GB2341802A

GB2341802A - Compounds for improved treatment of Parkinson's disease

Info

Publication number: GB2341802A
Application number: GB9922194A
Authority: GB
Inventors: Malcolm J Steiger
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-09-22
Filing date: 1999-09-21
Publication date: 2000-03-29
Also published as: GB9922194D0; GB9820489D0

Abstract

A medicament for the treatment of Parkinson's disease associated dementia, gait and balance problems comprising a reversible competitive acetylcholinesterase inhibitor. In a preferred embodiment the acetylcholinesterase inhibitor is galanthamine hydrobromide, and it is administered in conjunction with levodopa.

Description

1 2341802 Title: Compounds for improved treatment of Parkinson's Disease.

DESCRIPTION

The present invention relates to a group of compounds for the improved treatment of Parkinson's disease, particularly in relation to the treatrnent of dementia and gait and balance problems associated with Parkinson's disease.

Parkinson! s Disease is a neurological disorder characterised by tremor, muscular rigidity, bradykinesia (slowness of movement) and disturbances in posture. The cause of the disease is still unknown but affects a large number of people with approximately 10 to 20, per 100,000 new cases per year. The symptoms result from a degeneration of dopaminecontaining neurons that project from the substantia nigra to the striatum in the region of the brain (the basal ganglia) which is involved in motor control.

The symptoms of Parkinson's Disease are conventionally treated by the replacement of lost dopamine by L-DOPA administration and/or treatment with muscarinic antagonists, such as atropine. However, such treatments can induce mental disturbances associated with the use of anticholinergic drugs.

Alzheirnees Disease has a number of symptoms which are similar to those experienced by patients suffering from Parkinson!s disease, due to both diseases causing neuronal degeneration which results in a cholinergic deficiency. However, neurologists will instinctively believe that the treatment of Parkinsonism with procholinergic drugs will increase muscular rigidity and tremor and hence, will tend not to use such drugs in fear of worsening the movement disorder.

2 Alzheirnef s Disease has been treated relatively successfully using a centrally acting non-competitive reversible acetylcholinesterase inhibitor Tacrine (1,2,3,4-tetrahydro-9acridinamine-monohydrochloride). Tacrine mainly inhibits the cholinesterase enzyme, butyrIcholinesterase which is responsible for hydrolysing a neurotransmitter found mainly in cardiac and smooth muscle, skin and some glands. Thus, prevention of breakdown of the transmitter leads to an increase in cholinergic activity. The similarities between Alzheimer's Disease and Parkinsods Disease (P.D. ) would suggest that Tacrine may be a suitable treatment for P.D. However, it has been found that Tacrine actually exacerbates Parkinsonism (Ott, BR, Lannon MC. Exacerbation of Parkinsonism by Tacrine. Clinical Neuropharmacology 1992; 4: 322-325.). Additionally, Tacrine is nonselective and thus acts on areas having normal cholinergic activity thereby causing cholinergic side effects, such as nausea, dyspepsia and diarrhoea.

It is an aim of the present invention to provide compounds for the improved treatment of dementia associated with Parkinson's disease.

It is a fin-ther aim of the present invention to provide compounds for the improved treatment of gait and balance problems associated with Parkinson's Disease.

Another aim of the present invention is to provide compounds for the improved treatment of Parkinson's Disease which produce fewer side effects.

Accordingly, a first aspect of the present invention provides the use of a reversible competitive acety1cholinesterase inhibitor for the manufacture of a medicament for the therapeutic treatment of Parkinson's Disease associated dementia.

A second aspect of the present invention provides the use of a reversible competitive acetylcholinesterase inhibitor for the manufacture of a medicament for the therapeutic treatment of gait and balance problems associated with Parkinson's Disease.

A third aspect of the present invention provides the use of a reversible competitive acetylcholinesterase uihibitor for the manufacture of a medicament for the combined therapeutic treatment of Parkinson's Disease associated dementia and the gait and balance problems associated with Parkinson's Disease.

