Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding BIAL.
Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT ...inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects.
To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations.
This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014.
The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time.
A total of 427 patients (258 men 60.4% and 169 women 39.6%; mean SD age, 63.1 8.8 years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was -64.5 (14.4) minutes for the placebo group, -101.7 (14.9) minutes for the 25-mg/d opicapone group, and -118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, -54.3 95% CI, -96.2 to -12.4 minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, -37.2 95% CI, -80.8 to 6.4 minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (-126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase.
Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated.
clinicaltrials.gov Identifier: NCT01227655.
This was a double-blind, randomised, placebo-controlled study to investigate the pharmacokinetics and safety of trans-resveratrol. In four groups of ten healthy adult subjects (five males and five ...females), two subjects were randomized to receive placebo and eight subjects to receive trans-resveratrol 25, 50, 100 or 150 mg, six times/day, for thirteen doses. Peak plasma concentrations of trans-resveratrol were reached at 0.8-1.5 h postdose. Following the 13th dose of trans-resveratrol 25, 50, 100 and 150 mg, mean peak plasma concentration (Cmax) was 3.89, 7.39, 23.1 and 63.8 ng/mL and mean area under the plasma concentration-time curve (AUC₀₋τ) was 3.1, 11.2, 33.0 and 78.9 ng·h/mL. Interindividual variability was high, with coefficients of variation >40%. Trans-resveratrol half-life was 1-3 h following single-doses and 2-5 h following repeated dosing. Trough (Cmin) concentrations were less, not equals1 ng/mL following 25 and 50 mg, 3 ng/mL following 100 mg and < 10 ng/mL following 150 mg. Trans-resveratrol pharmacokinetics showed circadian variation. Adverse events were mild in severity and similar between all groups. In conclusion, repeated administration was well-tolerated but produced relatively low plasma concentrations of trans-resveratrol, despite the high doses and short dosing interval used. Bioavailability was higher after morning administration.
This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BIA 10‐2474, a fatty acid amide hydrolase (FAAH) inhibitor, after first administration to healthy male and ...female participants. Participants (n = 116) were recruited into this phase I, double‐blind, randomized, placebo‐controlled, single ascending dose and multiple ascending dose (10‐day) study. The primary outcome was the safety and tolerability of BIA 10‐2474. Secondary outcomes were pharmacokinetics of BIA 10‐2474 and pharmacodynamics, considering plasma concentrations of anandamide and three other fatty acid amides (FAAs) and leukocyte FAAH activity. Single oral doses of 0.25–100 mg and repeated oral doses of 2.5–50 mg were evaluated. BIA 10‐2474 was well tolerated up to 100 mg as a single dose and up to 20 mg once daily for 10 days. In the cohort receiving repeated administrations of 50 mg, there were central nervous system adverse events in five of six participants, one with fatal outcome, which led to early termination of the study. BIA 10‐2474 showed a linear relationship between dose and area under plasma concentration‐time curve (AUC) across the entire dose range and reached steady state within 5–6 days of administration, with an accumulation ratio, based on AUC0–24h, of <2 on Day 10. BIA 10‐2474 was rapidly absorbed with a mean terminal elimination half‐life of 8–10 hours (Day 10). BIA 10‐2474 caused reversible, dose‐related increases in plasma FAAs. In conclusion, we propose that these data, as well as the additional data generated since the clinical trial was stopped, do not provide a complete mechanistic explanation for the tragic fatality.
The efficient single‐pot oxidative functionalisation of alkanes and alcohols under mild conditions was catalysed by Au nanoparticles supported on Al2O3, Fe2O3, ZnO and TiO2. The obtained materials ...were tested for cyclohexane oxidation under mild conditions (60 °C, atmospheric pressure) using an environmentally friendly oxidant (H2O2). The materials were also tested in the oxidation of benzyl alcohol and methylbenzyl alcohol in the presence of tert‐butylhydroperoxide as the oxidant under microwave irradiation. With regard to cyclohexane oxidation, all materials were highly selective towards the formation of cyclohexanol and cyclohexanone. No traces of byproducts were detected under the optimised conditions. Au on Fe2O3 led to the best results (13.5 % yield). This system showed an interesting almost exclusive formation of cyclohexanol at 4 h reaction time. Catalyst recycling was tested in up to five cycles, and the catalyst maintained almost the original level of activity after three cycles with no significant leaching. With regard to oxidation of benzyl alcohol and methylbenzyl alcohol, all materials were highly selective towards the formation of benzaldehyde or acetophenone, respectively. No traces of byproducts were detected. Addition of Au increased alcohol conversion from 5 (TiO2) to 91 % (Au/TiO2). The recycling of Au/TiO2 was tested in up to 10 cycles, and the catalytic activity remained high in the first four cycles.
