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The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects.

Langenickel TH, Tsubouchi C, Ayalasomayajula S, Pal P, Valentin MA, Hinder M, Jhee S, Gevorkyan H, Rajman I - Br J Clin Pharmacol (2016)

Bottom Line: LCZ696 had no significant effect on CSF AUEC(0,36 h) of the aggregable Aβ species 1-42 or 1-40 compared with placebo (estimated treatment ratios 0.98 [95% CI 0.73, 1.34; P = 0.919] and 1.05 [95% CI 0.82, 1.34; P = 0.702], respectively).LCZ696 did not cause changes in CSF levels of aggregable Aβ isoforms (1-42 and 1-40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin.The clinical relevance of the increase in soluble CSF Aβ 1-38 is currently unknown.

View Article: PubMed Central - PubMed

Affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.

No MeSH data available.


Related in: MedlinePlus

Individual subject ping‐pong plots of amyloid‐β isoform AUEC(0,36 h) at baseline and at day 14 for LCZ696 (left‐hand graph of each panel) and placebo (right‐hand graph of each panel) groups, (A) amyloid‐β 1–42 in cerebral spinal fluid, (B) amyloid‐β 1–40 in cerebral spinal fluid, (C) amyloid‐β 1–38 in cerebral spinal fluid and (D) amyloid‐β 1–40 in plasma
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bcp12861-fig-0002: Individual subject ping‐pong plots of amyloid‐β isoform AUEC(0,36 h) at baseline and at day 14 for LCZ696 (left‐hand graph of each panel) and placebo (right‐hand graph of each panel) groups, (A) amyloid‐β 1–42 in cerebral spinal fluid, (B) amyloid‐β 1–40 in cerebral spinal fluid, (C) amyloid‐β 1–38 in cerebral spinal fluid and (D) amyloid‐β 1–40 in plasma

Mentions: To assess trends within treatment groups, individual CSF Aβ isoform AUEC(0,36 h) and AUEC(0,24 h) values at baseline and day 14 were plotted (Figure 2 for AUEC(0,36 h)). Visual inspection did not reveal any apparent differences or unidirectional trends in Aβ 1–42 and 1–40 AUEC(0,36 h) values or group imbalances in either treatment group. The individual exhibiting the largest increase in, and highest post‐treatment value of, CSF Aβ 1–42 AUEC(0,36 h) received placebo (Figure 2A, B). Subjects in the LCZ696 group appeared to have an increase in CSF Aβ 1–38 AUEC(0,36 h) values, compared with placebo. As above, the individual exhibiting the largest increase in, and highest post‐treatment value of, CSF Aβ 1–38 AUEC(0,36 h) received placebo (Figure 2C). Individual CSF Aβ isoform AUEC(0,24 h) analyses were comparable and supportive of AUEC(0,36 h) data outlined above (data not shown).


The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects.

Langenickel TH, Tsubouchi C, Ayalasomayajula S, Pal P, Valentin MA, Hinder M, Jhee S, Gevorkyan H, Rajman I - Br J Clin Pharmacol (2016)

Individual subject ping‐pong plots of amyloid‐β isoform AUEC(0,36 h) at baseline and at day 14 for LCZ696 (left‐hand graph of each panel) and placebo (right‐hand graph of each panel) groups, (A) amyloid‐β 1–42 in cerebral spinal fluid, (B) amyloid‐β 1–40 in cerebral spinal fluid, (C) amyloid‐β 1–38 in cerebral spinal fluid and (D) amyloid‐β 1–40 in plasma
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834603&req=5

bcp12861-fig-0002: Individual subject ping‐pong plots of amyloid‐β isoform AUEC(0,36 h) at baseline and at day 14 for LCZ696 (left‐hand graph of each panel) and placebo (right‐hand graph of each panel) groups, (A) amyloid‐β 1–42 in cerebral spinal fluid, (B) amyloid‐β 1–40 in cerebral spinal fluid, (C) amyloid‐β 1–38 in cerebral spinal fluid and (D) amyloid‐β 1–40 in plasma
Mentions: To assess trends within treatment groups, individual CSF Aβ isoform AUEC(0,36 h) and AUEC(0,24 h) values at baseline and day 14 were plotted (Figure 2 for AUEC(0,36 h)). Visual inspection did not reveal any apparent differences or unidirectional trends in Aβ 1–42 and 1–40 AUEC(0,36 h) values or group imbalances in either treatment group. The individual exhibiting the largest increase in, and highest post‐treatment value of, CSF Aβ 1–42 AUEC(0,36 h) received placebo (Figure 2A, B). Subjects in the LCZ696 group appeared to have an increase in CSF Aβ 1–38 AUEC(0,36 h) values, compared with placebo. As above, the individual exhibiting the largest increase in, and highest post‐treatment value of, CSF Aβ 1–38 AUEC(0,36 h) received placebo (Figure 2C). Individual CSF Aβ isoform AUEC(0,24 h) analyses were comparable and supportive of AUEC(0,36 h) data outlined above (data not shown).

Bottom Line: LCZ696 had no significant effect on CSF AUEC(0,36 h) of the aggregable Aβ species 1-42 or 1-40 compared with placebo (estimated treatment ratios 0.98 [95% CI 0.73, 1.34; P = 0.919] and 1.05 [95% CI 0.82, 1.34; P = 0.702], respectively).LCZ696 did not cause changes in CSF levels of aggregable Aβ isoforms (1-42 and 1-40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin.The clinical relevance of the increase in soluble CSF Aβ 1-38 is currently unknown.

View Article: PubMed Central - PubMed

Affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.

No MeSH data available.


Related in: MedlinePlus