Temporal profile of forced expiratory lung function in allergen-challenged Brown–Norway rats

Celly, Chander; House, Aileen; Sehring, Susan; Zhang, Xiang Y; Jones, Howard; Hey, John A.; Egan, Robert W.; Chapman, Richard W.

doi:10.1016/j.ejphar.2006.04.020

Cited by 16 publications

(12 citation statements)

References 23 publications

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“…In addition to significant increases in FOT parameters following MCh provocation, we also observed significant changes when using the NPFE technique. Therefore, we found, as in previous studies [7-12], that NPFE can be used as an indicator of bronchoconstriction in mice.…”

Section: Discussionsupporting

confidence: 83%

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Combined forced oscillation and forced expiration measurements in mice for the assessment of airway hyperresponsiveness

Shalaby

Gold²,

Schuessler³

et al. 2010

Respir Res

103

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BackgroundPulmonary function has been reported in mice using negative pressure-driven forced expiratory manoeuvres (NPFE) and the forced oscillation technique (FOT). However, both techniques have always been studied using separate cohorts of animals or systems. The objective of this study was to obtain NPFE and FOT measurements at baseline and following bronchoconstriction from a single cohort of mice using a combined system in order to assess both techniques through a refined approach.MethodsGroups of allergen- or sham-challenged ovalbumin-sensitized mice that were either vehicle (saline) or drug (dexamethasone 1 mg/kg ip)-treated were studied. Surgically prepared animals were connected to an extended flexiVent system (SCIREQ Inc., Montreal, Canada) permitting NPFE and FOT measurements. Lung function was assessed concomitantly by both techniques at baseline and following doubling concentrations of aerosolized methacholine (MCh; 31.25 - 250 mg/ml). The effect of the NPFE manoeuvre on respiratory mechanics was also studied.ResultsThe expected exaggerated MCh airway response of allergic mice and its inhibition by dexamethasone were detected by both techniques. We observed significant changes in FOT parameters at either the highest (Ers, H) or the two highest (Rrs, RN, G) MCh concentrations. The flow-volume (F-V) curves obtained following NPFE manoeuvres demonstrated similar MCh concentration-dependent changes. A dexamethasone-sensitive decrease in the area under the flow-volume curve at the highest MCh concentration was observed in the allergic mice. Two of the four NPFE parameters calculated from the F-V curves, FEV0.1 and FEF50, also captured the expected changes but only at the highest MCh concentration. Normalization to baseline improved the sensitivity of NPFE parameters at detecting the exaggerated MCh airway response of allergic mice but had minimal impact on FOT responses. Finally, the combination with FOT allowed us to demonstrate that NPFE induced persistent airway closure that was reversible by deep lung inflation.ConclusionsWe conclude that FOT and NPFE can be concurrently assessed in the same cohort of animals to determine airway mechanics and expiratory flow limitation during methacholine responses, and that the combination of the two techniques offers a refined control and an improved reproducibility of the NPFE.

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Section: Discussionsupporting

confidence: 83%

“…Forced expiratory manoeuvres have also been used to successfully assess airway hyperresponsiveness in the mouse [7-11] and rat [10,12]. In these experiments, rapid forced expiration was induced by subjecting the tracheostomized animals to a large negative pressure.…”

Section: Introductionmentioning

confidence: 99%

Combined forced oscillation and forced expiration measurements in mice for the assessment of airway hyperresponsiveness

Shalaby

Gold²,

Schuessler³

et al. 2010

Respir Res

103

View full text Add to dashboard Cite

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“…2, A-F). As previously reported elsewhere, these changes were prevented by treatment with budesonide (0.1-3 mmol/kg) (Celly et al, 2006) (Fig. 2, C and D).…”

Section: Effect Of Chf6001 and Reference Compounds On Forced Maneuversupporting

confidence: 65%

CHF6001 II: A Novel Phosphodiesterase 4 Inhibitor, Suitable for Topical Pulmonary Administration—In Vivo Preclinical Pharmacology Profile Defines a Potent Anti-Inflammatory Compound with a Wide Therapeutic Window

