CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis
CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis
复制标题
遗传性 ATTR 淀粉样变性患者的脑脊液/血浆水平、转甲状腺素蛋白稳定性和多剂量托卡朋的安全性
DOI：
10.1080/13506129.2022.2056011
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发表时间：
2022
期刊：
影响因子：
5.5
通讯作者：
Sekijima Yoshiki
中科院分区：
文献类型：
--
作者：
Takahashi Yusuke;Ohashi Nobuhiko;Takasone Ken;Yoshinaga Tsuneaki;Yazaki Masahide;Roberts Michael;Glidden Paul F.;Sekijima Yoshiki
目的探讨托卡朋对遗传性转甲状腺素蛋白（ATTRv）淀粉样变性患者脑脊液（CSF）转甲状腺素蛋白（TTR）四聚体稳定性的影响。方法共纳入9例患者（3名男性，50.3±14.4岁）。三名患者有中枢神经系统（CNS）受累。患者被分配接受托卡朋300毫克/天或600毫克/天，持续7天。在基线和最终托卡朋剂量后 2 小时收集血浆和脑脊液。结果 托卡朋使用 7 天后，平均脑脊液托卡朋和 3-O-甲基托卡朋 (3-OMT) 浓度分别为 39.4±36.3 ng/mL 和 26.0±4.9 ng/mL。剂量。在有或没有中枢神经系统症状的患者的脑脊液中检测到托卡朋和 3-OMT。 CSF 中的平均总研究药物（托卡朋 + 3-OMT）与 TTR 摩尔比为 1.15±0.59。在半变性条件下，口服托卡朋显着增加了脑脊液 TTR 浓度并降低了单体含量。 6 名患者报告了 8 项不良事件 (AE)。所有 AE 的严重程度均较轻且已得到缓解。结论托卡朋能够穿过血脑屏障，凸显其减少 ATTRv 淀粉样变性中枢神经系统表现的潜力。 ATTRv 淀粉样变性患者对托卡朋的耐受性良好。
PurposeTo investigate the effect of tolcapone on cerebrospinal fluid (CSF) transthyretin (TTR) tetramer stability in patients with hereditary transthyretin (ATTRv) amyloidosis.MethodsA total of 9 patients were enrolled in the study (3 men, 50.3 ± 14.4 years old). Three patients had central nervous system (CNS) involvement. Patients were assigned to receive tolcapone 300 mg/day or 600 mg/day for 7 days. Plasma and CSF were collected at baseline and 2 h after the final tolcapone dose.ResultsThe mean CSF tolcapone and 3-O-Methyltolcapone (3-OMT) concentration were 39.4 ± 36.3 ng/mL and 26.0 ± 4.9 ng/mL, respectively, after 7 days of tolcapone dosing. Tolcapone and 3-OMT were detected in the CSF of patients with or without CNS symptoms. The mean total study drug (tolcapone + 3-OMT) to TTR molar ratio in CSF was 1.15 ± 0.59. Orally administered tolcapone significantly increased CSF TTR concentration and decreased monomer content under semi-denaturing conditions. Eight adverse events (AEs) were reported in 6 patients. All AEs were mild in severity and resolved.ConclusionsTolcapone was able to cross the blood brain-barrier, highlighting its potential to decrease CNS manifestations of ATTRv amyloidosis. Tolcapone was well tolerated by patients with ATTRv amyloidosis.
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影响因子：
5.5
作者：
Carlos J. V. Simões;Zaida L Almeida;Ana L. Cardoso;Filipa Bezerra;M. R. Almeida;J. Beirão;T. M. Pinho e Melo;M. Saraiva;R. Brito
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HOLMGREN, G;ERICZON, BG;PEPYS, MB
通讯作者：
PEPYS, MB
影响因子：
16.6
作者：
Sant'Anna R;Gallego P;Robinson LZ;Pereira-Henriques A;Ferreira N;Pinheiro F;Esperante S;Pallares I;Huertas O;Almeida MR;Reixach N;Insa R;Velazquez-Campoy A;Reverter D;Reig N;Ventura S
通讯作者：
Ventura S
影响因子：
5.5
作者：
Sekijima, Yoshiki;Dendle, Maria A.;Kelly, Jeffery W.
通讯作者：
Kelly, Jeffery W.