Protocol 012 Investigators (2020). Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. The Lancet Respiratory Medicine.

The current study examined whether alterations in glucocorticoid receptor (GR) SR patients had two distinguishable GR binding abnormalities: 15 of the 17 SR patients demonstrated a significantly reduced GR binding affinity, as compared with SS patients (P = 0.0001 ) and normal controls (P = 0.0001). This defect was localized to T cells and reverted to normal after 48 h in culture media. However, incubation with a combination of IL-2 and IL-4 sustained this abnormality. The other two SR patients had an abnormally low GR number with normal binding affinity that was not limited to T cells. Furthermore, GR number failed to normalize after incubation in media alone or IL-2 and IL4. Therefore, SR asthma may be due to more than one abnormality, the majority related to a reversible cytokine-induced reduction in GR binding affinity and the second related to an irreversible reduction in GR number. These findings may have important implications for the design of alternative treatment approaches for recalcitrant asthma. (J. Clin. Invest. 1994.

In steroid-resistant (SR) asthma, there is a lack of clinical responsiveness to oral prednisone. Previous studies indicate that this may be explained by the effect of the combination of interleukin 2 (IL-2) and IL-4 on glucocorticoid receptor binding affinity. By contrast, steroid-sensitive (SS) asthmatics respond well to glucocorticoids, and this is accompanied by a decrease in the numbers of bronchoalveolar lavage (BAL) messenger RNA+ (mRNA+) cells expressing IL-4 and IL-5, and an increase in interferon gamma (IFN-gamma) transcripts. In the present study, we hypothesized that SR asthma is associated with alterations in T helper types 1/2 (Th2/Th1)-type cytokine gene expression. BAL was performed in six SR asthmatics and six SS asthmatics, before and after a 1-wk course of 40 mg daily prednisone. mRNA+ cells for IL-2, IL-4, IL-5, and IFN-gamma was measured by in situ hybridization using 35S-labeled RNA probes. Before prednisone therapy, there were significantly greater numbers of BAL cells (per 1,000) expressing IL-2 mRNA (p < 0.01) and IL-4 mRNA (p < 0.05) in SR asthmatics as compared with SS asthmatics, but no differences between the two groups in the numbers of BAL cells expressing IFN-gamma or IL-5 mRNA expression were observed. After a 1-wk course of prednisone, IL-2 expression was not altered in either group. However, SS asthmatics had a significant decrease in the numbers of BAL cells expressing mRNA for IL-4 (p < 0.01) and IL-5 (p < 0.001), and a rise in the numbers of IFN-gamma mRNA+ cells (p < 0.01). In contrast, after prednisone treatment, SR asthmatics had no significant change in either the number of BAL cells expressing mRNA for IL-4 or IL-5. Of note, there was an unexpected decrease in the numbers of IFN-gamma mRNA+ cells (p = 0.05). Our current findings indicate that SR asthma is associated with a dysregulation of the expression of the genes encoding for Th2/Th1 cytokines in airway cells and is compatible with the concept that a combination of IL-2 and IL-4 induce glucocorticoid (GR) binding affinity and T cell responsiveness to glucocorticoids.

BACKGROUNDPeanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS Randomization and BlindingEligible participants were randomly assigned, in a 3:1 ratio, to receive either AR101, a peanut-derived pharmaceutical product that was manufactured

The findings from this large, international patient registry documented widespread implementation of pnfC1-INH self-administration outside of a health care setting consistent with current HAE guidelines. These real-world data revealed pnfC1-INH usage for a variety of reasons in patients with HAE and showed a high level of safety regardless of administration setting or reason for use.