Pardoprunox as adjunct therapy to levodopa in patients with Parkinson's disease experiencing motor fluctuations: results of a double-blind, randomized, placebo-controlled, trial.

AIMS: To determine the efficacy and safety of pardoprunox in levodopa-treated patients with Parkinson's disease (PD) experiencing motor fluctuations. METHODS: Patients were randomized to pardoprunox (up to 42 mg/day, n = 150) or placebo (n = 144). Pardoprunox was titrated to an optimal dose over 7 weeks, followed by a 12-week stable dose period. The primary efficacy variable was the change from baseline to study endpoint in total daily OFF time, based on patient diaries. Secondary analyses included the change in ON time without troublesome dyskinesias, UPDRS-ADL + Motor ON, UPDRS-ADL OFF and PDQ-39. Subgroup analyses explored the impact of pardoprunox on dyskinesias (UPDRS items 32 + 33), depression (Hospital Anxiety Depression Scale) and pain (Visual Analogue Scale). RESULTS: Pardoprunox significantly reduced OFF time versus placebo (-1.62 h/day versus -0.92 h/day, respectively, p = 0.0215). Compared to placebo, pardoprunox improved ON time without troublesome dyskinesias (p = 0.0386), UPDRS-ADL + Motor ON (p = 0.0003), and UPDRS-ADL OFF (p < 0.0001), while no significant difference was observed on PDQ-39. A high drop-out rate due to adverse events (AEs) (pardoprunox, 37%; placebo, 12%) suggested that the selected dose range may have been too high, and/or titration was too rapid. CONCLUSIONS: Pardoprunox decreased OFF time and increased ON time without troublesome dyskinesias in levodopa-treated PD patients. The high drop-out rate at the selected doses justifies the investigation of lower doses. The impact of pardoprunox on dyskinesias and non-motor symptoms deserves further investigation.

Safety and tolerability of pardoprunox, a new partial dopamine agonist, in a randomized, controlled study of patients with advanced Parkinson's disease.

AIMS: To investigate the safety and tolerability of pardoprunox (SLV308), a novel partial dopamine agonist, as an adjunct to levodopa in patients with advanced Parkinson's disease, using two titration schedules. METHODS: Patients were randomized to pardoprunox (n = 51) or placebo (n = 11). Pardoprunox was titrated to the highest tolerated dose (range, 0.3-42 mg/day) over 7 weeks, using a gradual dose escalation without intermediate steps (group 1) or with intermediate steps (group 2). RESULTS: The cumulative drop-out rate was greater in group 1 (without intermediate steps, 56.0%) than in group 2 (with intermediate steps, 34.6%), or with placebo (9.1%). In group 2, doses up to 18 mg/day were well tolerated with a cumulative drop-out rate of 7.7% (2/26) and a drop-out rate due to adverse events of 4.0% (1/26). The most common adverse events reported were nausea, vomiting, headache, and dizziness. There was a trend for reduced OFF time (p = 0.054) in the combined pardoprunox group compared to placebo. CONCLUSIONS: The pardoprunox safety and tolerability profile as an adjunct to levodopa was improved using a gradual titration schedule that included intermediate dose steps. Using this titration, doses up to 18 mg/day were well tolerated.

Dynorphin modulates dopamine D1-receptor mediated turning behavior in 6-hydroxydopamine-lesioned rats.

We investigated if the potentiated turning response to a challenge with the partial dopamine D1 receptor agonist SKF-38393, as seen after priming with L-dihydroxyphenylalanine (DOPA) of unilaterally 6-hydroxydopamine-lesioned rats, can be modulated by infusion of dynorphin A (1-17) in the striatum. Seventeen days after the 6-hydroxydopamine lesion, rats received intrastriatal dynorphin (0. 08 or 3.85 microg) followed by L-DOPA (50 mg/kg i.p.) and were challenged 3 days later with SKF-38393 (3.0 mg/kg s.c.). Compared to controls, the lower dose of dynorphin caused an earlier onset of turning, while the higher dose decreased the response to SKF-38393. These findings suggest a dose-dependent modulatory role for striatal dynorphin in L-DOPA-priming of a D1-mediated behavioral response.

Priming with L-DOPA differently affects dynorphin and substance P mRNA levels in the striatum of 6-hydroxydopamine-lesioned rats after challenge with dopamine D1-receptor agonist.

In unilaterally 6-hydroxydopamine-lesioned rats, potentiation of D1-agonist-induced turning behavior by priming with l-DOPA was correlated with changes in striatal neuropeptide mRNA levels. In non-primed rats, administration of the D1-agonist SKF-38393 markedly increased dynorphin and substance P mRNA levels in the lesioned striatum. Priming with l-DOPA dissociated the response of the two neuropeptides to the D1-agonist, with higher dynorphin and reduced substance P mRNA levels.

Serotonin and carbachol induced suppression of synaptic excitability in rat CA1 hippocampal area: effects of corticosteroid receptor activation.

Serotonin (5HT) and the cholinergic analogue carbachol (CCh) act on neurons in the hippocampal CA1 area through pre- and post-synaptic receptors. Previously, it was shown that post-synaptic actions of 5HT and CCh are affected by corticosteroids: predominant activation of high affinity mineralocorticoid receptors resulted in small hyperpolarizing responses to 5HT and small depolarizing responses to CCh; additional activation of low affinity glucocorticoid receptors led to increased 5HT and CCh responses. In the present study, we examined the consequences of steroid modulation of these post-synaptic membrane effects and/or possible pre-synaptic effects by 5HT and CCh for the excitability in the CA1 area, using extracellular field potential or intracellular recordings from individual pyramidal neurons. Steroid treatment by itself did not affect the amplitude or paired pulse properties of synaptic responses. In slices from adrenally intact rats, both 5HT (3-30 microM) and CCh (1-10 microM) induced a dose-dependent suppression of the synaptic field responses evoked in the CA1 area by stimulation of the Schaffer collaterals. No changes in these transmitter effects were observed after adrenalectomy. The 5HT induced suppression of the population spike amplitude was, however, reduced after selective occupation of mineralocorticoid receptors. Intracellularly, no significant steroid dependent modulation of (pre-synaptic) 5HT evoked changes in synaptic responses was observed. These data suggest that the steroids modulate post-synaptic but not pre-synaptic 5HT effects and that this modulation is reflected in the excitability of the CA1 region. The CCh induced suppression of the population spike was not affected by corticosteroid receptor activation, indicating that the previously found steroid modulation of post-synaptic CCh effects has no clear consequences for the CA1 excitability.