Effects of cyclosporin A administered into the airways against antigen-induced airway inflammation and hyperreactivity in the rat.

The immunosuppressant cyclosporin A given orally has anti-asthma properties but carries an undesirable risk of systemic effects. We administered cyclosporin A to Brown Norway rats either orally (p.o.) or topically by intratracheal (i.t.) instillation into the airways before inhaled antigen. Cyclosporin A suppressed the antigen-induced accumulation of activated (CD25+) CD4+ T lymphocytes and eosinophils in the lung, interleukin-5 mRNA expression in lung tissue and airway hyperreactivity. Intratracheal cyclosporin A suppressed cell accumulation at a 10-fold lower dose than that required orally. Minimum effective doses were 3 mg x kg(-1) i.t. and 30 mg x kg(-1) p.o. Intratracheal administration reduced the plasma concentration and systemic exposure compared with an equieffective oral dose, but the reduction (4-5-fold) was not as large as anticipated. Our data suggests that although topical administration to asthmatics would provide some potential for an improved safety margin, it may not offer any major advantage over existing oral therapy. However, the data clearly demonstrate that a novel immunosuppressant with similar anti-inflammatory properties but reduced potential for systemic effects would offer an attractive therapy for severe asthma.

Uncoupler resistance in E. coli Tuv and Cuv is due to the exclusion of uncoupler by the outer membrane.

The uncoupler resistant bacterial strains E. coli Tuv and Cuv share the high deoxycholate sensitivity of the parent strain, Doc S. However, both Tuv and Cuv show greater resistance than Doc S to other detergents. Measurement of the periplasmic volume indicates that the outer membrane of Doc S is freely permeable to both TPP+ and hydroxymethylinulin. Tuv and Cuv are able to exclude these compounds. EDTA treatment was necessary prior to measuring membrane potential in Tuv and Cuv. Under conditions where delta phi could be measured, uncouplers acted to dissipate delta phi with equal potency in all strains. Uncoupler resistant proline uptake in Tuv and Cuv was abolished by EDTA treatment. Transduction experiments with phage P1 showed that uncoupler resistance could be transferred from Tuv to Doc S. Such transductants were no longer sensitive to novabiocin. The gene for uncoupler resistance cotransduced with the gene pyrE (82 min). Plating efficiency experiments with P1 suggests that detergent sensitivity in Doc S arises from an rfa (81 min) mutation. This mutation is no longer present in Tuv.

Cytochrome P-450 in the housefly: induction, substrate specificity and comparison to three rat hepatic isoenzymes.

1. Both phenobarbital and clofibrate pretreatment cause a qualitative change in cytochrome P-450 content in housefly (Musca domestica). Based on changes in substrate specificity, both inducing agents appear to cause induction of an isoenzyme (or group of isoenzymes) of cytochrome P-450 in housefly, and this response is similar in extent and effect to that described in rodents. 2. Using Western blot analysis and probing with antibodies to three rat hepatic isoenzymes (P450 IA1, P450 IIB1 and P450 IVA1), common structural epitopes with housefly cytochrome P-450 were sought. Despite similarities in patterns of induction and catalytic function, little evidence for structural commonality between the cytochrome P-450 in rat and housefly was observed.

High-performance liquid chromatography of pirimiphos methyl and five metabolites.

Pirimiphos methyl is an organophosphorus insecticide which is rapidly metabolised by plants and animals to several modified triesters and free hydroxyprimidines. A method is described for the determination by reversed-phase high-performance liquid chromatography of pirimiphos methyl and its five major metabolites in plasma and urine. Separations were performed by isocratic and gradient elutions from short columns packed with SAS-Hypersil, a relatively new column packing.