In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1

The detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC50, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy

Setting and meeting priorities in Indigenous health research in Australia and its application in the Cooperative Research Centre for Aboriginal Health

Priority setting is about making decisions. Key issues faced during priority setting processes include identifying who makes these decisions, who sets the criteria, and who benefits. The paper reviews the literature and history around priority setting in research, particularly in Aboriginal health research. We explore these issues through a case study of the Cooperative Research Centre for Aboriginal Health (CRCAH)'s experience in setting and meeting priorities

An hypothesis on the evolution of herpetostrongylinae (Trichostrongyloidea: Nematoda) in Australian marsupials, and their relationships with viannaidae, parasites of South American Marsupials

Herpetostrongylinae is redefined. A Woolleya-like parasite in Gondwanaland didelphoids is proposed as the ancestral stock of the Herpetostrongylinae parasitic in Australian marsupials. Three evolutionary lines are postulated for the radiation within the Herpetostrongylinae, each derived from a form resembling existing species of Woolleya Mawson, 1973, parasitic in Dasyuridae and Thylacinidae: (i) a short lineage restricted to Dasyuridae; (ii) Dasyuridae-Peramelidae and Myrmecobiidae, followed by re-invasion into Dasyuridae; (iii) Dasyuridae-Macropodidae-Potoroidae, Petauridae and Phalangeridea. W. hydromyos Mawson, 1973, and Paraustrostrongylus ratti Obendorf, 1979, are interpreted as secondary transfers of marsupial parasites to recent murid invaders. No evidence was found to support peramelid parasites giving rise to species parasitic in Diprotodontia. Herpetostrongylus and Vaucherus are considered as a distinct phylogenetic unit based on south-east Asia and parasitic in reptiles

Microbial Protemics

xvii;ill.;512hal.;27c

Compl\ue9ments morphologiques au genre Herpetostrongylus Baylis, 1931 (Nema toda, Trichostrongyloidea)

Volume: 3Start Page: 133End Page: 13