Zafirlukast is a broad-spectrum thiol isomerase inhibitor that inhibits thrombosis without altering bleeding times

Background and purpose Multiple members of the thiol isomerase (TI) family of enzymes are present in, and released by platelets. Inhibition of these enzymes results in diminished platelet responses including aggregation, adhesion and thrombus formation. In recent years, the therapeutic potential of TI inhibition has been recognised and drug-development technologies used to identify selective small molecule inhibitors. To date, few pan-TI inhibitors have been characterised and the most studied, bacitracin is known to be nephrotoxic which prohibits its systemic therapeutic usage. Experimental approach We therefore sought to identify novel broad-spectrum inhibitors of these enzymes and test their effects in vivo. 3641 compounds were screened for inhibitory effects on the redox activity of ERp5, PDI, ERp57, ERp72 and thioredoxin (TRX) in an insulin turbidity assay. Of the lead compounds identified, zafirlukast (ZFL) was selected for further investigation. Key results When applied to platelets, ZFL diminished platelet responses in vitro. ZFL was antithrombotic in murine models of thrombosis but did not impair responses in a model of haemostasis. Since thiol isomerases are known to modulate adhesion receptor function, we explored the effects of ZFL on cell migration. This was inhibited independently of cysteinyl leukotriene receptor expression and was associated with modulation of cell-surface free thiol levels consistent with alterations in redox activity on the cell surface. Conclusion and implications We identify zafirlukast to be a novel, potent, broad-spectrum TI inhibitor, with wide ranging effects on platelet function, thrombosis and integrin-mediated cell migration. ZFL is antithrombotic but does not cause bleeding

Remimazolam: A Novel Option for Procedural Sedation in High Risk Patients

Purpose: The purpose of this drug review was to explore the safety and efficacy of the newly approved benzodiazepine, remimazolam, in order to evaluate its place in therapy. Summary: Remimazolam has a faster onset of action and recovery time than midazolam when given as single IV doses. Additionally, it has no known CYP450 interactions that would contribute to drug-drug interactions. Patients with severe hepatic impairment may require dose titration as well as the elderly who should be closely monitored. Although remimazolam vials should be protected from light and must be reconstituted immediately before use, the reconstituted vial may be stored for later use at room temperature for up to 8 hours. Remimazolam is more expensive than current options used in practice, as such individual institutional formulary and provider preference will require review to see if its advantages are worth the additional cost and to determine its place in therapy. Conclusion: Remimazolam is a novel option when choosing a benzodiazepine for procedural sedation that has pharmacokinetic and pharmacodynamic advantages when compared to other commonly prescribed sedatives. Remimazolam has proved superior to midazolam when analyzing drug-drug interactions, onset, and time to alertness. Remimazolam also has a shorter elimination half-life and decreased volume of distribution when compared to midazolam

Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic

Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently discovered that zafirlukast, an FDA-approved medication for asthma, is a pan-thiol isomerase inhibitor. Zafirlukast inhibited the growth of multiple cancer cell lines with an IC50 in the low micromolar range, while also inhibiting cellular thiol isomerase activity, EGFR activation, and downstream phosphorylation of Gab1. Zafirlukast also blocked the procoagulant activity of OVCAR8 cells by inhibiting tissue factor-dependent Factor Xa generation. In an ovarian cancer xenograft model, statistically significant differences in tumor size between control vs treated groups were observed by Day 18. Zafirlukast also significantly reduced the number and size of metastatic tumors found within the lungs of the mock-treated controls. When added to a chemotherapeutic regimen, zafirlukast significantly reduced growth, by 38% compared with the mice receiving only the chemotherapeutic treatment, and by 83% over untreated controls. Finally, we conducted a pilot clinical trial in women with tumor marker-only (CA-125) relapsed ovarian cancer, where the rate of rise of CA-125 was significantly reduced following treatment with zafirlukast, while no severe adverse events were reported. Thiol isomerase inhibition with zafirlukast represents a novel, well-tolerated therapeutic in the treatment of ovarian cancer

Global Networks of Symbiodinium-Bacteria Within the Coral Holobiont

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Scleractinian corals form the framework of coral reefs and host abundant and diverse microbial communities that are fundamental to their success. A very limited number of studies have examined the co-occurrence of multiple partners within the coral ‘holobiont’ and their pattern of specificity over different geographical scales. In this study, we explored two molecular sequence datasets representing associations between corals and dinoflagellates in the genus Symbiodinium and between corals and bacteria, across the globe. Through a network theory approach, we characterised patterns of co-occurrences between bacteria and Symbiodinium with 13 coral genera across six water basins. The majority of the bacteria-Symbiodinium co-occurrences were specific to either a coral genus or water basin, emphasising both coral host and environment as important factors driving the diversity of coral assemblages. Yet, results also identified bacteria and Symbiodinium that were shared by multiple coral genera across several water basins. The analyses indicate that shared co-occurrences are independent of the phylogenetic and biogeographic relationship of coral hosts