Use of Vitex agnus-castus in patients with menstrual cycle disorders: a single-center retrospective longitudinal cohort study.

PURPOSE: To evaluate clinical characteristics, quality of life (QoL) and effectiveness in patients with menstrual cycle disorders (MCDs) including abnormal uterine bleeding, dysmenorrhea and mastodynia/mastalgia related to premenstrual syndrome taking the Vitex agnus-castus (VAC) products Cyclodynon® or Mastodynon® in a real-world setting. METHODS: A single-center retrospective longitudinal cohort study (3 ± 1 months), using data obtained from healthcare data archive and telephone interviews. The main study variables were changes in bleeding, menstrual pain, breast tenderness and patients' QoL. RESULTS: Data from 1700 women with a mean age of 30.2 years (± 6.3) were analyzed. The most common MCDs were dysmenorrhea (43.8%) and mastodynia/mastalgia (21.1%). Three-month treatment with VAC extract substantially decreased the percentage of patients with irregular cycle (from 9.1% to 0.1%) and breast tenderness (from 39.9% to 0.8%). Improvement in bleeding intensity, frequency and menstrual pain was experienced by 83.4%, 79.2%, and 85.2% of the patients, respectively. When analyzed by disease category, these parameters improved in almost all dysmenorrhea patients, while they improved to a lesser extent in mastodynia/mastalgia patients. QoL improved in all aspects, but was reported by a higher proportion of dysmenorrhea patients compared to mastodynia/mastalgia patients. Treatment was overall well tolerated with a favorable safety profile. CONCLUSION: These real-world data demonstrate the effectiveness of the VAC-containing products Cyclodynon® and Mastodynon® in the three-month treatment of MCDs, with a pronounced improvement in key disease symptoms and QoL. Intriguingly, while QoL was generally greatly improved, the response to VAC therapy varied depending on the type of underlying MCD.

Phytotherapy (BNO 1045) of Acute Lower Uncomplicated Urinary Tract Infection in Women Normalizes Local Host Responses.

INTRODUCTION: Acute lower uncomplicated urinary tract infection (uUTI) affects a large proportion of women. Increased antimicrobial resistance has created an urgent need for novel therapeutics and the phytotherapeutic drug BNO 1045 (Canephron® N) has previously been shown to be noninferior to standard antimicrobial stewardship. This sub-analysis from a randomized, double-blind, controlled phase III noninferiority clinical trial using BNO 1045 versus fosfomycin to treat uUTI aimed to determine how urine cytokine levels are altered by the two different treatments. METHODS: Urine samples from a predefined subset of women diagnosed with uUTI (18-70 years) and treated with BNO 1045 (n = 58) or fosfomycin (n = 69) were analyzed for urine levels of IL-6 and IL-8, using analyte-to-creatinine ratios. RESULTS: BNO 1045 treatment showed similar effects to fosfomycin treatment in reducing both urine IL-6 and IL-8 levels. Mean IL-6 and IL-8 levels were markedly reduced in all patients regardless of treatment. BNO 1045 treatment decreased urine IL-8 significantly (p = 0.0142) and showed a trend toward reduction of urine IL-6 (p = 0.0551). Fosfomycin treatment reduced both IL-6 and IL-8 levels significantly (p = 0.0038, <0.0001 respectively). CONCLUSION: BNO 1045 is, in addition to reducing symptoms, comparable to fosfomycin treatment in reducing the local inflammatory response associated with uUTI.

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.

Treatment of Urinary Tract Infections with Canephron® in Germany: A Retrospective Database Analysis.

Objective: The goal of the present study was to evaluate treatment with Canephron® compared to standard antibiotic treatment after diagnosis of acute cystitis or urinary tract infection (UTI), with regard to the risk of sporadic recurrent UTIs, frequent recurrent UTIs, UTI-related sick leave, additional antibiotic prescriptions, and renal complications (pyelonephritis). Methods: This retrospective cohort study was based on data from the IMS® Disease Analyzer database (IQVIA), and included outpatients in Germany with at least one diagnosis of acute cystitis or UTI with a prescription of either Canephron® or standard antibiotics between January 2016 and June 2019 and treated in general practitioner (GP), gynecologist, or urologist practices, from which the data were obtained. Multivariable regression models were used to investigate the association between Canephron® prescription and the amount of sporadic or frequent recurrent UTIs, as well as the duration of UTI-related sick leave, the number of additional antibiotic prescriptions, and cases of pyelonephritis. The effects of Canephron® were adjusted for age, sex, insurance status, and Charlson comorbidity score (CCI). Results: 2320 Canephron® patients and 158,592 antibiotic patients were available for analysis. Compared to antibiotic prescription, Canephron® prescription was significantly associated with fewer sporadic recurrences of UTI infections 30-365 days after the index date (odds ratio (OR): 0.66; 95%, confidence interval (CI): 0.58-0.72), as well as less frequent recurrences of UTI infections (OR: 0.61; 95% CI: 0.49-0.88), and also with reduced additional antibiotic prescription within 31-365 days (OR: 0.57; 95% CI: 0.52-0.63). No significant differences were observed between the Canephron® and antibiotic cohorts with regard to the likelihood of sick leave (OR: 0.99; 95% CI: 0.86-1.14), new antibiotic prescription within 1-30 days (OR: 1.01; 95% CI: 0.87-1.16), or occurrence of pyelonephritis (Hazard Ratio (HR): 1.00; 95% CI: 0.67-1.48). Conclusion: These real-world data show that Canephron® is an effective, safe symptomatic treatment for acute cystitis or UTI. It should be considered as an alternative treatment, particularly to also strengthen antimicrobial stewardship strategies.

Non-Antibiotic Herbal Therapy (BNO 1045) versus Antibiotic Therapy (Fosfomycin Trometamol) for the Treatment of Acute Lower Uncomplicated Urinary Tract Infections in Women: A Double-Blind, Parallel-Group, Randomized, Multicentre, Non-Inferiority Phase III Trial.

INTRODUCTION: This randomized, controlled, Phase III non-inferiority clinical trial aimed to determine whether herbal therapy with Canephron® N (BNO 1045) is non-inferior to fosfomycin trometamol (FT) in treating acute lower uncomplicated urinary tract infections (uUTIs). MATERIALS AND METHODS: Women aged 18-70 years with typical symptoms of newly diagnosed acute lower uUTIs were randomized to BNO 1045 (n = 325) or FT (n = 334), with corresponding matched placebo. The primary endpoint was the proportion of patients who received additional antibiotics (ABs) to treat uUTIs between Days 1 and 38 ±3. RESULTS: Between Days 1 and 38, 238 (83.5%) patients in the BNO 1045 group and 272 (89.8%) patients in the FT group received no additional ABs. At a 15% non-inferiority margin, BNO 1045 was non-inferior to FT in treating uUTIs (non-AB rate difference: -6.26%; 95% CI -11.99 to -0.53%; 2-sided p = 0.0014). Adverse event rates were similar between groups, with higher rates of gastrointestinal disorders in the FT group and pyelonephritis in the BNO 1045 group. During the trial, no patient died or discontinued due to a treatment-related adverse event. CONCLUSIONS: BNO 1045 has the potential to reduce outpatient use of ABs for uUTIs and thus may have a significant impact on antimicrobial stewardship strategies. TRIAL REGISTRATION: NCT02639520, EudraCT number 2013-004529-99.

Induction of the NFκ-B signal transduction pathway in response to Corynebacterium diphtheriae infection.

Corynebacterium diphtheriae, the causative agent of diphtheria, has been thoroughly studied with respect to toxin production and pili formation, while knowledge on host responses to C. diphtheriae infection is limited. In this study, we studied adhesion to and invasion of epithelial cells by different C. diphtheriae isolates. When NFκ-B reporter cell lines were used to monitor the effect of C. diphtheriae infection on human cells, strain-specific differences were observed. While adhesion to host cells had no effect, a correlation of invasion rate with NFκ-B induction was found, which indicates that internalization of bacteria is crucial for NFκ-B induction. Immunofluorescence microscopy experiments used to support the reporter assays showed that translocation of p65, as a hallmark of NFκ-B induction, was only observed in association with cell invasion by C. diphtheriae. Our data indicate that the response of epithelial cells to C. diphtheriae infection is determined by internalization of bacteria and that invasion of these cells is an active process; tetracycline-treated C. diphtheriae was still able to attach to host cells, but lost its ability to invade the cytoplasm. Recognition of pathogen-associated molecular patterns such as pili subunits by membrane-bound receptors facing the outside of the cell is not sufficient for NFκ-B induction.

Strain-specific differences in pili formation and the interaction of Corynebacterium diphtheriae with host cells.

BACKGROUND: Corynebacterium diphtheriae, the causative agent of diphtheria, is well-investigated in respect to toxin production, while little is known about C. diphtheriae factors crucial for colonization of the host. In this study, we investigated strain-specific differences in adhesion, invasion and intracellular survival and analyzed formation of pili in different isolates. RESULTS: Adhesion of different C. diphtheriae strains to epithelial cells and invasion of these cells are not strictly coupled processes. Using ultrastructure analyses by atomic force microscopy, significant differences in macromolecular surface structures were found between the investigated C. diphtheriae strains in respect to number and length of pili. Interestingly, adhesion and pili formation are not coupled processes and also no correlation between invasion and pili formation was found. Using RNA hybridization and Western blotting experiments, strain-specific pili expression patterns were observed. None of the studied C. diphtheriae strains had a dramatic detrimental effect on host cell viability as indicated by measurements of transepithelial resistance of Detroit 562 cell monolayers and fluorescence microscopy, leading to the assumption that C. diphtheriae strains might use epithelial cells as an environmental niche supplying protection against antibodies and macrophages. CONCLUSIONS: The results obtained suggest that it is necessary to investigate various isolates on a molecular level to understand and to predict the colonization process of different C. diphtheriae strains.

Corynebacterium diphtheriae invasion-associated protein (DIP1281) is involved in cell surface organization, adhesion and internalization in epithelial cells.

BACKGROUND: Corynebacterium diphtheriae, the causative agent of diphtheria, is well-investigated in respect to toxin production, while little is known about C. diphtheriae factors crucial for colonization of the host. In this study, we investigated the function of surface-associated protein DIP1281, previously annotated as hypothetical invasion-associated protein. RESULTS: Microscopic inspection of DIP1281 mutant strains revealed an increased size of the single cells in combination with an altered less club-like shape and formation of chains of cells rather than the typical V-like division forms or palisades of growing C. diphtheriae cells. Cell viability was not impaired. Immuno-fluorescence microscopy, SDS-PAGE and 2-D PAGE of surface proteins revealed clear differences of wild-type and mutant protein patterns, which were verified by atomic force microscopy. DIP1281 mutant cells were not only altered in shape and surface structure but completely lack the ability to adhere to host cells and consequently invade these. CONCLUSIONS: Our data indicate that DIP1281 is predominantly involved in the organization of the outer surface protein layer rather than in the separation of the peptidoglycan cell wall of dividing bacteria. The adhesion- and invasion-negative phenotype of corresponding mutant strains is an effect of rearrangements of the outer surface.

Nitrogen control in Mycobacterium smegmatis: nitrogen-dependent expression of ammonium transport and assimilation proteins depends on the OmpR-type regulator GlnR.

The effect of nitrogen regulation on the level of transcriptional control has been investigated in a variety of bacteria, such as Bacillus subtilis, Corynebacterium glutamicum, Escherichia coli, and Streptomyces coelicolor; however, until now there have been no data for mycobacteria. In this study, we found that the OmpR-type regulator protein GlnR controls nitrogen-dependent transcription regulation in Mycobacterium smegmatis. Based on RNA hybridization experiments with a wild-type strain and a corresponding mutant strain, real-time reverse transcription-PCR analyses, and DNA binding studies using cell extract and purified protein, the glnA (msmeg_4290) gene, which codes for glutamine synthetase, and the amtB (msmeg_2425) and amt1 (msmeg_6259) genes, which encode ammonium permeases, are controlled by GlnR. Furthermore, since glnK (msmeg_2426), encoding a PII-type signal transduction protein, and glnD (msmeg_2427), coding for a putative uridylyltransferase, are in an operon together with amtB, these genes are part of the GlnR regulon as well. The GlnR protein binds specifically to the corresponding promoter sequences and functions as an activator of transcription when cells are subjected to nitrogen starvation.