Establishment of a human nasal epithelium model of histamine-induced inflammation to assess the activity of fexofenadine as an inverse agonist and its link to clinical benefit.

Background: Fexofenadine (FEX) is an antihistamine that acts as an inverse agonist against histamine (HIS) receptor 1 (H1R), which mediates the allergic reaction. Inverse agonists may be more potent than neutral antagonists, as they bind the same receptor as the agonist (HIS) but stabilize the inactive form and induce an opposite pharmacological response, suppressing the basal activity of H1R and preventing HIS from binding. This study aims to establish and validate a model of HIS-induced inflammation based on fully reconstituted human nasal epithelial tissue to assess the activity of FEX as an inverse agonist in this model and explore its link to clinical benefit. Methods: The model was developed using nasal MucilAir™ (Epithelix) in vitro epithelium challenged by HIS. Two conditions were assessed in a side-by-side comparison: tissue was exposed to HIS + FEX with or without FEX pre-treatment (one-hour prior to HIS challenge). Tissue functionality, cytotoxicity, H1R gene expression, and inflammatory cytokines were assessed. Results: HIS at 100 µM induced significant 3.1-fold and 2.2-fold increases for inflammatory biomarkers interleukin (IL)-8 and IL-6, respectively (p < 0.0001), as well as rapid upregulation of H1R mRNA. Inflammatory biomarkers were inhibited by FEX and H1R expression was significantly reduced (p < 0.0001). FEX alone decreased H1R expression at all doses tested. With one-hour FEX pre-treatment, there was significantly higher downregulation of IL-8 (p < 0.05) and further downregulation of H1R expression and IL-6 versus without FEX pre-treatment; the effects of FEX were improved from 22% to 40%. Conclusion: A model of HIS-induced airway inflammation was established based on IL-8, IL-6 and H1R gene expression and was validated with FEX. FEX works as an inverse agonist, with a higher effect when used before+during versus only during the HIS challenge. Taking FEX before+during allergen exposure, or when symptoms first occur, may reduce basal activity and H1R gene expression, providing stronger protection against the worsening of symptoms upon allergen exposure.

Assessing 2-month clinical prognosis in hospitalized patients with advanced solid tumors.

PURPOSE: The aim of this study was to assess clinical, laboratory, and subjective (patient's preferences) prognostic factors in hospitalized patients with advanced solid tumors. PATIENTS AND METHODS: This prospective study surveyed 177 patients from two French hospitals who had not reached the stage of active dying but had an estimated survival of less than 6 months (median survival, 58 days). RESULTS: Univariate analysis showed that 10 of the 13 clinical and laboratory factors reported in the literature affected survival at 2 months. Poor prognostic factors were number of metastatic sites, cerebral metastasis, low Karnofsky index, dyspnea at rest, anorexia, edema, confusion, low serum albumin, extremely high leukocyte counts, and high lactate dehydrogenase (LDH) levels. The patient's desire to continue curative treatment was also associated with survival. The multivariate analysis selected four independent criteria: Karnofsky index (in three classes: or= 70%), number of metastatic sites (>or= two or < two), low serum albumin (in three classes: or= 33 g/L), and LDH concentration (>or= 600 IU or < 600 IU). The combination of these four criteria assessed prognosis better than the Karnofsky index alone, producing three prognostic profiles: one with short survival (< 2 months: no patient survived to 4 months); one with an expectation of intermediate survival (25% were alive at 4 months), and a final group surviving for several months (80% were alive at 4 months). CONCLUSION: The prognostic profiles defined by combinations of these four factors may be potentially useful but need further validation before their application in the daily practice.