Asthma. Eosinophils and neutrophils.

Eosinophils are strongly implicated as a major proinflammatory cell in the pathogenesis of asthma. Basic proteins from the crystalloid granule may be responsible for damage to mucosal epithelium whereas membrane-derived lipid mediators (particularly platelet activating factor and leukotriene C4) might directly influence bronchial smooth muscle contraction, microvascular permeability and mucus hypersecretion. The numbers of eosinophils and their products correlated with the severity of disease whereas successful treatment is usually associated with a resolution of local eosinophilia. Neutrophils may also be implicated in the pathogenesis of asthma but the evidence that this cell per se plays an important role remains controversial. Neutrophil products have the potential for altering airway function. More research is required to define the precise role of this cell type in asthma. It needs to be emphasised that the inflammation associated with bronchial asthma is complex and involves several cell types (i.e. T lymphocytes, mast cells and macrophages) in addition to the eosinophil and neutrophil.     

Novel euglycemic and hypolipidemic agents. 4. Pyridyl- and quinolinyl-containing thiazolidinediones.

A series of substituted pyridyl- and quinolinyl-containing 2, 4-thiazolidinediones having interesting cyclic amine as a linker have been synthesized. Both unsaturated thiazolidinediones 5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL-49653, respectively. Some of the potent compounds were converted to various salts in order to obtain improved activities. Among all the salts evaluated, the maleate salt of unsaturated TZD 5a was found to be a very potent euglycemic and hypolipidemic compound. Some of the more interesting compounds have also been evaluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL-49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies of PPARgamma by 5a/5a maleate did not show any significant transactivation of PPARalpha or PPARgamma.