Neurology and Therapy最新文献

{"title":"Use of Stiripentol in Patients with Dravet Syndrome: Common Practice Among Experts in Spain.","authors":"Juan José García-Peñas, Rocío Calvo-Medina, Adrián García-Ron, Antonio Gil-Nagel, Vicente Villanueva, Rocío Sánchez-Carpintero","doi":"10.1007/s40120-024-00677-8","DOIUrl":"https://doi.org/10.1007/s40120-024-00677-8","url":null,"abstract":"<p><strong>Background: </strong>Despite considerable evidence for the efficacy and safety of stiripentol in Dravet syndrome (DS), some aspects of stiripentol use remain challenging in clinical practice, such as dose titration and the adjustment of concomitant antiseizure medications (ASMs) to prevent potential adverse effects.</p><p><strong>Aim: </strong>To (1) provide practical recommendations on the initiation of stiripentol treatment in patients with DS, (2) evaluate its effectiveness in the patient, and (3) guide the management of drug interactions and other aspects of treatment monitoring.</p><p><strong>Methods: </strong>Six Spanish neurologists (the authors) with expertise in the management of pediatric and adult patients with DS held a meeting in early 2024 to develop expert recommendations regarding the use of stiripentol in DS, based on a review of the literature and their common clinical experience.</p><p><strong>Results: </strong>According to these recommendations, stiripentol can be administered to patients with DS of any age, although its initiation and titration vary according to age group. Individualized adjustment of concomitant ASMs, such as valproic acid and clobazam or drugs specifically for DS (i.e., fenfluramine), at initiation and during stiripentol treatment, can mitigate drug interactions, thereby increasing the long-term tolerability of stiripentol treatment. In specific cases, stiripentol doses of > 50 mg/kg/day may be contemplated, and acute stiripentol administration may be considered to control refractory status epilepticus. Blood tests should be performed before starting stiripentol, at 3, 6, and 12 months after starting treatment, and then annually, except in the event of adverse effects, when additional testing may be necessary. Most adverse effects can be adequately managed by adjusting concomitant medications.</p><p><strong>Conclusion: </strong>These practical recommendations may be easily adapted for use in different countries, and should increase physicians' confidence in the initiation and monitoring of stiripentol treatment, thus facilitating effective management of patients with DS and improving clinical outcomes.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quality of Life in Mild Cognitive Impairment and Mild Dementia Associated with Alzheimer's Disease: A Systematic Review.","authors":"Joanna Campbell, Louis Lavoie, Mariana Farraia, Rachel Huelin, Quanwu Zhang, Amir Abbas Tahami Monfared","doi":"10.1007/s40120-024-00676-9","DOIUrl":"https://doi.org/10.1007/s40120-024-00676-9","url":null,"abstract":"<p><p>Mild cognitive impairment (MCI) and Alzheimer's disease (AD) have a profound impact on patients' quality of life (QoL), with progressive declines occurring as the disease advances. This systematic review aims to summarize the published evidence on patient-reported outcomes (PROs) in individuals with MCI due to AD and mild AD dementia. Comprehensive searches were conducted across five major databases to identify studies reporting on utility values, disutilities, and QoL measures in these patient populations. A total of 23 studies were included that utilized various QoL assessment tools, including EQ-5D (n = 14), SF-36/SF-12 (n = 4), and QOL-AD (n = 11). Reported EQ-5D scores ranged from 0.81 to 0.92 for patients with MCI and from 0.67 to 0.85 for those with mild AD, indicating a noticeable decline in QoL as the disease progresses. QOL-AD scores ranged from 33.8 to 42.5 for MCI and from 32.4 to 38.1 for mild AD, equally reflecting the greater impairment in QoL with disease advancement. Interventions were generally associated with smaller declines in PROs compared to placebo, suggesting a positive impact of treatment in mitigating QoL deterioration. The findings underscore the significant QoL differences between MCI and mild AD, emphasizing the potential benefit of early intervention to preserve QoL and delay disease progression. This review highlights the importance of continued research to better understand QoL in patients with MCI and mild AD dementia, particularly in terms of capturing comprehensive patient-reported outcomes and evaluating the effectiveness of interventions over time. These findings can contribute to a more informed approach in clinical practice and support decision-making in the management of early-stage AD.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lecanemab's Path Forward: Navigating the Future of Alzheimer's Treatment in Europe Amidst the EMA's Rejection.","authors":"Alessandro Martorana, Chiara Giuseppina Bonomi, Martina Gaia Di Donna, Caterina Motta","doi":"10.1007/s40120-024-00675-w","DOIUrl":"https://doi.org/10.1007/s40120-024-00675-w","url":null,"abstract":"<p><p>Lecanemab (Leqembi^©, Biogen), a humanized anti-amyloid-beta monoclonal antibody, has been approved for early-stage Alzheimer's disease (AD) in several countries, including the US and Japan. However, the European Medicines Agency (EMA) recently issued a negative opinion on its marketing authorization, reflecting concerns over the clinical value and manageability of anti-amyloid treatments. This decision highlights the ongoing disconnect between research advancements and clinical practice, where the focus on biological markers over tangible clinical improvements remains contentious. Despite promising biological effects, lecanemab's clinical outcomes have been modest, raising questions about its therapeutic role. The EMA's refusal underscores the need to address doubts surrounding the real-world effectiveness and safety of such treatments, especially concerning amyloid-related imaging abnormalities (ARIAs), a common side effect observed in clinical trials. The recent approval of lecanemab by the UK's Medicines and Healthcare products Regulatory Agency, despite the National Institute for Health and Care Excellence's rejection on cost-effectiveness grounds, further fuels the debate on the feasibility of anti-amyloid therapies. This commentary emphasizes the importance of real-world data on lecanemab's impact on cognitive decline, daily functioning, and side-effect management. As the global clinical use of lecanemab increases, continuous and standardized reporting on its outcomes is crucial for guiding future regulatory decisions and for potentially bridging the gap between research and practice in AD treatment.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors and Reasons Associated with Hesitating to Seek Care for Migraine: Results of the OVERCOME (US) Study.","authors":"Robert E Shapiro, Eva Jolanda Muenzel, Robert A Nicholson, Anthony J Zagar, Michael L Reed, Dawn C Buse, Susan Hutchinson, Sait Ashina, Eric M Pearlman, Richard B Lipton","doi":"10.1007/s40120-024-00668-9","DOIUrl":"https://doi.org/10.1007/s40120-024-00668-9","url":null,"abstract":"<p><strong>Introduction: </strong>Despite a variety of available treatment options for migraine, many people with migraine do not seek medical care, thereby reducing opportunities for diagnosis and effective treatment and potentially leading to missed opportunities to reduce the burden of disease. Understanding why people hesitate to seek care for migraine may help healthcare professionals and advocates address barriers and improve outcomes. The aim of this study, in a large adult population sample in the United States (US), was to identify factors associated with and reasons for hesitating to seek healthcare for migraine.</p><p><strong>Methods: </strong>The web-based OVERCOME (US) survey study identified adults with active migraine in a demographically representative US sample who answered questions about hesitating to seek care from a healthcare provider for migraine and reasons for hesitating. Supervised machine learning (random forest, least absolute shrinkage and selection operator) identified factors associated with hesitation; logistic regression models assessed association of factors on hesitation.</p><p><strong>Results: </strong>The study results show that of the 58,403 participants with active migraine who completed the OVERCOME (US) baseline survey and provided responses to the question on hesitating to seek care for migraine, 45.1% (n = 26,330/58,403) with migraine indicated that they had ever hesitated to seek care for migraine. Factors most associated with hesitating to seek care were hiding migraine (odds ratio [OR] = 2.69; 95% confidence interval [CI]: 2.50, 2.89), experiencing migraine-related stigma (OR = 2.13; 95% CI 1.95, 2.33), higher migraine-related disability (OR = 1.30; 95% CI 1.23, 1.38), and higher ictal cutaneous allodynia (OR = 1.26; 95% CI 1.19, 1.35). The most common reasons participants stated for hesitating included (1) 44.2% wanting to try and take care of migraine on their own, (2) 33.8% feeling that their migraine or headache would not be taken seriously, (3) 29.2% thinking that their migraine was not serious/painful enough, and (4) 27.4% not being able to afford it or not wanting to spend the money. The main limitation of the study includes the requirement for respondents to have internet, access which may have reflected cohort bias, and the quota sampling rather than random sampling to create a demographically representative sample.</p><p><strong>Conclusions: </strong>Hesitating to seek migraine care is common and is most strongly associated with hiding the disease and migraine-related stigma. Those experiencing higher migraine-related burden are more hesitant to seek the care that might alleviate the burden. These findings suggest that migraine's social context (e.g., stigma) is a major determinant of hesitance to seek migraine care.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Characteristics and Outcomes in Patients with Ruptured Middle Cerebral Artery Aneurysms: A Multicenter Study in Northern China.","authors":"Xiuhu An, Jingliang Su, Bingxin Duan, Long Zhao, Bangyue Wang, Yan Zhao, Tianxing Li, Shuai Zhou, Xinyu Yang, Zhenbo Liu","doi":"10.1007/s40120-024-00673-y","DOIUrl":"https://doi.org/10.1007/s40120-024-00673-y","url":null,"abstract":"<p><strong>Introduction: </strong>The long-term prognosis of ruptured middle cerebral artery aneurysms (MCAAs) in northern China remains unclear. The aim of this study is to analyze the epidemiological characteristics and long-term outcomes of ruptured MCAAs in northern China.</p><p><strong>Methods: </strong>We included patients who were consecutively admitted for ruptured MCAAs to 12 tertiary care centers in northern China from January 2017 to December 2020. Kaplan‒Meier curves were used to compare survival in hazard strata. The Cox proportional hazards model was used to analyze risk factors and mortality risk, whereas logistic regression was used to identify factors influencing 2-year survival. Subgroup analyses were performed to verify the robustness of the results.</p><p><strong>Results: </strong>Data on 959 patients with ruptured MCAAs were analyzed; 16.4% of these patients had ruptured intracranial aneurysms (RIAs) and were registered in the Chinese cerebral aneurysm database. The mean follow-up duration was 3.0 years (range 0-6.2 years). The 3-month and 2-year mortality rates were 15.5% and 18.2%, respectively. The risk factors for mortality were identified via Cox regression and were as follows: age > 70 years, previous stroke, combined intracerebral hemorrhage (ICH)/intraventricular hemorrhage (IVH), poor Hunt and Hess grade, multiple aneurysms, and conservative treatment (CT). The positive association between the risk of death and CT was consistent across subgroups. According to logistic regression, hypertension, previous stroke, combined ICH/IVH, Hunt and Hess grade, and WFNS (World Federation of Neurological Surgeons) score were identified as factors negatively influencing 2-year survival.</p><p><strong>Conclusion: </strong>We detail the epidemiologic characteristics and long-term outcomes of MCAAs. The risk factors for mortality included age > 70 years, previous stroke, combined ICH/IVH, poor Hunt and Hess grade, and multiple aneurysms. Compared with microsurgical treatment (MST), CT is associated with an increased risk of mortality, while the risk of mortality associated with endovascular treatment (EVT) is not significantly different. Two-year survival was associated with hypertension, previous stroke, ICH/IVH, and poor grades at admission.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Huntington Disease Health Related Quality of Life, Function and Well Being: The Patient's Perspective.","authors":"Jesús Pérez-Pérez, Sofía García-López, Tamara Fernández Valle, Cèlia Painous, Maria Rosa Querol-Pascual, Pedro J García Ruiz, Elena Bellosta Diago, Esther Cubo Delgado, Barbara Vives Pastor, María Carmen Peiró Villaplana, Idaira Martín Santana, Marta Blázquez Estrada, Matilde Calopa Garride, Pablo Mir, Carmen Álvarez, Jorge Maurino, Anna de Prado, José Luis López-Sendón","doi":"10.1007/s40120-024-00655-0","DOIUrl":"10.1007/s40120-024-00655-0","url":null,"abstract":"<p><strong>Background: </strong>Limited information is available on patients' experience living with Huntington's disease (HD). The primary objective of this study was to assess the health-related quality of life and well being of patients with HD.</p><p><strong>Methods: </strong>A non-interventional, cross-sectional study was conducted in 17 hospitals-based movement disorders units in Spain. Patients aged ≥ 18 years, genetically HD diagnosed [with a diagnostic confidence level score of 4, and an Independence Scale (IS) score ≥ 70] were included. The primary variables were the Huntington's Disease Health-related Quality of Life (HDQLIFE) scores and results of the Satisfaction with Life Scale (SWLS). Secondary outcomes include the Unified HD Rating Scale (UHDRS), Beck Hopelessness Scale (BHS), Stigma Scale for Chronic Illness (SSCI-8), Beck Depression Inventory-Fast Screen (BDI-FS) and Problem Behaviours Assessment for HD short Version (PBA-S).</p><p><strong>Results: </strong>A total of 102 patients were included. The mean age (SD) was 53.1 (12.1) years and 56% were male. Most of the patients (99.0%) showed motor symptoms (87.3%), behavioural and psychiatric disturbances (59.8%), or cognitive impairment (20.6%). HDQLIFE domain score means (SD) includes concern with death and dying 45.97 (9.60) end-of-life planning 37.91 (8.84), and meaning and purpose 44.74 (9.05). SWLS score mean was 24.25 (7.33). Depressive symptoms were found in 37.4% of patients and moderate-to-severe feelings of hopelessness in 32.9%. The prevalence of stigma was 55.9% (n = 57).</p><p><strong>Conclusion: </strong>HD impacted quality of life, with prevalent motor, psychiatric symptoms and cognitive impairment. Patient perspectives may provide complementary information to implement specific interventions.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Effectiveness of Satralizumab in Japanese Patients with Neuromyelitis Optica Spectrum Disorder: A 6-month Interim Analysis of Post-marketing Surveillance.","authors":"Takashi Yamamura, Noriko Isobe, Izumi Kawachi, Chiyoko Nohara, Yusei Miyazaki, Minami Tomita, Takahiko Tsumuraya, Katsuhisa Yamashita, Jin Nakahara, Ichiro Nakashima, Kazuo Fujihara","doi":"10.1007/s40120-024-00640-7","DOIUrl":"10.1007/s40120-024-00640-7","url":null,"abstract":"<p><strong>Introduction: </strong>Satralizumab, an anti-interleukin-6 receptor antibody, is approved in Japan for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and is undergoing post-marketing surveillance (PMS) of clinical use. We aimed to describe the real-world safety and effectiveness of satralizumab in Japanese patients with NMOSD.</p><p><strong>Methods: </strong>This is an ongoing PMS (planned completion: February 2027). This 6-month interim analysis assessed the safety and effectiveness of satralizumab in Japanese patients with NMOSD using data collected from August 2020 to July 2021.</p><p><strong>Results: </strong>Among 570 patients who participated, 523 (91.75%) were female and the mean ± standard deviation (SD) age was 52.4 ± 14.1 years. At baseline, NMOSD expanded disability status scale mean ± SD was 4.19 ± 2.19; 490 (85.96%) patients used glucocorticoids and 277 (48.59%) patients used immunosuppressants concomitantly. Of 570 satralizumab-treated patients, 85 (14.91%) had discontinued satralizumab treatment at 6 months. For the overall adverse drug reactions (ADRs), 76.22 (66.07-87.48) events/100 person-years occurred in 118 (20.70%) patients, and infections occurred in 28 (4.91%) patients. Serious infections occurred in 18 (3.15%) patients, with an event rate of 9.05 (5.80-13.47) events/100 person-years. Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common serious infection events. One fatal ADR (septic shock) suspected to be related to satralizumab was reported. The mean ± SD glucocorticoid dose reduced from 12.28 ± 10.17 mg/day at the index date to 8.11 ± 7.30 mg/day at 6 months. The Kaplan-Meier cumulative relapse-free rate (95% confidence interval) was 94.59% (92.25-96.23) at 6 months.</p><p><strong>Conclusion: </strong>In this study, satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice. The results are consistent with those of previous clinical trials. The safety and effectiveness of satralizumab in Japanese patients with NMOSD will be analyzed over the 6-year surveillance period.</p><p><strong>Trial registration: </strong>UMIN Clinical Trials Registry, UMIN000041047.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":"1361-1383"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Analysis of White Matter Hyperintensities as a Predictor of 1-Year Risk for Ischemic Stroke Recurrence.","authors":"Yi Sun, Wenping Xia, Ran Wei, Zedong Dai, Xilin Sun, Jie Zhu, Bin Song, Hao Wang","doi":"10.1007/s40120-024-00652-3","DOIUrl":"10.1007/s40120-024-00652-3","url":null,"abstract":"<p><strong>Introduction: </strong>This study evaluates the role of quantitative characteristics of white matter hyperintensities (WMHs) in predicting the 1-year recurrence risk of ischemic stroke.</p><p><strong>Methods: </strong>We conducted a retrospective analysis of 1061 patients with ischemic stroke from January 2018 to April 2021. WMHs were automatically segmented using a cluster-based method to quantify their volume and number of clusters (NoC). Additionally, two radiologists independently rated periventricular and deep WMHs using the Fazekas scale. The cohort was divided into a training set (70%) and a testing set (30%). We employed Cox proportional hazards models to develop predictors based on quantitative WMH characteristics, Fazekas scores, and clinical factors, and compared their performance using the concordance index (C-index).</p><p><strong>Results: </strong>A total of 180 quantitative variables related to WMHs were extracted. A higher NoC in deep white matter and brainstem, advanced age (> 90 years old), specific stroke subtypes, and absence of discharge antiplatelets showed stronger associations with the risk of ischemic stroke recurrence within 1 year. The nomogram incorporating quantitative WMHs data showed superior discrimination compared to those based on the Fazekas scale or clinical factors alone, with C-index values of 0.709 versus 0.647 and 0.648, respectively, in the testing set. Notably, a combined model including both WMHs and clinical factors achieved the highest predictive accuracy, with a C-index of 0.735 in the testing set.</p><p><strong>Conclusion: </strong>Quantitative assessment of WMHs provides a valuable neuro-imaging tool for enhancing the prediction of ischemic stroke recurrence risk.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":"1467-1482"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of Nusinersen in Adolescents and Adults with Spinal Muscular Atrophy: Systematic Review and Meta-analysis.","authors":"Tim Hagenacker, Lorenzo Maggi, Giorgia Coratti, Bora Youn, Stephanie Raynaud, Angela D Paradis, Eugenio Mercuri","doi":"10.1007/s40120-024-00653-2","DOIUrl":"10.1007/s40120-024-00653-2","url":null,"abstract":"<p><strong>Introduction: </strong>Nusinersen clinical trials have limited data on adolescents and adults with 5q-associated spinal muscular atrophy (SMA). We conducted a systematic literature review (SLR) and meta-analysis to assess effectiveness of nusinersen in adolescents and adults with SMA in clinical practice.</p><p><strong>Methods: </strong>Our search included papers published 12/23/2016 through 07/01/2022 with ≥ 5 individuals ≥ 13 years of age and with ≥ 6 months' data on ≥ 1 selected motor function outcomes [Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), and Six-Minute Walk Test (6MWT)]. For meta-analysis, effect sizes were pooled using random-effects models. To understand treatment effects by disease severity, subgroup meta-analysis by SMA type and ambulatory status was conducted.</p><p><strong>Results: </strong>Fourteen publications including 539 patients followed up to 24 months met inclusion criteria for the SLR. Patients were age 13-72 years and most (99%) had SMA Type II or III. Modest improvement or stability in motor function was consistently observed at the group level. Significant mean increases from baseline were observed in HFMSE [2.3 points (95% CI 1.3-3.3)] with 32.1% (21.7-44.6) of patients demonstrating a clinically meaningful increase (≥ 3 points) at 18 months. Significant increases in RULM were consistently found, with a mean increase of 1.1 points (0.7-1.4) and 38.3% (30.3-47.1) showing a clinically meaningful improvement (≥ 2 points) at 14 months. Among ambulatory patients, there was a significant increase in mean 6MWT distance of 25.0 m (8.9-41.2) with 50.9% (33.4-68.2) demonstrating a clinically meaningful improvement (≥ 30 m) at 14 months. The increases in HFMSE were greater for less severely affected patients, whereas more severely affected patients showed greater improvement in RULM.</p><p><strong>Conclusions: </strong>Findings provide consolidated evidence that nusinersen is effective in improving or stabilizing motor function in many adolescents and adults with a broad spectrum of SMA.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":"1483-1504"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic Modeling and Simulation for Dose Optimization of GB-5001, a Long-Acting Intramuscular Injection of Donepezil, in Healthy Participants.","authors":"Juyoung Khwarg, Heeyong Lee, Kyung-Sang Yu, Eunyoung Seol, Jae-Yong Chung","doi":"10.1007/s40120-024-00643-4","DOIUrl":"10.1007/s40120-024-00643-4","url":null,"abstract":"<p><strong>Introduction: </strong>GB-5001 is an intramuscular (IM) formulation of donepezil under development for the treatment of Alzheimer's disease. The objective of this study was to develop a population pharmacokinetic (PK) model for donepezil in both IM and oral formulations, and to optimize the IM dosage of GB-5001 using bioequivalence (BE) simulation.</p><p><strong>Methods: </strong>A population PK model of donepezil was developed using NONMEM. It was based on plasma concentration data from a Phase 1 dose escalation study, which involved a single administration of donepezil IM formulation at doses of 70, 140, and 280 mg, and the oral formulation at 10 mg. The model was evaluated based on goodness-of-fit plots, conditional weighted residuals, visual predictive checks, and bootstrapping. BE simulations were conducted using a parallel design between various doses of the IM formulation and the 10-mg dose of oral formulation.</p><p><strong>Results: </strong>The PKs of donepezil were best described by a two-compartment model, which incorporated distinct absorption compartments for the IM (dual first-order absorption and simultaneous zero-order absorption with lag time) and oral (first-order absorption with lag time) formulations. Based on the simulation results, an IM dosage range of 210-215 mg in a sample size of over 92 was estimated to achieve a success rate of approximately 80% for BE.</p><p><strong>Conclusion: </strong>The population PK model well explained the PKs of donepezil following administration of both the IM and oral formulations. This model could be applied for the design and dose selection of future BE trials.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier, NCT05525780.</p>","PeriodicalId":19216,"journal":{"name":"Neurology and Therapy","volume":" ","pages":"1453-1466"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}