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Pulmonary safety profile of a Transient Receptor Potential Vanilloid-1 (TRPV1) agonist in guinea-pigs
Abstracts
Poster No: 191 Pulmonary safety profile of a Transient Receptor Potential Vanilloid-1 (TRPV1) agonist in guinea-pigs Peter W. Stengel a,b, Bin Lui a, Karen Ellis a, David O. Calligaro a a b
Eli Lilly and Company, Indianapolis, IN, USA Pulmonary Concepts LLC, Indianapolis, UN, USA
The prototypical TRPV1 agonist capsaicin causes airway smooth muscle contraction and plasma protein extravasation, thus bronchoconstriction and pulmonary edema are potential safety concerns of TRPV1 agonists under development for treating pain. Guinea-pigs are the only small laboratory animals that develop airway obstruction and pulmonary edema after capsaicin. We used excised lung gas volume (ELGV) and lung wet/dry weight (W/D) as indicators of invivo airway obstruction and acute lung injury, respectively, after intravenous (IV) capsaicin (0.003–1 mg/kg) or compound X (0.1– 10 mg/kg) in guinea-pigs. Next, we examined the TRPV1 antagonist capsazepine (10 mg/kg) against both agonists. Also, we compared ELGV values and plasma levels after IV (0.5 mg/kg) or oral (5– 150 mg/kg) compound X and ELGV values after IV (0.1–3 mg/kg) or oral (10–300 mg/kg) bethanechol, a muscarinic receptor agonist. Finally, we examined plasma exposure and ELGV over 24 h after a single 50 mg/kg oral dose of compound X. Although potencies varied for capsaicin and compound X, maximum ELGV and W/D values were similar. Capsazepine antagonized both agonists. Bronchospasm occurred after IV but not oral compound X, although plasma levels were similar for IV (0.5 mg/kg, 123 ± 4 ng/mL)- and oral (50 mg/kg, 141 ± 42 ng/mL)-treated animals. Even at an oral dose of 150 mg/kg, 300 times its half-maximal IV dose, bronchospasm was not apparent following oral compound X although airway obstruction was evident after IV and oral bethanechol. In conclusion, we found: (1) ELGV and W/D to be simple and objective measures of TRPV1 agonist-evoked airway responses and; (2) differential airway effects of IV and oral compound X may relate more to rate of receptor occupancy than systemic exposure. This study validates the use of ELGV and W/D for examining potentially adverse pulmonary drug-related events.
doi:10.1016/j.vascn.2011.03.196
Poster No: 192 Characterization of gastrointestinal function in NMRI and C57BL/6 mice: Intestinal motility and gastric acid secretion Sonia Goineau, Philippe Guillaume, Sandra Picard, Daniel Provost, Guillaume Froget Porsolt & Partners Pharmacology, Boulogne-Billancourt, France Mice are widely used for efficacy or safety studies. These models need however to be well characterized in regard of possible strainrelated specificities. This work was aimed at drawing the gastrointestinal (GI) profile of male NMRI and C57BL/6 mice (n = 4 to 10/ group) using appropriate references: morphine in the small intestinal (charcoal meal) or colonic (bead expulsion) transit tests and histamine in the gastric acid secretion assay. In controls, both strains showed similar gastric content and small intestinal and colonic transit, whereas NMRI exhibited higher gastric acid secretion than C57BL/6 (gastric volume: 0.72 ± 0.08 vs 0.39 ± 0.08 ml; total gastric acidity: 37.5 ± 7.1 vs 16.2 ± 4.8 μEq/2 h). Morphine (8 mg/kg i.p.) decreased the small intestinal transit similarly in NMRI and C57BL/6 mice (− 53% and −34%, respectively, p < 0.001 for
e57
each) and lengthened the bead expulsion time more markedly in C57BL/6 (+0:53:13 and + 3:12:58 h:min:s, respectively, p < 0.001 for each). It also increased the gastric content in NMRI (+ 191% p < 0.001) but not in C57BL/6. In NMRI, histamine (10 mg/kg s.c.) decreased the gastric fluid volume (−0.30 ml p < 0.05) without modifying the total gastric acidity. In contrast, in C57BL/6, histamine increased the total gastric acidity (+ 23.1 μEq/2 h p < 0.05) without affecting the gastric fluid volume. These findings demonstrate mice strain-related differences in basal gastric acid secretion but not in basal GI transit. They also show strain-dependent pharmacological responsiveness to the effects of histamine or morphine on gastric acid secretion and GI motility. doi:10.1016/j.vascn.2011.03.197
