CNS drugs最新文献

Since the publication of the first gene therapy clinical trial in Parkinson's disease (PD) in 2007, rapid advances have resulted in escalating interest in applying this technology to manipulate various cellular processes altered in PD. There is now a rich literature describing the various approaches taken, including modulating aberrant networks, restoring dopamine, and mitigating deleterious effects of known gene mutations or as a restorative therapy. Evidence has accrued supporting feasibility, safety, and tolerability of initial gene therapy approaches, as well as providing initial indications of efficacy in several cases. However, there have also been unexpected challenges, and technology is still evolving, making this an important time point to evaluate what has been learned and to place it in context to support ongoing and future efforts. In this review, we focus on the potential of gene therapy to ameliorate symptoms and modify disease progression in PD. We critically review previous clinical research, we address potential benefits and predicted limitations, and we address pipeline approaches aiming to bring a gene therapy approach to the clinic.

Background and objectives: Augmentation, a long-term complication of dopamine agonist treatment for restless legs syndrome (RLS), is preceded by a gradual loss of response. We investigated whether prior long-term dopaminergic treatment affects current and future responses to dopaminergic and non-dopaminergic drugs, which would suggest broader changes in RLS pathophysiology.

Methods: We retrospectively analysed two previously published, double-blind, randomized, crossover, placebo-controlled studies with the adenosine transport inhibitor dipyridamole and the orexin receptor antagonist suvorexant. Post hoc analyses compared responses between dopaminergic (DA)-naïve and dopaminergic (DA)-treated patients with RLS. None of these patients met the diagnostic criteria for augmentation. After a 2-week washout, patients received active treatment (10-20 mg suvorexant or 200-300 mg dipyridamole) or placebo for 2 weeks, followed by crossover. Efficacy was assessed using the International RLS Rating Scale (IRLS), Clinical Global Impressions-Severity scale (CGI-S), multiple suggested immobilization test (m-SIT), periodic leg movements of sleep (PLMS) and other polysomnographic measures.

Results: A total of 28 patients participated in the dipyridamole study (DA-pretreated, n = 10; DA-naïve group, n = 18), and 40 participated in the suvorexant study (DA-pretreated, n = 9; DA-naïve group, n = 31). Compared with DA-naïve patients, DA-pretreated patients responded significantly worse to both treatments on the basis of the IRLS, CGI-S, m-SIT, PLMS indices. There were no differences in sleep parameters.

Conclusions: Our results suggest that previous long-term dopaminergic treatment, even before clinical augmentation is reached, induces pathophysiological changes in RLS that impair future responses to both dopaminergic and non-dopaminergic therapies. Our findings confirm previous results with gabapentin enacarbil and suggest that these changes develop well before clinical augmentation appears. Pathophysiological implications for the understanding of dopaminergic augmentation are discussed. Our results support the American Academy of Sleep Medicine (AASM) recommendation against using dopamine agonists as the initial choice for RLS treatment.

Medication management in women with bipolar disorder (BD) in the perinatal period is challenging, given that many patients taper or stop medication during pregnancy, and the postpartum period is an extremely high-risk period for relapse. The objective of this narrative review was to investigate the perinatal efficacy as well as potential adverse effects on the child of common treatments for bipolar disorder. These treatments include lithium, lamotrigine, other antiepileptics, quetiapine, olanzapine, aripiprazole, other antipsychotics, antidepressants, benzodiazepines, Z-drugs, and other sleep medication. Despite the worldwide decline in lithium use, it remains the gold standard for acute and maintenance treatment of BD, and we continue to advise its use in women of reproductive age. In contrast, medications with a high risk for teratogenicity such as valproate and carbamazepine should be avoided in women of childbearing potential. Women with bipolar disorder are at very high risk of relapse after delivery, but this risk is more than twofold lower with adequate pharmacological prophylaxis. We advise to make a written perinatal bipolar relapse prevention plan in collaboration with the patient, family, and healthcare professionals, which includes a description of: (1) maintenance treatment during pregnancy, (2) preferred mode of delivery, (3) medication immediately after delivery and the first months postpartum for relapse prevention, (4) preferred plan for feeding (breast-feeding versus bottle-feeding), (5) strategies to assist women in ensuring adequate sleep and stable circadian rhythm in the first weeks after delivery, and (6) how to recognize the first symptoms of relapse and which intervention strategies to take.

