Multicenter, Open-Label, Trial of Sarizotan in Parkinson Disease Patients With Levodopa-Induced Dyskinesias (the SPLENDID Study)

Olanow, C. Warren; Damier, Philippe; Goetz, Christopher G.; Mueller, Thomas; Nutt, John G.; Rascol, Olivier; Serbanescu, Alexandru; Deckers, F.; Russ, Hermann

doi:10.1097/00002826-200403000-00003

Cited by 167 publications

(99 citation statements)

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“…There have been previous reports of the ability of other 5-HT 1a receptor agonists to inhibit levodopa-induced dyskinesia in MPTP-treated macaques and in PD (Bibbiani et al, 2001;Kannari et al, 2002;Olanow et al, 2004). Activation of 5-HT 1a autoreceptors reduces the release of levodopa-derived dopamine in the striatum .…”

Section: Discussionmentioning

confidence: 98%

“…Recently, a variety of studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in adult cynomolgus monkeys primed with levodopa to express dyskinesia and in patients with PD showing involuntary movements have suggested that drugs possessing 5-HT 1a receptor agonist activity, such as clozapine, buspirone, tandospirone, sarizotan, and mirtazapine, reduce the duration and intensity of dyskinesia (Bonifati et al, 1994;Durif et al, 1997;Durif, 1999;Hadj Tahar et al, 2000;Bibbiani et al, 2001;Kannari et al, 2002;Meco et al, 2003;Olanow et al, 2004). However, none of the 5-HT 1a agonists so far examined is specific for 5-HT 1a receptors; they possess other pharmacologically relevant actions.…”

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confidence: 99%

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In 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Primates, the Selective 5-Hydroxytryptamine 1a Agonist (R)-(+)-8-OHDPAT Inhibits Levodopa-Induced Dyskinesia but Only with\ Increased Motor Disability

Iravani

Tayarani-Binazir

Chu

et al. 2006

J Pharmacol Exp Ther

109

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5-Hydroxytryptamine 1a (5-HT 1a ) receptor agonists, such as sarizotan and tandospirone, are reported to reduce levodopainduced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and in Parkinson's disease without worsening motor disability. However, these compounds are not specific for 5-HT 1a receptors and also possess dopamine antagonist actions. We now report on the effects of (2R), a selective 5-HT 1a agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets. Administration of (R)-(ϩ)-8-OHDPAT (0.2, 0.6, and 2.0 mg/kg s.c), in conjunction with levodopa/carbidopa (12.5 mg/kg each p.o.) to levodopa-primed animals, dose-dependently reduced levodopa-induced chorea but did not affect dystonic movements. However, (R)-(ϩ)-8-OHDPAT treatment also reduced locomotor activity and the reversal of motor disability. Administration of (R)-(ϩ)-8-OHDPAT alone had no effects of motor behaviors. The effects of (R)-(ϩ)-8-OHDPAT on levodopa-induced motor behaviors were antagonized by the 5-HT 1a recep-(1.0 mg/kg s.c.). Administration of (R)-(ϩ)-8-OHDPAT (0.6 mg/kg s.c.) also reduced chorea produced by the administration of the D 2 /D 3 dopamine receptor agonist pramipexole (0.06 mg/kg p.o.) to levodopa-primed MPTP-treated animals. However, again the increase in locomotor activity and reversal of motor disability produced by pramipexole were also inhibited. These data suggest that selective 5-HT 1a agonists do not provide an effective means of suppressing levodopa-induced dyskinesia, except with worsening of parkinsonism.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

In 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Primates, the Selective 5-Hydroxytryptamine 1a Agonist (R)-(+)-8-OHDPAT Inhibits Levodopa-Induced Dyskinesia but Only with\ Increased Motor Disability

Iravani

Tayarani-Binazir

Chu

et al. 2006

J Pharmacol Exp Ther

109

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“…20,21 But even here there is a hint that amantadine may blunt the antiparkinsonian response in primates, 22 as is true with another proposed antidyskinetic drug, sarizotan. 23 It is important to point out some caveats about this study. First, it is retrospective, examining studies done in our clinical research center using identical protocols but for other purposes.…”

