oxadiazoles and Dyskinesia--Drug-Induced

Topics: Administration, Oral; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Dyskinesia, Drug-Induced; Humans; Levodopa; Nitriles; Oxadiazoles; Parkinson Disease

Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa compared with placebo or entacapone in patients with Parkinson's disease and motor fluctuations.. We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinson's disease with end-of-dose motor fluctuations. Patients aged 30-83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14-15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov, NCT01568073.. Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was -56·0 min (SE 13·4; 95% CI -82·3 to -29·7) for placebo, -96·3 min (13·4; -122·6 to -70·0) for entacapone, -91·3 min (13·5; -117·7 to -64·8) for opicapone 5 mg, -85·9 min (13·7; -112·8 to -59·1) for opicapone 25 mg, and -116·8 min (14·0; -144·2 to -89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline -60·8 min, 95% CI -97·2 to -24·4; p=0·0015) and non-inferior to entacapone (-26·2 min, -63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group.. The addition of opicapone 50 mg to levodopa treatment in patients with Parkinson's disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit.. BIAL.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Double-Blind Method; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Europe; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Outcome Assessment, Health Care; Oxadiazoles; Parkinson Disease

Studies of neurotransmitter release in guinea pig and human brain indicate that the 5-HT terminal autoreceptor is the 5-HT1D subtype and that it regulates the depolarization evoked release of 5-HT. Thus, blockade of the terminal 5-HT autoreceptor should enhance 5-HT release in vivo. In the present study, we have used the recently described, selective and potent 5-HT1D receptor antagonist, GR127935, to determine if blockade of the terminal 5-HT autoreceptor enhanced 5-HT neurotransmission in the guinea pig. Neurochemical studies showed that GR127935 (0.1, 0.3 and 1.0 mg/kg i.p.) significantly increased 5-HT metabolism in forebrain regions but not in the raphe nucleus of the guinea pig. However, using in vivo dialysis, GR127935 did not significantly increase cortical 5-HT efflux when given either systemically (1 and 5 mg/kg i.p.) or by infusion via the probe directly into the cortex (10, 33 and 100 microM). Fast cyclic voltammetry studies in the guinea pig dorsal raphe slice in vitro failed to observe any significant effects of GR127935 (0.01-1 microM) on electrically evoked 5-HT release. Behavioural studies in the guinea pig were also unable to demonstrate any effects of GR127935 (0.1-3.0 mg/kg i.p.) per se or in combination with the 5-HT precursor 5-hydroxytryptophan. Taken together, results from the present neurochemical and behavioral studies in the guinea pig provide little substantial evidence that blockade of the terminal 5-HT autoreceptor following the acute administration of GR127935 increased brain 5-HT neurotransmission in vivo.

Topics: Animals; Biogenic Monoamines; Brain; Dyskinesia, Drug-Induced; Electric Stimulation; Fluoxetine; Guinea Pigs; Humans; In Vitro Techniques; Male; Methiothepin; Oxadiazoles; Paroxetine; Piperazines; Raphe Nuclei; Serotonin Antagonists; Synaptic Transmission; Tryptophan

Administration of 3,3'-iminodipropionitrile (IDPN) (1 g/kg, i.p. for 3 days) in mice leads to the development of a characteristic syndrome consisting of lateral and vertical head and neck movements, hyperactivity, random circling, increased locomotor activity, and increased startle response. Nifedipine, verapamil, and diltiazem (10 mg/kg) inhibited significantly the symptoms of IDPN-induced dyskinesia. However, there was no change in the affinity (KD) or the density of PN 200-110 binding sites (Bmax) in whole brains of IDPN-treated mice. Similarly, the K(+)-depolarization-dependent Ca2+ uptake in synaptosomes from whole brain, cortex, or striatum was not altered following IDPN treatment. However, IDPN caused a significant increase in the Bmax value (from 157 +/- 7 fmol/mg to 237 +/- 31 fmol/mg in control and treated groups, respectively) of PN 200-110 binding to the striatum without change of KD value (38 +/- 4.7 pM versus 33 +/- 1.6 pM). IDPN also caused a slight but significant decrease in the KD value (from 68 +/- 10.1 pM to 45 +/- 4.5 pM in control and treated groups, respectively), without significant change of Bmax value (563 +/- 51 fmol/mg versus 485 +/- 41 fmol/mg) of PN 200-110 binding to the cortex. IDPN did not alter omega-conotoxin binding in whole brain, striatum, or cortex. The behavioral effects of chronic IDPN treatment as inhibited by L-type calcium channel antagonists and this may be associated with the observed increase in striatal L-type calcium channels.

Topics: Animals; Brain; Calcium; Calcium Channel Blockers; Calcium Channels; Cerebral Cortex; Corpus Striatum; Dyskinesia, Drug-Induced; Isradipine; Male; Mice; Nitriles; Oxadiazoles; Synaptosomes