators selected from nicotinic antagonist and or nicotinic agonist and or muscarinic agonists and or a cholinesterase inhibitor or pharmaceutically effective salts thereof. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving measurable brain electrical function and or improving cognition.

[0020] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more psycho-stimulants or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more or pharmaceutically norepinephrine transporter (NET) reuptake inhibitor with or without dopamine transporter inhibitor effects. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function and or improving cognition.

[0021] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more serotonin active compounds that may include an SSRI or a selective 5HT agonist or 5HT antagonist and or combinations thereof or pharmaceutically effective salts thereof; and (b) a pharmaceutically effective amount of one or more or pharmaceutically norepinephrine transporter (NET) reuptake inhibitor with or without dopamine transporter inhibitor effects. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function and or improving cognition.

[0022] In another embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more or pharmaceutically norepinephrine transporter (NET) reuptake inhibitor with or without dopamine transporter inhibitor effects and (b) a pharmaceutically effective amount of one or more cholinergic modulators selected from nicotinic antagonist and or nicotinic agonist and or muscarinic agonists and or a cholinesterase inhibitor or pharmaceutically effective salts thereof. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function and or improving cognition.

[0023] In another t embodiment the present invention provides a composition comprising: (a) a pharmaceutically effective amount of one or more serotonin active compounds that may include an SSRI or a selective 5HT agonist or 5HT antagonist and or combinations thereof or pharmaceutically effective salts thereof; and (b) a pharmaceutically effective amount of one or more or pharmaceutically psycho-stimulants and or other dopaminergic acting agents. This combination is effective in modulating working memory and or improving symptoms of ADHD and or improving brain electrical function and or improving cognition.

[0024] Yet another embodiment of the present invention provides a method for treating or preventing the disorder ADHD of the central nervous system comprising administering a therapeutically effective amount of the above composition to a mammal. In most instances, the mammal will be a human, and the disease or disorder to be treated is neurological and or psychiatric condition causing ADHD.

[0025] Yet another embodiment of the present invention provides a method for modulating dopamine receptors via treating the patient with a 5 alpha-reductase enzyme inhibitor. [0026] Yet another embodiment of the present invention provides a method for modulating dopamine receptors via treating the patient with a 5 alpha-reductase enzyme inhibitor in order to induce a more favourable response from use of at least one or more psycho-stimulants or Dl agonists or atypical anti-psychotic or D4 agonist or D2 antagonist.

[0027] Yet in another aspect of the invention a cannabinoid receptor agonist and or antagonist can be combined with any treatment compound listed in this specification to obtain a treatment benefit affect in ADHD.

[0028] Yet in another aspect of the present invention serotonin agents are used to modulate acetylcholine in the brain.

[0029] A further embodiment of the present invention comprises the use of the above composition to prepare a medicament for treating or preventing diseases or disorders of the central nervous system that result in attention and or working memory deficits. The combinational therapy outlined with in the invention can be used to improve these cognitive conditions. [0030] It is a desirable feature of the present invention to provide a novel composition having biological activity for the modulation and or stabilization of ADHD within the same individual.

[0031] It is a further desirable feature of the present invention to provide a method for treating or preventing diseases of ADHD that result cognitive and or overt physical problems by using the novel compositions of the present invention.

[0032] It is a further desirable feature of the present invention to provide an effective treatment for ADHD as measured by Cognition and Brain Function tests.

[0033] It is a further desirable feature of the present invention to identify those individuals at risk or in need of the said drug combination by providing a genetic test to screen for polymorphisms in the genes of dopaminergic and cholinergic origin.

[0034] A further additional object of the present invention is to show in those individuals at risk or in need of the said drug combination for improving cognition in ADHD and verified by the use of at least one of the following, EEG mapping, Event related potentials, functional MRI, autonomic measures, heart rate and or analysis of the ECG or blood pressure waveforms, cognitive testing using computerised and or pen and paper tests.

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Preferred embodiments of the present invention will now be described with reference to the accompanying drawings in which:

[0036] Fig. 1 illustrates a flow chart of the steps involved in determining a treatment combination. DETADLED DESCRIPTION OF THE PREFERRED EMBODIMENT

In describing the preferred embodiment, certain terminology will be utilized for the sake of clarity. Such terminology is intended to encompass the recited embodiment, as well as all technical equivalents which operate in a similar manner for a similar purpose to achieve a similar result.

[0037] ADHD is defined and extensively described in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, Washington, D.C., 1994. Persons suffering from ADHD exhibit a persistent pattern of inattention and/or hyperactivity- impulsivity that is more frequent and severe than typically observed in persons at a comparable level of development.

Three subtypes are recognized: ADHD, Combined Type; ADHD, Predominantly Inattentive Type; and ADHD, Predominantly Hyper-active-Impulsive Type. The Predominantly Inattentive Type is characterized by failure to give close attention to details, making careless mistakes in various tasks, messy and carelessly performed work product exhibiting a lack of considered thought. Such individuals often have difficulty sustaining attention in tasks or play activities and find it difficult to persist with tasks until completion. They often appear as if their mind is elsewhere or as if they are not listening or did not hear what has just been said. This last characteristic is frequently referred to as "spacey" in clinical practice. Tasks that require sustained mental effort are experienced by such individuals as unpleasant and, consequently typically avoided. [0038] The predominantly Hyperactive-impulsive subtype is characterized by fidgetiness, excessive unproductive movement when inappropriate such as fidgeting with objects, tapping hands, shaking legs or feet, excessive talking or making noise. Symptoms in adults or adolescents frequently take the form of feelings of restlessness and difficulty in engaging in quiet sedentary activities.

[0039] On the other hand, impulsivity manifests itself as impatience, difficulty in delaying responses, blurting out answers before questions have been completed, difficulty awaiting one's turn, frequently interrupting or intruding on others, making comments out of turn, failing to listen to directions, initiating conversations at inappropriate times, grabbing objects form others, touching things they are not supposed to touch and clowning around.

[0040] In addition to the theoretical focus in this invention including that the brain is a highly interconnected system, the profile of brain timing disturbances are considered to vary along a continuum. Therefore, it will be appreciated that those skilled in the art that the combinational may target one subtype or some subtypes or all subtypes of ADHD and or related symptoms and or cognitive problems related to these subtypes of ADHD.

[0041] The novel composition of different chemical entities is used to treat components of a disorder ADHD, such as cognition and or symptoms and or signs of the disorder. Aspects of cognition and or symptoms and or signs of the disorder ADHD are improved with the use of the first chemical entity being a dopaminergic modulator and the second chemical entity being a cholinergic modulator.

[0042] It will also be recognized that improvement in ADHD may be determined subjectively and objectively using either patient feedback and or via the use of external examination, for example using clinical tools that provide validated measures of ADHD and or functional information on the performance of brain regions that regulate either cognitive changes and or symptoms and or signs in ADHD.

[0043] "Beneficial effect" is an observable improvement over the baseline clinically observable signs and symptoms. For example, a beneficial effect in cognitive disorders such as ADHD can be determined by a history of improved job performance; educational performance; better organization; improved goal selection, planning and attainment; improvement in teacher rated behavior. [0044] A beneficial effect in cognitive disorders can also be determined from various standardized tests, such as the Brain Resource Company Ltd computer-based and or web-based cognitive test batteries, which are sensitive to errors of omission and commission, executive function deficits and can report a variety of cognitive impairments, including spatial short-term memory, spatial working memory, set-shifting ability, planning ability, spatial recognition memory, delayed matching to sample, and pattern recognition memory.

