Sharon K. Shields

Novel steroid‐based inhibitors of lung inflammation

It is now well-recognized that eosinophil products contribute to the mucosal damage which is a prominent feature of bronchial asthma. Eosinophils migrate to the bronchial epithelium following allergen inhalation in sensitive subjects, and increases in eosinophil numbers are associated with late-phase broncho-conslrictions [I]. The eosinophils capacity to generate lipid mediators [2.3] and the presence of cytotoxic. highly-charged, arginine-rich proteins in the eosinophil granules implicate this cell further as a contributor to mucosal inflammation. An attractive goal in the search for novel anti-asthma drugs would be to discover and develop compounds which inhibit eosinophil activation and/or prevent the influx of eosinophils into the airways. Steroids arc probably the most efficacious drugs currently available for the treatment of asthma, and improvements in symptoms in patients treated with steroids have been associated with a parallel reduction in blood eosinophil counts [4]. Corticosteroids have also been shown to abrogate the development of late-phase asthmatic reactions with a parallel reduction in eosinophil activity as measured by serum eosinophil cationic protein (ECP) levels [5]. Inhaled glucocorticoids which demonstrate few side-effects are increasingly being used worldwide as a prophylactic treatment for the disease. Novel inhaled glucocorticoids which have been designed to break down rapidly after reaching the systemic circulation are currently being developed and are even less likely to suppress the hypothalamo-pituitary adrenal axis. In this paper we have reviewed some of the novel. steroid-based molecules currently in clinical development for treating asthma. In addition we emphasize the change in direction the pharmaceutical industry has taken towards the use of inflammation-based animal models for the screening of novel compounds, and we also describe the activity of some novel, non-glucocorticoid. 21 -aminosteroids which may prove useful in the treatment of asthma.

Anti-inflammatory/antiarthritic ketonic bisphosphonic acid esters

Bisphosphonate ester 2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds 6e, 6i, 6j, and 6m, which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.

Chasing the elusive animal model of late-phase bronchoconstriction: Studies in dogs, guinea pigs and rats

SummaryAntigen inhalation in sensitized dogs, guinea pigs and rats resulted in a marked, late-phase, eosinophil-rich, influx of inflammatory cells into the bronchial lumen. Attempts to demonstrate an associated late-phase bronchoconstriction were disappointing. We were unable to demonstrate a late-phase bronchoconstriction in either rats or dogs, even when dogs were pretreated with metyrapone to reduce blood cortisol levels. In ovalbumin-sensitized guinea pigs, challenged with low doses of ovalbumin, we observed an immediate bronchoconstriction, a late-phase bronchopulmonary eosinophilia but no late-phase bronchoconstriction. However, inhalation of very high doses of antigen in mepyramine-treated sensitized guinea pigs did induce a moderate late-phase bronchoconstriction.

New Anti-Inflammatory/Anti-Arthritic Heterocyclic Bisphosphonates

Abstract. In the course of research toward a safe and effective treatment for rheumatoid arthritis, we identified new pyrazolo[1,5-a]pyrimidine and 4-pyrimidinone bisphosphonate esters, which are potent inhibitors of a murine model of chronic, cutaneous inflammation (delayed type hypersensitivity granuloma) and a murine antigen induced arthritis model. 9a has EC30 values of 0.01 and 0.005 mg/kg respectively and represents a new class of antiinflammatory/antiarthritic bisphosphonate ester.

The inflammatory potential of IL-2: local induction of a specific chronic granulomatous lesion in mice

Subcutaneous injection of recombinant human interleukin‐2 (rhuIL‐2) at 102‐104 U/mouse induced delayed (48 h) accumulation of mononuclear leukocytes with diffuse granulocytes, including eosinophils. Subcutaneous local infusion of rhuIL‐2 or recombinant murine IL‐2 (102–104 U/mouse) via implanted Alzet miniosmotic pumps in mice induced chronic inflammatory lesions characterized by infiltration of large vacuolated mononuclear leukocytes, lymphoid cells, and eosinophil foci; neovascularization, with high endothelial‐like cells, was prominent, exhibiting intravascular trapping and migration of large mononuclear leukocytes. Leukocyte infiltrates comprised T lymphocytes (CD4+; CD8+), B lymphocytes, and macrophages. Control infusions of bovine serum albumin (BSA) induced weak fibrotic lesions with sparse macrophage infiltration and minimal accumulation of lymphocytes; VLA4+ and ICAM‐1+ leukocyte infiltrates were significantly greater in IL‐2‐induced lesions compared with BSA‐induced lesions. Quantitative image analysis showed significantly increased lesion size in the IL‐2‐induced lesions compared with those induced by BSA infusion. The vascularity of IL‐2‐induced lesions assessed by immunostaining for platelet‐endothelial cell adhesion molecule was increased compared with control, BSA‐induced lesions mainly due to neovascularization. ICAM‐1 and VCAM‐1 expression was significantly enhanced in IL‐2 lesions. No systemic pathological changes were observed following IL‐2 infusion. We conclude that local slow‐release of IL‐2 causes the evolution and maintenance of a specific chronic inflammatory lesion.