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@ARTICLE{Leithold:810068,
      author       = {Leithold, Leonie H. E. and Jiang, Nan and Post, Julia and
                      Niemietz, Nicole and Schartmann, Elena and Ziehm, Tamar and
                      Kutzsche, Janine and Shah, N. J. and Breitkreutz, Jörg and
                      Langen, Karl-Josef and Willuweit, Antje and Willbold,
                      Dieter},
      title        = {{P}harmacokinetic properties of tandem d-peptides designed
                      for treatment of {A}lzheimer's disease},
      journal      = {European journal of pharmaceutical sciences},
      volume       = {89},
      issn         = {0928-0987},
      address      = {New York, NY [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2016-02949},
      pages        = {31 - 38},
      year         = {2016},
      abstract     = {Peptides are more and more considered for the development
                      of drug candidates. However, they frequently exhibit severe
                      disadvantages such as instability and unfavourable
                      pharmacokinetic properties. Many peptides are rapidly
                      cleared from the organism and oral bioavailabilities as well
                      as in vivo half-lives often remain low. In contrast, some
                      peptides consisting solely of d-enantiomeric amino acid
                      residues were shown to combine promising therapeutic
                      properties with high proteolytic stability and enhanced
                      pharmacokinetic parameters. Recently, we have shown that D3
                      and RD2 have highly advantageous pharmacokinetic properties.
                      Especially D3 has already proven promising properties
                      suitable for treatment of Alzheimer's disease. Here, we
                      analyse the pharmacokinetic profiles of D3D3 and RD2D3,
                      which are head-to-tail tandem d-peptides built of D3 and its
                      derivative RD2. Both D3D3 and RD2D3 show proteolytic
                      stability in mouse plasma and organ homogenates for at least
                      24 h and in murine and human liver microsomes for 4 h.
                      Notwithstanding their high affinity to plasma proteins, both
                      peptides are taken up into the brain following i.v. as well
                      as i.p. administration. Although both peptides contain
                      identical d-amino acid residues, they are arranged in a
                      different sequence order and the peptides show differences
                      in pharmacokinetic properties. After i.p. administration
                      RD2D3 exhibits lower plasma clearance and higher
                      bioavailability than D3D3. We therefore concluded that the
                      amino acid sequence of RD2 leads to more favourable
                      pharmacokinetic properties within the tandem peptide, which
                      underlines the importance of particular sequence motifs,
                      even in short peptides, for the design of further
                      therapeutic d-peptides.},
      cin          = {INM-4 / ICS-6 / JARA-BRAIN},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-4-20090406 / I:(DE-Juel1)ICS-6-20110106 /
                      $I:(DE-82)080010_20140620$},
      pnm          = {573 - Neuroimaging (POF3-573)},
      pid          = {G:(DE-HGF)POF3-573},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000376655600004},
      pubmed       = {pmid:27086111},
      doi          = {10.1016/j.ejps.2016.04.016},
      url          = {https://juser.fz-juelich.de/record/810068},
}