ABSTRACT
INTRODUCTION: Allergic rhinitis (AR) is a common inflammatory condition of the nasal mucosa affecting approximately 20% of the population worldwide. Current therapies include intranasal antihistamines, corticosteroids, subcutaneous and sublingual immunotherapy (SLIT). This review and meta-analysis assess the efficacy of SLIT in the management of grass pollen-induced AR in adults. METHODS: Ovid EMBASE, Ovid EBM Reviews, Cochrane Central Register of Controlled Trials, Ovid MedLine and PubMed were searched using the following terms: 'sublingual immunotherapy', 'SLIT', 'rhinitis', 'allergic rhinitis', 'rhinosinusitis' and 'rhino-conjunctivitis'. All included studies were double-blind, placebo-controlled and randomised trials. Primary outcome was symptom score and secondary outcome included quality of life and safety profile. Meta-analysis of symptom improvement was carried out. RESULTS: Six studies were identified with 979 subjects randomly allocated to SLIT and 992 to a placebo control. All studies reported an improvement in symptoms with SLIT, with five reaching statistical significance (P < .05). Four studies reported statistically significant improvement in quality of life (P < .05). Oral pruritus was the most common adverse event reported. The overall risk of bias was high in 50% of the studies. CONCLUSIONS: Sublingual immunotherapy was a safe and effective treatment for grass pollen-induced AR in adults, and therefore, consideration should be given to its use for moderate-to-severe disease in the UK-wide population.
Subject(s)
Rhinitis, Allergic/therapy , Sublingual Immunotherapy , Adolescent , Adult , Aged , Allergens , Humans , Middle Aged , Pollen , Rhinitis, Allergic/diagnosis , Rhinitis, Allergic/etiology , Young AdultABSTRACT
The search for novel targeted inhibitors active on glioblastoma multiforme is crucial to develop new treatments for this unmet clinical need. Herein, we report the results from a screening campaign against glioma cell lines using a proprietary library of 100 structurally-related pyrazolopyrimidines. Data analysis identified a family of compounds featuring a 2-amino-1,3-benzoxazole moiety (eCF309 to eCF334) for their antiproliferative properties in the nM range. These results were validated in patient-derived glioma cells. Available kinase inhibition profile pointed to blockade of the PI3K/mTOR pathway as being responsible for the potent activity of the hits. Combination studies demonstrated synergistic activity by inhibiting both PI3Ks and mTOR with selective inhibitors. Based on the structure activity relationships identified in this study, five new derivatives were synthesized and tested, which exhibited potent activity against glioma cells but not superior to the dual PI3K/mTOR inhibitor and lead compound of the screening eCF324.
Subject(s)
Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , TOR Serine-Threonine Kinases/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Glioma/metabolism , Glioma/pathology , Humans , Phosphatidylinositol 3-Kinases/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Signal Transduction/drug effects , Structure-Activity Relationship , TOR Serine-Threonine Kinases/antagonists & inhibitorsABSTRACT
A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthogonal generation of 5-fluorouracil from a biologically inert precursor by heterogeneous Pd(0) catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd(0)-functionalized resins exhibits comparable antiproliferative properties to the unmodified drug in colorectal and pancreatic cancer cells. Live-cell imaging and immunoassay studies demonstrate that the cytotoxic activity of the prodrug/Pd(0)-resin combination is due to the in situ generation of 5-fluorouracil. Pd(0)-resins can be carefully implanted in the yolk sac of zebrafish embryos and display excellent biocompatibility and local catalytic activity. The in vitro efficacy shown by this masking/activation strategy underlines its potential to develop a bioorthogonally activated prodrug approach and supports further in vivo investigations.