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Discussion on non-clinical aspects
Ivacaftor increased in vitro the chloride transport of multiple mutant CFTR forms associated with a
variety of protein defects and disease severity.
The increase of chloride transport by ivacaftor was most pronounced in cells expressing CFTR gating
mutations when compared to other types of CFTR mutations. This group included, G551D, G178R,
S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D. The fold increase in chloride
transport for all 10 studied gating mutation proteins was greater than 10.
Ivacaftor also potentiated chloride transport, of cells carrying CFTR mutations that are associated with
residual CFTR function, although to a lesser extent than that observed for CFTR gating mutations,
including CFTR conductance mutations (R117H, D110H, R117C, R347H and R352Q), mild CFTR
processing mutations (E56K, P67L, L206W, A455E, D579G, S945L, R1070W and F1074L) and CFTR
mutations with uncharacterized defects in the CFTR protein (D110E, D1152H, S1235R and D1270N).
Finally, ivacaftor showed minimal effects in vitro on mutant CFTR forms that were associated with
minimal chloride transport, including severe CFTR conductance mutations (R334W, T338I, R347P and
L927P), severe CFTR processing mutations (F508del, A46D, G85E, E92K, S492F, I507del, V520F,
A559T, R560T, R560S, A561E, H1054D, G1061R, L1065P, L1065P, R1066C, R1066H, R1066M,
L1077P, H1085R, M1101K and N1303K) and CFTR synthesis mutations (G542X, W1282X, 2184InsA
and 2789+5G->A).
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Source: Cystic Fibrosis DNA and Mutations Forum - Category: Respiratory Medicine Authors: ladybird Tags: DNA and Mutations Source Type: forums
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