CNS drugs最新文献

Tofersen (QALSODY^®) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Tofersen is an antisense oligonucleotide that induces SOD1 mRNA degradation. In the 28-week, placebo-controlled, multinational, phase III VALOR trial, intrathecally administered tofersen reduced plasma concentrations of neurofilament proteins (biomarker for neuro-axonal injury) and total SOD1 protein in cerebrospinal fluid in patients with SOD1 mutation-associated ALS. These reductions were sustained in a long-term, open-label extension study. The decline in functional outcomes was not significantly reduced with tofersen treatment compared with placebo in the 28-week phase III trial, although in the longer-term open-label study, early tofersen initiation was associated with slowed functional decline versus delayed tofersen initiation. Tofersen had an acceptable tolerability profile in clinical trials with a favourable benefit-to-risk balance. In summary, tofersen is a new disease-modifying therapy for patients with ALS attributed to an SOD1 mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.

Background: Previous studies on cenobamate (CNB) have generally reported neutral to positive effects on objective cognitive performance in patients with epilepsy, but are limited to dosages up to 250 mg/day. However, a case report (Witt et al. in Neurocase 30:91-96, 2024) noted severe memory deterioration at 400 mg/day.

Objective: The purpose of this study was to examine dose-dependent effects of CNB on cognition.

Methods: In this retrospective longitudinal real-world study, executive functions and episodic memory were assessed in adult patients with pharmacoresistant epilepsy during CNB therapy and compared with baseline. Subgroups were stratified by daily CNB doses of ≥ 300 mg versus < 300 mg. Executive functions were assessed using the EpiTrack^®, verbal memory via the VLMT or an abbreviated version, and figural memory with the DCS-R.

Results: The study included 84 patients, 24 (28.6%) of them with a CNB dose of ≥ 300 mg. With a mean CNB dose of 200.6 ± 114.3 mg (range 12.5-400.0 mg), seizure freedom was achieved in 11.9% with no significant difference between the lower and the higher dose group. Repeated measures analysis of covariance (ANCOVA) revealed a significant decline in executive functions at ≥ 300 mg (n = 84; F = 6.35, p = 0.014) compared to baseline. Changes were correlated with CNB dose (r = - 0.31, p = 0.004). Individual level analyses indicated that 50.0% of patients on higher versus 16.7% on lower CNB doses deteriorated according to reliable change indices (RCI). In a subgroup undergoing extensive memory testing, verbal retention showed a significant negative, dose-independent effect at the group level (n = 22; F = 7.95, p = 0.011), with intraindividual declines in 28.6% (≥ 300 mg) versus 13.3% (< 300 mg). Other memory parameters were unaffected.

Conclusions: The results of this real-world study investigating objective cognitive performance under CNB suggest possible, partially dose-dependent negative effects of CNB on cognition. Daily CNB doses of ≥ 300 mg were associated with a significant decline in executive functions. Furthermore, a dose-independent negative effect on verbal retention was observed in a subgroup of patients undergoing extensive memory assessment. Given the limitations of retrospective audits, our findings prompt further, larger scope studies to confirm the results. However, a careful balance between seizure control at the lowest CNB dose possible and potential cognitive side effects appears advisable, which requires the implementation of cognitive monitoring in standard care where possible.

Background: Levodopa, dopamine agonists (DA) and monoamine oxidase inhibitors (MAOI) are all approved first-line therapies for Parkinson's disease (PD), as monotherapy or in combination. Data on their use in the early management of patients with PD in real-life are lacking. Our objective was to assess the impact of early therapeutic strategies on the development of motor and neuropsychiatric complications using a nationwide PD cohort.

Methods: NS-PARK is a cohort of patients with PD recruited between 2011 and 2021 from 26 expert centres for PD in France. We analysed the patients with less than 5-years disease duration and no motor complications at inclusion. We used interval censoring survival models to assess the associations between therapeutic strategies (levodopa monotherapy, levodopa alternative therapies or levodopa combinations) and motor fluctuations, dyskinesia, impulse control and related behaviours (ICRBs), apathy, psychosis/hallucination and daytime sleepiness. Analyses were adjusted for sex, age, disease duration, dopaminergic dose and disease severity.

Results: We included 1722 patients (38.4% female, median age 67.7 years). At inclusion, 41% received levodopa monotherapy, 31% received levodopa alternative therapies and 28% received levodopa combinations. Compared with levodopa monotherapy, levodopa alternative therapies were associated with a lower dyskinesia risk (hazard ratio (HR) 0.48, 95% confidence interval (CI)[0.28-0.84]), but there was no significant difference in motor fluctuations. Both levodopa alternative and combinations therapies increased ICRBs risk (HR 4.06, 95% CI [2.48-6.67]; HR 5.16, 95% CI [3.00-8.86]) and decreased apathy risk (HR 0.36, 95% CI [0.26-0.49]; HR 0.52, 95% CI [0.39-0.69]). No association was found with psychosis/hallucination or daytime sleepiness.