[0045] It will be appreciated by those skilled in the art that ADHD may be influenced not in the same direction in the one patient to gain a positive outcome for that patient. It will also be appreciated that it is not necessary for there to be an improvement in either working memory or attention or cognitive processing or overt signs or symptoms for there to be a therapeutic effect for the combination therapy described. That is the use of at least one dopamine drug and at least one cholinergic drug may be equally effective in slowing down the worsening of either working memory or attention or cognitive processing or overt signs or symptoms and thereby be effective, while not actually causing an improvement in either attention or working memory or physical traits. [0046] Hence there is some scope to modulate attention or working memory or learning or cognition or mood or behaviour or symptoms or signs such that it is favourable outcome to the patient with respect to the disorder ADHD causing problems and or potential future problems caused by the condition ADHD.

[0047] The compositions to treat ADHD can also be used to treat any of the diseases or disorders of the central nervous system that can influence cognition and or attention and or working memory and or motor disturbances within the same individual. Such diseases and disorders are defined in The Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV - American Psychiatric Association, 1994). To the extent necessary for completion, the contents of this reference and all of the defined diseases or disorders are expressly incorporated by reference and can benefit from the said compositions outlined within this specification.

[0048] Representative diseases or disorders include, but are not limited to the following: mild cognitive impairment, Alzheimer's disease, obesity, depression, schizophrenia, a stress related disease (e.g. general anxiety disorder), panic disorder, a phobia, obsessive compulsive disorder, post- traumatic-stress syndrome, immune system depression, incontinence, a stress induced problem with the urinary, gastrointestinal or cardiovascular system (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine headaches, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, generalized anxiety disorder, an inhalation disorder, an intoxication disorder, a movement disorder (e.g., Tourette's syndrome), oppositional defiant disorder, a pain disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder, seasonal affective disorder, a sleep disorder, a specific developmental disorder, and selective serotonin reuptake inhibition (SSRI) syndrome.

[0049] The preferred embodiments include the utilization of a discovery platform or system for Personalized Medicine (Personalized Medicine Platform). The Personalized Medicine Platform involves the use of Markers (distinctive measures of either genomic, brain or cognition) that delineate any clinical group from controls, and predict treatment response at an individual level.

[0050] The methodology of utilization of the Personalized Medicine Platform is illustrated in Fig. 1 and includes the utilization of the following five major steps:

1. The first component 10 is the standardization of the methodology (all hardware and software is identical) and integration (bringing together elements about the brain that are normally studied in isolation, namely genomics, brain and cognition). One example standardized system can be that disclosed in US Patent Application 11/091048 (Publication Number 20050273017) entitled "Collective Brain Measurement System and Method", the contents of which are hereby incorporated by cross reference. Although, other standardized Platforms could be utilized.

2. The next step 11 is to utilize the Personalized Medicine Platform to find the distinguishing markers that distinguish ADHD with their age matched normative controls. These markers provide the distinctive signatures that determine whether each person belongs to that disorder category.

This step includes utilizing the Platform to carry out a series of test whereby the ADHD patients are distinguished from normal patients. The actual tests carried out can be determined by resource expenditure considerations and sensitivity studies.

In various studies carried out by the Applicant, different levels of sensitivity of markers for ADHD versus matched healthy, normative controls were found. Using the above system carried out in US Patent Application 11/091048 preliminary results were obtained for different number of marker tests. The results of test carried out on 175 ADHD patients and

175 matched healthy peers showed that increasing the level of combination of markers is more effective at distinguishing an individual child with ADHD from controls, than is any single marker alone.

These results are illustrated 20 in Fig. 2. In a first single test of cognition, namely the Continuous Performance Test (CPT) has sensitivity (correctly identifying people with ADHD from controls) of 68%. On the other hand, a combination of general software cognition tests yielded a sensitivity of 83%. When further measures of the brain's electrical activity (in particular raised theta EEG activity in the case of ADHD), the sensitivity is increased to 87%, and when markers of body function and brain function measures of arousal are added, the sensitivity is above 90%.

It can therefore be seen that by utilizing a wide range of tests from the research literature, increased levels of sensitivity can be obtained at the expense of providing an increased level of resource expenditure. It is evident that the preferred embodiments suggest continued test refinement and expansion in an ongoing manner.

3. Returning to Fig. 1, the next step is to test an individual patient on the relevant markers to determine the levels of each marker. These can then be compared to the marker levels for the

ADHD group and the control group to predict a treatment response at an individual patient level. The markers utilized for the Personalized Medicine (treatment prediction) do not necessarily have to be the same markers that are the signature markers that distinguish between whether the person has a disorder (compared to their age matched normative controls), provided marker correlations exist.

4. After conducting a large number of test on the effect of drugs on the relevant markers with the Personalized Medicine Platform, the individual patient test results can be used to derive rules based on this discovery platform methodology and standardized database as to whether an individual person should:

a. Be treated with a drug or not.

b. Be treated with a single drug, and which drug that should be.

c. Whether they should be treated with multiple drugs.

The study of the effect of individual drugs on the markers allows for combination therapies to be more readily undertaken. Given the brain's 100 billion highly inter-connected neurons and over 100 interacting chemicals, it is unlikely that a single drug can redress an imbalance. Further, each individual will have specific marker scores allowing for customization of the treatment regime for that individual.

The profile signature pattern in each person will determine the most likely drugs that a person should take. For example, in ADHD, children with the markers associated with general cognition are more likely to benefit from a stimulant medication, whereas children with markers associated with social cognition and anxiety, are more likely to respond to non- stimulant medication. By formulating distance measures between an individual's markers, the corresponding marker values of the group of ADHD sufferers and the marker values of the group of normative subjects, an individualized combination therapy can be prescribed. Standard statistical algorithms can then be utilized to determine a probability matrix as to which individual person should go on to which combinations of drugs. The algorithms can draw upon the diverse data already in the Personalized Medicine Platform.

5. Finally, there is the step of monitoring the effectiveness of any individual drug or drug combination to determine whether each individual patient is normalizing (moving to a sufficient extent towards the age and gender matched controls for that individual subject).

[0051] Treatment of the above diseases or disorders is accomplished by delivering a therapeutically effective amount of the considered composition to a mammal such that mood and memory is influenced and or treated. In most cases this will be a human being, but treatment of food animals (e.g., livestock and poultry) and companion animals (e.g., dogs, cats and horses) is expressly covered herein.

[0052] The combinational therapy used in the preferred embodiments includes at least one drug and or compound and or agent that affects / effects dopaminergic transmission and or the dopamine receptor.

[0053] In another aspect of the preferred embodiments, a CNS stimulant is used in combination with other cholinergic modulating compounds.

[0054] In a preferred embodiment the psycho-stimulant or analeptic agents are a CNS stimulant selected from the group consisting of amphetamine, d-amphetamine, amphetaminil, bemegride, benzphetamine, brucine, chlorphentermine, clofenciclan, clortermine, deanol acetamidobenzoate, demanyl, dexoxadrol, diethpropion, doxapram, N-ethylamphetamine, ethamivan, etifelmin, etryptamine, fencamfamine, fenethylline, fenosolone, fenfluramine, flurothyl, hexacyclonate, homocamfin, mazindol, megexamide, methamphetamine, nicotinic agonists, nikethamide, pemoline, pentylenetetrazole, phenidimetrazine, phenmetrazine, phentermine, picrotoxin, pipradrol, prolintane, pyrovalerone, racephedrine, tetrahydrobenzothienopyridines, and pharmacologically acceptable salts thereof.

[0055] In a preferred embodiment the CNS stimulant is a psycho-stimulant is methylphenidate. In another preferred embodiment the CNS stimulant is methylphenidate. In another preferred embodiment suitable CNS stimulants compounds are selected from suitable FDA approved pharmaceuticals that include DEXEDRINE. RTM., which is a sustained release capsule containing dextroamphetamine sulfate, available from SmithKline Beecham Pharmaceuticals; RITALIN.RTM., which is a tablet containing methylphenidate hydrochloride, available from Ciba Pharmaceutical Company; and CYLERT.RTM., which is a tablet containing premoline, available from Abbott Laboratories.

[0056] Methylphenidate has been used to treat nervous system disorders including Attention Deficit Disorder (ADD), a commonly diagnosed nervous system illness in children, Attention Deficit Hyperactivity Disorder (ADHD), and cognitive decline in patients with Acquired Immunodeficiency Syndrome (AIDS) or AIDS related conditions. See, e.g., Brown, G., Intl. J. Psych. Med. 25(1): 21-37 (1995); Holmes et al., J. Clin. Psychiatry 50: 5-8 (1989). The racemic form of methylphenidate also has been proposed to improve cognitive function in patients receiving large doses of medication. See, for example, Bruera et al., Pain (1992) 163-166, Yee et al., Journal of Pain and Symptom Management (1994), Vol. 9, No.2, 122-125, and Meyers et al., Journal of Clinical Oncology (1998) Vol. 16, No. 7, 2522-2527. [0057] In another preferred embodiment D-threo methylphenidate that is substantially free of L-threo methylphenidate and of erythro forms of methylphenidate is used in combinational therapy to treat ADHD.

[0058] The preferred quantity of D-threo methylphenidate to be used in a dosage for treating a particular patient can be readily determined by one skilled in the art. Factors determining the appropriate dosage include the weight and age of the patient, the type and extent of the disorder being treated, and other conditions of the patient including other disorders and other medications, if any, that the patient is taking. Generally, the dosage of D-threo methylphenidate will be from about 0.01 mg/kg of patient body weight to about 1 mg/kg of patient body weight. Appropriate quantities can be determined by one skilled in the art. For example, a relatively small child will generally require a dose of from about 0.03 to about 0.3 mg/kg, while a larger child or an adult may require a dose of from about 0.1 mg/kg to about 0.4 or 0.5 mg/kg.

[0059] In another embodiment an antipsychotic drug is used in combination with a cholinergic modulator to treat ADHD. [0060] Antipsychotic drugs have been used to treat schizophrenia whereby it is understood to be caused by hyperactivity in the brain dopaminergic system. For this reason, some drugs were developed with strong dopaminergic receptor blocking activity. These typical antipsychotic drugs are effective in the treatments for the positive symptoms of schizophrenia, which include hallucinations, delusions and the like. During the last decade, a variety of atypical antipsychotic drugs have been developed, which include clozapine, risperidone, olanzapine, quetiapine, aripiprazole, amisulpride. These drugs have less extrapyramidal not risperidone, which does in doses higher then 3mg in kids and 6mg in adults side effects, and have other activities in addition to their DA-receptor blocking activities. In contrast to typical antipsychotic drugs, such as chlorpromazine, haloperidol, etc., it is reported that atypical antipsychotic drugs are more effective against the negative symptoms and cognitive impairments associated with schizophrenia than typical antipsychotic drugs, and atypical antipsychotic drugs also have less extrapyramidal side effects, although this may emerge on dosing, such as with risperidone (S. Miyamoto, G. E. Duncan, R. B. Mailman and J. A. Lieberman: Current Opinion in CPNS Investigational Drugs, Vol. 2, pp. 25, (2000)). More recently in a single small clinical trial has shown that Risperidone has a positive treatment affect in ADHD - see Prim Care Companion J Clin Psychiatry 2005; 7; 221-224) but with increased risk on higher doses of extrapyramidal side effects by "going typical" in the words of Kaipur.

[0061] Whilst not wishing to be bound by theory, it is understood by the inventor that this would leave theoretically more dopamine to interact with Dl receptors in the PFC, but would not be advantageous in the hippocampus where Dl receptors may interfere with gamma fast activity - see Eur J Neurosci. 2003 Nov;18(9):2573-80. Hence the inventor appreciates that cholinergic modulators can have an advantageous affect on fast gamma activity for cognitive function and prescribes the combination of a cholinergic modulator in the presence of either a Dl agonist and or an antipsychotic. [0062] In one preferred embodiment the anti-psychotic drug is an "atypical" anti-psychotic drug. In another preferred embodiment the anti-psychotic drug is any compound with D2 antagonist properties. In another preferred embodiment the anti-psychotic drug is Risperidone and administered in a dosage of l-3mg daily.

[0063] Examples and doses of suitable anti-psychotic medications include the following: "Typical" antipsychotics are conventional antipsychotics such as phenothiazine, butryophenones, thioxantheses, dibenzoxazepines, dihydroindolones, and diphenylbutylpiperidines. "Atypical" antipsychotics are a new generation of antipsychotics which generally act on the dopamine D.sub.2 and 5HT.sub.2a serotonin receptor and have high levels of efficacy. Examples of typical antipsychotics (and examples of suitable daily (d) dosages) include Chlorpromazine (5-2000 mg/d, e.g., 30-800 mg/d), Thioridazine (5-2000 mg/d, e.g., 20-800 mg/d), Mesoridazine (1-1000 mg/d, e.g., 30-400 mg/d), Fluphenazine (0.5-200 mg/d, e.g., 1-40 mg/d), Perphenazine (0.5-300 mg/d, e.g., 10-65 mg/d), Trifluoperazine (0.5- 200 mg/d, e.g., 2-40 mg/d), Thiothixene (1-200 mg/d, e.g., 6-60 mg/d), Haloperidol (0.25-500 mg/d, e.g., 1-100 mg/d), Loxapine (1-1000 mg/d e.g., 20-250 mg/d), Molindone (1-1000 mg/d, e.g., 15-225 mg/d), Acetophenazine (10-2000 mg/d, e.g., 30-500 mg/d), Chlorprothixene (5-2000 mg/d, e.g., 30- 500 mg/d), Droperidol (0.25-500 mg/d, e.g., 1-100 mg/d), Pimozide (0.25-500 mg/d, e.g., 1-100 mg/d). Examples of atypical antipsychotics (and examples of suitable daily dosages) include Clozapine (5-2000 mg/d, e.g., 12-900 mg/d), Risperidone (0.25-500 mg/d, e.g., 2-16 mg/d over 6mg there are potential side effects), Olanzapine (1-100 mg/d, e.g., 5-10 mg/d), and Quetiapine (1-2000 mg/d, e.g., 50-750 mg/d). Depot antipsychotics also can be used, e.g., Haloperidol decanoate (10- 1000 mg/month, e.g., 100-450 mg/month), Fluphenazine decanoate (5-1000 mg/month, e.g., 25-150 mg/month), and Fluphenazine enanthate (5-1000 mg/month, e.g., 25-200 mg/month). Additional antipsychotics include Butaperazine (0.5-500 mg/d, e.g., 1-200 mg/d), Carphenazine, (0.5-3000 mg/d, e.g., 1-1000 mg/d), Remoxipride (0.5-5000 mg/d, e.g., 1-2000 mg/d), Piperacetazine (0.5-500 mg/d, e.g., 1-2000 mg/d), Sulpiride (0.5-5000 mg/d, e.g., 1-2000 mg/d), and Ziprasidone (0.5-500 mg/d, e.g., 1-200 mg/d).

