PMID- 23692516
OWN - NLM
STAT- MEDLINE
DCOM- 20131022
LR  - 20211021
IS  - 1528-1167 (Electronic)
IS  - 0013-9580 (Print)
IS  - 0013-9580 (Linking)
VI  - 54
IP  - 8
DP  - 2013 Aug
TI  - Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG 
      responses in patients with epilepsy.
PG  - 1437-43
LID - 10.1111/epi.12224 [doi]
AB  - PURPOSE: To assess the effects of ICA-105665, an agonist of neuronal Kv7 
      potassium channels, on epileptiform EEG discharges, evoked by intermittent photic 
      stimulation (IPS), the so-called photoparoxysmal responses (PPRs) in patients 
      with epilepsy. METHODS: Male and female patients aged 18-60 years with 
      reproducible PPRs were eligible for enrollment. The study was conducted as a 
      single-blind, single-dose, multiple-cohort study. Four patients were enrolled in 
      each of the first three cohorts. Six patients were enrolled in the fourth cohort 
      and one patient was enrolled in the fifth cohort. PPR responses to 14 IPS 
      frequencies (steps) were used to determine the standard photosensitivity range 
      (SPR) following placebo on day 1 and ICA-105665 on day 2. The SPR was quantified 
      for three eye conditions (eyes closing, eyes closed, and eyes open), and the most 
      sensitive condition was used for assessment of efficacy. A partial response was 
      defined as a reduction in the SPR of at least three units at three separate time 
      points following ICA-105665 compared to the same time points following placebo 
      with no time points with more than three units of increase. Complete suppression 
      was defined by no PPRs in any eye condition at one or more time points. KEY 
      FINDINGS: Six individual patients participated in the first three cohorts (100, 
      200, and 400 mg). Six patients participated in the fourth cohort (500 mg), and 
      one patient participated in the fifth cohort (600 mg). Decreases in SPR occurred 
      in one patient at 100 mg, two patients receiving 400 mg ICA-105665 (complete 
      abolishment of SPR occurred in one patient at 400 mg), and in four of six 
      patients receiving 500 mg. The most common adverse events (AEs) were those 
      related to the nervous system, and dizziness appeared to be the first emerging 
      AE. The single patient in the 600 mg cohort developed a brief generalized seizure 
      within 1 h of dosing, leading to the discontinuation of additional patients at 
      this dose, per the predefined protocol stopping rules. SIGNIFICANCE: ICA-105665 
      reduced the SPR in patients at single doses of 100 (one of four), 400 (two of 
      four), and 500 mg (four of six). This is the first assessment of the effects of 
      activation of Kv7 potassium channels in the photosensitivity proof of concept 
      model. The reduction of SPR in this patient population provides evidence of 
      central nervous system (CNS) penetration by ICA-105665, and preliminary evidence 
      that engagement with neuronal Kv7 potassium channels has antiseizure effects.
CI  - Wiley Periodicals, Inc. (c) 2013 International League Against Epilepsy.
FAU - Kasteleijn-Nolst Trenite, Dorothee G A
AU  - Kasteleijn-Nolst Trenite DG
AD  - Department of Medical Genetics, Utrecht University, Utrecht, The Netherlands. 
      dkasteleijn@planet.nl
FAU - Biton, Victor
AU  - Biton V
FAU - French, Jacqueline A
AU  - French JA
FAU - Abou-Khalil, Bassel
AU  - Abou-Khalil B
FAU - Rosenfeld, William E
AU  - Rosenfeld WE
FAU - Diventura, Bree
AU  - Diventura B
FAU - Moore, Elizabeth L
AU  - Moore EL
FAU - Hetherington, Seth V
AU  - Hetherington SV
FAU - Rigdon, Greg C
AU  - Rigdon GC
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
DEP - 20130520
PL  - United States
TA  - Epilepsia
JT  - Epilepsia
JID - 2983306R
RN  - 0 (Anticonvulsants)
RN  - 0 (KCNQ Potassium Channels)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Anticonvulsants/pharmacology/*therapeutic use
MH  - Area Under Curve
MH  - Cohort Studies
MH  - Dose-Response Relationship, Drug
MH  - Electroencephalography
MH  - Epilepsy/*drug therapy/*physiopathology
MH  - Evoked Potentials/*drug effects
MH  - Female
MH  - Humans
MH  - KCNQ Potassium Channels/*agonists/metabolism
MH  - Male
MH  - Middle Aged
MH  - Photic Stimulation
MH  - Single-Blind Method
MH  - Time Factors
MH  - Young Adult
PMC - PMC3838622
OTO - NOTNLM
OT  - Epilepsy
OT  - ICA-105665
OT  - Ion channel
OT  - Kv7 potassium channel
OT  - Photoparoxysmal response
OT  - Photosensitivity
OT  - Proof of concept model
EDAT- 2013/05/23 06:00
MHDA- 2013/10/23 06:00
CRDT- 2013/05/23 06:00
PHST- 2013/04/17 00:00 [accepted]
PHST- 2013/05/23 06:00 [entrez]
PHST- 2013/05/23 06:00 [pubmed]
PHST- 2013/10/23 06:00 [medline]
AID - 10.1111/epi.12224 [doi]
PST - ppublish
SO  - Epilepsia. 2013 Aug;54(8):1437-43. doi: 10.1111/epi.12224. Epub 2013 May 20.