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Cegla J, Cuenco J, Minnion J, et al. Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo. Lancet. 2015;385:S28doi: 10.1016/S0140-6736(15)60343-9.
Cegla, J., Cuenco, J., Minnion, J., Ghourab, S., Hostomska, K., Tan, T., & Bloom, S. (2015). Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo. Lancet (London, England), 385S28. https://doi.org/10.1016/S0140-6736(15)60343-9
Cegla, Jaimini, et al. "Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo." Lancet (London, England) vol. 385 (2015): S28. doi: https://doi.org/10.1016/S0140-6736(15)60343-9
Cegla J, Cuenco J, Minnion J, Ghourab S, Hostomska K, Tan T, Bloom S. Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo. Lancet. 2015 Feb 26;385:S28. doi: 10.1016/S0140-6736(15)60343-9. PMID: 26312850.
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Lancet. 2015 Feb 26;385:S28. doi: 10.1016/S0140-6736(15)60343-9.

Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo.

Lancet (London, England)

Jaimini Cegla, Joyceline Cuenco, James Minnion, Samar Ghourab, Klara Hostomska, Tricia Tan, Stephen Bloom

Affiliations

  1. Division of Diabetes, Endocrinology & Metabolism, Imperial College London, London, UK. Electronic address: [email protected].
  2. Division of Diabetes, Endocrinology & Metabolism, Imperial College London, London, UK.

PMID: 26312850 DOI: 10.1016/S0140-6736(15)60343-9

Abstract

BACKGROUND: Obesity is an emergent epidemic associated with morbidity, mortality, and psychosocial effects. One of the key gut hormones that controls appetite is peptide tyrosine-tyrosine 3-36 (PYY3-36) whose circulating half-life is only 8 min. A long-acting analogue of PYY3-36 would therefore have great potential as an antiobesity agent. The aims of this study were to investigate the effect of various aminoacid modifications of PYY3-36 on pharmacokinetics and their ability to suppress food intake.

METHODS: To investigate the pharmacokinetics of PYY3-36 and three modified analogues, serial sampling of plasma peptide levels via cannulation of the jugular vein was performed after subcutaneous injection of the peptide in rats (n=4 per peptide, 80 nmol/kg). To investigate the effect of these peptides on food intake, mice were injected subcutaneously (1000 nmol/kg) and food intake was assessed at timed intervals over 24 h (n=8 per peptide).

FINDINGS: One-way ANOVA with post-hoc Dunnett's test was used in which each comparison was with the PYY3-36 or saline group. Plasma concentrations of the modified analogue, PYY-AP3H, were significantly higher than PYY3-36 up to 24 h post injection (p=0·0008 at 4 h, p=0·0028 at 24 h). The results confirm that modification of the native peptide, by addition of an α-helix stabilising sequence and histidine residues, lengthens the pharmacokinetic profile. Furthermore, PYY-AP3H significantly reduced food intake for up to 24 h compared with saline (p<0·0001) and native PYY3-36 (p<0·0001).

INTERPRETATION: The rationally designed analogue, PYY-AP3H, has potential as a once-a-day subcutaneously administered preparation for the treatment of obesity.

FUNDING: UK Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institute for Health Research (NIHR), an Integrative Mammalian Biology (IMB) Capacity Building award, an FP7-HEALTH-2009-241592 EuroCHIP grant, NIHR Imperial Biomedical Research Centre Funding Scheme.

Copyright © 2015 Elsevier Ltd. All rights reserved.

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