[0064] In another aspect of the present invention dopaminergic function is modulated by dopamine D4 receptors. It is preferable that the D4 receptors are modulated with a D4 ligand, using a dopamine D4 ligand. Suitable compounds include but not limited to administering a pyrido[l,2a]pyrazine derivative, benzimidazole derivative, bicyclic compound, spirocyclic benzo furan derivative, indole derivative or a related compound that is a dopamine D4 receptor ligand.

[0065] Pyrido[l,2a]pyrazine derivatives, benzimidazole derivatives, bicyclic compounds, spirocyclic benzofuran derivatives, indole derivatives or related compounds that exhibit activity as dopamine D4 receptor ligands have been described in the following patent / patent applications U.S. Pat. No. 5,852,031, issued on Dec. 22, 1998; U.S. Pat. No. 5,883,094, issued on Mar. 16, 1999; U.S. Pat. No. 5,889,010, issued on Mar. 30, 1999; PCT International Application PCT/IB97/00978, published as WO98/08835 on Mar. 5, 1998; U.S. patent application Ser. No. 5,877,317 issued on Mar. 2, 1999; U.S. patent application Ser. No. 5,021,420, issued on Jun. 4, 1991 ; U.S. patent application Ser. No. 5,633,376, issued on May 27, 1997; U.S. patent application, Ser. No. 5,432,177, issued on Nov. 9, 1994; U.S. patent application Ser. No. 5,622,950, issued on Apr. 22, 1997, PCT International Application No. PCT/EP93/01438, published as WO94/00458 on Jan. 6, 1994; PCT International Application No. PCT/IB98/01198, published as WO99/09025 on Feb. 25, 1999; U.S. patent application Ser. No. 5,998,414, issued on Dec. 7, 1999; U.S. patent application Ser. No. 5,968,478, issued on Oct. 19, 1999; U.S. patent application Ser. No. 6,040,448, issued on Mar. 21, 2000; U.S. patent application Ser. No. 6,051,605, issued on Apr. 18, 2000; U.S. patent application Ser. No. 5,945,421, issued on Aug. 31, 1999; and U.S. patent application Ser. No. 5,798,350, issued on Aug. 25, 1998.

[0066] In another embodiments, a D.sub.4 receptor antagonist is used to positively affect hyperactivity. A particularly preferred antagonist is 7R,S-(4-fluoro-phenoxymethyl)-2-(5-fluoro- pyrimidin-2-yl)-octahydropyrido[ l,2-.alpha.]pyrazine, known as CP-293,019. CP-293,019 is a highly D.sub.4 receptor-selective, full antagonist with more than 1000-times greater potency at D.sub.4 receptors than at D.sub.2 or other DA receptors, with negligible affinity for non-dopaminergic receptors except for moderate or low potency at serotonin 5-HT.sub.lA and 5-HT.sub.2A receptors (K.sub.i =150 and 500 .mu.M, respectively). See Sanner et al., supra. CP-293,019 can be used to treat humans with ADHD.

[0067] In another embodiments, an agent can be used for enhancement of dopaminergic transmission high-affinity, sodium and energy-dependent transport systems to increase dopamine levels. For example, the biological actions of the brain neurotransmitter dopamine are terminated at the synapse by a high-affinity, sodium and energy-dependent transport system (neuronal re-uptake) present within the limiting membrane of the presynaptic dopamine-containing nerve terminal. Inhibition of this transport mechanism would extend the actions of dopamine at the synapse and therefore enhance dopamine synaptic transmission. Examples or compounds that are Inhibitors of Dopamine Re-Uptake are Desmethylselegiline and or Ent-Desmethylselegiline. Effective dosages are a daily dose of at least about 0.015 mg/kg of body weight. [0068] In another embodiments, 5-HT.sub.6 receptor antagonists can be used to selectively increases activity of the nigrostriatal dopamine pathway and can therefore, specifically alleviate dopamine abnormalities associated with ADHD. The compounds can have additional effects on the central nervous system, namely, an increase in cognitive function.

[0069] The embodiments relate to methods for the prevention or treatment of disorders characterized by an alteration in normal neurotransmitter release, such as dopamine release. The present invention also relates to methods for the prevention or treatment of disorders, such as central nervous system (CNS) disorders, which are characterized by an alteration in normal neurotransmitter release as found in ADHD. The methods involve as described in USA patent application 6,525,065 administering to a subject an effective amount of an endo or exo form of a l-aza-2-(3-pyridyl)bicyclo[2.2.1]heptane, a l-aza-2-(3-pyridyl)bicyclo[2.2.2]octane, a l-aza-2-(3 pyridyl)bicyclo[3.2.2]nonane, a l-aza-7-(3- pyridyl)bicyclo[2.2.1]heptane, a l-aza-3-(3-pyridyl)bicyclo[3.2.2]nonane, or a l-aza-7-(3- pyridyl)bicyclo[3.2.2]nonane are appropriate for combinational therapy in ADHD.

[0070] In a further alternative embodiment, an antidepressant that inhibits dopamine reuptake can be used such as Bupropion can be utilised. [0071] In one preferred embodiment a norepinephrine reuptake inhibitor is used to enhance dopamine transmission in the brain. The norepinephrine reuptake can be selective for noradrenaline only or alternatively can be non-selective. Examples of norepinephrine reuptake inhibitors that could be used according to the invention with selective norepinephrine reuptake inhibitors being particularly preferred. This list of norepinephrine reuptake inhibitor compounds includes, but is not limited to the following: tandamine, pirandamine, ciclazindol, fluparoxan, lortalamine, talsupram, talopram, prindamine, nomifensine, viloxazine, tomoxetine, duloxetine, venlafaxine, milnacipran and reboxetine. In a preferred embodiment the norepinephrine transporter (NET) reuptake inhibitor is Atomoxetine. [0072] In a preferred embodiment the selective norepinephrine reuptake inhibitor is reboxetine, 2- [.alpha.-((2-ethoxyphenoxy)benzyl]-morpholine, and its pharmaceutically acceptable salts, in either its enantiomeric (particularly the (S, S) enantiomer) or racemic form. Synthesis of racemic reboxetine is described in greater detail in U.S. Pat. No. 4,229,449. Individual stereoisomers of reboxetine can be obtained by resolution of the racemic mixture of enantiomers using conventional methods generally known by those skilled in the art. Such methods include, but are not limited to, resolution by simple crystallization and chromatographic techniques, for example, as set forth in GB 2, 167,407. Other methods of preparation are described in U.S. Pat. Nos. 5,068,433 and 5,391,735. Reboxetine can be a free base form, or it can be in salt form, preferably the methanesulfonate salt (also called reboxetine mesylate). [0073] The selection of the dosage for a nor-adrenaline re-uptake inhibitor is that which can provide relief to the ADHD patient. The dosage of this component can depend on several factors such as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, the severity of the condition to be treated, and the like. This is considered to be within the skill of the artisan and one can review the existing literature on the components to determine optimal dosing. By way of example, desirably, when reboxetine is selected as the active agent, the daily dose contains from about 0.1 mg. to about 10 mg. More preferably, each dose of the component contains about 0.5 to about 8 mg of the active ingredient, and even more preferably, each dose contains from about 0.5 to about 5 mg of the active ingredient. This dosage form permits the full daily dosage to be administered in one or two oral doses. This will allow for final formulations containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9. 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 mg of active. More than once daily or twice daily administrations (e.g., 3, 4, 5 or 6 administrations per day) are also expressly contemplated herein.