Preferably, the competitive acetyleholinesterase inhibitor is the naturally occurring alkaloid, Galanthamine of the formula- OH 0 CH30.........

N CH3 Alternatively, the compound may be Galanthamme hydrobromide or [4AS(4A,6b, 8aRO]-4a,5,9,10,11,12-hexahydro-3-methoxy-I 1-methyl-6H-benzofuro [3a,3, 2efl[2]benzazepin-6-ol hydrobromide.

The compound may be administered in conjunction with other treatments, such as levodopa. The compound may be administered orally or by other suitable means, such as 4 injection. The compound may be administered in conjunction with a carrier material.

The present invention will now be further illustrated by means of the following Example.

Examnle In Parkinson's disease (PD), axial and cognitive symptons often respond inconsistently to doparninergic treatment. Previous studies suggest degeneration of several nondopaminergic pathways, including the cholinergic systems. Acetylcholine is an important neurotransmitter in cognition and the mesencephalic control of balance and locomotion. The inventors hypothesize that cholinergic replacement therapy can improve both cognition and axial motor functions in the later stages of PD. An open label pilot study was performed at the Department of Neurology, Walton Centre for Neurology and Neurosurgery, Liverpool on the use of a reversible cholinesterase inhibitor, galantamine, as an add-on therapy to patients with PD exhibiting (a) gait and balance disturbances, and (b) cognitive impairment. The motor outcomes were measured during both "best on" and "worst off' clinical periods by videotaped United PD Rating ScaleMotor subsection (UPDRS-IH) and motor timed tests; and cognitive outcomes during "best on" by Alzheimer's Disease Assessment Scale-Cognitive subsection (ADAS-Cog) and computerized Cambridge Neuropsychological Automated Battery (CANTAB). So far, five patents have been recruited of whom two have been followed for at least 15 weeks. Galantamine was well tolerated. Motor improvement was apparent in both "worst off' and "best on" motor states at week 15 when compared with baseline: UPDRS-IH score fell by six points, motor timed tests improved by 20%. Furthermore, within UPDRS-III, there was a notable improvement in axial features including postural stability and the number of recorded falls. The ADAS-Cog score improved by seven points. These preliminary results suggest that galantamine can improve both motor and cognitive deficits in PD. The favorable effects of cholinergic therapy on gait and balance point to a potentially new approach to treating non-dopaminergic responsive motor deficits associated with Parkinson's disease.

Thus, it has been found that the use of the reversible, competitive anticholinesterase Galantharnine assists in reducing dementia and the gait and balance problems associated with Parkinson's Disease and furthermore, causes less severe side effects than other anticholinesterases, such as Tacrine. It is believed that the ability of the compound to bind competitively with the enzyme acetylcholinesterase, found mainly in the brain, provides the desired effect, having a selective activity which prevents increased activity at muscarinic sites which would worsen movement disorder. The competitive nature of the compound results in the areas which have normal acetylcholine activity being less effected by the compound than those experiencing a reduced level of the transmitter. This reduces the cholinergic side effects which have been experienced with earlier inhibitors used in the treatment of Alzheimer's Disease.

Additionally, the bioavailability of is far higher than Tacrine (90% and 5% respectively) thereby producing less variability in plasma levels of Galanthamine and accordingly, less variability in clinical effects. The hepatoxicity experienced with Tacrine is also reduced by the use of Galanthamine.

Galanthamine is a naturally occurring alkaloid which can be isolated from a plant 6 extract, for example that sold under the trade mark NivalinR by Waldheim Pharmaceuticals.

Previously, the compound has been used in the treatment of, for example, myalgic encephalitis and chronic fatigue syndrome.

Galanthamine has surprisingly been found to assist not only in the lessening of dementia experienced with P.D. but also in the reduction of gait and balance problems.

