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Long-term neprilysin inhibition - implications for ARNIs.

Abstract Neprilysin has a major role in both the generation and degradation of bioactive peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI (dual-acting angiotensin-receptor-neprilysin inhibitor) drug class, contains equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more than valsartan alone in patients with hypertension. In the PARADIGM-HF study, LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for the treatment of heart failure with reduced ejection fraction, and LCZ696 was approved by the FDA for this purpose in 2015. This approval was the first for chronic neprilysin inhibition. The many peptides metabolized by neprilysin suggest many potential consequences of chronic neprilysin inhibitor therapy, both beneficial and adverse. Moreover, LBQ657 might inhibit enzymes other than neprilysin. Chronic neprilysin inhibition might have an effect on angio-oedema, bronchial reactivity, inflammation, and cancer, and might predispose to polyneuropathy. Additionally, inhibition of neprilysin metabolism of amyloid-β peptides might have an effect on Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy. Much of the evidence for possible adverse consequences of chronic neprilysin inhibition comes from studies in animal models, and the relevance of this evidence to humans is unknown. This Review summarizes current knowledge of neprilysin function and possible consequences of chronic neprilysin inhibition that indicate a need for vigilance in the use of neprilysin inhibitor therapy.
PMID
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Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

Authors

Mayor MeshTerms
Keywords
Journal Title nature reviews. cardiology
Publication Year Start




PMID- 27974807
OWN - NLM
STAT- Publisher
DA  - 20161215
LR  - 20170112
IS  - 1759-5010 (Electronic)
IS  - 1759-5002 (Linking)
DP  - 2016 Dec 15
TI  - Long-term neprilysin inhibition - implications for ARNIs.
LID - 10.1038/nrcardio.2016.200 [doi]
AB  - Neprilysin has a major role in both the generation and degradation of bioactive
      peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI
      (dual-acting angiotensin-receptor-neprilysin inhibitor) drug class, contains
      equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, 
      a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more
      than valsartan alone in patients with hypertension. In the PARADIGM-HF study,
      LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for 
      the treatment of heart failure with reduced ejection fraction, and LCZ696 was
      approved by the FDA for this purpose in 2015. This approval was the first for
      chronic neprilysin inhibition. The many peptides metabolized by neprilysin
      suggest many potential consequences of chronic neprilysin inhibitor therapy, both
      beneficial and adverse. Moreover, LBQ657 might inhibit enzymes other than
      neprilysin. Chronic neprilysin inhibition might have an effect on angio-oedema,
      bronchial reactivity, inflammation, and cancer, and might predispose to
      polyneuropathy. Additionally, inhibition of neprilysin metabolism of amyloid-beta
      peptides might have an effect on Alzheimer disease, age-related macular
      degeneration, and cerebral amyloid angiopathy. Much of the evidence for possible 
      adverse consequences of chronic neprilysin inhibition comes from studies in
      animal models, and the relevance of this evidence to humans is unknown. This
      Review summarizes current knowledge of neprilysin function and possible
      consequences of chronic neprilysin inhibition that indicate a need for vigilance 
      in the use of neprilysin inhibitor therapy.
FAU - Campbell, Duncan J
AU  - Campbell DJ
AD  - St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria
      3065, Australia.
AD  - University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
LA  - eng
PT  - Review
PT  - Journal Article
DEP - 20161215
PL  - England
TA  - Nat Rev Cardiol
JT  - Nature reviews. Cardiology
JID - 101500075
EDAT- 2016/12/16 06:00
MHDA- 2016/12/16 06:00
CRDT- 2016/12/16 06:00
AID - nrcardio.2016.200 [pii]
AID - 10.1038/nrcardio.2016.200 [doi]
PST - aheadofprint
SO  - Nat Rev Cardiol. 2016 Dec 15. doi: 10.1038/nrcardio.2016.200.

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