Sabine Pestel
Boehringer Ingelheim
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Sabine Pestel.
Journal of Pharmacology and Experimental Therapeutics | 2010
Thierry Bouyssou; Paola Casarosa; Emmanuel Naline; Sabine Pestel; Ingo Konetzki; Philippe Devillier; Andreas Schnapp
The preclinical pharmacological profile of 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-2H-1,4-benzoxazin-3(4H)-one monohydrochloride (olodaterol, previously known as BI 1744 CL), a novel, enantiomeric pure, inhaled human β2-adrenoceptor (hβ2-AR) agonist, was compared with marketed drugs, such as salmeterol and formoterol. In vitro, olodaterol showed a potent, nearly full agonistic response at the hβ2-AR (EC50 = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold towards the hβ1- and hβ3-ARs, respectively). Likewise, olodaterol was able to potently reverse contraction induced by different stimuli in isolated human bronchi. In vivo, antagonistic effects of single doses of olodaterol and formoterol were measured against acetylcholine challenges in anesthetized guinea pigs and dogs for up to 24 h by using the Respimat Soft Mist inhaler. Heart rate and metabolic parameters (serum potassium, lactate, and glucose) were monitored to evaluate systemic pharmacodynamic effects in the dog model. In both models, olodaterol provided bronchoprotection over 24 h. Formoterol applied at an equally effective dose did not retain efficacy over 24 h. In both models olodaterol showed a rapid onset of action comparable with formoterol. Taken together, the preclinical behavior of olodaterol suggests that this novel β2-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile.
Bioorganic & Medicinal Chemistry Letters | 2010
Thierry Bouyssou; Christoph Hoenke; Klaus Rudolf; Philipp Lustenberger; Sabine Pestel; Peter Sieger; Ralf Lotz; Claudia Heine; Frank Büttner; Andreas Schnapp; Ingo Konetzki
Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human beta2-adrenoceptor with a high beta1/beta2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile.
Toxicology and Applied Pharmacology | 2013
Junnat Hamdam; Swaminathan Sethu; Trevor Smith; Ana Alfirevic; Mohammad Alhaidari; Jeffrey Atkinson; Mimieveshiofuo Ayala; Helen Box; Michael J. Cross; Annie Delaunois; Ailsa Dermody; Karthik Govindappa; Jean-Michel Guillon; Rosalind E. Jenkins; Gerry Kenna; Björn Lemmer; Ken Meecham; Adedamola Olayanju; Sabine Pestel; Andreas Rothfuss; James E. Sidaway; Rowena Sison-Young; Emma Smith; Richard Stebbings; Yulia Tingle; Jean-Pierre Valentin; Awel Williams; Dominic P. Williams; Kevin Park; Christopher E. Goldring
Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds.
Journal of Pharmacological and Toxicological Methods | 2008
Kai Lienemann; Thomas Plötz; Sabine Pestel
INTRODUCTION The aim of safety pharmacology is early detection of compound-induced side-effects. NMR-based urine analysis followed by multivariate data analysis (metabonomics) identifies efficiently differences between toxic and non-toxic compounds; but in most cases multiple administrations of the test compound are necessary. We tested the feasibility of detecting proximal tubule kidney toxicity and phospholipidosis with metabonomics techniques after single compound administration as an early safety pharmacology approach. METHODS Rats were treated orally, intravenously, inhalatively or intraperitoneally with different test compounds. Urine was collected at 0-8 h and 8-24 h after compound administration, and (1)H NMR-patterns were recorded from the samples. Variation of post-processing and feature extraction methods led to different views on the data. Support Vector Machines were trained on these different data sets and then aggregated as experts in an Ensemble. Finally, validity was monitored with a cross-validation study using a training, validation, and test data set. RESULTS Proximal tubule kidney toxicity could be predicted with reasonable total classification accuracy (85%), specificity (88%) and sensitivity (78%). In comparison to alternative histological studies, results were obtained quicker, compound need was reduced, and very importantly fewer animals were needed. In contrast, the induction of phospholipidosis by the test compounds could not be predicted using NMR-based urine analysis or the previously published biomarker PAG. DISCUSSION NMR-based urine analysis was shown to effectively predict proximal tubule kidney toxicity after single compound administration in rats. Thus, this experimental design allows early detection of toxicity risks with relatively low amounts of compound in a reasonably short period of time.
BioMed Research International | 2013
Christina Schreier; Werner Kremer; Fritz Huber; Sindy Neumann; Philipp Pagel; Kai Lienemann; Sabine Pestel
Introduction. Spectroscopic analysis of urine samples from laboratory animals can be used to predict the efficacy and side effects of drugs. This employs methods combining 1H NMR spectroscopy with quantification of biomarkers or with multivariate data analysis. The most critical steps in data evaluation are analytical reproducibility of NMR data (collection, storage, and processing) and the health status of the animals, which may influence urine pH and osmolarity. Methods. We treated rats with a solvent, a diuretic, or a nephrotoxicant and collected urine samples. Samples were titrated to pH 3 to 9, or salt concentrations increased up to 20-fold. The effects of storage conditions and freeze-thaw cycles were monitored. Selected metabolites and multivariate data analysis were evaluated after 1H NMR spectroscopy. Results. We showed that variation of pH from 3 to 9 and increases in osmolarity up to 6-fold had no effect on the quantification of the metabolites or on multivariate data analysis. Storage led to changes after 14 days at 4°C or after 12 months at −20°C, independent of sample composition. Multiple freeze-thaw cycles did not affect data analysis. Conclusion. Reproducibility of NMR measurements is not dependent on sample composition under physiological or pathological conditions.
Archive | 2003
Thierry Bouyssou; Frank Buettner; Ingo Konetzki; Sabine Pestel; Andreas Schnapp; Hermann Schollenberger; Kurt Schromm; Claudia Heine; Klaus Rudolf; Philipp Lustenberger; Christoph Hoenke
Archive | 2003
Thierry Bouyssou; Frank Buettner; Ingo Konetzki; Sabine Pestel; Andreas Schnapp; Hermann Schollenberger; Kurt Schromm; Claudia Heine
Archive | 2003
Thierry Bouyssou; Frank Buettner; Ingo Konetzki; Sabine Pestel; Andreas Schnapp; Hermann Schollenberger; Kurt Schromm; Claudia Heine
Archive | 2005
Ingo Konetzki; Thierry Bouyssou; Philipp Lustenberger; Michael P. Pieper; Andreas Schnapp; Christoph Hoenke; Sabine Pestel; Klaus Rudolf; Michel Pairet
Journal of Pharmacological and Toxicological Methods | 2006
Sabine Pestel; Hans-Juergen Martin; Gerd-Michael Maier; Brian Guth