8 RESEARCH & DEVELOPMENT

thma re arch - alternati e approach

Airway epithelium plays a central role Airway epithelial cells can play a central role

in airway inflammation and the understanding of these cells may facilitate a new therapeutic intervention in airway diseases, suggests researchers from the University of Tokyo, Japan.

In asthma, injury of the epithelial cells occurs, with marked inflammatory cell infiltration, especially eosinophils.

The composition of the cell membrane glycolipids has been postulated to playa role in inflammatory diseases. Quantitative and qualitative changes in these glycolipids can occur in inflammation.

The researchers suggest that it is possible that airway epithelial cells express antigen, as do other cells, e.g. I antigen, involved in diffuse pan bronchiolitis (DPB), a chronic airway inflammatory condition.

Additionally, certain tumour-associated antigens are cell membrane glycolipids (e.g. SLX and CAI9-9, which are reported t. be elevated in patients with OPB). Additionally, bacteria attach to cell surfaces by way of receptors on cell membranes, most of which are glycolipid. Takizawa H. Ohta K. Ito K. Airway epithelial cells and airway inflammation. Kokyu Respiration Research 10: 1488·1495. Dec 1991 [Abstract; original in Japanese)

Symposium on airways inflammation

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Interleukin 5, FcERII receptors and adhesion molecules represent attractive targets for drug therapy for asthma, says independent consultant Dr Michael J Parnham, Germany, in summing' up the meeting, New Concepts in Asthma. The symposium was held on IS-20th September 1991 and was organised by Pierre Fabre Medicaments.

There is a relationship between eosinophil infiltration/activation and airways hyper­reactivity. 19E is a pathological factor involved in allergy. Receptors for 19EFc.RII are present on eosinophils, macrophages and platelets. The expression of this receptor is enhanced on macrophages in atopic disorders.

Interleukin 5 is involved in eosinophil differentiation and is only important in the induction of inflammation in association with other mediators, such as platelet activating factor.

Endothelial cell adhesion molecules which bind leucocytes, are also thought to pl~y a role in asthma. The presence of endothelial cells facilitates eosinophil viability, and the expression of these adhesion molecules is enhanced in patients with asthma. In animal studies, monoclonal antibodies to specific adhesion molecules can inhibit eosinophil infiltration and activation in response to antigen challenge in chronically inflamed airways.

Dr Parnham concludes that there can be little doubt of a close relationship between airway inflammation and bronchial hyper-reactivity.

However the eosinophil is not the only cell involved, and airways hyper-responsiveness can be a distinctly separate process from airways inflammation.

Parnham MJ. New concepts in asthma. Drua News and Perspectives 4: 559·562. Nov 1991 .. "

Roche's leukotriene antagonist potent Roche researchers report that preclinical

studies demonstrate that their novel antiasthma the~py, RO 24-5913 [in phase I studies], is actIve orally, parenterally and via inhalation, has good bioavailability, a long duration of action and is a selective leukotriene (L T) 04 antago~ist. The product has the potential to be clinically efficacious in diseases mediated by LT04.

Leukotrienes are thought to be involved in a variety of lung diseases, including asthma. ~mooth mu~le spasm, airway hyper-reactivity, lOcreased mIcrovascular permeability, mucus hypersecretion and decreased mucociliary transport effects are attributed to L T C4, 04 and E4 effects. Recently developed L TD4 antagonists ha,:e demonstrated protective effects against antIgen challenge in patients with mild asthma.

RO 24-5913 pretreatment significantly inhibited antigen-induced bronchoconstriction in a guinea­pig model, with the leukotriene component unmasked. This antagonism of bronchoconstriction was 3 to 6-fold greater than that against bronchoconstriction induced by exogenous leukotrienes. O'Donnell M, Crowley HJ, Yaremko B, O'Neill N, Welton AF. Pharmacologic actions of Ro 24-5913, a novel antaaonist of leukotriene 04. Journal of PharmacoloaY and Experimental Therapeutics 259: 751.758, Nov 1991

~ Editoritd comme"t: Roche are expected to begin clinical trials with RO 24·5913 this year.

Roche's PAF antagonist also promising

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Roche's platelet activating factor (PAF) antagonist, Ro 24-4736, is a promising candidate for clinical evaluation in asthma, state company researchers.

PAF is thOUght to be a mediator of allergen­induced bronchial asthma. It can induce a profile of effects which mimics many features of asthma including bronchoconstriction. '

Preclinical studies in a variety of asthma models with Ro 24-4736 indicate that it is potent, specific, orally active and has a long duration of action. Crowley HI, Yaremko B. Selia WM, Janero DR, BUrghardt C, et aI. Pharmacoloay of a potent p1atelet·activatina factor antaaonist Ro 24-4736. Journal of Pharmacoloay and Experimental Therapeutics 259: 78-85, Oct 1991

Nissan evaluate potassium channel opener Researchers from Nissan Chemical Industries

(Japan) report that their novel potassium channel

ISSNOl56-2703/92/0222.()()()8/S1 .00/0 © Add ~"'11CIIionaI lid

RESEARCH & DEVELOPMENT

opener, NIP-121 [preclinical], suppresses the spontaneous tone of isolated guinea pig trachea and also the tone induced by prostaglandin F2a and prostaglandin 02.

NIP-121 had 10 to 20-fold the relaxant effects of another potassium channel opener, cromakalim [SmithKline Beecham], in response to the prostanoid spasmogen. The suppressant effects of both NIP-121 and cromakalim were less effective against L T04, L TC4 and histamine spasmogens than against the prostanoid spasmogens. Shikada K-i. Yamamoto A. Tanaka S. NIP-I2I and cromakalim. potassium channel openers. preferentially suppress prostanoid-induced contraction of the guinea-pig isolated trachea. European Journal of Pharmacology 209: 69-73. 10 Dec I 991 ~'"

ISSN 0156-2703/92/0222-0009/$1.00/0 © Adis 1nIan ... 1iollollJd

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INPHARMA® 22 Feb 1992