Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-02
2001-10-30
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06310085
ABSTRACT:
The present invention relates generally to a method for the treatment and/or prophylaxis of neurological or neuropsychiatric disorders, in particular neurological or neuropsychiatric disorders associated with altered dopamine function.
The pineal body, situated in the epithalamus at the centre of the brain, synthesises and releases melatonin into the general circulation only during nocturnal darkness, irrespective of whether a species is nocturnal or diurnal in its behavioural activity pattern. In mammals, the rhythm of pineal nocturnal melatonin secretion is generated by a biological clock located at the suprachiasmatic nuclei (hereinafter referred to as “SCN”) of the anterior hypothalamus. After following a circuitous route through the brain, afferent pathways of the conarian nerves originating from the superior cervical ganglia end in sympathetic innervation on pinealocytes. In humans, the only natural phenomenon presently known to inhibit melatonin release is bright light. Melatonin release appears to be robust and resistant to change by a variety of potent stimuli. The stability of the melatonin rhythm makes melatonin an ideal candidate as a biological timing hormone, a role which is indisputable for rhythms in photo-sensitive seasonal breeding mammals and has been postulated for daily rhythms in non-seasonal breeders.
Daily injections of melatonin entrains free-running locomotor activity rhythms of rats housed in constant darkness or constant light, influences the speed and direction of re-entrainment to phase shifts in the light-dark cycle and reorganises and recyncronises the disrupted components of the circadian system. These entrainment effects are dependant upon on the integrity of the SCN biological clock which is a structure containing high affinity melatonin receptors. In addition to these effects of exogenous melatonin on the pattern of locomotor activity, there are early unconfirmed reports that melatonin injections, pineal extracts and pinealectomy affect the amount of locomotor activity. Although such reports are unconfirmed, they raise the possibility of a more direct action on the locomotor system per se, rather than the indirect effect via the SCN. This would be consistent with the more recent reports involving animal models of movement disorders such as those where a decrease in spontaneous motor activity in mice is found with both peripheral (1) and intranigral (2) injection of melatonin as well as melatonin blockade of L-Dopa induced movement (3) and melatonin modulation of apomorphine induced rotational behaviour (4). Against this background, early reports of amelioration of Parkinson's disease by administration of high doses of melatonin appears possible (5). In view of the role of dopamine in Parkinson's disease and other motor disorders, a common link between each of these disorders is a change in dopamine function.
Clinical studies examining the role of melatonin in neuropsychiatric disorders have been limited in number and are inconsistent in their reported findings and hypothesised role of this hormone. It was suggested by MacIsac (6) that melatonin was involved in the precipitation of many symptoms of schizophrenia. This hypothesis was in accordance with the conjecture that the pineal was overactive in this disorder (7). However, other clinical studies have revealed that nocturnal melatonin secretion is reduced in chronic schizophrenia (8) and some have paralleled the negative symptoms of this disease with those of Parkinson's disease (9) indicating that melatonin provides a protective effect against the development of the negative symptoms of schizophrenia and Parkinson's disease from the time puberty commences (10). This hypothesis is supported further by findings implicating pineal deficiency in schizophrenia (11). Additional confusion has arisen as to the role of melatonin in the aetiology of schizophrenia as a result of experiments where bovine pineal extract was administered to patient's suffering from this disorder causing a reversal of biochemical abnormalities and clinical improvement (12). However, later repetition of these studies did not yield results which were clinically meaningful ( 13).
The psychopharmacology of psychosis does not aid in clarifying the role of melatonin in these disorders. The administration of &bgr;-adrenergic blockers, sometimes used as an anti-psychotic medication, reduces plasma levels of melatonin (14) while chlorpromazine, increases melatonin (15). However, since other anti-psychotics do not elevate melatonin concentrations (16), the hypothesis that melatonergic function is altered in schizophrenics and that effective medications might work via the melatonergic system (17) have gained little support.
The picture becomes further obscured when the results from studies whereby melatonin was administered for prolonged periods to patients suffering from Parkinson's disease are considered. Daily doses of 1000-1200 mg of melatonin per day have been reported to produce a 20-36% amelioration of the clinical features (18) and a significant reduction in tremor (19). However, replication of that work, with similar doses over the same time period did not improve the cardinal features of Parkinson's disease (20). It has also been claimed that pineal secretory activity was diminished in this disease (21) and that melatonin itself could be useful in alleviating the symptoms of Parkinsonism (22). Consideration of the findings from other research (23) where the relationship between agonist therapy and melatonergic activity was examined, arrived at the conclusion that Parkinson's disease did not result from pathology of the melatonergic system. Later research (24) revealed no major changes in melatonin rhythm or changes in plasma melatonin concentrations after dopamine agonist therapy. Bearing in mind the antioxidant properties of melatonin (25) and the current trend in attempting to halt the progressive degeneration of Parkinson's disease by implementing antioxidants (26), this deflates any attempt to explain Parkinson's disease on the basis of pathological function of the pineal.
The role of melatonin in clinical disorders of appetite is believed to be of minimal significance. While plasma melatonin concentrations are significantly reduced in the sub-population of anorexics which exhibit depression(27), this has been attributed to the depression rather than a pathological feature of anorexia nervosa or anorexia bulimia(28). Changes in the circadian periodicity of melatonin secretion has been detected in about one third of patients suffering from anorexia nervosa or anorexia bulimia(29). However, the increase in melatonin was suggested as being due to chronic malnutrition or sustained physical exercise and lends little support to the interpretation that pathophysiology of the melatonergic system plays a significant role in such disorders.
We have now discovered the specific mechanism by which melatonin may be exacerbating motor disability and a number of related disorders of motor function. This finding provides a rational basis upon which neurological or neuropsychiatric disorders can be treated and is designed to block and/or inhibit the activity of melatonin.
According to one aspect of the present invention there is provided a method for the treatment and/or prophylaxis of a neurological or neuropsychiatric disorder associated with altered dopamine function which comprises subjecting a patient in need thereof to therapy which blocks and/or inhibits melatonin, precursors thereof and/or metabolic products thereof.
The present invention also provides the use of therapy which blocks and/or inhibits melatonin, precursors thereof and/or metabolic products thereof in the treatment and/or prophylaxis of a neurological or neuropsychiatric disorder associated with altered dopamine function.
Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a state
Clarencew Pty Ltd.
Jarvis William R. A.
Rothwell Figg Ernst & Manbeck
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