Werner Kramer

Publications (106) View all

• Article: Transporters, Trojan horses and therapeutics: suitability of bile acid and peptide transporters for drug delivery.

  Werner Kramer
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  ABSTRACT: Membrane transporters are major determinants for the pharmacokinetic, safety and efficacy behavior of drugs. Available technologies to study function and structure of transport proteins has strongly stimulated research in transporter biology and uncovered their importance for the drug discovery and development process, especially for drug absorption and disposition. Physiological transport systems are investigated as potential ferries to improve drug absorption and membrane permeation and to achieve organ-specific drug action. In particular, the bile acid transport systems in the liver and the small intestine and the oligopeptide transporters are of significant importance for molecular drug delivery.
  Biological Chemistry 01/2011; 392(1-2):77-94. · 2.96 Impact Factor
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  Available from: Werner Kramer

  Article: Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes.

  Ulrich Werner, Guido Haschke, Andreas W Herling, Werner Kramer
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  ABSTRACT: The glucagon-like peptide-1 (GLP-1) receptor represents an established therapeutic target in type 2 diabetes mellitus (T2DM). Agents that activate this receptor improve glucose tolerance alongside a low risk of hypoglycaemia, and have the potential to modify disease progression. Lixisenatide is a new potent and selective GLP-1 receptor agonist currently in development. The preclinical pharmacological profile of Lixisenatide suggests actions that are highly relevant to the long-term maintenance of glucose homeostasis. Lixisenatide protected Ins-1 cells (a rat-derived beta-cell line) from both lipid- and cytokine-induced apoptosis. More importantly, Lixisenatide also prevented lipotoxicity-induced insulin depletion in human islets and preserved insulin production, storage and pancreatic beta-cell function in vitro. Enhancement of insulin biosynthesis and pancreatic beta-cell volume could also be demonstrated in animal models of type 2 diabetes. The improvement of glucose-stimulated insulin secretion provided by Lixisenatide occurred in a strictly glucose-dependent manner. In animal models of diabetes, Lixisenatide improved basal blood glucose and HbA(1c) with a rapid onset and sustained duration of action, and prevented the deterioration of pancreatic responsiveness and glucose homeostasis. Lixisenatide also delayed gastric emptying and reduced food intake. The efficacy/safety profile of Lixisenatide is currently being studied further in an extensive ongoing Phase III clinical study programme. This article reviews the preclinical pharmacological profile of Lixisenatide.
  Regulatory Peptides 09/2010; 164(2-3):58-64. · 2.11 Impact Factor
• Article: Gallensäuren: Wiederentdeckt

  Günther Wess, Alfons Enhsen, Werner Kramer
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  ABSTRACT: Gallensäuren, für Verdauung und Resorption der Nahrung wesentlich, sind als Abbauprodukte des Cholesterins maßgeblich an dessen Homöostase beteiligt. Pharmakalogisch als Transportsysteme für leberspezifische Arzneimittel (Drug Targeting), zur Resorptionsverbesserung und als neue Cholesterinsenker interessant, bieten sie auch neue Möglichkeiten für Naturstoffsynthesen, molekulare Erkennung und Kombinatorik.
  Nachrichten aus der Chemie 04/2010; 43(10):1047 - 1055. · 0.19 Impact Factor
• Article: Profiling of energy metabolism in olanzapine-induced weight gain in rats and its prevention by the CB1-antagonist AVE1625.

  Michaela Liebig, Matthias Gossel, Jeremy Pratt, Mark Black, Guido Haschke, Ralf Elvert, Hans-Paul Juretschke, Claudia Neumann-Haefelin, Werner Kramer, Andreas W Herling
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  ABSTRACT: This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1-antagonist AVE1625 might attenuate OLZ-induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ-treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ-treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ-treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ-induced weight gain. Combination of OLZ treatment with the CB1-antagonist AVE1625 attenuated body weight gain in rats.
  Obesity 02/2010; 18(10):1952-8. · 4.28 Impact Factor
• Article: The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats.

  Wolfgang Linz, Paulus Wohlfart, Manuel Baader, Kristin Breitschopf, Eugen Falk, Hans-Ludwig Schäfer, Martin Gerl, Werner Kramer, Hartmut Rütten
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  ABSTRACT: To investigate the efficacy of the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, AVE8134, in cellular and experimental models of cardiac dysfunction and heart failure. In Sprague Dawley rats with permanent ligation of the left coronary artery (post-MI), AVE8134 was compared to the PPARgamma agonist rosiglitazone and in a second study to the ACE inhibitor ramipril. In DOCA-salt sensitive rats, efficacy of AVE8134 on cardiac hypertrophy and fibrosis was investigated. Finally, AVE8134 was administered to old spontaneously hypertensive rats (SHR) at a non-blood pressure lowering dose with survival as endpoint. In cellular models, we studied AVE8134 on hypertrophy in rat cardiomyocytes, nitric oxide signaling in human endothelial cells (HUVEC) and LDL-uptake in human MonoMac-6 cells. In post-MI rats, AVE8134 dose-dependently improved cardiac output, myocardial contractility and relaxation and reduced lung and left ventricular weight and fibrosis. In contrast, rosiglitazone exacerbated cardiac dysfunction. Treatment at AVE8134 decreased plasma proBNP and arginine and increased plasma citrulline and urinary NOx/creatinine ratio. In DOCA rats, AVE8134 prevented development of high blood pressure, myocardial hypertrophy and cardiac fibrosis, and ameliorated endothelial dysfunction. Compound treatment increased cardiac protein expression and phosphorylation of eNOS. In old SHR, treatment with a low dose of AVE8134 improved cardiac and vascular function and increased life expectancy without lowering blood pressure. AVE8134 reduced phenylephrine-induced hypertrophy in adult rat cardiomyocytes. In HUVEC, Ser-1177-eNOS phosphorylation but not eNOS expression was increased. In monocytes, AVE8134 increased the expression of CD36 and the macrophage scavenger receptor 1, resulting in enhanced uptake of oxidized LDL. The PPARalpha agonist AVE8134 prevents post-MI myocardial hypertrophy, fibrosis and cardiac dysfunction. AVE8134 has beneficial effects against hypertension-induced organ damages, resulting in decreased mortality. The compound exerts its protective properties by a direct effect on cardiomyocyte hypertrophy, but also indirectly via monocyte signaling and increased endothelial NO production.Acta Pharmacologica Sinica (2009) 30: 935-946; doi: 10.1038/aps.2009.58; published online 8 June 2009.
  Acta Pharmacologica Sinica 07/2009; 30(7):935-46. · 1.95 Impact Factor