Villetti

Carnini

Battipaglia

et al. 2015

J Pharmacol Exp Ther

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CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide] is a novel phosphodiesterase 4 (PDE4) inhibitor designed for use in pulmonary diseases by inhaled administration. Intratracheal administration of CHF6001 to ovalbumin-sensitized Brown-Norway rats suppressed the antigen-induced decline of lung functions (ED 50 5 0.1 mmol/kg) and antigen-induced eosinophilia (ED 50 5 0.03 mmol/kg) when administered (0.09 mmol/kg) up to 24 hours before antigen challenge, in agreement with CHF6001-sustained lung concentrations up to 72 hours after intratracheal treatment (mean residence time 26 hours). Intranasal, once daily administration of CHF6001 inhibited neutrophil infiltration observed after 11 days of tobacco smoke exposure in mice, both upon prophylactic (0.15-0.45 mmol/kg per day) or interventional (0.045-0.45 mmol/kg per day) treatment. CHF6001 was ineffective in reversing ketamine/xylazine-induced anesthesia (a surrogate of emesis in rat) up to 5 mmol/kg administered intratracheally, a dose 50-to 150-fold higher than anti-inflammatory ED 50 observed in rats. When given topically to ferrets, no emesis and nausea were evident up to 10 to 20 mmol/kg, respectively, whereas the PDE4 inhibitor GSK-256066 (6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methylquinoline-3-carboxamide) induced nausea at 1 mmol/kg intratracheally. A 14-day inhalation toxicology study in rats showed a no-observed-adverse-effect level dose of 4.4 mmol/kg per day for CHF6001, lower than the 0.015 mmol/kg per day for GSK-256066. CHF6001 was found effective and extremely well tolerated upon topical administration in relevant animal models, and may represent a step forward in PDE4 inhibition for the treatment of asthma and chronic obstructive respiratory disease.

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“…Nonsensitized rats received two doses of aluminum hydroxide (8 mg/kg) administered on day 1 and day 7. Pulmonary bronchoalveolar lavage (BAL) inflammation (total and differential cell counts) was assessed following ovalbumin sensitization and challenge on day 14 using method described in detail previously (Celly et al, 2006). In the first study, we profiled the dose-response characteristics of several PIK3d inhibitors, MSD-496486311 (0.3-30 mg/kg), MSD-126796721 (10-100 mg/kg), Idelalisib (10-100 mg/kg), Duvelisib (0.3-30 mg/kg), and the glucocorticoid agonist dexamethasone (0.003-3.0 mg/kg) for 2 days.…”

Section: Respiratory Rat Models Of Th2 and Th1 Inflammationmentioning

confidence: 99%

Characterizing Pharmacokinetic–Pharmacodynamic Relationships and Efficacy of PI3Kδ Inhibitors in Respiratory Models of TH2 and TH1 Inflammation

McLeod

Gil

Chen

et al. 2019

J Pharmacol Exp Ther

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We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship established with an oral phosphatidylinositol 3-kinase (PI3K)d inhibitor (Idelalisib) in a nasal allergen challenge study to determine whether a comparable PK/PD/efficacy relationship with PI3Kd inhibitors was observed in preclinical respiratory models of type 2 T helper cell (TH2) and type 1 T helper cell (TH1) inflammation. Results from an in vitro rat blood basophil (CD63) activation assay were used as a PD biomarker. IC 50 values for PI3Kd inhibitors, MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib, were 1.2, 4.8, 0.8, and 0.5 mM. In the ovalbumin Brown Norway TH2 pulmonary inflammation model, all PI3Kd inhibitors produced a dose-dependent inhibition of bronchoalveolar lavage eosinophils (maximum effect between 80% and 99%). In a follow-up experiment designed to investigate PK attributes [maximum (or peak) plasma concentration (Cmax), area under the curve (AUC), time on target (ToT)] that govern PI3Kd efficacy, MSD-496486311 [3 mg/kg every day (QD) and 100 mg/kg QD] produced 16% and 93% inhibition of eosinophils, whereas doses (20 mg/kg QD, 10 mg/kg twice per day, and 3 mg/kg three times per day) produced 54% to 66% inhibition. Our profiling suggests that impact of PI3Kd inhibitors on eosinophils is supported by a PK target with a ToT over the course of treatment close to the PD IC 50 rather than strictly driven by AUC, Cmax, or Cmin (minimum blood plasma concentration) coverage. Additional studies in an Altenaria alternata rat model, a sheep Ascaris-sensitive sheep model, and a TH1-driven rat ozone exposure model did not challenge our hypothesis, suggesting that an IC 50 level of TE (target engagement) sustained for 24 hours is required to produce efficacy in these traditional models. We conclude that the PK/PD observations in our animal models appear to align with clinical results associated with a TH2 airway disease.

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Temporal profile of forced expiratory lung function in allergen-challenged Brown–Norway rats

Cited by 16 publications

References 23 publications

Combined forced oscillation and forced expiration measurements in mice for the assessment of airway hyperresponsiveness

Combined forced oscillation and forced expiration measurements in mice for the assessment of airway hyperresponsiveness

CHF6001 II: A Novel Phosphodiesterase 4 Inhibitor, Suitable for Topical Pulmonary Administration—In Vivo Preclinical Pharmacology Profile Defines a Potent Anti-Inflammatory Compound with a Wide Therapeutic Window

Characterizing Pharmacokinetic–Pharmacodynamic Relationships and Efficacy of PI3Kδ Inhibitors in Respiratory Models of TH2 and TH1 Inflammation

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