[0074] The average daily adult dosage of the other nor-epinephrine reuptake inhibitors can be as follows. The dosages expressly include all numerical values, whole or fractional, within the stated range. Pediatric dosages may be less. Component Average Daily Dosage (mg/day/patient) Tandamine 7.5 to 3750 Pirandamine 7.5 to 3750 Ciclazindol 5 to 500 Fluparoxan .75 to 750 Lortalamine 1 to 200 Talsupram 1 to 3750 Talopram 1 to 3750 Prindamine 1 to 3750 Nomifensine 1 to 80 Viloxazine 1 to 3750 Tomoxetine 1 to 200 Duloxetine 5 to 500 Venlafaxine 2 to 200 Milnacipran 7.5 to 75

[0075] In another embodiment an alpha. -2 adrenergic agonist is used to modify dopaminergic transmission in the brain and treat ADHD in conjunction with the cholinergic modulating agent. A suitable alpha. -2 adrenergic agonist can be ((+)-(S)-4-[l-(2,3-dimethyl-phenyl)-ethyl]-l,3-dihydro- imidazole- 2-thione) from (+)-(S)-4-[l-(2,3-dimethyl-Phenyl)-ethyl]-lH-imidazole.

[0076] In another embodiment an alpha(2) adrenergic agonist, clonidine is used to increase the firing rate of meso-accumbens dopaminergic neurons in ADHD to enhance pre- frontal activity in the presence of the cholinergic modulator.

[0077] In another embodiment cholinergic modulators are combined with one or more CB 1 receptor antagonists and of one or more products which activate dopaminergic neurotransmission in the brain such that the combinational therapy exhibits a synergistic effect in the treatment of ADHD. CBl antagonists, of the azetidine derivatives have been disclosed in WO 00/15609 and would be appropriate therapeutics.

[0078] In addition to precursors of dopamine can be used for the present invention. Suitable dopaminergic agonists, of the following products: levodopa, bromocriptine (Novartis), cabergoline (Pharmacia Corp.), adrogolide (Abbott Laboratories), BAM-1110 (Maruko Seiyaku Co Ltd), Duodopa.RTM. (Neopharma), L-dopa, dopadose (Neopharma), CHF1512 (Chiesi), PNU-95666 (Pharmacia & Upjohn), ropinirole (GlaxoSmithKline Beecham), pramipexole (Boehringer,

Ingelheim), rotigotine (Discovery Therapeutics, Lohmann Therapy System), spheramine (Titan Pharmaceuticals), TVl 203 (Teva Pharmaceutical) or uridine (Polifarma).

[0079] In another embodiment, a Dl agonist is used to improve dopaminergic function in the prefrontal cortex in ADHD. A suitable Dl agonist is Adrogolide (ABT-431 ; DAS-431) is a chemically stable prodrug that is converted rapidly (<1 min) in plasma to A-86929, a full agonist at dopamine Dl receptors - see CNS Drug Rev. 2001 Fall;7(3):305-16.

[0080] In another embodiment low doses of dopamine D2 receptor agonists such as bromocriptine and pergolide are given in association with a cholinergic modulator to enhance working memory and executive functions in ADHD. [0081] In another embodiment Rotigotine a nonergolinic dopamine D3/D2/D1 receptor agonist delivered via a transdermal system in combinational therapy with a cholinergic modulator to treat ADHD. [0082] In preferred embodiments, the combinational therapy used includes at least one drug or compound that affects cholinergic function. The cholinergic function can be modulated by nicotine receptors. Nicotine, via tobacco and or in various forms, has been one of the most widely utilized drugs for centuries (Wilbert J, J Ethnopharmacol 32(1-3): 179-186, 1991). Nicotine is a potent modulator of nAChrs (Changeux J P, Sci Amer (November) pp. 58-62, 1993). Through these receptors, nicotine activates the presynaptic release of several neurotransmitters including acetylcholine, norepinephrine, serotonin and dopamine (Balfour D J K, Pharmacological Therapeutics 16: 269-282 1982).

[0083] In one preferred embodiment the drug affecting cholinergic function is a nicotinic antagonist. Preferably, the nicotine antagonist is mecamylamine, a stereoisomer, or a mecamylamine analog. The effective amount of mecamylamine is that which improves the individual's signs and symptoms.

Other compounds which may reasonably be expected to be active in this use but not limited to are disclosed in U.S. Pat. No. 4,837,218 (Alkylated Bicycloalkaneamines for Neurotoxic Injury), U.S.

Pat. No. 2,894,987 (N-allyl-2-aminoisocamphane), U.S. Pat. No. 3,148,118 (Analeptically Active Agents), U.S. Pat. No. 3,164,601 (Analeptically Active N-Substituted Aminonorcamphane

Derivatives).

[0084] In a related embodiment both a nicotinic agonist and antagonist are co-administered. This has been described in the U.S. Pat. No. 5,774,052 to Rose and Levin discloses agonist-antagonist of nicotine and the nicotinic antagonist mecamylamine. The effective amount of the mecamylamine or mecamylamine stereoisomer can be 0.005-1.00 mg/kg/day.

[0085] In a related embodiment agents are administed for modulating nicotinic receptors by use of analogs of galanthamine (alternatively galantamine) and or lycorarmine.

[0086] In another embodiments dopamine receptor populations are manipulated so as to achieve a better therapeutic response with drugs that increase or decrease available dopamine and or act as agonists or antagonists at the dopamine receptor. Those skilled in the art will realize that any of the molecular subtypes of dopamine receptor can be regulated and or normalized within a normal and or abnormal population range. Alternatively dopamine receptor subtype can move in opposite directions or in the same direction in terms of an increase or decrease in functional receptor subtype populations within global or specific brain regions. The inventor has identified the use of HMG-CoA reductase inhibitors to modify and or regulate dopamine receptor populations in the brain.

[0087] Thus in another embodiments, HMG-CoA reductase inhibitors can be used to facilitate a treatment response with a dopaminergic drug or modulator in ADHD that may or may not be combined with an cholinergic agent. A HMG-CoA reductase inhibitor may be selected from the group consisting of mevastatin, pravastatin, lovastatin, simvastatin, fluvastatin and atorvastatin but not limited to. It is preferable that a HMG-CoA reductase inhibitor is chosen that crosses the blood brain barrier.

[0088] In one preferred embodiment the drug affecting cholinergic function is an anti-cholinesterase. Anticholinesterase compounds suitable for delivery include Physostigmine, 1,2,3, 3a,8,8a-hexahydro- l,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol methylcarbamate, or a salt thereof, and structurally similar compounds.

[0089] As used above, the term "salt thereof is meant to include any nontoxic pharmaceutically suitable salt of a compound described above with the desired pharmacological properties in mammals. Preparation of such a salt is well-known to those skilled in pharmaceutical science. Pharmaceutically acceptable acid addition salts of the above compounds include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, salicylate, citrate, tartarate, bitartarate, lactate, phosphate, malate, maleate, fumarate, succinate, acetate and pamoate. Acid forms thereof.

