CNS drugs最新文献

Background: Huntington's disease (HD) is a rare, fatal, chronic progressive neurodegenerative disorder with a significant unmet medical need for effective treatments. Pridopidine is a novel, first-in-class, highly selective and potent sigma-1 receptor (S1R) agonist in development for HD. Pridopidine has been extensively studied in adult HD across the full spectrum of disease severity and age ranges, and its safety profile has been characterized in approximately 1600 participants across multiple studies and a broad range of doses. The specific objective of this study was to gain an in-depth understanding of pridopidine's safety profile at the recommended human dose of 45 mg twice daily (bid) in patients with HD.

Methods: An integrated safety analysis of pooled data from 1067 patients with HD enrolled in four double-blind, placebo-controlled studies was performed. The safety profile of pridopidine was compared with placebo.

Results: Pridopidine was found to be generally safe and well tolerated with an adverse event (AE) profile comparable to that of placebo. Moreover, there were no significant differences observed in the safety profile of pridopidine compared with placebo when analyzed by age, sex, baseline total functional capacity (TFC), cytosine-adenine-guanine (CAG) repeat length, use of antidopaminergic medications (ADMs), and region.

Conclusions: The integrated analysis replicated and corroborated the good safety profile observed in the individual studies. Despite the larger sample size, no new safety signals emerged. Long-term exposure to pridopidine, up to 6.5 years in open-label extension studies, revealed no new safety concerns, supporting its potential for long-term use in patients with HD.

BACKGROUND AND OBJECTIVES: Intensive or conventional antihypertensive treatment for acute intracerebral hemorrhage is still controversial. This study aimed to compare those antihypertensive regimens and analyze the efficacy of antihypertensive drugs.

Methods: Retrieval was conducted through four databases. Meta-analysis and Bayesian network meta-analysis were performed to evaluate the safety of antihypertensive treatments and the efficacy of antihypertensive drugs.

Results: A total of 9271 patients were included. Intensive strategy showed an advantage in 24-h hematoma enlargement (relative risk, RR = 0.76; 95% confidence intervals, CI = 0.67-0.87; P < 0.0001) and 90-day intracranial rebleeding (RR = 0.71, 95% CI = 0.52-0.96, P = 0.03) compared with conventional strategy. Meanwhile, the 90-day renal insufficiency (RR = 2.31, 95% CI = 1.05-5.05, P = 0.04) and renal failure (RR = 2.42, 95% CI = 1.20-4.86, P = 0.01) were increased. When cerebral hematoma volume was less than 15 ml, intensive strategy had a protective effect on 24-h hematoma enlargement (RR = 0.77, 95% CI = 0.67-0.89, P = 0.0003), but it increased 90-day renal failure (RR = 2.33, 95% CI = 1.07-5.04, P = 0.03). For the volume greater than 15 ml, it enhanced 90-day functional independence (RR = 0.78, 95% CI = 0.65-0.94, P = 0.01) and decreased intracranial rebleeding (RR = 0.68, 95% CI = 0.49-0.94, P = 0.02). Labetalol was the best, with the mortality risk probability of 0.09 and the surface under the cumulative ranking curve of 0.33.

Conclusions: This meta-analysis suggests that for intracerebral hematoma volume greater than 15 ml, intensive antihypertensive treatment can improve functional independence and reduce intracranial bleeding. Labetalol has the best effect among the four antihypertensive regimens studied.

Background: A growing body of evidence supports the effectiveness of cenobamate (CNB). This study aimed to assess the clinical response to add-on CNB through a time-to-event approach and explore the potential contribution of the concomitant classes of antiseizure medications (ASMs) to improve CNB clinical use.

Patients and methods: This study is a subgroup analysis of a larger retrospective, multicenter study on adults with focal-onset seizures participating in the Italian Expanded Access Program at five pre-established centers. The primary endpoint was the time-to-baseline seizure count; secondary endpoints included the rates of seizure response, seizure freedom (defined as no seizures' occurrence since at least the previous follow-up visit), treatment discontinuation, and adverse events (AEs).

