Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-20
2002-09-24
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S399000
Reexamination Certificate
active
06455536
ABSTRACT:
This is a 371 of PCT/GB99/02146 filed Jul. 16, 1999. The present invention relates to the treatment of dyskinesia.
Dyskinesias are characterised by the development in a subject of abnormal involuntary movements and may manifest as chorea (irregular, involuntary movements of the body, especially the face and extremities) or dystonia (disorder or lack of muscle tonicity).
One way in which dyskinesias may arise is as a side effect of dopamine replacement therapy for Parkinsonism or other basal ganglia-related movement disorders. Parkinsonism is a syndrome of symptoms characterised by slowness of movement (bradykinesia), rigidity and/or tremor. Parkinsonian symptoms are seen in a variety of conditions, most commonly in idiopathic parkinsonism (i.e. Parkinson's Disease) but also following treatment of schizophrenia, manganese poisoning, head injury and the like.
The use of dopamine-replacing agents (e.g. L-DOPA and apomorphine) as symptomatic treatments for conditions such as Parkinson's disease have undoubtedly been successful in increasing the quality of life of patients suffering from the conditions. However, dopamine-replacement therapy does have limitations, especially following long-term treatment. Problems can include a wearing-off of the anti-parkinsonian efficacy of the treatment and in particular the appearance of a range of side effects. These side effects may manifest as dyskinesias such as chorea and dystonia. Dyskinesia can be seen either when the patient is undergoing dopamine-replacement therapy (in the case of chorea and/or dystonia) or even when off therapy (when dystonia is prevalent). Ultimately, these side-effects severely limit the usefulness of dopaminergic treatments.
Many attempts have been made to develop agents which will prevent the development of, and/or treat, dyskinesias. For instance, attempts have been made to develop novel dopamine replacement therapies which will obviate or mitigate dyskinetic side effects although such attempts have met with limited success. There is therefore a need to develop ways by which dyskinesias may be treated.
According to a first aspect of the present invention, there is provided a use of a compound which inhibits selectively mu opioid receptor activity, or activation, for the manufacture of a medicament for the treatment of dyskinesia.
According to a second aspect of the present invention, there is provided a composition for use in the treatment of dyskinesia comprising a therapeutically effective amount of a compound which inhibits selectively mu opioid receptor activity, or activation, and a pharmaceutically acceptable vehicle.
According to a third aspect of the present invention, there is provided a method for the treatment of dyskinesia comprising administering to a person or animal in need of such treatment a therapeutically effective amount of a compound which inhibits selectively mu opioid receptor activity or activation.
Mu (&mgr;) opioid receptors are a subclass of opioid receptors which are found in neural tissues and may be activated by endogenous ligands such as endomorphin I and II.
By “selectively” we mean the compound has greater efficacy for inhibiting mu opioid receptor activity or activation than other types of opioid receptor (e.g. delta or kappa opioid receptors).
By “dyskinesia” we mean the development in a subject of abnormal involuntary movements. These movements may manifest as chorea (irregular, involuntary movements of the body, especially the face and extremities) or dystonia (disorder or lack of muscle tonicity). Such movements include ballistic movements and athetoid movements of the trunk, limbs and facial musculature.
The invention is based upon our studies relating to the neural mechanisms underlying L-DOPA-induced dyskinesia. Although we do not wish to be bound by any hypothesis, we believe that dyskinesias (e.g. L-DOPA-induced dyskinesia) is caused by decreased &ggr;-Aminobutyric acid (GABA) transmission in the lateral segment of the globus pallidus. This transmission is in turn mediated by the activation of D2 dopamine receptors. We believe that compounds which selectively inhibit mu opioid receptor activity or activation may be effective for treating dyskinesias because they regulate this GABA transmission.
We have found that compounds which inhibit selectively mu opioid receptor activity or activation are highly effective for the treatment of dyskinesias. For instance, we have found that dyskinesias (e.g. chorea and dystonia) do not develop, or are at least reduced, when compounds which inhibit mu opioid receptor activity are given to subjects on dopamine-replacement therapy for the treatment of a movement disorder.
We have found that compounds which selectively inhibit mu opioid receptor activity have several advantages over the use of non-selective opioid inhibitors (e.g. naltrexone), or compounds which selectively inhibit the activity of other classes of opioid receptor (e.g. delta or kappa-selective antagonists).
The inventor has established that not only do the compounds used according to the present invention have improved anti-dyskinetic action but they also minimise side effects associated with the blockade of other opioid receptors (e.g. kappa and delta opioid receptors). For instance, a role for kappa opioid receptor mediated transmission has been proposed in the negative regulation of glutamate transmission. Stimulation of kappa opioid receptors thus reduces glutamate release and the blockade of kappa receptors enhances glutamate transmission. Such an action may be associated with an increased pre-disposition towards epilepsy, psychiatric disorders (such as schizophrenia) and neurodegenerative processes (e.g. stroke, Huntington's disease and Alzheimer's disease). Furthermore Delta opioid receptors have been shown to play a role in anti-nociception, thus blockade of endogenous delta opioid transmission my lead to hyperalgesia. The use of selective inhibitors of mu opioid receptors not only results in less dyskinesia but also results in a reduction in the abovementioned side effects of agents which modulate kappa and delta opioid receptors.
Several classes of compound, which may be used according to the invention, are capable of inhibiting mu opioid receptor activity selectively. These compounds include:
(i) mu opioid receptor antagonists or partial agonists which block mu opioid receptors;
(ii) inverse agonists which inverse stimulate mu opioid neural transmission;
(iii) agents which block synthesis of endogenous agonists of mu opioid receptors or which prevent conversion of precursors of mu opioid receptor agonists into their active form;
(iv) agents which inhibit the release of mu opioid receptor agonists;
(v) agents which increase the rate of inactivation of mu opioid receptor agonists; and
(vi) agents which block mu opioid receptor expression and/or transcription.
Mu opioid receptor antagonists ((i) above) are preferred inhibitors for use according to the invention. Examples of selective mu opioid receptor antagonists which are suitable for treating dyskinesias include Clocinnamox. Etonitazenyl isothiocyanate, &bgr;-funaltrexamine, naloxonazine and cyprodime.
The inventor has found that other, less selective, opioid receptor antagonists, such as naloxone or naltrexone (which inhibit mu opioid receptors as well as other types of opioid receptor), have some efficacy for treating dyskinesias but are less effective than compounds used according to the present invention (see the Example).
The compounds (and compositions or medicaments containing them) may be used to treat many types of dyskinesia. For instance the compounds may be used to treat dyskinesia associated with Huntington's disease, idiopathic torsion dystonia, tardive dyskinesia or off-dystonia in Parkinson's disease and most particularly for dyskinesia associated with movement disorders such as parkinsonism (e.g. idiopathic Parkinson's disease, post-encephalitic parkinsonism or parkinsonism resulting from head injury), treatment of schizophrenia, drug intoxication, manganese p
Cook Rebecca
Nixon & Vanderhye P.C.
The Victoria University of Manchester
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