CNS drugs最新文献

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a cornerstone therapy for type 2 diabetes mellitus (T2DM) and heart failure, are emerging as a promising therapeutic class for the management of ischemic stroke (IS). Given that T2DM is a significant risk factor for IS, understanding the potential neuroprotective role of SGLT2i is of paramount clinical importance. This review provides a systematic and logically structured synthesis of the current evidence, beginning with foundational preclinical studies in animal models that consistently demonstrate a reduction in infarct volume and improved neurological outcomes. We then transition to the extensive clinical evidence, primarily from large-scale real-world observational studies, that has confirmed a significant reduction in stroke risk, particularly in high-risk T2DM populations. The strengths and limitations of this evidence base are critically appraised, highlighting the robustness of the findings while acknowledging the predominantly observational nature of the data and the lack of stroke-specific primary endpoints in major trials. The neuroprotective benefits of SGLT2i appear to be multifactorial; this review delves into the potential mechanisms, emphasizing a foundational, glucose-dependent pathway of ameliorating hyperglycemia-induced neurotoxicity, which is complemented by a suite of pleiotropic, glucose-independent effects, including the induction of mild ketosis, attenuation of neuroinflammation, and preservation of the neurovascular unit. Finally, we address the key clinical challenges to their application, such as the management of euglycemic ketoacidosis, and outline crucial directions for future research, underscoring the need for dedicated randomized trials.

The development of new and effective anticancer drugs remains a significant challenge owing to several factors, including the nonspecific nature of conventional therapies, the tendency of cancer cells to develop multidrug resistance, and the difficulty drugs face in crossing specialized barriers such as the blood-brain barrier (BBB) for cancers affecting the central nervous system (CNS). Repurposing existing, approved drugs for new therapeutic uses presents a promising approach to addressing these challenges at lower costs and in shorter time frames. Sigma receptors, particularly sigma-1, are widely distributed in the CNS and have garnered attention in neurodegeneration and pain research. Despite being overexpressed in many cancers, their potential role in cancer treatment has been largely overlooked. Sigma receptors are appealing therapeutic targets because they regulate cell survival, proliferation, and differentiation. Growing evidence links the sigma-1 receptor to the regulation of autophagy, a critical process in cancer development. Several neuroactive drugs, including haloperidol, rimcazole, fluoxetine, and donepezil, act as sigma receptor ligands and may offer anticancer benefits. This review explores the potential of these drugs for treating cancers, particularly those of the CNS, by examining their autophagic, anticancer, and sigma-receptor activities.

An extended-release once-daily oral capsule formulation of viloxazine (viloxazine ER; Qelbree^®), a norepinephrine reuptake inhibitor and serotonin receptor modulator, has been approved in the USA for the treatment of attention-deficit/hyperactivity disorder (ADHD) in paediatric patients and adults. This article reviews its use in adults with ADHD, with a brief overview of its pharmacological properties. In a randomized, double-blind, placebo-controlled, 6-week phase 3 trial, viloxazine ER significantly reduced the symptoms and severity of ADHD in adults, and improved executive function. Improvements were observed within 2-3 weeks and were sustained with continued treatment for over 24 months. Viloxazine ER was generally well tolerated in adults, with insomnia and headache being the most common adverse reactions. It has an acceptable safety profile, with no clinically significant cardiovascular or hepatic adverse effects. Current evidence supports viloxazine ER as a valuable addition to the therapeutic options available for adults with ADHD.

Acute ischemic stroke (AIS) remains a leading cause of mortality and long-term disability globally, with survivors at high risk of recurrent stroke, cardiovascular events, and post-stroke dementia. Statins, while widely used for their lipid-lowering effects, also possess pleiotropic properties, including anti-inflammatory, endothelial-stabilizing, and neuroprotective actions, which may offer added benefit in AIS management. This article synthesizes emerging evidence on statins' dual mechanisms of action and evaluates their role in reducing recurrence, improving survival, and mitigating cognitive decline. Key challenges limiting the full therapeutic potential of statins include interindividual variability in response and pharmacogenomic and biomarker-related resistance, inconsistencies across clinical guidelines, and limited central nervous system bioavailability. Innovations such as pharmacogenomic-guided therapy, pleiotropy-linked biomarkers, and advanced drug delivery systems (e.g., nanoparticle and intranasal formulations) may help overcome these barriers. Combination strategies with agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors, and targeted interventions against neuroinflammatory resistance, show promise in enhancing treatment efficacy. In doing so, we propose a shift from conventional statin use to a precision medicine paradigm that can better serve AIS survivors, especially those at risk of post-stroke dementia or those living in resource-constrained settings. While such innovations, for example, genetic testing and novel delivery methods, may not yet be feasible in all contexts, particularly low-resource environments, they represent long-term goals for equity-driven innovation. Equity in access to high-intensity statins and novel therapies remains a global priority, particularly in low- and middle-income countries. Future research should prioritize personalized, biomarker-driven approaches and inclusive clinical trials to optimize statin use across diverse AIS populations. By advancing these strategies, statins can evolve from cardiovascular agents into integral components of precision neurovascular medicine, improving long-term outcomes and quality of life for stroke survivors.

Background: TV-46000 is a long-acting subcutaneous injectable formulation of risperidone approved for treatment of schizophrenia in adults. The aim of this post hoc safety analysis of the phase 3 TV-46000 RISE (NCT03503318) and SHINE (NCT03893825) studies was to examine specific adverse events (AEs) of interest related to second-generation antipsychotic use in participants receiving TV-46000.

Methods: In RISE, participants with schizophrenia who underwent stabilization on oral risperidone were randomized to TV-46000 once monthly (q1m; dose range 50-125 mg) or once every 2 months (q2m; 100-250 mg) or placebo. In SHINE, newly recruited participants and those who completed the RISE study without relapse (rollover) received TV-46000 q1m or q2m. AEs, laboratory tests, vital signs, electrocardiogram, physical examination, and safety/tolerability assessments were recorded. This post hoc analysis evaluated specific antipsychotic-related AEs of interest and assessments related to affective, behavioral, neuromotor, endocrine, sexual/reproductive, and cardiometabolic safety and tolerability.

Results: In the two phase 3 studies, a total of 653 participants with schizophrenia were randomized to treatment, with 181 participants randomized to placebo in RISE (55 of whom were subsequently randomized to TV-46000 q1m or q2m in SHINE), 363 participants randomized to TV-46000 q1m or q2m in RISE, and 109 de novo participants randomized to TV-46000 q1m or q2m in SHINE. Among the groups in the RISE and SHINE studies, affective and behavioral AEs that occurred in ≥ 2% of participants were schizophrenia, anxiety, psychotic disorder, and depression; all occurred in ≤ 4% of participants in any group. The most common central nervous system or neuromotor AEs were headache (range, 0-6%), insomnia (< 1-6%), akathisia (< 1-4%), extrapyramidal disorder (0-4%), dizziness (0-4%), and somnolence (< 1-4%). Common metabolic-related AEs were weight increase (1-6%), increased appetite (0-3%), and hyperglycemia (0-4%). No cardiovascular AEs occurred in ≥ 2% of participants in any group. No clinically meaningful trends were observed in the results of safety assessments and AEs associated with second-generation antipsychotic use, with the exception of an increase in prolactin levels.

Conclusions: The safety profile of TV-46000 is favorable and consistent with other currently approved oral and long-acting injectable risperidone formulations.

Registration: ClinicalTrials.gov, NCT03503318, 18 April 2018; and NCT03893825; 27 March 2019.

Background and objective: Viloxazine ER (extended-release capsules; Qelbree^®) is a nonstimulant medication that has been approved by the United States Food and Drug Administration (FDA) for treatment of pediatric and adult attention-deficit/hyperactivity disorder (ADHD). This phase 3, open-label extension (OLE) trial evaluated the long-term safety and efficacy of viloxazine ER in children and adolescents with ADHD.

Methods: Participants completing the phase 2 or one of the four phase 3 double-blind, placebo-controlled clinical trials were eligible for the OLE trial. Upon entering the OLE, double-blind treatment was discontinued and participants were administered viloxazine ER 100 mg/day (children, aged 6-11 years) or 200 mg/day, (adolescents, aged 12-18 years), with dosage titration as needed over a 12-week dose-optimization period (up to 400 mg/day [children] or 600 mg/day [adolescents]). Participants then entered a maintenance period that continued through US FDA-approval (up to 72 months). Safety (primary objective) was assessed relative to OLE baseline using adverse event (AE), clinical laboratory tests, vital sign, ECG, and Columbia Suicide Severity-Rating Scale (C-SSRS) monitoring. Efficacy was assessed relative to double-blind baseline using the ADHD Rating Scale (ADHD-RS-IV/5) and the Clinical Global Impression-Improvement (CGI-I) scale. Study visits for these assessments occurred every ~ 3 months throughout maintenance treatment.

Results: Participants (N = 1100) included 646 children and 454 adolescents (66.5% male/33.5% female). Median (range) exposure to viloxazine ER in the OLE was 260 (1-1896) days, and the median modal (most frequently used) viloxazine ER doses were 300 mg/day for children and 400 mg/day for adolescents. AEs included (≥ 5% incidence) nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%), decreased appetite (6.0%), and fatigue (5.7%). AEs were mostly mild or moderate in severity (3.9% reported any severe AE); AEs led to discontinuation in 8.2% of participants. The mean ± SD changes from double-blind baseline in ADHD-RS IV/5 total score were -24.3 ± 12.0 at Month 3, -26.1 ± 11.5 at Month 12, and -22.4 ± 13.6 at participants' last OLE study visit.

Conclusions: The results of this large-scale safety trial support the long-term use of viloxazine ER as a generally well-tolerated and effective treatment option for pediatric ADHD. No new safety concerns emerged, and efficacy results suggest the potential for continued improvement over that seen during double-blind treatment.

Clinical trial registration: Clinicaltrials.gov identifier: NCT02736656.

Objective: To characterize multinational trends and patterns of opioid analgesic prescribing by sex and age.

Design, setting, and participants: We studied opioid analgesic prescribing from 2001 to 2019 with common protocol using population-based databases from eighteen countries and one special administrative region.

Main outcome measures: We measured opioid prescribing by geographical region, sex and age, estimating annual prevalent, incident, and nonincident opioid prescribing per 100 population with a 95% confidence interval (CI) and meta-analyzed the multinational and regional opioid prescribing with a random-effects model. Time trends were reported through average annual absolute changes, estimated using linear mixed models. We further explored the effect of sex and age on prevalent opioid prescribing in the multivariable analysis.

Results: Over 248 million individuals were included. Pooled multinational opioid prescribing prevalence was 9.0% amongst included countries/regions. Opioid prescribing prevalence in 2015 ranged from 2.7% in Japan to 19.7% in Iceland. Average annual absolute changes in opioid prescribing prevalence per year ranged from - 1.53% (95% CI - 2.06, - 1.00; United States Medicaid) to + 1.24% (95% CI 1.02, 1.46; South Korea). Pooled multinational incident opioid prescribing (4.9%; 95% CI 4.1, 5.9) was higher than pooled multinational nonincident opioid prescribing (3.7%; 95% CI 2.9, 4.8). The female sex and older age were associated with higher opioid prescribing. Main limitations of this study include the absence of data from study duration or individuals not covered by the data sources and the lack of information on medication adherence and indication.

Conclusions: Opioid prescribing remains unbalanced across geographical regions; however, results suggest a tendency to convergence across countries/regions. Differences in opioid prescribing by sex and age were identified.

Advances in pulmonary (PM) drug delivery through inhalation devices have enabled effective treatments for acute exacerbations of central nervous system (CNS) episodes, addressing previously unmet medical needs. While PM formulations of loxapine and levodopa are approved for agitation and off periods in Parkinson's disease (PD), respectively, there remains an unmet need for rapid-acting therapies for other acute exacerbations of neurologic disorders. In this review, the potential of PM delivery to address this gap in the management of acute CNS disorders is critically assessed, focusing on Staccato^® loxapine for agitation, Inbrija^® (levodopa) for PD, the investigational drug inhaler device Staccato^® alprazolam for epilepsy, and other investigational drug inhaler devices. PM delivery benefits from bypassing first-pass metabolism, utilizing inhalation devices to enable rapid drug delivery to the densely perfused alveolar space, arterial bloodstream, and brain. However, challenges include lung tissue sensitivity, low dose volume (compared with oral and intravenous administration), and difficulties with administration during certain acute episodes. Pharmacokinetic, efficacy, and safety data from approved or investigational PM therapies for agitation, PD, epilepsy, migraine, and insomnia present inhalation as a promising option for patients requiring acute episode management by facilitating fast absorption and onset of action and generally good tolerability. In particular, for epilepsy, on-demand medication that may be administered by patients or caregivers early at seizure onset may translate to improved patient outcomes. To enhance PM management of acute exacerbations of CNS disorders, further research and user training for optimal PM administration are required.