Poster No: 193 A potential algorithm for predicting drug-induced nausea in man Lorna Ewart a, J. Glab a, Will Redfern a, Karen Roels b, J. Scatchard c, G. Vickery a, Rob Wallis c, J.P. Valentin a a
AstraZeneca R&D, Alderley Park, UK Johnson & Johnson, Belgium c Pfizer Global Research, UK b
Although not life threatening, drug-induced nausea can impact on drug development programs, patient compliance, and drug efficacy. Nausea is a complex, multi-system reflex and there is currently no defined or validated animal model to assess the potential of a drug to cause nausea per se. In this cross-company project, data from rat charcoal meal studies (22 drugs), rat body weight measurements (34 drugs), and dog cardiovascular studies (58 drugs) have been investigated to ascertain whether individually or in combination they can predict nausea in Phase I. Preclinical signals assessed were emesis in dogs, inhibition of gastric emptying in rats, and body weight loss in rats. Emesis in dogs and nausea in man occurred concurrently in 13/58 drugs (22%), while 22/58 drugs (38%) caused neither emesis nor nausea. Inhibition of rodent gastric emptying correlated with nausea in man in 23% of drugs while 45% of drugs had no effect on gastric emptying or nausea. Body weight loss correlated with nausea in 15% of drugs. Creation of an algorithm stating that a drug would cause nausea in man if it had produced a response in at least 2 of the animal models studied enabled a more powerful approach to predicting nausea. This algorithm resulted in a sensitivity of 71%, a specificity of 100% and a predictive value of 87%. In conclusion, applying an integrated approach to data evaluation across multiple animal models can predict the presence of nausea in man, with reasonable accuracy. Applying this approach in risk assessment may reduce the severity and frequency of drug-induced nausea in the clinic. doi:10.1016/j.vascn.2011.03.198
Poster No: 194 Evaluation of a new GI-telemetry system for dogs Thomas Trautmann, Michael Markert, Anja Klumpp, Karin Mayer, Brian Guth, Thomas Trautmann Boehringer Ingelheim Pharma GmbH & Co KG, 88400 Biberach/Ri, Germany
Poster No: 191 Pulmonary safety profile of a Transient Receptor Potential Vanilloid-1 (TRPV1) agonist in guinea-pigs Peter W. Stengel a,b, Bin Lui a, Karen Ellis a, David O. Calligaro a a b
Eli Lilly and Company, Indianapolis, IN, USA Pulmonary Concepts LLC, Indianapolis, UN, USA
The prototypical TRPV1 agonist capsaicin causes airway smooth muscle contraction and plasma protein extravasation, thus bronchoconstriction and pulmonary edema are potential safety concerns of TRPV1 agonists under development for treating pain. Guinea-pigs are the only small laboratory animals that develop airway obstruction and pulmonary edema after capsaicin. We used excised lung gas volume (ELGV) and lung wet/dry weight (W/D) as indicators of invivo airway obstruction and acute lung injury, respectively, after intravenous (IV) capsaicin (0.003–1 mg/kg) or compound X (0.1– 10 mg/kg) in guinea-pigs. Next, we examined the TRPV1 antagonist capsazepine (10 mg/kg) against both agonists. Also, we compared ELGV values and plasma levels after IV (0.5 mg/kg) or oral (5– 150 mg/kg) compound X and ELGV values after IV (0.1–3 mg/kg) or oral (10–300 mg/kg) bethanechol, a muscarinic receptor agonist. Finally, we examined plasma exposure and ELGV over 24 h after a single 50 mg/kg oral dose of compound X. Although potencies varied for capsaicin and compound X, maximum ELGV and W/D values were similar. Capsazepine antagonized both agonists. Bronchospasm occurred after IV but not oral compound X, although plasma levels were similar for IV (0.5 mg/kg, 123 ± 4 ng/mL)- and oral (50 mg/kg, 141 ± 42 ng/mL)-treated animals. Even at an oral dose of 150 mg/kg, 300 times its half-maximal IV dose, bronchospasm was not apparent following oral compound X although airway obstruction was evident after IV and oral bethanechol. In conclusion, we found: (1) ELGV and W/D to be simple and objective measures of TRPV1 agonist-evoked airway responses and; (2) differential airway effects of IV and oral compound X may relate more to rate of receptor occupancy than systemic exposure. This study validates the use of ELGV and W/D for examining potentially adverse pulmonary drug-related events.
