Intranasal GSK2245035, a Toll-like receptor 7 agonist, does not attenuate the allergen-induced asthmatic response in a randomized, double-blind, placebo-controlled experimental medicine study.

BACKGROUND: Allergic asthma is a heterogenous disorder predominantly driven by a type 2 inflammatory response to aeroallergens. Therapeutic modulation to rebalance these type 2 responses may offer clinical benefit for allergic respiratory inflammatory diseases, with the potential for disease modification. GSK2245035, a selective toll-like receptor-7 agonist, preferentially stimulates the induction of type 1 interferon alpha, reducing type 2 responses. OBJECTIVE: This study investigated whether intranasal GSK2245035 reduced allergen-induced bronchial reactivity in mild allergic asthma. METHODS: This double-blind, placebo-controlled, parallel-group Phase IIa trial randomized (1:1) participants with mild allergic asthma to intranasal GSK2245035 20 ng or placebo once weekly for 8 weeks; follow-up was conducted 1, 4, and 12 weeks after treatment. Allergen-induced late asthmatic response 1 week after treatment was measured as minimum and weighted mean forced expiratory volume in 1 second (FEV1) 4-10 hours following bronchial allergen challenge (primary endpoint). Pharmacodynamic and allergic biomarkers, and adverse events, were assessed. A Bayesian analysis framework was used; a posterior probability >0.7 denoted primary endpoint success. RESULTS: Thirty-six participants were randomized (GSK2245035, n = 22; placebo, n = 14). The percentage attenuation in late asthmatic response was -4.6% (posterior probability: 0.385) and -10.5% (posterior probability: 0.303) for minimum and weighted mean FEV1, respectively. Type 2 responses were confirmed by changes in lung function, eosinophils (blood and sputum), interleukin-5 (sputum) and fractional exhaled nitric oxide biomarkers pre- and post-bronchial allergen challenge. However, no treatment effect was observed. Adverse events were reported by 10/14 (71%) and 21/22 (95%) participants in the placebo and GSK2245035 groups, respectively; headache was the most common. CONCLUSIONS AND CLINICAL RELEVANCE: Although target engagement was observed, weekly intranasal GSK2245035 20 ng for 8 weeks did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. Overall, treatment was well tolerated.

The influence of simulated immigration and chemical persistence on recovery of macroinvertebrates from cypermethrin and 3,4-dichloroaniline exposure in aquatic microcosms.

BACKGROUND: Chemical dissipation and organism immigration are considered important factors that influence recovery potential from perturbation of aquatic macroinvertebrates. Experiments were conducted to investigate the effect of simulated immigration on recovery of aquatic macroinvertebrates exposed in outdoor microcosms to ecotoxicologically similar concentrations of the rapidly dissipating pyrethroid insecticide cypermethrin (70 ng L(-1)) or the more persistent herbicide intermediate and degradate 3,4-dichloroaniline (10 mg L(-1)). Microcosms were covered with light-permeable mesh to prevent recolonisation. Immigration was simulated by the regular addition of organisms after treatment. RESULTS: Microcosms exposed to 3,4-dichloroaniline treatment suffered substantial loss of taxon richness and by 10 months after treatment had only recovered where invertebrates had been added. Those treated with cypermethrin underwent an initial decline in certain crustacean and insect populations. These populations showed some signs of recovery over a period of 5 months through internal processes alone. However, rate of recovery was further enhanced where immigration was simulated, and in this case recovery had occurred around 100 days after treatment. CONCLUSION: Although not the only factors involved, simulated immigration and chemical fate clearly influence the ability of communities to recover from chemical exposure. Consideration of immigration processes and development of models will help to increase the realism of risk assessments.