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The authors convey their thoughts on recommendations for future pandemic preparedness from the Hematology/Oncology Pharmacy Association Investigational Drug Services Special Interest Group. Topics mentioned include the role of the pharmacist in clinical research, reimagination of clinical trial patient care, and mailing of investigational drugs to patients.

It has been proposed that inhaled E-prostanoid 4 (EP 4 )-receptor agonists could represent a new class of bronchodilators for the treatment of asthma that are as effective as β 2 -adrenoceptor agonists. However, the genomic impact of such drugs is unknown despite being potentially deleterious to respiratory health. Herein, we used mRNA-seq to compare the transcriptomic responses produced by 2-[3-[(1R,2S,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-5-[2-(methoxymethyl)phenyl]pent-1-enyl]-5-oxo-cyclopentyl]sulphanylpropylsulphanyl] acetic acid (ONO-AE1-329; an EP 4 -receptor agonist) and vilanterol (a β 2 -adrenoceptor agonist) in BEAS-2B human airway epithelial cells. We also determined if an increase in cAMP mediated by different G protein-coupled receptors (GPCRs) promoted distinct transcriptional signatures by expanding this inquiry to include the adenosine A 2B - and I-prostanoid receptor agonists, 2-[[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide (Bay60-6583) and taprostene, respectively. Maximally-effective concentrations of ONO-AE1-329 and vilanterol significantly regulated ( q ≤ 0.05; ≥1.5-/≤0.67-fold) 232 and 320 genes, respectively of which 217 were shared. Spearman analysis showed these gene expression changes to be highly rank order correlated, indicating that the functional overlap between the two interventions should be considerable. Unexpectedly, the genomic effects of ONO-AE1-329, vilanterol, Bay 60-6583, and taprostene were also highly rank order correlated. This finding suggests that cAMP generated by any GPCR would initiate the same transcriptional program. Nevertheless, relative to vilanterol, ONO-AE1-329 typically behaved as a partial agonist that varied across transcripts. These data indicate that each ONO-AE1-329-regulated gene differs in sensitivity to cAMP and is defined by a unique receptor occupancy-response relationship. Moreover, if this relatively modest genomic response in BEAS-2B cells is retained in vivo, then inhaled EP 4 -receptor agonists could represent an alternative, and possibly safer, class of bronchodilators. SIGNIFICANCE STATEMENT: The genomic consequences of β 2 -adrenoceptor agonists in asthma are often overlooked despite being potentially harmful to lung health. We determined that ONO-AE1-329, an EP 4 -receptor agonist and effective bronchodilator, produced gene expression changes in BEAS-2B cells that were typically modest relative to the β 2 -adrenoceptor agonist vilanterol. Furthermore, ONO-AE1-329 behaved as a partial agonist that varied across transcripts. If this genomic activity is reproduced in vivo, then EP 4 -receptor agonists could represent an alternative, and possibly safer, class of bronchodilators., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Glucocorticoids act via the glucocorticoid receptor (GR; NR3C1) to downregulate inflammatory gene expression and are effective treatments for mild to moderate asthma. However, in severe asthma and virus-induced exacerbations, glucocorticoid therapies are less efficacious, possibly due to reduced repressive ability and/or the increased expression of proinflammatory genes. In human A549 epithelial and primary human bronchial epithelial cells, toll-like receptor (TLR)-2 mRNA and protein were supra -additively induced by interleukin-1 β (IL-1 β ) plus dexamethasone (IL-1 β +Dex), interferon- γ (IFN- γ ) plus dexamethasone (IFN- γ +Dex), and IL-1 β plus IFN- γ plus dexamethasone (IL-1 β +IFN- γ +Dex). Indeed, ∼34- to 2100-fold increases were apparent at 24 hours for IL-1 β +IFN- γ +Dex, and this was greater than for any single or dual treatment. Using the A549 cell model, TLR2 induction by IL-1 β +IFN- γ +Dex was antagonized by Org34517, a competitive GR antagonist. Further, when combined with IL-1 β , IFN- γ , or IL-1 β +IFN- γ , the enhancements by dexamethasone on TLR2 expression required GR. Likewise, inhibitor of κ B kinase 2 inhibitors reduced IL-1 β +IFN- γ +Dex-induced TLR2 expression, and TLR2 expression induced by IL-1 β +Dex, with or without IFN- γ , required the nuclear factor (NF)- κ B subunit, p65. Similarly, signal transducer and activator of transcription (STAT)-1 phosphorylation and γ -interferon-activated sequence-dependent transcription were induced by IFN- γ These, along with IL-1 β +IFN- γ +Dex-induced TLR2 expression, were inhibited by Janus kinase (JAK) inhibitors. As IL-1 β +IFN- γ +Dex-induced TLR2 expression also required STAT1, this study reveals cooperation between JAK-STAT1, NF- κ B, and GR to upregulate TLR2 expression. Since TLR2 agonism elicits inflammatory responses, we propose that synergies involving TLR2 may occur within the cytokine milieu present in the immunopathology of glucocorticoid-resistant disease, and this could promote glucocorticoid resistance. SIGNIFICANCE STATEMENT: This study highlights that in human pulmonary epithelial cells, glucocorticoids, when combined with the inflammatory cytokines interleukin-1 β (IL-1 β ) and interferon- γ (IFN- γ ), can synergistically induce the expression of inflammatory genes, such as TLR2. This effect involved positive combinatorial interactions between NF- κ B/p65, glucocorticoid receptor, and JAK-STAT1 signaling to synergistically upregulate TLR2 expression. Thus, synergies involving glucocorticoid enhancement of TLR2 expression may occur in the immunopathology of glucocorticoid-resistant inflammatory diseases, including severe asthma., (Copyright © 2023 by The Author(s).)