pardoprunox and Parkinson-Disease

Solvay is developing SLV-308 (SME-308), a partial dopamine D2 agonist and noradrenergic agonist with serotonin 5-HT1A agonist properties, for the potential oral treatment of Parkinson's disease (PD), panic and depression. By January 2001, SLV-308 had entered phase II trials for PD and phase I trials for anxiety and depression.

Topics: Animals; Antiparkinson Agents; Benzoxazoles; Clinical Trials as Topic; Drugs, Investigational; Humans; Parkinson Disease; Piperazines; Technology, Pharmaceutical

To determine the efficacy and safety of pardoprunox in levodopa-treated patients with Parkinson's disease (PD) experiencing motor fluctuations.. 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).. 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.. 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.

Topics: Adult; Aged; Antiparkinson Agents; Benzoxazoles; Double-Blind Method; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Pain Measurement; Parkinson Disease; Piperazines; Severity of Illness Index; Time Factors; Treatment Outcome

This report presents the results of 2 randomized trials-Rembrandt and Vermeer-on the efficacy and safety of pardoprunox in patients with early Parkinson's disease. Patients with Parkinson's disease with a Unified Parkinson's Disease Rating Scale-Motor score ≥ 10 and modified Hoehn and Yahr stage ≤ 3 were randomized to pardoprunox (fixed doses of 6 mg/day [n = 115] or 12 mg/day [n = 118] or a flexible-dose range of 12-42 mg/day [n = 116]) or placebo (n = 119) in Rembrandt and pardoprunox 12-42 mg/day (n = 108), pramipexole 1.5-4.5 mg/day (n = 116), or placebo (n = 110) in Vermeer. Pardoprunox showed a significant benefit over placebo in the primary efficacy variable, least-square mean change from baseline in Unified Parkinson's Disease Rating Scale-Motor score: Rembrandt-fixed doses of 6 and 12 mg/day, -6.0 and -4.7 points, respectively; flexible-dose 12-42 mg/day, -5.5 points; placebo, -2.9 points; Vermeer-flexible-dose 12-42 mg/day, -4.9 points; placebo, -2.5 points; pramipexole, -5.7 points. No minimum effective dose was established. Secondary efficacy parameters supported the results of the primary efficacy variable. Pardoprunox tolerability was dose related: flexible-dose 12-42 mg/day showed the highest dropout rate due to treatment-emergent adverse events (Rembrandt, 56.0%; Vermeer, 46.3%) and overall incidence of treatment-emergent adverse events (Rembrandt, 97.4%; Vermeer, 92.6%), primarily due to nausea, somnolence, and dizziness. Because pardoprunox showed similar efficacy across all dose groups, these observations suggest that the 12-42 mg/day dose range was higher than therapeutically required. Furthermore, the early onset of treatment-emergent adverse events and dropouts observed for pardoprunox suggest that titration was too rapid. Pardoprunox significantly improved motor symptoms in patients with early Parkinson's disease, but further investigation into the dose and titration schedule is required to improve tolerability.

Topics: Aged; Antiparasitic Agents; Benzoxazoles; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Parkinson Disease; Piperazines; Severity of Illness Index; Time Factors; Treatment Outcome

The objective of this study was to establish temporal stability characteristics for objective components of the Unified Dyskinesia Rating Scale (UDysRS). The UDysRS has strong internal consistency and a reliable factor structure, but the important issue of temporal stability has not been established.. Using intraclass correlation coefficient (ICC) analyses, we examined UDysRS temporal stability for the objective scale components (Part III and IV) over an 8-hour observation period. We assessed ICCs for the single centralized rater, the on-site raters, and the agreement between the single centralized rater and the on-site raters. Kappa statistic assessed agreement between the single centralized and on-site raters for clinical state (ON vs OFF).. For both the single centralized rater and the on-site raters, there was high temporal stability of the UDysRS Part III, Part IV, and Total Objective UDysRS in both ON and OFF states, with ICCs ranging from 0.822 (P < .0005) to 0.513 (P < .013). The agreement between the 2 rating techniques (centralized vs on-site) was significant for ON and OFF ratings of Part III, Part IV, and Total Objective UDysRS, ranging from 0.821 (P < .0005) to 0.703 (P < .0005).. The UDysRS is highly stable for ON and OFF. Our data suggest that a single UDysRS evaluation for ON and for OFF states is highly representative of that state regardless of time. Likewise, if appropriate protocols need to assess dyskinesia in a field or community setting, the UDysRS can be filmed without an on-site rater and rated centrally with retained validity.

Topics: Aged; Benzothiazoles; Benzoxazoles; Disability Evaluation; Dopamine Agonists; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neurologic Examination; Observer Variation; Parkinson Disease; Piperazines; Pramipexole; Reproducibility of Results; Videotape Recording

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.. 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).. 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.. 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.

Topics: Aged; Benzoxazoles; Chemotherapy, Adjuvant; Dopamine Agonists; Double-Blind Method; Female; Humans; Levodopa; Male; Middle Aged; Multivariate Analysis; Parkinson Disease; Piperazines; Treatment Outcome

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.

Topics: Animals; Benzoxazoles; Binding, Competitive; Brain; CHO Cells; Colforsin; Cricetinae; Cyclic AMP; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Interactions; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Lisuride; Male; Molecular Structure; Parkinson Disease; Piperazines; Quinpirole; Radioligand Assay; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Receptors, Dopamine D3; Recombinant Fusion Proteins; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists