Abstract:
OBJECTIVE:Infantile spasm syndrome (ISS) is an epileptic encephalopathy without established treatment after the failure to standard of care based on steroids and vigabatrin. Converging lines of evidence indicating a role of NR2B subunits of the N-methyl-D-aspartate (NMDA) receptor on the onset of spams in ISS patients, prompted us to test radiprodil, a negative allosteric NR2B modulator in preclinical seizure models and in infants with ISS. METHODS:Radiprodil has been tested in three models, including pentylenetetrazole-induced seizures in rats across different postnatal (PN) ages. Three infants with ISS have been included in a phase 1b escalating repeated dose study. RESULTS:Radiprodil showed the largest protective seizure effects in juvenile rats (maximum at PN12, corresponding to late infancy in humans). Three infants resistant to a combination of vigabatrin and prednisolone received individually titrated doses of radiprodil for up to 34 days. Radiprodil was safe and well tolerated in all three infants, and showed the expected pharmacokinetic profile. One infant became spasm-free and two showed clinical improvement without reaching spasm-freedom. After radiprodil withdrawal, the one infant continued to be spasm-free, while the two others experienced seizure worsening requiring the use of the ketogenic diet and other antiepileptic drugs. INTERPRETATION:Radiprodil showed prominent anti-seizure effect in juvenile animals, consistent with the prevalent expression of NR2B subunit of the NMDA receptor at this age in both rodents and humans. The clinical testing, although preliminary, showed that radiprodil is associated with a good safety and pharmacokinetic profile, and with the potential to control epileptic spasms.
journal_name
Ann Clin Transl Neuroljournal_title
Annals of clinical and translational neurologyauthors
Auvin S,Dozières-Puyravel B,Avbersek A,Sciberras D,Collier J,Leclercq K,Mares P,Kaminski RM,Muglia Pdoi
10.1002/acn3.50998subject
Has Abstractpub_date
2020-03-01 00:00:00pages
343-352issue
3issn
2328-9503journal_volume
7pub_type
杂志文章abstract:OBJECTIVE:To evaluate whether structural and microstructural brain abnormalities in neonates with congenital heart disease (CHD) correlate with neuronal network dysfunction measured by analysis of EEG connectivity. METHODS:We studied a prospective cohort of 20 neonates with CHD who underwent continuous EEG monitoring ...
journal_title:Annals of clinical and translational neurology
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章,多中心研究
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journal_title:Annals of clinical and translational neurology
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pub_type: 杂志文章
doi:10.1002/acn3.749
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doi:10.1002/acn3.569
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pub_type: 杂志文章
doi:10.1002/acn3.309
更新日期:2016-04-13 00:00:00
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pub_type: 杂志文章
doi:10.1002/acn3.733
更新日期:2019-02-21 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.118
更新日期:2014-11-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.50888
更新日期:2019-09-01 00:00:00
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doi:10.1002/acn3.50966
更新日期:2020-01-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.51047
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pub_type: 杂志文章
doi:10.1002/acn3.50917
更新日期:2019-11-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/acn3.51073
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doi:10.1002/acn3.646
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pub_type: 临床试验,杂志文章
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更新日期:2018-08-15 00:00:00
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pub_type: 杂志文章
doi:10.1002/acn3.203
更新日期:2015-06-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.51179
更新日期:2020-12-18 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.787
更新日期:2019-05-08 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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更新日期:2018-12-28 00:00:00
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pub_type: 杂志文章
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.50912
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