Conclusions: In this real-life cohort, our data supported an association between levodopa alternative therapies and a lower risk of dyskinesia and apathy, but a higher risk of ICRBs compared with levodopa monotherapy.

Clinicaltrials:

Gov identifier: NCT04888364. Registered June 2021.

Psychedelics have been studied since the 1950s as a potential treatment for alcohol use disorder (AUD), with over a dozen clinical trials of lysergic acid diethylamide (LSD), and several contemporary trials of psilocybin and ayahuasca for this indication. Herein, we characterize foundational studies from the 1950s to the present, with emphasis on key design factors that varied considerably between published studies. Critically, those design factors include pharmacological factors, such as presence or absence of a placebo control and the nature of the placebo (e.g., ephedrine, dextroamphetamine, diphenhydramine, or low-dose LSD), and non-pharmacological factors, such as the treatment setting and the presence or absence of psychotherapy. We found that observational studies nearly uniformly show promising results, but trials in which psychedelics were tested against placebo or standard of care control groups have been more inconsistent in both outcomes and methodologies. Given the inconsistency in published results, we review candidate mechanisms of action for psychedelics in the context of AUD. We take a biopsychosocial approach, reviewing mechanisms spanning several different hierarchical levels of analysis, including cellular neuroplasticity, cognitive neuroscience, subjective experience, and social connection. Taken together, this review highlights key findings on both the efficacy and potential mechanisms of psychedelics for the treatment of AUD, which could motivate future studies in this rapidly developing field.

Background and objectives: Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that can lead to hemorrhage, focal neurologic deficits, and seizures. Rho-associated kinase (ROCK) overactivation plays a critical role in the development of CCMs, and a novel, selective ROCK2 inhibitor, NRL-1049, mitigated lesion burden and bleeding in mouse models of CCM. This study examined the safety, tolerability, and pharmacokinetics of NRL-1049 in healthy volunteers.

Methods: In this first-in-human, randomized, double-blind, single-ascending dose study, participants received a single, oral dose of NRL-1049 (25, 75, 150, or 250 mg) or placebo in a fasted state (period 1). In period 2, participants received 150 mg NRL-1049 or placebo 30 min after a standardized high-fat, high-calorie meal. Blood samples for pharmacokinetic analysis were collected pre-dose and at post-dose time points from 5 min to 48 h. Treatment-emergent adverse events (TEAEs) were recorded and pharmacokinetic parameters determined, including maximum drug concentration (C_max), time to C_max (t_max), and area under the concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC_0-t) and extrapolated to infinity (AUC_0-∞).

Results: Of the 24 participants in period 1 who received NRL-1049 (fasted), 9 (37.5%) experienced ≥ 1 TEAE, with 8 (33.3%) reporting ≥ 1 treatment-related TEAE. TEAEs appeared to correlate with dose, and 150 mg was the maximum tolerated dose following single-dose administration in this study. The most common TEAEs (> 5%) were dizziness (16.7%), headache (8.3%), and syncope (8.3%). In period 2 (n = 10), four (40.0%) participants who received 150 mg NRL-1049 (fed) reported ≥ 1 TEAE, and three (30.0%) reported a treatment-related TEAE. There were no reports of serious TEAEs or discontinuations due to a TEAE. NRL-1049 was rapidly absorbed in the fasted state, with median t_max ranging from 0.50 to 0.75 h. Mean C_max increased over the dose range of 25-250 mg (3.66-58.0 ng/mL). As NRL-1049 dose increased in a ratio of 1:3:6:10, mean C_max similarly increased (1:5:10:16), while AUC_0-t and AUC_0-∞ increased in a greater-than-dose proportional manner (1:5:11:25 and 1:4:10:21, respectively; P < 0.001). In the fed state (150 mg NRL-1049), mean C_max (18.5 ng/mL) was lower compared with the fasted state (34.9 ng/mL). For the active metabolite, NRL-2017, in the fasted state, median t_max was 0.88-1.63 h, and mean C_max increased over the dose range (54.2-1520 ng/mL). Mean C_max (1:6:14:28), AUC_0-t (1:4:7:14), and AUC_0-∞ (1:3:6:13) of NRL-2017 increased in a greater-than-dose proportional manner (P < 0.001). In the fed state, mean C_max was lower compared with the fasted state.

Conclusions: