Efficacy and effectiveness of the herbal medicinal product BNO 1016 in the management of acute rhinosinusitis in the context of antibiotic stewardship.

OBJECTIVES: To substantiate the clinical efficacy and investigate the real-world effectiveness of the herbal medicinal product BNO 1016 in acute rhinosinusitis (ARS) in the context of antibiotic stewardship. METHODS: We performed a meta-analysis of the clinical trials ARhiSi-1 (EudraCT No. 2008-002794-13) and ARhiSi-2 (EudraCT No. 2009-016682-28) comprising 676 patients, analyzing the reduction of the Major Symptom Score (MSS) and improvement of the Sino-Nasal Outcome Test 20 (SNOT-20) by the herbal medicinal product BNO 1016. In addition, we performed a retrospective cohort study including 203,382 patients, comparing the real-life effectiveness of BNO 1016 in reducing ARS-related adverse outcomes in comparison to antibiotics and several other established therapies. RESULTS: Treatment with BNO 1016 ameliorated symptoms of ARS by reducing MSS by 1.9 points (p < 0.0001) and improved quality of life (QoL) for patients by improving SNOT-20 by 3.5 points (p = 0.001) in comparison to placebo. In patients with moderate/severe symptoms, the positive effects of BNO 1016 were even more pronounced (MSS: -2.3 points (p < 0.0001); SNOT-20: -4.9 points (p = 0.0158)). In addition, treatment with BNO 1016 was as effective or significantly more effective in reducing the risk for adverse ARS-related outcomes such as follow-up antibiotic prescriptions, sick leave ≥7 days or medical appointments due to ARS, especially when compared to antibiotics. CONCLUSION: BNO 1016 is a safe and effective treatment for ARS that can help reduce the overuse of antibiotics.

Prevalence of Antibiotic Prescription in Patients with Acute Rhinosinusitis Treated by General Practitioners and Otolaryngologists in Germany-A Retrospective Cohort Study.

(1) Background: The goal of this retrospective cohort study, based on real-world data and conducted in Germany, was to investigate the prevalence of antibiotic (AB) prescription in patients with acute rhinosinusitis (ARS). (2) Methods: Data from the Disease Analyzer database were used for this cross-sectional study. Patients aged ≥18 years diagnosed with acute sinusitis by general practitioners (GPs) and ear, nose, throat (ENT) specialists between January 2012 and December 2020 were included. The main outcome of the study was the proportion of patients with ARS who received an AB prescription on the day of diagnosis or within three days afterwards. The proportion was estimated separately for patients treated by GPs and ENTs, and also for five age groups, as well as women and men. (3) Results: In total, 308,095 patients were diagnosed with ARS (187,838 by GPs and 120,257 by ENTs). 50.9% of patients treated by GPs and 50.0% treated by ENTs received an AB prescription. AB prevalence increased with age from 46.9% in the age group 18−30 years to 55.5% in the age group > 60 years. (4) Conclusions: We have shown a high prevalence of potentially inappropriate AB prescription for adult patients with ARS in both GP and ENT practices and also among both women and men and in several age groups. There is an urgent need for interventions to reduce inappropriate AB use.

Contribution of Symptomatic, Herbal Treatment Options to Antibiotic Stewardship and Microbiotic Health.

Epithelial surfaces in humans are home to symbiotic microbes (i.e., microbiota) that influence the defensive function against pathogens, depending on the health of the microbiota. Healthy microbiota contribute to the well-being of their host, in general (e.g., via the gut-brain axis), and their respective anatomical site, in particular (e.g., oral, urogenital, skin, or respiratory microbiota). Despite efforts towards a more responsible use of antibiotics, they are often prescribed for uncomplicated, self-limiting infections and can have a substantial negative impact on the gut microbiota. Treatment alternatives, such as non-steroidal anti-inflammatory drugs, may also influence the microbiota; thus, they can have lasting adverse effects. Herbal drugs offer a generally safe treatment option for uncomplicated infections of the urinary or respiratory tract. Additionally, their microbiota preserving properties allow for a more appropriate therapy of uncomplicated infections, without contributing to an increase in antibiotic resistance or disturbing the gut microbiota. Here, herbal treatments may be a more appropriate therapy, with a generally favorable safety profile.

Effectiveness and tolerability of the thyme/ivy herbal fluid extract BNO 1200 for the treatment of acute cough: an observational pharmacy-based study.

