Resolution of the oedema associated with allergic pulmonary inflammation in rats assessed noninvasively by magnetic resonance imaging

Tigani, Bruno; Cannet, Catherine; Zurbrügg, Stefen; Schaeublin, Elisabeth; Mazzoni, Lazzaro; Fozard, John R.; Beckmann, Nicolau

doi:10.1038/sj.bjp.0705429

Cited by 37 publications

(36 citation statements)

References 19 publications

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“…Both RPL554 and RPL565 when delivered as a dry powder significantly attenuated plasma protein extravasation induced by histamine in the guinea pig. This is in agreement with previous studies demonstrating that the PDE4-selective inhibitors NVP-ABE171 and YM976 inhibited antigen-induced edema in the airways (Aoki et al, 2001;Tigani et al, 2003). Together, these studies demonstrated the effectiveness of this class of drug on edema formation in the airways.…”

Section: Discussionsupporting

confidence: 82%

The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 [9,10-Dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]

Boswell-Smith

Spina²,

Oxford³

et al. 2006

J Pharmacol Exp Ther

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The pharmacology of two novel, trequinsin-like PDE3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido-[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one], has been investigated in a number of in vitro and in vivo assays. Electrical field stimulation-induced contraction of guinea pig superfused isolated tracheal preparations was significantly inhibited by RPL554 (10 M) and RPL565 (10 M) (percentage control; 93 Ϯ 1.2 and 84.4 Ϯ 2.7, respectively). Contractile responses were suppressed for up to 12 h after termination of superfusion with RPL554 demonstrating a long duration of action. RPL554 and RPL565 inhibited, in a concentration-dependent manner, lipopolysaccharide-induced tumor necrosis factor ␣ release from human monocytes [IC 50 ; 0.52 M (0.38 -0.69) and 0.25 M (0.18 -0.35), respectively] and proliferation of human mononuclear cells to phytohemagglutinin [IC 50 ; 0.46 M (0.24 -0.9) and 2.90 M (1.6 -5.4), respectively]. The inhibitory effect of these drugs in vitro was translated into anti-inflammatory activity in vivo. RPL554 (10 mg/kg) and RPL565 (10 mg/kg) administered orally significantly inhibited eosinophil recruitment following antigen challenge in ovalbumin-sensitized guinea pigs. Likewise, inhalation of dry powder containing RPL554 by conscious guinea pigs (25% in micronized lactose) 1.5 h before antigen exposure significantly inhibited the recruitment of eosinophils to the airways. Exposure of conscious guinea pigs to inhalation of dry powder containing RPL554 (2.5%) and RPL565 (25%) in micronized lactose significantly inhibited histamine-induced plasma protein extravasation in the trachea and histamine-induced bronchoconstriction over a 5.5-h period. Thus, RPL554 and RPL565 are novel, long-acting PDE 3/4 inhibitors exhibiting a broad range of both bronchoprotective and anti-inflammatory activities.It is now recognized that the second messenger cAMP plays a pivotal role in the regulation of cell function, and cyclic nucleotide phosphodiesterases (PDEs) are a diverse family of enzymes (1-11) responsible for the degradation of cAMP and are therefore potential drug targets for modulating cell function (Essayan, 2001). In the context of lung diseases, it is of particular interest that inhibiting the PDE3 and PDE4 isoenzymes can modulate the function of a variety This work was supported by Vernalis Plc. Article, publication date, and citation information can be found at

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Section: Discussionsupporting

confidence: 82%

The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 [9,10-Dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]

Boswell-Smith

Spina²,

Oxford³

et al. 2006

J Pharmacol Exp Ther

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“…Unfortunately, this technique has not been shown to be a useful assessment of airway inflammation in asthmatics [15], unless under conditions of a segmental allergen challenge [16,17], most likely because neutrophils, a cell-type with a debatable association to allergic asthma, use more glucose than other cell types when activated [18,19]. Magnetic resonance imaging has also been used to detect inflammatory changes [20][21][22] as well as functional disruption after allergen exposure [23] in experimental models of asthma. Although this modality provides superior soft tissue contrast with no known deposition of radiation, CT is more widely available and is more commonly associated with PET and single photon emission CT (SPECT) radio-imaging technologies.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of allergic lung inflammation by computed tomography in a rat model in vivo