Section: Dyskinesia and Antiparkinsonian Responsementioning

confidence: 90%

Dyskinesia and the antiparkinsonian response always temporally coincide

Nutt

Chung²,

Holford

2010

Neurology

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Objective: To clinically characterize the temporal relationship between dyskinesia and the antiparkinsonian response when dyskinesia first emerges during long-term levodopa therapy and to determine if it is consistent with the hypothesized mechanism by which dyskinesia develops.Methods: Dyskinesia and the antiparkinsonian response to levodopa during 2-hour levodopa infusions were monitored at intervals through the first 4 years of long-term levodopa therapy in 20 subjects with idiopathic Parkinson disease (PD) and previously untreated with levodopa. The onset and offset of the antiparkinsonian response and dyskinesia were compared when dyskinesia first appeared during the 4 years. The findings were compared to 20 subjects with PD on longterm levodopa with dyskinesia and motor fluctuations. Results:The onset and offset of the antiparkinsonian response and dyskinesia generally coincided when dyskinesia first appeared during the 4 years and did not suggest any temporal dissociation of the 2 responses. Further, the latency to the onsets of dyskinesia and the antiparkinsonian response tended to shorten during long-term levodopa therapy, suggesting that both responses were sensitized by long-term levodopa. Conclusions:The similar onsets and offsets of the antiparkinsonian response and dyskinesia when dyskinesia first appears are not consistent with the postulated progressive decrease in threshold for dyskinesia during long-term levodopa therapy. Other mechanisms for the development of dyskinesia need to be considered. Neurology Levodopa-induced dyskinesia is postulated to result from repeated pulsatile dopaminergic stimulation which progressively lowers the threshold for dyskinesia by sensitization.1 At the beginning of levodopa therapy, the threshold for dyskinesia is much higher than the peak plasma levodopa concentrations. Conversely, the threshold for the antiparkinsonian response is envisioned to be lower than that for dyskinesia. The hypothesized different thresholds allow dissociation of the antiparkinsonian response and dyskinesia. Continued levodopa therapy lowers the threshold for dyskinesia and dyskinesia occurs briefly at peak concentrations. Eventually, similar concentrations produce dyskinesia and the antiparkinsonian response, making the responses inseparable ( figure 1A). This hypothesis assumes 1) the antiparkinsonian response and dyskinesia have distinctly different dose responses and 2) they are altered differently during long-term levodopa therapy.Evidence for this hypothesized scenario is from temporal extremes. Initial levodopa therapy rarely produces dyskinesia, consistent with a high threshold for dyskinesia.2,3 After years of levodopa therapy, dyskinesia and the antiparkinsonian response occur together, 2,3 e-Pub ahead of print on March 10, 2010, at www.neurology.org.

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“…Sarizotan, a full, but nonselective, 5-HT 1A receptor agonist also reduced dyskinesia in MPTP-lesioned, parkinsonian macaques, but compromised L-DOPA antiparkinsonian action at higher doses (Grégoire et al, 2009). In humans, the antidyskinetic efficacy of sarizotan was variable across studies and, although sarizotan was able to reduce dyskinesia consistently in phase II studies, it impaired L-DOPA antiparkinsonian action at higher doses (Olanow et al, 2004;Goetz et al, 2007Goetz et al, , 2008.…”

Section: -Ht 1a Agonist R-(ϩ)-8-oh-dpatmentioning

confidence: 98%

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

Huot¹,

Fox²,

Newman‐Tancredi³

et al. 2011

J Pharmacol Exp Ther

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L-DOPA remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT 1A ) receptor agonists and serotonergic type 2A (5-HT 2A ) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair L-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT 1A and 5-HT 2A receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT 1A -and 5-HT 2A -modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT 1A and 5-HT 2A receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively.

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Multicenter, Open-Label, Trial of Sarizotan in Parkinson Disease Patients With Levodopa-Induced Dyskinesias (the SPLENDID Study)

Cited by 167 publications

References 8 publications

In 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Primates, the Selective 5-Hydroxytryptamine 1a Agonist (R)-(+)-8-OHDPAT Inhibits Levodopa-Induced Dyskinesia but Only with\ Increased Motor Disability

In 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Primates, the Selective 5-Hydroxytryptamine 1a Agonist (R)-(+)-8-OHDPAT Inhibits Levodopa-Induced Dyskinesia but Only with\ Increased Motor Disability

Dyskinesia and the antiparkinsonian response always temporally coincide

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

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