Review of efficacy of ciclesonide for the treatment of asthma in children.

Background: Ciclesonide (CIC) is an inhaled corticosteroid (ICS) approved for the maintenance treatment of asthma in patients ages ≥ 12 years. The prodrug aspect of CIC is associated with a safety profile that may make it ideal for children. Objective: The objective was to summarize efficacy results from the eight phase III, randomized, double-blind, controlled trials in children with asthma conducted during CIC clinical development. Methods: Four trials compared CIC 40, 80, or 160 µg/day with placebo. Two trials compared CIC 160 µg/day with fluticasone propionate 200 µg/day, one trial compared CIC 80 or 160 µg/day with fluticasone 200 µg/day, and one trial compared CIC 160 µg/day with budesonide 400 µg/day. Results: The primary end point was met by at least two CIC doses versus placebo in the trials in which the primary end point was the change from baseline in lung function outcome (forced expiratory volume in 1 second [FEV1] % predicted or morning peak expiratory flow [PEF]). A trial that compared CIC with placebo did not meet the primary end point of superiority in time-to-first severe wheeze exacerbation or lack of improvement. The primary end point of noninferiority to the active control (fluticasone or budesonide) in the change from baseline in a lung function outcome (FEV1, morning PEF, evening PEF) was met with the CIC 160-µg dose in all active control trials. CIC generally demonstrated statistically significant improvements in forced expiratory flow at 25%-75% of forced vital capacity, asthma symptoms, rescue medication use, and asthma control when compared with placebo and noninferiority for these outcomes compared with fluticasone or budesonide. Conclusion: In children with asthma, once-daily CIC significantly improved large and small airway function, asthma symptoms, and asthma control, and reduced rescue medication use compared with placebo. CIC was comparable with other ICS used to treat asthma in children, which demonstrated its worth for the pediatric population.

Safety of ciclesonide in children with asthma: A review of randomized controlled trials.

Background: Parental concerns about the adverse effects of asthma medications can lead to nonadherence and uncontrolled asthma in children. Ciclesonide (CIC) is a prodrug, with low oropharyngeal deposition and bioavailability that may minimize the risk of local and systemic adverse effects. CIC is U.S. Food and Drug Administration approved for asthma in children ages ≥ 12 years. Objective: To summarize safety results from the 13 phase II or III randomized controlled trials conducted in children with asthma during CIC clinical development. Methods: Four 12- to 24-week trials compared the safety of once-daily CIC 40, 80, or 160 µg/day with placebo; four 12-week trials compared the safety of CIC 80 or 160 µg/day with either fluticasone or budesonide; one 12-month trial compared the long-term safety of CIC 40, 80, or 160 µg/day with fluticasone; one 12-month trial compared growth velocity of CIC 40 or 160 µg/day with placebo; and three cross-over trials compared short-term growth velocity and hypothalamic-pituitary-adrenal (HPA) axis effects of CIC 40, 80, or 160 µg/day with placebo or fluticasone. Results: In all, 4399 children were treated with CIC. The incidence of treatment-emergent adverse events (AE) was similar among the CIC doses and between CIC and placebo in short-term studies and between CIC and fluticasone in the long-term safety study. No CIC-related serious AEs were reported in any study. The incidence of treatment-related oral candidiasis was low and similar between CIC (≤0.5%) and placebo (≤0.7%) or active controls (≤0.5%) in the short-term studies. There was no clinically relevant HPA axis suppression or reduction in growth velocity associated with CIC. Conclusion: Data from 13 studies demonstrate that CIC is associated with low rates of oropharyngeal AEs, with no indication of clinically relevant systemic effects in children with asthma. The favorable safety profile and demonstrated improvements in asthma control make CIC an ideal inhaled corticosteroid for the treatment of asthma in children.

Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation.

Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.

Transcription-frequency-dependent modulation of an attenuator in a ribosomal protein-RNA polymerase operon requires an upstream site.

Although the attenuator located between the ribosomal protein and RNA polymerase gene domains of the Escherichia coli rplKAJLrpoBC operon has a maximum termination efficiency of 80%, the level of termination is diminished with decreasing transcription frequency. In this report, the use of transcriptional fusions to further investigate the mechanism of transcription-frequency-dependent regulation is described. The termination efficiency of two other weak terminators was assayed over a wide range of transcription frequencies programmed by different strength promoters. The results indicated that a decrease in termination efficiency with decreasing transcription frequency is not an inherent property of weak terminators. Deletion of the 165 bp segment located 439-274 bp upstream of the attenuator abrogated the difference in termination efficiency normally seen between high and low levels of transcription. This suggests that a cis-acting site located in this upstream region is necessary for transcription-frequency-dependent modulation of the attenuator's function. However, this site apparently works only in combination with the attenuator, since it did not cause transcription-frequency-dependent modulation when placed upstream of two other weak terminators. Analysis of the readthrough frequencies of single or tandem copies of the attenuator indicated that the transcription complexes which pass through the attenuator have not been converted to termination-resistant complexes in a manner analogous to the N-mediated antitermination system of lambda. Finally, an examination of termination efficiency in three nusA mutants suggested that although NusA increases readthrough at the attenuator it is not directly involved in transcription-frequency-dependent modulation.