Although levodopa is the gold standard for treating motor symptoms of Parkinson's disease (PD), long-term therapy leads to levodopa-induced dyskinesia (LID). Dyskinesia refers to involuntary movements other than tremor and most commonly consists of chorea that occurs when levodopa-derived dopamine is peaking in the brain ("peak-dose dyskinesia"). However, dyskinesia can also consist of dystonia or myoclonus and occur during other parts of the levodopa dosing cycle. New validated rating scales and home diaries can better help the health care provider assess the timing and severity of dyskinesia. The exact etiology of LID is unknown, but there is evidence that abnormal pulsatile stimulation of dopamine receptors may be contributory. Treatment of LID includes adjustment of PD medications to maximize "on" time without troublesome dyskinesia. Amantadine is the only medication available with demonstrated ability to reduce the expression of established LID without reducing antiparkinsonian benefit. Other medications that are currently being studied to treat established LID include antiepileptics and serotonergic medications. Deep brain stimulation of the subthalamic nucleus is now the most commonly used surgical procedure for PD patients, and it is very effective in treating LID.
"During MPTP Administration scale. ☆ Relevant conflict of interest/financial disclosures: JBK and JMB hold shares in Atuka Inc.; PS holds shares in Clera, Inc.; KJ is a former employee and consultant to Clera Inc. 1998; Zesiewicz et al., 2007), none of these approaches have succeeded in Phase III clinical trials. "
[Show abstract][Hide abstract] ABSTRACT: 3,4-Dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) is compromised by motor side effects, such as dyskinesia and non-motor problems, including psychosis. Because of the marked reduction in brain dopamine in PD and the resultant dopamine D2 receptor supersensitivity, it is impossible to use standard potent dopamine D2 receptor antagonists such as haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of L-DOPA. Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism. CLR151 (100mg/kg p.o.) reduced L-DOPA-induced dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action. CLR151 (100mg/kg) also reduced psychosis-like behaviour (i.e. reduced apparent visual hallucinations by 78%). Nevertheless, this dose of CLR151 significantly reduced the duration of anti-parkinsonian action of L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2 dopamine receptor antagonists, with D2-off-rate values close to those for CLR151, are unlikely to be useful in the treatment of dyskinesia and psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2013; 43. DOI:10.1016/j.pnpbp.2012.12.008 · 3.69 Impact Factor
"Levodopa therapy has been shown to increase life expectancy in PD, is available at a low cost, and is usually well tolerated, even in the elderly patient.7,47 The major downside of levodopa therapy is its short half-life and the resultant pulsatile stimulation of dopamine receptors, leading to the development of motor fluctuations after several years of treatment.48 Motor fluctuations consist of periods of excessive movements or dyskinesias (most commonly at peak dose of levodopa), and periods of “off time”, with paucity of movement, or akinesia. "
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease is the second most common neurodegenerative disorder, currently affecting 1.5 million people in the US. In this review, we describe the diagnostic and pathological features of Parkinson's disease, as well as its clinical course. We then review pharmacologic treatments for the disease, with a particular focus on therapies adjunctive to levodopa and specifically the role of rasagiline. We review the four pivotal rasagiline trials, and discuss rasagiline and its use as adjunctive therapy for Parkinson's disease. Finally, we discuss potential side effects, drug interactions, and other practical aspects concerning the use of rasagiline in Parkinson's disease.
"Levodopa therapy in Parkinson's disease (PD) reverses motor deficits but prolonged treatment and disease progression leads to the development of motor complication, including dyskinesia (Nutt, 1990; Chase et al., 1998; Fahn, 2000; Zesiewicz et al., 2007; Jenner, 2008). The pathogenic mechanisms leading to the induction of dyskinesia remain unclear but there is an almost absolute requirement for nigral dopaminergic neuronal loss (Schneider 1989; Boyce et al., 1990; Nutt, 1990). "
[Show abstract][Hide abstract] ABSTRACT: Hyperinnervation of the striatum by serotoninergic (5-HT) terminals occurs after destruction of the dopaminergic nigro-striatal pathway. Recent studies have suggested that non-physiological release of dopamine (DA) formed from levodopa in these serotoninergic terminals underlies abnormal involuntary movement (AIMs) induction in 6-OHDA lesioned rats. In the present study, we used tryptophan hydroxylase (TPH) immunohistochemistry to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and the induction of dyskinesia by levodopa alter the morphology of 5-HT fibres in the striatum of common marmosets. The caudate-putamen of normal monkeys contained numerous fine and smooth TPH positive fibres and numerous varicose fibres, but a marked hyperinnervation of TPH positive fibres characterised by a significant increase in the number and diameter of TPH positive axon varicosities was noted in the dorsal caudate and putamen of MPTP-intoxicated monkeys but not the globus pallidus. In MPTP-intoxicated marmosets that had received chronic levodopa treatment to induce dyskinesia, a further increase in the number and enlargement of TPH positive axonal varicosities in both caudate nucleus and putamen was evident. Following LID induction, a similar pattern of increase was also observed in the external segment of the globus pallidus, but only a significant varicosity enlargement was seen in the internal pallidal segment. These results confirm that striatal 5-HT hyperinnervation follows nigro-striatal pathway loss and provide the first evidence in primates that chronic levodopa treatment and the onset of dyskinesia are associated with a marked hypertrophy of striatal 5-HT axonal varicosities. These findings support the concept that altered 5-HT function may contribute to the genesis or expression of LID.
Neurobiology of Disease 12/2010; 40(3):599-607. DOI:10.1016/j.nbd.2010.08.004 · 5.08 Impact Factor
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