Jobse

Johnson²,

Farncombe³

et al. 2009

European Respiratory Journal

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The ability of micro-computed tomography (CT) to noninvasively evaluate allergic pulmonary inflammation in an experimental model was investigated. In addition, two image segmentation methods and the value of respiratory gating were investigated in the context of this model.Brown Norway rats were exposed to one of four doses of house dust mite (HDM) extract (0, 0.15, 15 or 150 mg) delivered intratracheally every 24 h for 10 days. CT scanning was performed at baseline and after several longitudinal HDM exposures.Both thoracic-and lung-segmentation methods yielded similar results when standardisation practices were employed. While tissue histology correlated well with CT images, cell counts from bronchoalveolar lavage depicted greater inflammation than did density measures from CT images. Evidence from representative CT slices and transaxial density distribution indicated that inflammation was primarily associated with major airways and extended into the periphery from these focal points. Respiratory gating demonstrated that images of the inspiratory state provided greater contrast of inflammatory processes. Lastly, decreases in tidal volumes indicated significant mechanical respiratory changes in animals exposed to both 15 and 150 mg.In summary, CT image segmentation can extract pertinent data on in vivo allergic airway/lung inflammation. Furthermore, respiratory gating provides additional contrast and insight into these quantification practices.

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“…The MRI signals after OVA challenge correlated significantly with a variety of inflammatory parameters determined in the BAL fluid recovered from the same animals. It is noteworthy that the fluid signals detected by MRI correlated significantly with the perivascular edema assessed by histology (Tigani et al, 2003a;Blé et al, 2008). Micro-CT also has been used to quantify edema in a rat model of allergic lung inflammation (Jobse et al, 2009).…”

Section: Imaging In Respiratory Diseases: From Animal Models To Patientsmentioning

confidence: 99%

“…When assessing the effects of anti-inflammatory drugs administered before disease induction in these models, a doserelated reduction of the MRI signals has been shown for compounds such as the glucocorticosteroids budesonide (Beckmann et al, 2001a;Tigani et al, 2003a;Blé et al, 2009a) (Fig. 2) and mometasone (Tigani et al, 2003a) and a mitogen-activated protein kinase inhibitor (Tigani et al, 2003a).…”

Section: Imaging In Respiratory Diseases: From Animal Models To Patientsmentioning

confidence: 99%

See 1 more Smart Citation

A View on Imaging in Drug Research and Development for Respiratory Diseases

Echteld¹,

Beckmann²

2011

J Pharmacol Exp Ther

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With the incidence of respiratory diseases increasing throughout the world, new therapies are needed. This review provides a short overview of different imaging techniques of interest for drug discovery and development within the pulmonary disease area. The focus is on studies performed in both animals and humans, which are of importance for understanding pathophysiological aspects and evaluating new drugs. Rather than emphasizing particular lung diseases, the noninvasive diagnosis and quantification of a number of characteristics related to several pathological conditions of the lung are addressed: inflammation, mucus secretion and clearance, emphysema, ventilation, perfusion, fibrosis, airway remodeling, and pulmonary arterial hypertension. Techniques are discussed based on their present use or potential future utilization in the context of drug studies.

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Resolution of the oedema associated with allergic pulmonary inflammation in rats assessed noninvasively by magnetic resonance imaging

Abstract: 1 Magnetic resonance imaging (MRI) was used to study noninvasively the effects of compounds to resolve inflammation induced by ovalbumin (OVA) challenge in the lungs of actively sensitised rats.

Cited by 37 publications

References 19 publications

Evaluation of allergic lung inflammation by computed tomography in a rat model in vivo

A View on Imaging in Drug Research and Development for Respiratory Diseases

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