Treatment of tremor with histamine h3 inverse agonists or histamine h3 antagonists

Agent: Merck And Co., Inc - Rahway, NJ, US

Inventors: Michael J. Marino, Guy R. Seabrook

USPTO Applicaton #: 20080242657 - Class: 51421113 (USPTO)

The Patent Description & Claims data below is from USPTO Patent Application 20080242657.

Brief Patent Description

BACKGROUND OF THE INVENTION

Diseases of the extrapyramidal motor systems cause either a loss of movement (akinesia) accompanied by an increase in muscle tone (rigidity) or abnormal involuntary movements (dyskinesias) often accompanied by a reduction in muscle tone. The akinetic-rigid syndrome called parkinsonism, and the dyskinesias represent opposite ends of the spectrum of movement disorders (for review see C. D. Marsden in Oxford Textbook of Medicine, 3rd Edition, Oxford University Press, 1996, vol. 3, pages 3998-4022).

Essential tremor is a disorder that affects 5-10 million persons in the United States. It is characterized primarily by an action and postural tremor most often affecting the arms, but it can also affect other body parts. Essential tremor is a progressive neurologic disorder and can cause substantial disability in some patients. Although there currently is no cure for essential tremor, pharmacologic and surgical treatments can provide some benefit. The clinical diagnosis of essential tremor is reviewed by Pahwa et al., Am. J. Medicine, 115, 134-142 (Aug. 1, 2003), and current treatments for essential tremor are reviewed by Lyons et al., Drug Safety, 26(7): 461-481 (2003).

Treatment of akinetic-rigid conditions such as parkinsonism typically involves the use of levodopa, anticholinergics or dopamine agonists. Levodopa is converted into dopamine in the brain by the enzyme dopa decarboxylase. However, this enzyme is also present in the gut wall, liver, kidney and cerebral capillaries, thus the peripheral formation of levodopa metabolites may give rise to side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension. This peripheral decarboxylation is largely prevented by the addition of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which themselves do not penetrate the brain. Levodopa combined with carbidopa (SINEMET™) or benserazide (MADOPAR™) is now the treatment of choice when levodopa is indicated. Even then, this combination therapy may be associated with side-effects such as dyskinesias and psychiatric disturbances.

Tremor, chorea, myoclonus, tics and dystonias, are treated with a variety of pharmacological agents. Thus, for example, tremor may be treated with benzodiazepines such as diazepam; chorea may be treated with diazepam, a phenothiazide or haloperidol, or tetrabenazine; tics may be controlled with neuroleptics such as haloperidol or pimozide; and dystonias tend to be treated with levodopa, benzodiazepines such as diazepam, anticholinergics such as benzhexyl, phenothiazines and other neuroleptics such as haloperidol, and tetrabenazine.

Treatment of psychotic disorders with neuroleptic agents, such as haloperidol may be at the expense of a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function. PCT Patent Publication WO 01/30346 discloses the use of histamine H3 agonists for the treatment of dyskinesia.

There exists a patient population in whom tremor is inadequately treated with existing neuroleptic therapy. Furthermore, some patients may be adversely affected by the side-effects of neuroleptic drugs. In view of the shortcomings of existing therapy, there is a need for new, safe and effective treatment for tremor and movement disorders.

SUMMARY OF THE INVENTION

The present invention is directed to the use of a histamine H3 inverse agonist or antagonist, alone or in combination with a neuroleptic agent, for treating or preventing movement disorders, including tremor, such as essential tremor, and tremor associated with Parkinson's disease, cranofacial trauma, multiple sclerosis, stroke, dystonia, neuropathic induced tremor, toxic induced tremor, or drug induced tremor.

DESCRIPTION OF THE INVENTION

The present invention is directed to the use of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof, alone or in combination with a neuroleptic agent, for treating or preventing movement disorders, including tremor, such as essential tremor, and tremor associated with Parkinson's disease, cranofacial trauma, multiple sclerosis, stroke, dystonia, neuropathic induced tremor, toxic induced tremor, drug induced tremor, or tremor associated with dyskinesia, tardive diskinesia, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonian-ALS dementia complex, basal ganglia calcification, akinesia, akinetic-rigid syndrome, bradykinesia, dystonia, medication-induced parkinsonian, Gilles de la Tourette syndrome, Huntingon disease, chorea, myoclonus, and tick disorder.