Studies have determined that the more severe the degree of intellectual impairment of a ParkinsoVs patient, the greater the cortical cholinergic deficiency. Galanthamine prevents the breakdown of acetylcholine in the cholinergic systems associated with the brain thus resulting in the reduction or arrest of dementia without significantly exacerbating poverty of movement (bradykinesia) or tremor which is experienced with Tacrine probably due to its activity on muscarinic receptors.

The gait and balance problems of Parkinson!s Disease are poorly understood.

However, the inventor has recognised that such problems may also be a result of reduced cholinergic activity. Frequent falling due to postural instability is a common problem in P.D. and becomes more prevalent in patients with long disease duration. Unlike limb bradykinesia and rigidity experienced with P.D. which remain responsive to levodopa preparations throughout the course of the disease, the postural instability that emerges with disease progression is thought to be less responsive or unresponsive to levodopa. Evidence suggests that the problem of axial motor control (i.e., gait and balance) involves cholinergic transmission. Thus, the use of a compound which inhibits the breakdown of acetylcholine may assist in improving the problems associated with balance and gait by modulating nicotinic 7 acetylcholine receptors.

Thus, the present invention provides a compound which improves not only gait and balance problems associated with Parkinsonism but assists in reducing or arresting dementia with fewer side effects due to its greater specificity and its ability to modulate nicotinic receptors rather than muscarinic receptors.

8

Claims

The use of a reversible competitive acetylcholinesterase inhibitor for the manufacture of a medicament for the therapeutic treatment of Parkinson's Disease associated dementia.

2. The use of an inhibitor as defined in claim 1, wherein the competitive acetyleholinesterase inhibitor is a naturally occurring alkaloid. The use of an inhibitor as defined in claim 2, wherein the naturally occurring alkaloid is Galanthamine, having the formula:- OH CH30 0 N CH3 4. The use of an inhibitor as defined in claim 2, wherein the compound is Galanthamine hydrobromide or [4AS-(4A,6b,8aRO]-4a,5,9,10,11,12-hexahydro3 3-methoxy-l 1-methyl-6H-benzofuro [3:)a,3,2-efl[2]benzazepin-6-ol hydrobTomide.

5. The use of an inhibitor as defined in any one of claims I to 4, wherein the inl-ibitor is administered in conjunction with other treatments.

9 6. The use of an inhibitor as defined in claim 5, wherein the inhibitor is administered with levopoda.

7. The use of a reversible competitive acetyleholinesterase inhibitor for the manufacture of a medicament for the therapeutic treatment of gait and balance problems associated with Parkinson's Disease.

8. The use of an inhibitor as defined in claim 7, wherein the competitive acetylcholinesterase inhibitor is a naturally occurring alkaloid.

9. The use of an inhibitor as defined in claim -8, wherein the naturally occurring alkaloid is Galanthamine, having the formula:- OH 0 CH30 CH3 10. The use of an inhibitor as defined in claim 8, wherein the compound is Galanthamine hydrobromide or [4AS-(4A,6b,8aR70]-4a,5,9,10,11,12hexahydro3-methoxy- I I -methyl-6H-benzofiiro [3a,3,2-efl [2]benzazepin-6ol hydrobiomide.

11. The use of an inhibitor as defined in any one of claims 7 to 10, wherein the inhibitor is administered in conjunction with other treatinents.

12. The use of an inhibitor as defmed in claim 11, wherein the inhibitor is administered with levopoda.

13. The use of a reversible competitive acetylcholinesterase inhibitor for the manufacture of a medicament for the combined therapeutic treatment of Parkinson's Disease associated dementia and the gait and balance problems associated with Parkinson's Disease.

14. T'he use of a reversible competitive acetylcholinesterase inhibitor for the manufacture of a medicament for the combined treatment of Parkinson's Disease associated dementia and the gait and balance problems associated with Parkinson's Disease substantially as hereinbefore described and with reference to the accompanying Example.