MECANISME DE L'HYPERREACTIVITE BRONCHIQUE A L'ADENOSINE INDUITE PAR UNE PROVOCATION ALLERGENIQUE CHEZ DES RATS BROWN NORWAY ACTIVEMENT SENSIBILISES

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Magnetic resonance imaging in drug discovery: lessons from disease areas.

Imaging technologies are presently receiving considerable attention in the pharmaceutical area owing to their potential to accelerate the drug discovery and development process. One of the principal imaging modalities is magnetic resonance imaging (MRI). The multiparametric nature of MRI enables anatomical, functional and even molecular information to be obtained non-invasively from intact organisms at high spatial resolution, thereby enabling a comprehensive characterization of a disease state and the corresponding drug intervention. The non-invasiveness of MRI strengthens the link between pre-clinical and clinical drug studies, making the technique attractive for pharmaceutical research

Proton MRI of lung parenchyma reflects allergen-induced airway remodeling and endotoxin-aroused hyporesponsiveness: a step toward ventilation studies in spontaneously breathing rats.

Proton signals from lung parenchyma were detected with the use of a gradient-echo sequence to noninvasively obtain information on pulmonary function in models of airway diseases in rats. Initial measurements carried out in artificially ventilated control rats revealed a highly significant negative correlation between the parenchymal signal and the partial pressure of oxygen (pO2) in the blood, for different amounts of oxygen administered. The magnitude of the signal intensity variations caused by changes in the oxygen concentration was larger than expected solely from the paramagnetic properties of molecular oxygen. Inhomogeneous line-broadening induced by lung inflation may explain the observed signal amplification. Experiments carried out in spontaneously breathing animals challenged with allergen or endotoxin revealed parenchymal signal changes that reflected the oxygenation status of the lungs and were consistent with airway remodeling or hyporesponsiveness. The results suggest that proton MRI of parenchymal tissue is a sensitive tool for probing the functional status of the lung in rat models of respiratory diseases. The method is complementary to the recently described noninvasive assessment by MRI of pulmonary inflammation in small rodents. Overall, these techniques provide invaluable information for profiling anti-inflammatory drugs in models of airway diseases

Suppression of Adenosine A 3 Receptor-Mediated Hypotension and Mast Cell Degranulation in the Rat by Dexamethasone

ABSTRACT Dexamethasone increases the expression of adenosine A 3 receptors and augments degranulation in response to their activation in the rat basophilic leukemia cell line, RBL-2H3. We have studied the effects of dexamethasone on mast cell activation induced by A 3 receptor stimulation in vivo

Two-dimensional electrophoresis protein profiling and identification in rat bronchoalveolar lavage fluid following allergen and endotoxin challenge.

The protein content of bronchoalveolar lavage fluid (BALF) from actively sensitised Brown Norway (BN) rats challenged with allergen (ovalbumin, OA) and from naïve Brown Norway rats challenged with endotoxin (lipopolysaccharide, LPS) was analyzed and compared to healthy controls treated with vehicle only. BALF proteins were analyzed by one-dimensional (1-D) and two-dimensional (2-D) gel electrophoresis and identified by peptide mass fingerprinting matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS) or nanoliquid chromatography-tandem MS (nanoLC-MS/MS) after in-gel trypsin digestion of selected 2-D gel spots. Our study shows that the BALF protein profile is significantly different in animals after allergen (OA) or endotoxin (LPS) challenge as compared to controls, concerning the content of proteins derived from plasma or produced locally in the lung. In both challenges the following proteins presented patterns which differed qualitatively compared to control: T-kininogen I and II, alpha-1-antitrypsin, calgranulin A, fetuin A and B, and haptoglobin. Other proteins were diminished in both challenges, such as Clara cell 10 kDa secretory protein (CC10) and pulmonary surfactant associated protein B (SP-B); c-reactive protein increased in the OA-challenge and decreased in the LPS-challenge, and pulmonary surfactant associated protein A (SP-A) was decreased in the OA-challenge and was not significantly changed in the LPS-challenge. The identified proteins could be important not only for the diagnosis but have also interesting implications for medical treatment of lung inflammatory conditions. Furthermore, even if based on a limited number of animals, our results are of interest for the identification of lung protein markers and a better understanding of the mechanisms involved in the pathogenesis of lung diseases