OBJECTIVE: Efficacy and safety of an oral thyme/ivy syrup for the treatment of acute cough was previously demonstrated in a randomized clinical trial. Here, we present real-life data from a pharmacy-based, observational study on the effectiveness and tolerability of another thyme/ivy combination (BNO 1200, Bronchipret drops). METHODS: This observational, prospective, uncontrolled study was conducted in 305 German pharmacies. Cough and associated symptoms, cough severity and health related quality of life (HRQoL) were assessed at baseline, after 4 days and at individual end of treatment (EoT) in patients with acute cough due to upper respiratory tract infections who bought BNO 1200. Patients took BNO 1200 until resolution of cough and completed three validated questionnaires: patient-adapted Bronchitis Severity Score (BSS), cough severity visual analogue scale (VAS) and the Leicester Cough Questionnaire (LCQ-acute). They also rated speed of onset of treatment action on a VAS and tolerability. RESULTS: A total of 749 patients participated in the study; 730 were included in the analysis. Mean treatment duration was 7.0 ± 3.6 days. Symptom severity assessed by BSS improved from 8.7 ± 3.8 score points (baseline) to 2.4 ± 2.6 at EoT (p < .0001). Clinically relevant improvements (MCID = 17 mm) in cough severity were reported by 87.2% of patients at EoT. HRQoL improved significantly (12.2 ± 3.3 points at baseline vs. 18.5 ± 2.7 at EoT; p < .0001), exceeding the MCID (=2 points) in 90.0% of patients. Tolerability was rated "good" or "very good" by 98.0% of patients. No adverse drug reactions were reported. CONCLUSION: Patients with acute cough taking BNO 1200 had a significant reduction in BSS, cough severity and improvement in HRQoL confirming RCT data with the syrup formulation. BNO 1200 was well tolerated.

c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells.

Abdominal-type HoxA genes in combination with Meis1 are well-documented on-cogenes in various leukemias but it is unclear how they exert their transforming function. Here we used a system of conditional transformation by an inducible mixed lineage leukemia-eleven-nineteen leukemia (MLL-ENL) oncoprotein to overexpress Hoxa9 and Meis1 in primary hematopoietic cells. Arrays identified c-Myb and a c-Myb target (Gstm1) among the genes with the strongest response to Hoxa9/Meis1. c-Myb overexpression was verified by Northern blot and quantitative reverse transcription-polymerase chain reaction (RT-PCR). Also MLL-ENL activated c-Myb through up-regulation of Hoxa9 and Meis1. Consequently, short-term suppression of c-Myb by small inhibitory RNA (siRNA) efficiently inhibited transformation by MLL-ENL but did not impair transformation by transcription factor E2A-hepatic leukemia factor (E2A-HLF). The anti c-Myb siRNA effect was abrogated by coexpression of a c-Myb derivative with a mutated siRNA target site. The introduction of a dominant-negative c-Myb mutant had a similar but weaker effect on MLL-ENL-mediated transformation. Hematopoietic precursors from mice homozygous for a hypo-morphic c-Myb allele were more severely affected and could be transformed neither by MLL-ENL nor by E2A-HLF. Ectopic expression of c-Myb induced a differentiation block but c-Myb alone was not transforming in a replating assay similar to Hoxa9/Meis1. These results suggest that c-Myb is essential but not sufficient for Hoxa9/Meis1 mediated transformation.

The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin.

Mixed lineage leukemia (MLL) fusion proteins are derived from translocations at 11q23 that occur in aggressive subtypes of leukemia. As a consequence, MLL is joined to different unrelated proteins to form oncogenic transcription factors. Here we demonstrate a direct interaction between several nuclear MLL fusion partners and present evidence for a role of these proteins in histone binding. In two-hybrid studies, ENL interacted with AF4 and AF5q31 as well as with a fragment of AF10. A structure-function analysis revealed that the AF4/AF5q31/AF10 binding domain in ENL coincided with the C-terminus that is essential for transformation by MLL-ENL. The ENL/AF4 association was corroborated by GST-pulldown experiments and by mutual coprecipitation. Both proteins colocalized in vivo in a nuclear speckled pattern. Moreover, AF4 and ENL coeluted on sizing columns together with the known ENL binding partner Polycomb3, suggesting the presence of a multiprotein complex. The overexpression of ENL alone activated a reporter construct and a mutational screen indicated the conserved YEATS domain as essential for this function. Overlay and pulldown-assays finally showed a specific and YEATS domain-dependent association of ENL with histones H3 and H1. In summary, our studies support a common role for nuclear MLL fusion partners in chromatin biology.

Direct physical and functional interaction of the NuA4 complex components Yaf9p and Swc4p.

Saccharomyces cerevisiae Yaf9p and the mammalian leukemia-associated protein ENL share a high degree of similarity. To investigate the biological function of Yaf9p, this protein was used to search for interacting proteins in a two-hybrid system. Here, we demonstrate that Yaf9p binds directly to Swc4p, the yeast homolog of the mammalian DNA-methyltransferase-associated protein 1. Yaf9p and Swc4p associate through C-terminal domains, and both proteins coprecipitate in vitro in pull-down experiments and in vivo by immunoprecipitation. In living cells, Swc4p is present in a megadalton protein complex that shows a fractionation behavior in gel filtration similar to that of Esa1p, the histone acetyltransferase of the NuA4 complex. Recruitment of Yaf9p to DNA leads to promoter-specific transcriptional activation that can be inhibited by dominant negative Swc4p lacking the Yaf9p binding domain. Interference with Swc4p function also increases sensitivity to the microtubule toxin benomyl, a trait that corresponds to the known phenotype of a yaf9(-) knockout strain. In summary, the results suggest that Yaf9p and Swc4p form a protein pair that has a role in chromatin modification with possible implications also for the function of their mammalian counterparts.