Results: Data on 92 participants were extracted, with a median age of 44 (first quartile (Q₁)-third quartile (Q₃): 29.25-50.75) years. The number of seizures recorded during the 90-day baseline was reached by 59/92 (64.1%) subjects during the 12-month follow-up. A higher, but not statistically significant probability of reaching the baseline seizures count was shown in the subgroups of subjects taking CNB with sodium channel blockers (SCBs) (hazard ratio [HR] 2.75; 95% confidence interval [CI] 0.79-9.61, p = 0.112) and both SCBs and GABAergics (HR 1.48; 95% CI 0.43-5.09, p = 0.536) compared with subjects taking GABAergics without SCBs. At 12 months, the rates of seizure response, seizure-freedom, and treatment discontinuation were 42.0%, 13.6%, and 23.9%, respectively. A total of 47/92 (51.1%) subjects experienced AEs (mainly somnolence, dizziness, and balance disorders) at a median time of 61 (Q₁-Q₃: 30-101) days. There was a higher, but not statistically significant risk of AEs occurrence in subjects treated with both SCBs and GABAergics and in those taking SCBs without GABAergics (HR 2.24; 95% CI 0.51-9.82, p = 0.286 and HR 1.40; 95% CI 0.31-6.39, p = 0.661, respectively) compared with those taking GABAergics without SCBs. The main limitations are the retrospective design and the small sample size.

Conclusions: This time-to-event analysis added new insights to the currently available evidence about the real-world effectiveness of add-on CNB. Explorative estimates suggested favorable trends for subjects treated with concomitant GABAergics and without SCBs, who seemed to reach baseline seizure count and experience AEs less frequently and later than subjects treated with other concomitant ASMs. Further studies are needed to identify the best combinations of CNB with other ASMs to maximize seizure control and tolerability.

Attention deficit hyperactivity disorder (ADHD) is notably overrepresented in substance use treatment centers, with an estimated prevalence of 21-23% when screening practices are implemented. Many adults in these settings receive an ADHD diagnosis for the first time, highlighting the frequent underdiagnosis of ADHD among individuals seeking treatment for alcohol and substance use issues. Additionally, those entering treatment programs represent only a small fraction of the broader population with problematic alcohol use. This review explores the research on the prevalence and treatment of co-occurring ADHD and substance use disorders (SUD), with a particular emphasis on alcohol use disorders (AUD) as the most common SUD. It also provides clinical guidelines for the screening and diagnosis of ADHD in patients with active alcohol and substance use and offers recommendations to enhance screening practices and improve access to treatment for individuals with co-occurring ADHD and AUD.

Traumatic brain injury (TBI) is a prevalent cause of morbidity and mortality worldwide. A focus on neuroprotective agents to prevent the secondary injury cascade that follows moderate-to-severe TBI has informed the field greatly but has not yielded any viable therapeutic options to date. New strategies and pharmacotherapy options for neuroprotection continue to be evaluated, including tranexamic acid, progesterone, cerebrolysin, cyclosporin A, citicholine, memantine, and lactate. Biomarkers of injury that can aid in diagnosis and prognosis have also been elucidated and are incrementally being used in clinical practice. The spectrum of TBI severity has also gained increasing attention as it relates to mild TBI or concussion, blast injury, and subacute or chronic subdural hematomas. In this review, we review the pathophysiology, recent clinical trials, and future directions for acute TBI.

Background: Opioid prescribing to injured workers has increased despite evidence demonstrating that risks often outweigh the benefits. High-risk prescribing and persistent opioid use are often associated with harm. However, there are limited data on what predicts early high-risk and persistent opioid prescribing in Australian workers with back and neck-related injuries or disorders.

Objective: The purpose of this study was to determine the prevalence and identify determinants of early high-risk and persistent opioid prescribing in Australian workers with back and neck conditions.

Methods: A retrospective cohort study was carried out with injured workers with workers' compensation claims for back and neck conditions who filled at least one opioid prescription within the first 90 days after injury from 1 January 2010 to 31 December 2019. High-risk opioid prescribing practices in the first 90 days were measured using one of four indicators of risk (high-total opioid volume on first dispensing occasion-exceeding 350 mg oral morphine equivalent in the first week, average high-dose over 90 days-higher than 50 mg oral morphine equivalent, early supply with long-acting opioids, and concurrent psychotropic prescriptions). Persistent opioid use was determined using group-based trajectory modeling over the subsequent 1-year. Multivariable logistic regression was used to identify predictors of high-risk opioid prescribing in the first 90 days and persistent opioid use in the subsequent year.

Results: A total of 6278 injured workers prescribed opioids were included. At least one indicator of high-risk opioid prescribing was identified in 67.1% of the sample in the first 3 months. Persistent opioid use was identified in 22.8% of the sample over the subsequent year. Early high-risk opioid prescribing was associated with double the odds of persistent use (aOR 2.19, 95% CI 1.89-2.53). Injured workers residing in rural areas (inner regional and outer regional/remote Australia) had higher odds of high-risk prescribing (aOR 1.26, 95% CI 1.11-1.44) and (aOR 1.43, 95% CI 1.10-1.87), respectively, compared with those in major cities. Similarly, workers residing in areas with most disadvantaged and advantaged socioeconomic quintile had higher (aOR 1.18, 95% CI 1.01-1.39) and lower (aOR 0.68, 95% CI 0.56-0.82) odds of persistent opioid use, respectively, compared with those in the middle socioeconomic quintiles.

