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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

Panels (A)–(C) show individual scatter plots of cerebral spinal fluid concentrations of amyloid‐β isoforms vs. LBQ657 concentrations on day 14 following oral administration of LCZ696 at 400 mg once daily (open circles) or placebo (plus signs), (A) amyloid‐β 1–42, (B) amyloid‐β 1–40 and (C) amyloid‐β 1–38. The solid line represents the regression (r2). Panel (D) shows mean amyloid‐β 1–42 concentrations in cerebral spinal fluid (solid line, left y‐axis) and LBQ657 concentrations in cerebral spinal fluid (dashed lines, right y‐axis) vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily
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bcp12861-fig-0004: Panels (A)–(C) show individual scatter plots of cerebral spinal fluid concentrations of amyloid‐β isoforms vs. LBQ657 concentrations on day 14 following oral administration of LCZ696 at 400 mg once daily (open circles) or placebo (plus signs), (A) amyloid‐β 1–42, (B) amyloid‐β 1–40 and (C) amyloid‐β 1–38. The solid line represents the regression (r2). Panel (D) shows mean amyloid‐β 1–42 concentrations in cerebral spinal fluid (solid line, left y‐axis) and LBQ657 concentrations in cerebral spinal fluid (dashed lines, right y‐axis) vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily

Mentions: The relationship between LBQ657 levels and Aβ isoform levels was explored through analysis of scatter plots (Figure 4). The R‐square values for LBQ657 CSF concentration and CSF Aβ 1–42, 1–40, and 1–38 were 0.022, 0.010 and 0.008, respectively (Figure 4A–C). Similar results were obtained through analysis of LBQ657 CSF area under the concentration–time curve at steady‐state (AUC(0,τss)) and CSF Aβ isoform levels (data not shown). Mean concentration‐time profiles of CSF LBQ657 and Aβ 1–42 (Figure 4D) also support that there was no relationship between LBQ657 and Aβ CSF concentrations.


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)

Panels (A)–(C) show individual scatter plots of cerebral spinal fluid concentrations of amyloid‐β isoforms vs. LBQ657 concentrations on day 14 following oral administration of LCZ696 at 400 mg once daily (open circles) or placebo (plus signs), (A) amyloid‐β 1–42, (B) amyloid‐β 1–40 and (C) amyloid‐β 1–38. The solid line represents the regression (r2). Panel (D) shows mean amyloid‐β 1–42 concentrations in cerebral spinal fluid (solid line, left y‐axis) and LBQ657 concentrations in cerebral spinal fluid (dashed lines, right y‐axis) vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

bcp12861-fig-0004: Panels (A)–(C) show individual scatter plots of cerebral spinal fluid concentrations of amyloid‐β isoforms vs. LBQ657 concentrations on day 14 following oral administration of LCZ696 at 400 mg once daily (open circles) or placebo (plus signs), (A) amyloid‐β 1–42, (B) amyloid‐β 1–40 and (C) amyloid‐β 1–38. The solid line represents the regression (r2). Panel (D) shows mean amyloid‐β 1–42 concentrations in cerebral spinal fluid (solid line, left y‐axis) and LBQ657 concentrations in cerebral spinal fluid (dashed lines, right y‐axis) vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily
Mentions: The relationship between LBQ657 levels and Aβ isoform levels was explored through analysis of scatter plots (Figure 4). The R‐square values for LBQ657 CSF concentration and CSF Aβ 1–42, 1–40, and 1–38 were 0.022, 0.010 and 0.008, respectively (Figure 4A–C). Similar results were obtained through analysis of LBQ657 CSF area under the concentration–time curve at steady‐state (AUC(0,τss)) and CSF Aβ isoform levels (data not shown). Mean concentration‐time profiles of CSF LBQ657 and Aβ 1–42 (Figure 4D) also support that there was no relationship between LBQ657 and Aβ CSF concentrations.

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