[0090] Also suitable for buccal/sublingual delivery or administration using other cholinesterase inhibitors such as Metrifonate, Donepezil, and structurally similar compounds would be useful. [0091] A pharmaceutical compound containing an anti-cholinesterase to be combined with at least one compound with dopamine affinity can be prepared by processes that are known in the art and described, for example, in U.S. Pat. No. 4,895,841, WO 98/39000, and Japanese Patent Application Nos. 4-187674 and 4-21670, the disclosures of each of which are incorporated by reference herein in their entirety. For example, Donepezil hydrochloride, a preferred cholinesterase inhibitor for use in the methods described herein, is commercially available as ARICEPT.RTM. from Eisai Inc., Teaneck, NJ.

[0092] In another embodiments, 5-HT2 agonists are used to facilitate ACh release. For example 5- HT2 receptors have been exploited in animal models in the regulation of acetylcholine (ACh) release within the medial prefrontal cortex and hippocampus. The 5-HT(2A/2C) agonist +/-l-(2,5- dimethoxy-4-iodophenyl) -2- aminopropane hydrochloride (DOI) (1 and 2 mg/kg, i.p.) significantly increased the extracellular concentration of ACh in both brain regions, and this response was attenuated in rats treated with the 5-HT(2A/2B/2C) antagonist LY-53,857 (3 mg/kg, i.p.) - see Synapse. 2004 Sep 15;53(4):202-7.

[0093] In another embodiments, a selective 5-hydroxytryptamine (serotonin) (5-HT)(IA) receptor partial agonist such as S 15535 [4-(benzodioxan-5-yl)l-(indan-2-yl)piperazine] is used to increase extra-cellular Ach in the brain. Serotonin plays a role in several neurological and psychiatric disorders, including Alzheimer's disease, depression, nausea and vomiting, eating disorders, and migraine. (See Rasmussen et al., "Chapter 1. Recent Progress in Serotonin 5HT.sub. lA Receptor Modulators", in Annual Reports in Medicinal Chemistry, Vol. 30, Section I, pp. 1-9, 1995, Academic Press, Inc.). WO 00/16777 discloses that a .sup.5HT.sub. IA receptor agonist, buspirone is efficacious in treating a variety of symptoms associated with ADHD, and that combined use of a D2 receptor agonist and 5-HT.sub. IA agonist provides effective treatments for ADHD and Parkinson's disease. The inventor has extended this combinational therapy by adding a further cholinergic modulator. Additionally the inventor has also found that it is not always efficacious to add a D2 receptor agonist but the patient can benefit from a D2 antagonist typically found in anti-psychotic medications. Additionally the inventor proposes that by adding the novel combination of a Dl agonist and buspirone there will be superior treatment effects in the patient.

[0094] In another embodiments, blockade of both postsynaptic 5-HT(IA) receptors and 5-HT(IA) autoreceptors are manipulated in ADHD as part of the combinational therapy.

[0095] In another embodiments, a combined 5-HT(3) receptor antagonist such as ondansetron and a ABA(A) receptor benzodiazepine site antagonist such as flumazenil is used to increase prefrontal Ach brain levels - see Neuropharmacology. 2004 Aug;47(2):225-32

[0096] In another embodiments, 5-HT(6) receptor antagonists can be used to facilitate ACh release and thereby improve learning and memory and or cognitive processes in combination with classical ADHD stimulant medication and or with the use of atypical anti-psychotics. Preferred compounds of this invention include those disclosed in patent applications WO 98/27081 (SmithKline Beecham p.l.c.) and WO 99/02502 (SmithKline Beecham p.l.c). In other embodiments, one or more 5HT receptors are targeted with a compound to facilitate cholinergic transmission in the prefrontal cortex and or hippocampus.

[0097] The dosage regimen for treating the diseases described herein with the cholinesterase inhibitors described herein is selected in accordance with a variety of factors, including the age, weight, sex, and medical condition of the patient, the severity of the disease affecting mood and memory, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular cholinesterase inhibitor used and the type of drug delivery system used. Importantly consideration will be given to the combination therapy that includes at least one other dopamine modifying agent that is used in combination with the cholinesterase inhibitor. Thus, the dosage regimen actually used may vary widely and may deviate from the preferred dosage regimen described herein. [0098] In preferred embodiments, the cholinesterase inhibitors of the present invention are administered to treat the consequences of ADHD described herein in doses of about 0.1 milligram to about 300 milligrams per day, preferably about 1 milligram to about 100 milligrams per day, more preferably about 5 milligrams to about 10 milligrams per day. The doses can be administered in one to four portions over the course of a day, preferably once a day. One skilled in the art will recognize that when the cholinesterase inhibitors of the present invention are administered to children, the dose may be smaller than the dose administered to adults, and that the dose can be dependent upon the size and weight of the patient. In preferred embodiments, a child can be administered the cholinesterase inhibitors of the present invention in doses of about 0.5 milligrams to about 10 milligrams per day, preferably about 1 milligram to about 3 milligrams per day.

[0099] In preferred embodiments of the methods described herein, a physician can administer patients donepezil hydrochloride, which is commercially available as ARICEPT.RTM. (Eisai Inc., Teaneck, N. J.), as film-coated tablets containing 5 milligrams donepezil hydrochloride or 10 milligrams donepezil hydrochloride. The tablets can be administered one to about four times a day. In preferred embodiments, one 5 milligram or one 10 milligram ARICEPT.RTM. tablet is administered once a day for the methods described herein. One skilled in the art will appreciate that when donepezil hydrochloride is administered to children, the dose may be smaller than the dose that is administered to adults. In preferred embodiments, a child can be administered donepezil hydrochloride in doses of about 0.5 milligrams to about 10 milligrams per day, preferably about 1 milligram to about 3 milligrams per day.

[00100] In one embodiment the anti-cholinesterase agent is not a classical drug but an antisense oligonucleotide targeted to the coding region of the human acetylcholinesterase (AChE), which selectively suppresses the AChE-R isoform of the enzyme. The antisense oligonucleotide is a nucleotide comprising essentially a reverse complementary sequence to a sequence of AChE mRNA. The nucleotide is preferably an oligodeoxynucleotide, but also ribonucleotides or nucleotide analogues, or mixtures thereof, can be contemplated. The antisense oligonucleotide may be linear, or may comprise a secondary structure. It may also comprise enzymatic activity, such as ribozyme activity. The antisense oligodeoxynucleotide of the invention combination therapy typically corresponds but not limited to the reverse complement of human AChE mRNA sequence, from nucleotide 795-5' to nucleotide 3 '-814

[00101] In another embodiments, one component of the combination therapy is a psychostimulant and the other is anti-sense oligonucleotide targeted to the coding region of the human acetyl-cholinesterase (AChE).

[00102] Compositions can conveniently be administered in a pharmaceutical composition containing the active components in combination with a suitable excipient. Such pharmaceutical compositions can be prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed., 1975). To the extent necessary for completion, this reference is hereby incorporated by reference. The compositions of the present invention can be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally, intranasally, intravaginally, or rectally, with oral administration being particularly preferred.

