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Safety and pharmacokinetics of a kinin B1 receptor peptide agonist produced with different counter-ions

  • Martin Savard , Jérôme Côté , Luc Tremblay , Witold Neugebauer , Domenico Regoli , Sébastien Gariépy , Nathalie Hébert und Fernand Gobeil EMAIL logo
Veröffentlicht/Copyright: 12. November 2015
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 397 Heft 4

Abstract

Several studies have shown the potential therapeutic utility of kinin B1 receptor (B1R) peptide agonists in neurological and ischemic cardiovascular diseases and brain cancer. Preclinical safety studies are a prerequisite for further drug development. The objectives of this study were to determine the acute toxicity and pharmacokinetics of the peptide B1R agonist, SarLys[dPhe8]desArg9-bradykinin (NG29), as trifluoroacetate (TFacetate) or acetate salt form, following intravenous injection in rats. A maximum tolerated dose (MTD) of NG29-TFacetate was established at 75 mg/kg from the results of a dose range-finding study (up to 200 mg/kg). The short-term (4-day) repeat-dose toxicity study of NG29, using its MTD value, showed that NG29-acetate exhibited minimal non-adverse clinical pathology changes in hematology, coagulation, clinical chemistry and urine parameters and severe kidney histopathological changes characterized by renal tubular degeneration. No such effects were observed with NG29-TFacetate. At the injection site, NG29-TFacetate was considered to be more locally irritating when compared to the acetate form. The extent of exposure and half-life values of NG29-TFacetate were comparable to the acetate form (AUC0–α of 10.2 mg/l*h vs. 9.9 mg/l*h; T1/2 of 2.3 h vs. 2.4 h). This study shows that in rats NG29-TFacetate exhibits a superior tolerability profile compared with the peptide acetate form.

Keywords: anion-exchange; B1 receptors; kinin agonist; rats; safety/pharmacokinetics
Corresponding author: Fernand Gobeil Jr, Department of Pharmacology and Physiology, Université de Sherbrooke, 3001, 12th avenue North, Sherbrooke J1H 5N4, Québec, Canada; and Institute of Pharmacology, Faculty of medicine and health sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada, e-mail:

Acknowledgments

We recognize the expert assistance of Anne Provencher, Elaine Debien and Maggie Roy (Charles River, Sherbrooke, Canada). We acknowledge the particular assistance of Prof. Luc Paquet (former Director of the Institute of Pharmacology, Sherbrooke) in initiating the collaboration with Charles River. F.G. is a senior scholar from the Fonds de recherche du Québec-Santé (FRQS) and a member of the FRQS-funded Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke (CRCHUS). This work was supported by the Canadian Institute for Health Sciences (CIHR; PPP-120206), internal financial aid program (PAFI) of the CRCHUS and in-kind contributions provided by Charles River (Sherbrooke, Canada). Part of this work was previously presented at the 2015 Kinin & Peptide Receptors International Meeting (São Paulo, Brazil).

Conflict of interest statement: W.N., D.R. and F.G. from the Université de Sherbrooke hereby declare a duality of interest in view of their holding a patent made available to the public in 2006 for the use of peptide B1R agonists in the treatment of brain cancer (publication No. WO 2006/128293 A1). F.G. has received an in-kind contribution from Charles Rivers (Sherbrooke, Canada). This company has no proprietary or financial interest in the outcome of the research.

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Supplemental Material:

The online version of this article (DOI: 10.1515/hsz-2015-0246) offers supplementary material, available to authorized users.

Received: 2015-9-8
Accepted: 2015-11-7
Published Online: 2015-11-12
Published in Print: 2016-4-1

©2016 by De Gruyter

Artikel in diesem Heft

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: Kinin 2015 at São Paulo, Brazil
  4. Kinin 2015 – International Meeting on Kinin System and Peptide Receptors
  5. Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis
  6. Kinins and peptide receptors
  7. The role of N-terminal and C-terminal Arg residues from BK on interaction with kinin B2 receptor
  8. Genetic analysis of hereditary angioedema in a Brazilian family by targeted next generation sequencing
  9. Cellular localisation of the kinin B1R in the pancreas of streptozotocin-treated rat and the anti-diabetic effect of the antagonist SSR240612
  10. New mutations in SERPING1 gene of Brazilian patients with hereditary angioedema
  11. Differential effect of intranasally administrated kinin B1 and B2 receptor antagonists in Alzheimer’s disease mice
  12. Kinin B1 receptor mediates memory impairment in the rat hippocampus
  13. Safety and pharmacokinetics of a kinin B1 receptor peptide agonist produced with different counter-ions
  14. Minireview
  15. Functional organization of human SAMHD1 and mechanisms of HIV-1 restriction
  16. Corrigendum
  17. Corrigendum to: Defects of corneocyte structural proteins and epidermal barrier in atopic dermatitis
https://doi.org/10.1515/hsz-2015-0246
Schlagwörter für diesen Artikel
anion-exchange; B1 receptors; kinin agonist; rats; safety/pharmacokinetics

Artikel in diesem Heft

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: Kinin 2015 at São Paulo, Brazil
  4. Kinin 2015 – International Meeting on Kinin System and Peptide Receptors
  5. Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis
  6. Kinins and peptide receptors
  7. The role of N-terminal and C-terminal Arg residues from BK on interaction with kinin B2 receptor
  8. Genetic analysis of hereditary angioedema in a Brazilian family by targeted next generation sequencing
  9. Cellular localisation of the kinin B1R in the pancreas of streptozotocin-treated rat and the anti-diabetic effect of the antagonist SSR240612
  10. New mutations in SERPING1 gene of Brazilian patients with hereditary angioedema
  11. Differential effect of intranasally administrated kinin B1 and B2 receptor antagonists in Alzheimer’s disease mice
  12. Kinin B1 receptor mediates memory impairment in the rat hippocampus
  13. Safety and pharmacokinetics of a kinin B1 receptor peptide agonist produced with different counter-ions
  14. Minireview
  15. Functional organization of human SAMHD1 and mechanisms of HIV-1 restriction
  16. Corrigendum
  17. Corrigendum to: Defects of corneocyte structural proteins and epidermal barrier in atopic dermatitis
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