Author: Jean-Marie Zahm ; Béatrice Nawrocki-Raby ; Férial Toumi ; Malcolm Johnson ; Franck Delavoie ; Claire Kileztky ; Christelle Coraux ; Jean Michel ; Philippe Birembaut ; Gérard Balossier

BACKGROUNDStaphylococcus aureus releases virulence factors (VF) that may impair the innate protective functions of airway cells. The aim of this study was to determine whether a long-acting beta2 adrenergic receptor agonist (salmeterol hydroxynaphthoate, Sal) combined with a corticosteroid (fluticasone propionate, FP) was able to regulate ion content and cytokine expression by airway glandular cells after exposure to S. aureus supernatant.METHODSA human airway glandular cell line was incubated with S. aureus supernatant for 1 h and then treated with the combination Sal/FP for 4 h. The expression of actin and CFTR proteins was analyzed by immunofluorescence. Videomicroscopy was used to evaluate chloride secretion and X-ray microanalysis to measure the intracellular ion and water content. The pro-inflammatory cytokine expression was assessed by RT-PCR and ELISA.RESULTSWhen the cells were incubated with S. aureus supernatant and then with Sal/FP, the cellular localisation of CFTR was apical compared to the cytoplasmic localisation in cells incubated with S. aureus supernatant alone. The incubation of airway epithelial cells with S. aureus supernatant reduced by 66% the chloride efflux that was fully restored by Sal/FP treatment. We also observed that Sal/FP treatment induced the restoration of ion (Cl and S) and water content within the intracellular secretory granules of airway glandular cells and reduced the bacterial supernatant-dependent increase of pro-inflammatory cytokines IL8 and TNFalpha.CONCLUSIONSOur results demonstrate that treatment with the combination of a corticosteroid and a long-acting beta2 adrenergic receptor agonist after bacterial infection restores the airway glandular cell function. Abnormal mucus induced by defective ion transport during pulmonary infection could benefit from treatment with a combination of beta2 adrenergic receptor agonist and glucocorticoid.

01 May 2010·Human & Experimental ToxicologyQ4 · MEDICINE

The preclinical toxicology of salmeterol hydroxynaphthoate

Q4 · MEDICINE

Article

Author: Beck, SL ; Damment, SJP ; Owen, K.

An extensive toxicology programme on salmeterol hydroxynaphthoate (SereventTM), a marketed long-acting β2-adrenoceptor agonist, has been carried out. The studies evaluated both the local (respiratory tract) and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential. High acute doses were well tolerated and caused no specific target organ toxicity. In repeat dose studies, animals tolerated salmeterol very well both locally and systemically. No significant effects on the respiratory tract of dogs were seen and only minor laryngeal changes, typical of those occurring with many inhaled medicines, were noted in rats. The high systemic concentrations achieved resulted in a number of changes that are considered to be the result of excessive and prolonged β 2-adrenoceptor stimulation. These included tachycardia, skeletal muscle hypertrophy and minor haematological and blood biochemical changes in general toxicity studies, foetal effects in rabbit organogenesis studies and increased incidences of smooth muscle tumours of the mesovarium in the rat and of the uterus in the mouse oncogenicity studies. Salmeterol showed no evidence of any genotoxic potential. Results of the extensive toxicology programme provide good assurance of the safety for the inhaled use of salmeterol in patients; this has ben confirmed by many years of clinical experience during its development and marketing.

01 Jun 2003·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Chemical synthesis and cytotoxicity of dihydroxylated cyclopentenone analogues of neocarzinostatin chromophore

Q4 · MEDICINE

Article

Author: Lisa M Frost ; Derek N Woolfson ; Stephen Caddick ; Michael D Urbaniak ; Lloyd R Kelland ; John A Hartley ; John P Bingham

Compounds containing the naphthoate moiety of Neocarzinostatin chromophore or 2-hydroxynaphthoate have been synthesized and evaluated for cytotoxic activity against a leukemia cell line and a small panel of human-tumor cell lines. Those compounds containing a cyclopentenone moiety were active, with the carbonyl group being essential for biological activity.

100 Deals associated with Bephenium Hydroxynaphthoate

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-	Bephenium Hydroxynaphthoate	P02CX02	-

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