Sold on gold: Efficient single‐pot oxidative functionalization of cyclohexane and benzyl and methylbenzyl alcohols under mild conditions with high selectivity was catalyzed by reusable Au nanoparticles on Al2O3, Fe2O3, ZnO, and TiO2. Au nanoparticles on Fe2O3 led to an unusual almost exclusive formation of cyclohexanol by control of reaction time, but Au nanoparticles on TiO2 had a remarkable catalytic effect on acetophenone yield.
Levodopa remains the gold-standard Parkinson's disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery.
Peripheral ...inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once 'wearing-off' has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in 'fluctuating' disease, but it has not yet been included in the algorithm for early treatment.
This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease.
Prediabetes and type 2 Diabetes Mellitus (T2DM) are characterized by increased blood sugar concentration and insulin resistance. Although there are only a few reports of potential benefits of ...flaxseed’s consumption on different metabolic parameters, there is no evidence of its effect among people with these conditions.
The present systematic review and meta-analysis aimed to assess the effect of flaxseed supplementation on glycemic control variables and insulin resistance in prediabetes and T2DM.
A literature search was conducted through PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, to identify Randomized Control Trials (RCTs) that evaluated the effect of milled or ground flaxseed supplementation on fasting blood glucose, HbA1c, insulin concentrations, or HOMA-IR. The data were analyzed using Comprehensive Meta-Analysis (CMA) software version 3.3 in a fixed-effect model.
Seven studies were included in the systematic review and the meta-analysis, the results showed a significant reduction on fasting blood sugar (SMD: −0.392, 95% CI: −0.596, −0.187, p = <0.001, I2 = 64.81%) insulin concentrations, (SMD: −0.287, 95% CI: −0.534, −0.041, p = 0.022, I2 = 32.53%), HbA1c (SMD: −0.442, 95% CI: −0.770, −0.114, p = 0.008, I2 = 11.058%), and HOMA-IR (SMD: −0.284, 95% CI: −0.530, −0.038, p = 0.024, I2 = 0.00%) after flaxseed supplementation.
Flaxseed supplementation seems to improve glycemic control variables and insulin resistance in prediabetes and T2DM; however, more RCTs are needed to have more decisive evidence about doses, method of supplementation, and the possible effect of synergy with the dietetic treatment.
•Flaxseed supplementation may improve glycemic control in prediabetes and type 2 diabetes mellitus.•Flaxseed supplementation may improve insulin concentrations and insulin resistance in prediabetes and type 2 diabetes mellitus.•Further studies are needed to address methodological aspects, such as the administration, dosage, and the combined effect with other treatments.
The benefit of mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to large vessel intracranial occlusions is directly related to the technical success of the procedures in achieving fast ...and complete reperfusion. While a precise definition of refractoriness is lacking in the literature, it may be considered when there is reperfusion failure, long procedural times, or high number of passes with the MT devices. Detailed knowledge about the causes for refractory MT in AIS is limited; however, it is most likely a multifaceted problem including factors related to the vascular anatomy and the underlying nature of the occlusive lesion amongst other factors. We aim to review the impact of several key unfavorable anatomical factors that may be encountered during endovascular AIS treatment and discuss potential bail-out strategies to these challenging situations.
In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily “OFF”-time relative to placebo in adults with Parkinson's disease (PD) and motor ...fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize “OFF”-times around nighttime sleep and to explore the effects of opicapone 50 mg.
“OFF” before sleep (OBS), “OFF during the nighttime sleep period” (ODNSP), early morning “OFF” (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits.
At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (−0.9 vs. −0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (−1.0 vs. −0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (−12.8 % vs. −4.5 %, P < 0.05).
“OFF”-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period “OFF” episodes.
•“OFF” episodes can interrupt sleep in patients with Parkinson's disease.•Opicapone reduced “OFF”-times before, during, and after nighttime sleep periods.•Opicapone significantly improved sleep metrics in patients with night-time “OFF”.
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