1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats

The simultaneous effect of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying was evaluated with the test compound NVS308, a novel CRF1 antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pre-treatment of rats with 100 mg/kg oral. ABT administered 2 hours prior to a semi-solid caloric test meal, markedly delayed gastric emptying. ABT increased stomach weights by 2-fold, this is likely to be attributed to a pro-secretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS308 and increased Tmax 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasma-concentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of co-administered compounds can be expected due to a disturbance of gastrointestinal transit

Near-infrared fluorescence imaging and histology confirm anomalous edematous signal distribution detected in the rat lung by MRI after allergen challenge.

PURPOSE: To address the issue concerning the predominant location, on the left anatomic side, of edematous signals detected by magnetic resonance imaging (MRI) in the lungs of actively sensitized rats following intratracheal (IT) allergen challenge. MATERIALS AND METHODS: Near-infrared fluorescence (NIRF) imaging was used to detect the lobular distribution in the lungs of normal rats of an IT instilled fluorescent dye, Cy5.5. Actively sensitized Brown Norway rats were examined by MRI 24 hours after IT administration of ovalbumin. The perivascular edema was quantified by histology in the different lobes of lungs removed from the same animals immediately after the MRI acquisitions. RESULTS: An uneven distribution of Cy5.5 was found, predominantly on the left lobe, paralleling the localized development of allergic pulmonary inflammation in the left lobe detected as edematous signal by MRI and confirmed by histology. The patterns of the distributions of the dye between and within the lobes were very similar to those of perivascular edema assessed histologically. CONCLUSION: The data indicate a relationship between the molecular deposition of the dye detected by NIRF in the lungs and the distribution of allergen eliciting the development of pulmonary inflammation in actively rats. The combination of MRI with NIRF imaging may provide important information in preclinical pharmacologic research in the area of airway diseases. While MRI is able to address the effects of compounds on the inflammatory response in models of airways diseases, NIRF imaging may provide important insights on drug distribution and interaction in the lung, being thus suited for molecular imaging studies

Title Page 1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats

Non-standard abbreviations: ABT, 1-aminobenzotriazole; AUC, area under the concentration-time curve; C max , Highest drug concentration observed in plasma after administration of extravascular dose; P450, cytochrome P450; LC-MS/MS, liquid chromatography tandem mass spectrometry; T max , Time at which highest concentration occurs after extravascular dose. DMD#056408 3 Abstract The simultaneous effect of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying was evaluated with the test compound NVS-CRF38, a novel CRF 1 antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pre-treatment of rats with 100 mg/kg oral ABT administered 2 hours prior to a semi-solid caloric test meal, markedly delayed gastric emptying. ABT increased stomach weights by 2-fold, this is likely to be attributed to a prosecretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS-CRF38 and increased T max 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasmaconcentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of co-administered compounds can be expected due to a disturbance of gastrointestinal transit. DMD#05640

Lung MRI for experimental drug research.

Current techniques to evaluate the efficacy of potential treatments for airways diseases in preclinical models are generally invasive and terminal. In the past few years, the flexibility of magnetic resonance imaging (MRI) to obtain anatomical and functional information of the lung has been explored with the scope of developing a non-invasive approach for the routine testing of drugs in models of airways diseases in small rodents. With MRI, the disease progression can be followed in the same animal. Thus, a significant reduction in the number of animals used for experimentation is achieved, as well as minimal interference with their well-being and physiological status. In addition, under certain circumstances the duration of the observation period after disease onset can be shortened since the technique is able to detect changes before these are reflected in parameters of inflammation determined using invasive procedures. The objective of this article is to briefly address MRI techniques that are being used in experimental lung research, with special emphasis on applications. Following an introduction on proton techniques and MRI of hyperpolarized gases, the attention is shifted to the MRI analysis of several aspects of lung disease models, including inflammation, ventilation, emphysema, fibrosis and sensory nerve activation. The next subject concerns the use of MRI in pharmacological studies within the context of experimental lung research. A final discussion points towards advantages and limitations of MRI in this area