[00103] For oral therapeutic administration, the inventive composition may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, foods and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 0.1 to about 100% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[00104] The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. The above listing is merely representative and one skilled in the art could envision other binders, excipients, sweetening agents and the like. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active components may be incorporated into sustained-release preparations and devices including, but not limited to, those relying on osmotic pressures to obtain a desired release profile.

[00105] The inventive composition, containing the two active components, may be administered in the same physical form or concomitantly according to the above-described dosages and in the above- described delivery vehicles. The dosages for each active component can be measured separately and can be given as a single combined dose or given separately. They may be given at the same or at different times as long as both actives are in the patient at one time over a 24-hour period. Concomitant or concurrent administration means the patient takes one drug within about 5 minutes of taking the other drug. Because the goal is to provide rapid symptomatic relief to the patient, in most cases when treatment is started the two drugs would be administered to the patient close in time and typically concomitantly; thereafter, the timing of each drug's administration may not be as important. [00106] In another embodiments, a muscarinic agonist is used as part of the combinational therapy with a dopaminergic modulating drug. Muscarinic ACh receptors play important roles in many physiological functions, including memory and learning, and are widely distributed throughout the body. Five subtypes of muscarinic receptors (M1-M5) have been identified which differ in their molecular structure, distribution and function. Muscarinic receptors have been found to act via the activation of various guanos ine nucleotide binding proteins (G-prbteins) which activate second messengers via coupling of different effector enzymes. Ml, M3 and M5 receptors are coupled to phospholipase C while M2 and M4 receptors inhibit adenylyl cyclase. The two main types of muscarinic receptors are Ml and M2; the Ml muscarinic receptor predominates in the human brain whereas M2 receptors are mainly located in the heart. Stimulating the Ml receptors produces a positive feedback to increase ACh release whereas stimulating M2 receptors, and to a lesser extent, M4 receptors, serves as negative feedback to decrease ACh release. Thus, both M 1 agonists and M2 antagonists should increase the release of endogenous ACh.

[00107] In one embodiment a Ml agonist is used to treat ADHD in combination with a dopaminergic modulating agent or pharmaceutical compound. Suitable agents but not limited to include Xanomeline a transdermal Ml agonist and YM 796 Ml agonist. In another embodiment an M 1 and or M4 agonist is used to treat ADHD.

[00108] In another embodiment, nicotine is used to improve cognitive function in ADHD by enhancing the effects of a atypical anti-psychotic and or stimulant used to treat ADHD. For example, nicotine, when added to or substituted for haloperidol neuroleptic treatment, produced rapid and marked relief from tics and other symptoms of TS not controlled by neuroleptics alone. Using neuroleptic-induced catalepsy as a model for understanding the therapeutic actions of neuroleptics and nicotine in TS patients, it was initially proposed that nicotine potentiates the actions of D2 antagonists on catalepsy by activating disinhibited striatal cholinergic interneurons which innervate striatopallidal GABA projection neurons.

[00109] In another embodiments, nicotine antagonists are administered as part of the combinational dopaminergic therapy for treating ADHD, particularly mecamylamine (3-methylamino-2,2,3- trimethylnorcamphane). In one embodiment the preferred nicotine antagonists are mecamylamine, a mecamylamine analog, or a mecamylamine stereoisomer. The effective amount of the nicotine antagonist is 0.005-1.00 mg/kg/day. Alternatively, the method utilizes a partial nicotine agonist. Other compounds which may reasonably be expected to be active in this use are disclosed in U.S. Pat. No. 4,837,218 (Alkylated Bicycloalkaneamines for Neurotoxic Injury), U.S. Pat. No. 2,894,987 (N-allyl- 2-aminoisocamphane), U.S. Pat. No. 3,148,118 (Analeptically Active Agents), U.S. Pat. No. 3, 164,601 (Analeptically Active N-Substituted Aminonorcamphane Derivatives). [00110] In another embodiments, a.alpha.7 nicotinic receptor agonist are useful for the treatment of ADHD in combination with a dopaminergic modulator.

[00111] In another embodiments, a combined nicotinic agonist and antagonist are used. Conceptually a nicotinic agonist could include an alpha.7 nicotinic receptor agonist. U.S.A. Patent. No. 5,774,052 to Rose and Levin discloses agonist-antagonist combinations to improve neuronal dysfunction.

[00112] Physiological and anatomical evidence, suggest the corelease of glutamate from DA and/or non-DA neurons in the VTA that can serve to transmit this temporally precise signal. In contrast, DA acts in a protracted manner to provide spatially and temporally diffuse modulation of PFC pyramidal neurons and interneurons. This modulation occurs first via a relatively rapid depolarization of fast- spiking interaeurons that acts on the order of seconds. This is followed by a more protracted modulation of a variety of other ionic currents on timescales of minutes to hours, which may bias the manner in which cortical networks process information. However, the prolonged actions of DA may be curtailed by counteracting influences, which likely include opposing actions at Dl and D2-like receptors that have been shown to be time- and concentration-dependent. In this way, the mesocortical DA system optimizes the characteristics of glutamate, GABA, and DA neurotransmission both within the midbrain and cortex to communicate temporally precise information and to modulate network activity patterns on prolonged timescales. Thus in other embodiments there may be the requirement to modulate dopamine, cholinergic and glutamate and GABA within the one individual. In this context antagonists of mGluRl and mGluR5 may also be used to overcome deficits evoked via dopamine.

[00113] In another embodiments, drugs that act as glutamate modulators can be used for example ketamine, riluzole, and AMPA receptor potentiators can be used.

[00114] In another aspect of the invention NMDA receptor currents are modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5).

[00115] Drugs that are useful for modulating the NMDA receptor include glycine, D-serine, D- cycloserine, or ampakine CX516. [00116] In another aspect of the current invention glutamate uptake systems (EAATs) are modulated with in the brain. Glutamate reuptake results in subsequent conversion into glutamine. Antibiotics or there targets can be used to modulate gene expression of subtypes of EAATs, offering a novel mechanism for modulation of synaptic glutamate concentrations and or resultant glutamate excitoxicity.

[00117] In another aspect of the invention cholinergic and dopaminergic systems are modulated in the same individual as well as a compound selected from the following NMDA receptor antagonists, metabotropic glutamate receptor (mGluR) agonists and antagonists, and positive modulators of AMPA receptors.

[00118] In a preferred embodiment the NMDA receptor antagonist is Memantine, a low affinity antagonist to glutamate NMDA receptors.

[00119] In particular, the inventive composition is to be used in the treatment of ADHD. While not wishing to be bound to any specific scientific theory, it is believed that the addition of a combined dopaminergic and cholinergic modulator can significantly reduce side effects and or improve treatment outcomes and or provide benefit for ADHD.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:-

1. A method of determining a treatment regime for a single patient for the treatment of ADHD symptoms, the method comprising the steps of:

(a) providing a series of ADHD brain tests to a group of ADHD sufferers and a group of normative patients to determine a series of brain markers for each with the ADHD suffers having, on average, a distinguishing set of brain markers from the normative patient group;

(b) determining an expected effect of a series of candidate drugs on the brain markers;

(c) for the single patient, providing a series of ADHD brain tests to determine a likely value of at least some of said brain markers for the single patient; (d) determining the likely effect of a combination of said series of candidate drugs on the brain markers for the single patient,

(e) selecting a likely combination of candidate drugs for the single patient that are likely to draw the markers of the single patient closer to the markers of the normative group; and

(f) administering the likely combination of candidate drugs to the single patient.