An embodiment of the present invention is directed to a method for treating, controlling, ameliorating or reducing the risk of a movement disorder in a patient in need thereof that comprises administering to the patient a therapeutically effective amount of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof.

Although a histamine H3 inverse agonist or antagonist is useful alone for movement disorders, it will be appreciated that a combination of a conventional antiparkinsonian drug with a histamine H3 inverse agonist or antagonist may provide an enhanced effect in the treatment of tremor or akinetic-rigid disorders such as parkinsonism. Such a combination may enable a lower dose of the antiparkinsonian agent to be used without compromising the efficacy of the antiparkinsonian agent, thereby minimizing the risk of adverse side-effects.

It will be further appreciated that a combination of a conventional neuroleptic drug with a histamine H3 inverse agonist or antagonist or a pharmaceutically acceptable salt thereof may provide an enhanced effect in the treatment of dyskinesias. Such a combination may enable a lower dose of the neuroleptic agent to be used without compromising the efficacy of the neuroleptic agent, thereby minimising the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of a histamine H3 inverse agonist or antagonist, adverse side-effects caused by the neuroleptic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.

The present invention also provides a method for the treatment or prevention of dyskinesias, which method comprises administration to a patient in need of such treatment of an amount of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof and an amount of a neuroleptic agent, such that together they give effective relief.

Diseases of the extrapyramidal motor systems cause either a loss of movement (akinesia) accompanied by an increase in muscle tone (rigidity) or abnormal involuntary movements (dyskinesias) often accompanied by a reduction in muscle tone. The akinetic-rigid syndrome called parkinsonism, and the dyskinesias represent opposite ends of the spectrum of movement disorders (for review see C. D. Marsden in Oxford Textbook of Medicine, 3rd Edition, Oxford University Press, 1996, vol. 3, pages 3998-4022).

Essential tremor is a disorder that affects 5-10 million persons in the United States. It is characterized primarily by an action and postural tremor most often affecting the arms, but it can also affect other body parts. Essential tremor is a progressive neurologic disorder and can cause substantial disability in some patients. Although there currently is no cure for essential tremor, pharmacologic and surgical treatments can provide some benefit. The clinical diagnosis of essential tremor is reviewed by Pahwa et al., Am. J. Medicine, 115, 134-142 (Aug. 1, 2003), and current treatments for essential tremor are reviewed by Lyons et al., Drug Safety, 26(7): 461-481 (2003).

Treatment of akinetic-rigid conditions such as parkinsonism typically involves the use of levodopa, anticholinergics or dopamine agonists. Levodopa is converted into dopamine in the brain by the enzyme dopa decarboxylase. However, this enzyme is also present in the gut wall, liver, kidney and cerebral capillaries, thus the peripheral formation of levodopa metabolites may give rise to side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension. This peripheral decarboxylation is largely prevented by the addition of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which themselves do not penetrate the brain. Levodopa combined with carbidopa (SINEMET™) or benserazide (MADOPAR™) is now the treatment of choice when levodopa is indicated. Even then, this combination therapy may be associated with side-effects such as dyskinesias and psychiatric disturbances.

Tremor, chorea, myoclonus, tics and dystonias, are treated with a variety of pharmacological agents. Thus, for example, tremor may be treated with benzodiazepines such as diazepam; chorea may be treated with diazepam, a phenothiazide or haloperidol, or tetrabenazine; tics may be controlled with neuroleptics such as haloperidol or pimozide; and dystonias tend to be treated with levodopa, benzodiazepines such as diazepam, anticholinergics such as benzhexyl, phenothiazines and other neuroleptics such as haloperidol, and tetrabenazine.

Treatment of psychotic disorders with neuroleptic agents, such as haloperidol may be at the expense of a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function. PCT Patent Publication WO 01/30346 discloses the use of histamine H3 agonists for the treatment of dyskinesia.

There exists a patient population in whom tremor is inadequately treated with existing neuroleptic therapy. Furthermore, some patients may be adversely affected by the side-effects of neuroleptic drugs. In view of the shortcomings of existing therapy, there is a need for new, safe and effective treatment for tremor and movement disorders.