Conclusions: A total of two-thirds of injured workers receiving opioids in the first 90 days show evidence of high-risk prescribing, with nearly one-quarter exhibiting persistent opioid use over the subsequent year. Early high-risk opioid prescribing doubles the odds of opioid persistence. There is a need for further research and careful scrutiny of opioid prescribing in this population.

Background: Opioids are prescribed for postsurgical pain management, but a balance between achieving adequate pain control and minimising opioid-related harm is required. This study aimed to investigate the effectiveness of different opioid regimens, in daily dose or treatment duration, prescribed at surgical discharge.

Methods: A systematic search of MEDLINE, EMBASE, CENTRAL, and ICTRP was performed from inception to 12 January 2025. Randomised controlled trials (RCTs) and non-RCTs comparing different daily doses or treatment durations of opioid analgesics were included. All surgeries were included, except those related to cancer treatment or palliative care. Eligible populations were adults (≥ 18 years) or individuals classified as adults according to the criteria of the respective studies. Data were extracted at immediate-term (≤ 3 days), short-term (> 3 to ≤ 7 days), medium-term (> 7 to ≤ 30 days), and long-term (> 30 days). Data from RCTs were pooled using a random-effects model. Risk of bias was assessed. Certainty of evidence from RCTs was evaluated with Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). The primary outcome was pain intensity. Adverse events were also measured.

Results: A total of 8432 records were identified. In total, 12 RCTs with 7128 patients and 24 non-RCTs with 118,849 patients were included. Studies included orthopaedic, gynaecology and obstetric surgeries, ranging from minor to major procedures. Higher-doses of opioids were more effective than lower-doses in reducing immediate pain intensity (mean difference (MD) 4.36, 95% confidence interval (CI) 0.50-8.23, n = 364, three studies, I² = 0%, high certainty). No difference in pain was found between higher-doses and lower-doses at other time points (moderate to high certainty). Longer-durations of opioid treatment showed no difference in pain at any time point (low to moderate certainty). More adverse events were reported with higher doses of opioids.

Conclusions: Higher-dose opioids provide a slight reduction in immediate post-discharge pain intensity but may lead to more adverse events. Longer durations of opioid treatment are probably not more effective in reducing pain than shorter treatment durations. Our findings suggest that clinicians may choose to prescribe lower doses of opioids or shorter durations of opioids without compromising pain control, even for major surgery.

Trauma is prevalent, with lifetime estimates of traumatic exposure ranging from 70% for a single event to 31% for multiple events. While many recover, a subset develop post-traumatic stress disorder (PTSD), a debilitating condition characterized by distressing memories, avoidance behaviors, hyperarousal, and mood disturbances. The National Comorbidity Survey reports a lifetime PTSD prevalence of 6.8%, with higher rates among women and veterans. PTSD is strongly associated with suicidality, depression, and substance use, and its chronic nature can cause significant functional impairment. Despite extensive research, only two US Food and Drug Administration (FDA)-approved medications, the selective serotonin reuptake inhibitors paroxetine and sertraline, are available for PTSD. Psychotherapy, including trauma-focused cognitive behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing (EMDR), has shown efficacy. Recent interest has grown in using psychedelics and entactogens such as 3,4-methylenedioxymethamphetamine (MDMA) for PTSD. Early-phase clinical trials of MDMA-assisted therapy (MDMA-AT) showed promising results, leading the FDA to grant breakthrough therapy status to MDMA-AT in 2017. Phase 3 randomized controlled trials demonstrated significant reductions in PTSD symptoms, with nearly 70% of participants no longer meeting diagnostic criteria. However, in 2024, the FDA voted against MDMA approval, citing concerns about trial design (including blinding failure and lack of certain safety assessments including QT prolongation and abuse liability assessments), as well as concerns about allegations of potential misconduct. Ongoing research must address key challenges, including blinding, long-term safety, and variability in psychotherapy, to better understand the therapeutic potential of MDMA in PTSD treatment. The FDA's recent guidance on psychedelic trials provides a framework for future research. The objective of this article is to explore the potential of MDMA-AT in PTSD treatment, evaluate regulatory challenges following the FDA's recent decision, and highlight the need for ongoing research to address safety, efficacy, and therapeutic implementation.