2. A method as claimed in claim 1 further comprising the step of:

(g) monitoring the difference of the value of at least some of the brain markers from the markers of the normative group for the single patient upon utilisation of the selected drugs to determine if the expected change is operative.

3. A method as claimed in claim 1 wherein said likely combination of candidate drugs includes comprising the administration to a subject requiring such treatment of a therapeutically effective amount of at least one dopaminergic agent and at least one cholinesterase agent.

4. The method of claim 3 in which the cholinergic agent is selected from the group consisting of a norepinephrine uptake inhibitor, serotonin norepinephrine uptake inhibitor, anti-cholinesterase inhibitor, 5-HT2 agonists, selective 5-hydroxytryptamine (serotonin) (5-HT)(IA) receptor partial agonist, 5-HT(3) receptor antagonist, 5-HT(6) receptor antagonists, muscarinic agonists of the M₁ and or M₂ and or M₄ receptor, alpha.7 nicotinic receptor agonist, nicotinic antagonist, a combination of a nicotinic agonist and antagonist, or a combination thereof.

5. The method of claim 3 in which the dopaminergic agent is selected from one or more of the following: a psycho-stimulant drugs, analeptic agents, methylphenidate, typical antipsychotic drugs, atypical antipsychotic drugs, dopamine Dl receptor agonist, dopamine D2 receptor antagonist, dopamine D4 receptors agonist, antagonist, 5-HT.sub.6 receptor antagonists, Bupropion, norepinephrine reuptake inhibitor, dopamine transport re-uptake inhibitor, alpha. -2 adrenergic agonist, alpha. -2 adrenergic antagonist, CBl receptor antagonists, precursors of dopamine, a nonergolinic dopamine D3/D2/D1 receptor agonist, serotonin modulators, HMG-CoA reductase inhibitor (statins), or a combination thereof.

6. The method according to any one of claims 1-3, effective in treatment of cognition.

7. The method according to any one of claims 1-3 where the treatment is effective in treating the symptoms of ADHD.

8. The method according to any one of claims 1-3 where the treatment is effective for any subtype of ADHD that has been defined and described in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, Washington, D. C, 1994.

9. The method according to any one of claims 1 -3 where the treatment is effective for any subtype of ADHD and wherein there is improvement in brain function.

10. The method according to any one of claims 1-3 where the treatment is effective for any subtype of ADHD and wherein there is improvement in brain electrical function as assessed by EEG.

11. The method according to any one of claims 1 -3 where the treatment is effective in improving learning.

12. The method according to any one of claims 1 -3 where the treatment is effective in improving memory.

13. The method according to any one of claims 1-3 where the treatment is effective in improving behaviour.

14. The method according to any one of claims 1-3 where the treatment is effective in improving bodily activity.

15. The method according to any one of claims 1-3 where the treatment is effective in improving signs and/or symptoms of ADHD.

16. The method according to any one of claims 1-3 3 where the treatment is effective in improving mood in ADHD.

17. The method according to any one of claims 1-3 where the treatment is effective in improving any cognitive condition.

18. Method of treating attention deficit hyperactivity disorder (ADHD) comprising the administration of a therapeutically effective amount of at least one dopaminergic agent and at least one cholinesterase agent and one or more agents selected from NMDA receptor antagonists and/or metabotropic glutamate receptor (mGluR) agonists and/or antagonists and/or positive modulators of AMPA receptors.

19. Method of treating ADHD comprising administration to a subject requiring such treatment of a Dl receptor agonist and a nicotinic agonist, and/or anti-cholinest erase.

20. The method according to any one of claims 1 to 17, wherein the treatment regulates or modulates EEG networks in ADHD in the theta, gamma, delta, beta and alpha ranges.

21. A method of treating attention deficit hyperactivity disorder (ADHD) comprising the administration to a subject requiring such treatment of a therapeutically effective amount of at least one dopaminergic agent and at least one cholinesterase agent.

22. The method of claim 21 in which the cholinergic agent is selected from the group consisting of a norepinephrine uptake inhibitor, serotonin norepinephrine uptake inhibitor, anti-cholinesterase inhibitor, 5-HT2 agonists, selective 5-hydroxytryptamine (serotonin) (5-HT)(IA) receptor partial agonist, 5-HT(3) receptor antagonist, 5-HT(6) receptor antagonists, muscarinic agonists of the Mi and or M₂ and or M₄ receptor, alpha.7 nicotinic receptor agonist, nicotinic antagonist, a combination of a nicotinic agonist and antagonist, or a combination thereof.

23. The method of claim 21 in which the dopaminergic agent is selected from one or more of the following: a psycho-stimulant drugs, analeptic agents, methylphenidate, typical antipsychotic drugs, atypical antipsychotic drugs, dopamine Dl receptor agonist, dopamine D2 receptor antagonist, dopamine D4 receptors agonist, antagonist, 5-HT.sub.6 receptor antagonists, Bupropion, norepinephrine reuptake inhibitor, dopamine transport re-uptake inhibitor, alpha. -2 adrenergic agonist, alpha.-2 adrenergic antagonist, CBl receptor antagonists, precursors of dopamine, a nonergolinic dopamine D3/D2/D1 receptor agonist, serotonin modulators, HMG-CoA reductase inhibitor (statins), or a combination thereof.

24. The method according to any one of claims 21-23, effective in treatment of cognition.

25. The method according to any one of claims 21-23 where the treatment is effective in treating the symptoms of ADHD.

26. The method according to any one of claims 21-23 where the treatment is effective for any subtype of ADHD that has been defined and described in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, Washington, D. C, 1994.

27. The method according to any one of claims 21-23 where the treatment is effective for any subtype of ADHD and wherein there is improvement in brain function.

28. The method according to any one of claims 21-23 where the treatment is effective for any subtype of ADHD and wherein there is improvement in brain electrical function as assessed by EEG.

29. The method according to any one of claims 21 -23 where the treatment is effective in improving learning.

30. The method according to any one of claims 21 -23 where the treatment is effective in improving memory.

31. The method according to any one of claims 21-23 where the treatment is effective in improving behaviour.

32. The method according to any one of claims 21-23 where the treatment is effective in improving bodily activity.

33. The method according to any one of claims 21-23 where the treatment is effective in improving signs and/or symptoms of ADHD.

34. The method according to any one of claims 21-23 where the treatment is effective in improving mood in ADHD.

35. The method according to any one of claims 21-23 where the treatment is effective in improving any cognitive condition.

36. Method of treating attention deficit hyperactivity disorder (ADHD) comprising the administration of a therapeutically effective amount of at least one dopaminergic agent and at least one cholinesterase agent and one or more agents selected from NMDA receptor antagonists and/or metabotropic glutamate receptor (niGluR) agonists and/or antagonists and/or positive modulators of AMPA receptors.

37. Method of treating ADHD comprising administration to a subject requiring such treatment of a Dl receptor agonist and a nicotinic agonist, and/or anti-cholinesterase.

38. The method according to any one of claims 21 to 37, wherein the treatment regulates or modulates EEG networks in ADHD in the theta, gamma, delta, beta and alpha ranges.

39. The method according to any one of claims 21 to 37, wherein the treatment is delivered by oral, transdermal, intramuscular, nasal, depot, injection, time-release capsules or suppository route.

40. A method of treating ADHD substantially as hereinbefore described with reference to the accompanying drawings.