Background and objectives: Baclofen, a traditional treatment for spasticity, is gaining interest for its use in alcohol use disorder (AUD). To assist clinicians in using baclofen for effective and safe treatment of AUD, we investigated the optimal target dosage of baclofen through a systematic review and dose-response meta-analysis.

Methods: We searched Cochrane, EMBASE, MEDLINE via PubMed, PsycINFO, ClinicalTrials.gov, and the International Clinical Trials Registry Platform for randomized controlled trials on 1 and 2 April 2024. Inclusion criteria were patients aged ≥ 18 years diagnosed with AUD according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV, DSM-IV-TR, or International Classification of Diseases (ICD)-10, and treated with baclofen monotherapy. Continuous outcomes-percent days abstinent, drinks per drinking day, heavy drinking days (HDDs), craving, and anxiety-were analyzed as mean or standardized mean differences. Binary outcomes-relapse and dropout, including due to adverse events-were analyzed as odds ratios. Each outcome was assessed using the Cochrane Risk of Bias 2.0 tool. A one-stage random-effects dose-response meta-analysis was performed using restricted cubic splines with fixed knots at 10%, 50%, and 90% percentiles.

Results: A total of 14 trials (1344 patients) were included. Increasing the dose of baclofen up to 50-60 mg/day was associated with a higher percent days abstinent and reduced craving. However, a higher baclofen dose increases the risk of dropout due to adverse events. Commonly observed adverse events were drowsiness, sedation, somnolence and fatigue. Baclofen up to 50-60 mg/day did not significantly affect drinks per drinking day, HDDs, anxiety, relapse or dropout. Doses > 60 mg/day lacked reliable evaluation due to limited data and study heterogeneity.

Conclusions: Baclofen up to 50-60 mg/day may increase percent days abstinent and reduce craving, but may increase dropout due to adverse events. Clinicians should carefully consider individual patient factors when prescribing baclofen to patients with AUD.

Background: The widespread pain and muscular fatigue characteristics of fibromyalgia are believed to be mediated by central mechanisms. Low-dose naltrexone (LDN) has emerged as a new treatment option for fibromyalgia, possibly modulating central mechanisms via glial or opioid receptors.

Methods: In the randomized, placebo-controlled FINAL trial, 99 women with fibromyalgia were treated with LDN or placebo for 12 weeks. In this secondary analysis, we examined the potential effects of LDN versus placebo on changes from baseline in pain tolerance, temporal summation of pain, and conditioned pain modulation (CPM) in the complete case population (45 versus 47 participants). Measures of muscular fatigue were evaluated using the 30-s chair stand test and a shoulder abduction test.

Results: Of the five examined outcomes, only change in CPM showed a significant between-group difference with greater enhancement following LDN treatment (2.0 kPa; 95% confidence interval (CI) 0.4-3.7 kPa) compared with placebo. Within-group changes in CPM showed an increase of 1.2 kPa (95% CI 0.05-2.4 kPa) in the LDN group and a possible decrease of 0.8 kPa (95% CI - 1.9 to 0.4 kPa) in the placebo group.

Conclusions: We found a significant between-group difference in CPM change in favor of LDN. However, this difference was partly explained by a decrease in CPM in the placebo group. Sensitivity analyses showed no association between changes in CPM and clinical pain improvement, suggesting that the group-difference in CPM is a random finding.

Study registration: ClinicalTrials.gov (NCT0427877; registered on 30 January 2020).

Cenobamate (Ontozry^®) is a once-daily oral antiseizure medication (ASM) approved in the EU for the adjunctive treatment of focal-onset seizures, with or without secondary generalisation, in adults with epilepsy that have not been adequately controlled despite previous treatment with ≥ 2 anti-epileptic drugs. In clinical studies, its short-term use significantly reduced seizure frequency and was associated with significantly higher odds of achieving a ≥ 50% reduction in seizure frequency in adults with uncontrolled focal-onset seizures despite treatment with 1-3 concomitant ASMs. Seizure freedom rates were also improved. All these benefits were sustained over up to 48 months. Cenobamate was generally well tolerated across both the short- and longer-term (up to 94 months) clinical studies, with its low starting dosage (12.5 mg/day) and slow (12-week) titration schedule appearing to result in fewer severe treatment-emergent adverse events (TEAEs) during the titration period. Somnolence, dizziness and fatigue were the most frequently reported TEAEs. The effectiveness and adverse events of cenobamate in real-world studies were consistent with those seen in the clinical studies. Thus, cenobamate continues to represent a useful adjunctive treatment option in adults with uncontrolled focal-onset seizures.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a severely disabling autoimmune disease that predominantly impacts the optic nerves and spinal cord. It is often linked to immunoglobulin G (IgG) antibodies targeting the aquaporin-4 water channel (AQP4-IgG). Rituximab, which depletes CD20-positive B cells, is effective in reducing the frequency of NMOSD relapses. The objective of this retrospective, 5-year observational study was to evaluate the effectiveness and safety of rituximab in patients with AQP4-IgG-positive NMOSD.

