背景:α-突触核蛋白病是无法治愈的神经退行性疾病。Abelson酪氨酸激酶抑制剂(AblTKIs)可以是疾病改善疗法。本系统综述,荟萃分析,和meta回归评估了AblTKIs在治疗中的使用。
方法:我们搜索了PubMed,Embase,和Cochrane数据库,用于在帕金森病和路易体痴呆患者中使用AblTKIs进行试验,直到2023年7月为止。结果是MDS-UPDRS-III(运动障碍协会赞助的统一帕金森病评定量表III修订)的变化。DerSimonian-Laird随机效应模型用于计算合并效应估计值。采用留一林地块进行敏感性分析,并进行meta回归(限制性最大似然).
结果:纳入5项研究(197例患者)。尼洛替尼300mg的效应量为-1.154(95%置信区间[CI],-3.000至0.692)。尼洛替尼150mg和博舒替尼100mg与安慰剂相比产生0.82(95%CI,-3.76至5.41)。敏感性分析显示,1项试验改变了尼洛替尼300mg单臂分析的意义(MD=-1.723;95%CI,-2.178至-1.268)。Meta回归显示,较低的年龄(EC=-0.9103,SE=0.2286,P<0.0001)和较高的基线MDS-UPDRS-III评分(EC=0.1210,SE=0.0168,P<0.0001)可以解释尼洛替尼300mg的无效性。
结论:尼洛替尼(300mg)经敏感性分析证明有效,与低剂量和博舒替尼治疗帕金森病/路易体痴呆不同。AblTKIs在年轻人中显示出疗效降低,更多受损患者,这表明需要对患有早期但发病较晚的疾病的患者进行更高效的药物进一步测试。
BACKGROUND: Alpha-synucleinopathies are incurable neurodegenerative diseases. Abelson tyrosine kinase inhibitors (Abl TKIs) may be disease-modifying therapies. This systematic
review, meta-analysis, and meta-regression evaluated the use of Abl TKIs in their treatment.
METHODS: We searched PubMed, Embase, and Cochrane databases for trials using Abl TKIs in patients with Parkinson\'s disease and Lewy body dementia published until July 2023. The outcome was the change in the MDS-UPDRS-III (Movement Disorder Society-Sponsored Revision of the Unified Parkinson\'s Disease Rating Scale III). DerSimonian-Laird random-effects model was used to calculate the pooled effect estimates. Leave-one-out forest plots were used for the sensitivity analysis, and meta-regression (restricted maximum likelihood) was performed.
RESULTS: Five studies (197 patients) were included. Nilotinib 300 mg had an effect size of -1.154 (95% confidence interval [CI], -3.000 to 0.692). Nilotinib 150 mg and bosutinib 100 mg versus placebo yielded 0.82 (95% CI, -3.76 to 5.41). Sensitivity analysis showed that 1 trial changed the significance of the nilotinib 300 mg single-arm analysis (MD = -1.723; 95% CI, -2.178 to -1.268). Meta-regression revealed that lower age (EC = -0.9103, SE = 0.2286, P < 0.0001) and higher baseline MDS-UPDRS-III scores (EC = 0.1210, SE = 0.0168, P < 0.0001) could explain the inefficacy of nilotinib 300 mg.
CONCLUSIONS: Nilotinib (300 mg) proved effective postsensitivity analysis, unlike lower doses and bosutinib in Parkinson\'s disease/Lewy body dementia. Abl TKIs showed reduced efficacy in younger, more impaired patients, indicating the need for further testing with higher-potency drugs in patients who have diseases that are in the early stage but with a later onset.