doi:10.1016/j.vascn.2011.03.196
Poster No: 192 Characterization of gastrointestinal function in NMRI and C57BL/6 mice: Intestinal motility and gastric acid secretion Sonia Goineau, Philippe Guillaume, Sandra Picard, Daniel Provost, Guillaume Froget Porsolt & Partners Pharmacology, Boulogne-Billancourt, France Mice are widely used for efficacy or safety studies. These models need however to be well characterized in regard of possible strainrelated specificities. This work was aimed at drawing the gastrointestinal (GI) profile of male NMRI and C57BL/6 mice (n = 4 to 10/ group) using appropriate references: morphine in the small intestinal (charcoal meal) or colonic (bead expulsion) transit tests and histamine in the gastric acid secretion assay. In controls, both strains showed similar gastric content and small intestinal and colonic transit, whereas NMRI exhibited higher gastric acid secretion than C57BL/6 (gastric volume: 0.72 ± 0.08 vs 0.39 ± 0.08 ml; total gastric acidity: 37.5 ± 7.1 vs 16.2 ± 4.8 μEq/2 h). Morphine (8 mg/kg i.p.) decreased the small intestinal transit similarly in NMRI and C57BL/6 mice (− 53% and −34%, respectively, p < 0.001 for
e57
each) and lengthened the bead expulsion time more markedly in C57BL/6 (+0:53:13 and + 3:12:58 h:min:s, respectively, p < 0.001 for each). It also increased the gastric content in NMRI (+ 191% p < 0.001) but not in C57BL/6. In NMRI, histamine (10 mg/kg s.c.) decreased the gastric fluid volume (−0.30 ml p < 0.05) without modifying the total gastric acidity. In contrast, in C57BL/6, histamine increased the total gastric acidity (+ 23.1 μEq/2 h p < 0.05) without affecting the gastric fluid volume. These findings demonstrate mice strain-related differences in basal gastric acid secretion but not in basal GI transit. They also show strain-dependent pharmacological responsiveness to the effects of histamine or morphine on gastric acid secretion and GI motility. doi:10.1016/j.vascn.2011.03.197
Poster No: 193 A potential algorithm for predicting drug-induced nausea in man Lorna Ewart a, J. Glab a, Will Redfern a, Karen Roels b, J. Scatchard c, G. Vickery a, Rob Wallis c, J.P. Valentin a a
AstraZeneca R&D, Alderley Park, UK Johnson & Johnson, Belgium c Pfizer Global Research, UK b
Although not life threatening, drug-induced nausea can impact on drug development programs, patient compliance, and drug efficacy. Nausea is a complex, multi-system reflex and there is currently no defined or validated animal model to assess the potential of a drug to cause nausea per se. In this cross-company project, data from rat charcoal meal studies (22 drugs), rat body weight measurements (34 drugs), and dog cardiovascular studies (58 drugs) have been investigated to ascertain whether individually or in combination they can predict nausea in Phase I. Preclinical signals assessed were emesis in dogs, inhibition of gastric emptying in rats, and body weight loss in rats. Emesis in dogs and nausea in man occurred concurrently in 13/58 drugs (22%), while 22/58 drugs (38%) caused neither emesis nor nausea. Inhibition of rodent gastric emptying correlated with nausea in man in 23% of drugs while 45% of drugs had no effect on gastric emptying or nausea. Body weight loss correlated with nausea in 15% of drugs. Creation of an algorithm stating that a drug would cause nausea in man if it had produced a response in at least 2 of the animal models studied enabled a more powerful approach to predicting nausea. This algorithm resulted in a sensitivity of 71%, a specificity of 100% and a predictive value of 87%. In conclusion, applying an integrated approach to data evaluation across multiple animal models can predict the presence of nausea in man, with reasonable accuracy. Applying this approach in risk assessment may reduce the severity and frequency of drug-induced nausea in the clinic. doi:10.1016/j.vascn.2011.03.198
Poster No: 194 Evaluation of a new GI-telemetry system for dogs Thomas Trautmann, Michael Markert, Anja Klumpp, Karin Mayer, Brian Guth, Thomas Trautmann Boehringer Ingelheim Pharma GmbH & Co KG, 88400 Biberach/Ri, Germany