Methods: We conducted a multicenter, retrospective study using prospectively collected data from 23 multiple sclerosis (MS) and NMOSD centers (22 in Italy, 1 in Switzerland). The study cohort included patients with AQP4-IgG-positive NMOSD who had completed rituximab induction therapy, with data collected up to May 2024. Two maintenance strategies were used-fixed 6-monthly infusions or reinfusions guided by flow cytometry-on the basis of CD19⁺ or CD27⁺ memory B-cell repopulation thresholds. Clinical outcomes included annualized relapse rate (ARR), time to first relapse (TTFR), and Expanded Disability Status Scale (EDSS) worsening, which was assessed both overall and between relapses to indirectly evaluate the possibility of inter-attack disability progression. Safety outcomes encompassed infusion-related reactions and adverse events.

Results: A total of 138 patients were analyzed. ARR significantly decreased from 1.54 (95% confidence interval (CI) 1.34-1.75) before rituximab to 0.15 (95% CI 0.12-0.19) over the 5-year follow-up. Approximately 33% of patients experienced at least one relapse during treatment, after a median time of 5.21 months. Higher pre-rituximab relapse rates were associated with shorter TTFR. Subtle increases of 0.5-1 points in EDSS between relapses were observed in one third of patients. Mild infections were common, and 21% of patients experienced infusion-related reactions. In addition, six patients developed malignancies.

Conclusions: Over 5 years, rituximab consistently reduced the incidence of relapses in patients with NMOSD, though 33% of them still experienced a relapse during this period, generally within the first 6 months of treatment. No unexpected adverse events were identified. While safety monitoring remains crucial, further studies are needed to better understand rituximab's impact on NMOSD management.

Background: Tranexamic acid (TXA) is widely used to manage acute brain injuries, including subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury. Despite its common usage, there is limited evidence on its safety in these conditions. We aimed to evaluate the impact of TXA on mortality and thromboembolic events in patients with acute brain injury.

Methods: A systematic search of MEDLINE/PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted from inception to May 2024. We included randomized controlled trials (RCTs) comparing TXA with placebo in patients aged 15 years or older with confirmed acute brain injury. Two reviewers independently assessed study quality using the revised Cochrane Risk of Bias tool and extracted data on patient demographics, intervention details, and outcomes, including mortality, thromboembolic events, and seizures. Meta-analyses were performed using random effects models.

Results: Twenty-five RCTs with 16,677 participants (8584 TXA, 8093 control) were included. The relative risk (RR) for overall mortality was 0.96 (95% confidence interval (CI) 0.91-1.03, p = 0.2433), indicating a nonsignificant difference between the groups, with no substantial heterogeneity (I² = 0% [0-45%]). Additionally, no significant differences were observed in 30-, 90-, or 180-day mortality. The RR for total thromboembolic events was 1.11 (95% CI 0.97-1.28, p = 0.1236), indicating a nonsignificant difference between the groups, with low heterogeneity (I² = 15% [0-51%]). Similarly, no significant differences were observed in the incidences of deep vein thrombosis or pulmonary embolism, ischemic stroke or transient ischemic attack, acute coronary syndrome or myocardial infarction, or seizures. However, the administration of TXA for more than 1 day was associated with a significant increase in thromboembolic events (RR 1.22, 95% CI 1.03-1.44). Administering TXA beyond 8 h of injury was also associated with a significant increase in thromboembolic events (RR 1.16, 95% CI 1.02-1.33).

Conclusions: TXA administration does not significantly affect overall mortality or increase the risk of thromboembolic events in patients with acute brain injuries. However, prolonged use or delayed administration may be associated with an increased risk of thromboembolic events. These findings highlight the need for careful consideration of the duration and timing of TXA administration in clinical practice.