Assessment of the Efficacy and Safety of Ivy Leaf (Hedera helix) Cough Syrup Compared with Acetylcysteine in Adults and Children with Acute Bronchitis.

INTRODUCTION: Acute bronchitis is defined as a sudden inflammation of the bronchial tubes in the lung mainly caused by viral infection. It is characterized by a persistent cough which can be productive or dry. It is the most common disease in industrialized countries, and thus herbal expectorants enjoy a high popularity in many European countries due to their favorable risk-benefit ratio. OBJECTIVE: The present noninterventional study was intended to gain further data on the application of a cough syrup containing ivy leaf extract EA 575® by evaluating its efficacy and safety in children and adults with symptoms of acute bronchitis. Acetylcysteine (ACC) was chosen as comparator drug (common mono preparations). Material and Methods. The study was conducted at 25 medical practices throughout Switzerland as prospective, open, noninterventional study. RESULTS: At entry visit, all clinical assessments including coughing fits, sputum, dyspnoea, rales, severity of the diseases, and coughing quality were rated with moderate intensity in both groups. At the final visit after seven days of treatment, there was a comparable improvement in both groups for all assessments except dyspnoea and number of cough attacks which showed a higher improvement in the EA 575® group compared with ACC. Further, cough-associated sleeping disorders improved more in the EA 575® group. Both, physicians and patients described the efficacy of EA 575® comparable with acetylcysteine. Observations of the tolerability were comparable for both products. The study results indicate that ivy leaf extract might be an effective alternative to acetylcysteine with respect to the improvement of respiratory function in children and adults at a slightly better evaluation of efficacy.

Effect of the fixed combination of valerian, lemon balm, passionflower, and butterbur extracts (Ze 185) on the prescription pattern of benzodiazepines in hospitalized psychiatric patients-A retrospective case-control investigation.

Stress is an increasing problem that can result in various psychiatric and somatoform symptoms. Among others, benzodiazepines and valerian preparations are used to treat stress symptoms. The aim of this study was to investigate whether the prescription of a fixed herbal extract combination of valerian, lemon balm, passionflower, and butterbur (Ze 185) changes the prescription pattern of benzodiazepines in hospitalized psychiatric patients. In a retrospective case-control study, anonymized medical record data from 3,252 psychiatric in-house patients were analysed over a 3.5-year period. Cases (n = 1,548) with a prescription of Ze 185 and controls (n = 1,704) were matched by age, gender, hospitalization interval, and main International Classification of Diseases, Version 10 F-diagnoses. The primary objective was to investigate the effect of Ze 185 on the prescription pattern of benzodiazepines. Secondary objectives investigated the prescriptions of concomitant drugs and effectiveness of the hospital stay. Distribution of drug classes was analysed using the WHO's anatomic-therapeutic-chemical code. Data showed that both treatment modalities had a comparable clinical effectiveness but with significantly less prescriptions of benzodiazepines in the Ze 185 group (p = .006). This is of clinical importance because suitable alternatives to benzodiazepines are desirable. To obtain more support for this hypothesis, a dedicated randomized, controlled clinical trial monitoring drug safety is required.

Effect of CIMicifuga racemosa on metaBOLIC parameters in women with menopausal symptoms: a retrospective observational study (CIMBOLIC).

PURPOSE: To compare the influence of Cimicifuga racemosa extract (CR, Ze 450) and menopausal hormone therapy (MHT) on metabolic parameters and body weight in symptomatic menopausal women. METHODS: In this monocentric retrospective cohort study, women over 40 years old with a first consultation between 2009 and 2016 were screened. Included in the final analysis were women treated with either MHT or CR and having at least one follow-up consultation. Metabolic serum parameters (lipids, glucose, insulin, and HOMA-IR), body weight, and menopausal symptoms [Menopause Rating Scale (MRS)-II] were the main outcome measures. Statistical analysis by uni- and multi-variable linear mixed-effects regression models assuming a linear effect of time. RESULTS: 174 women were included in the final analysis (CR n = 32, MHT n = 142). There was no difference between the groups regarding baseline characteristics (age, BMI, serum metabolic parameters, hormones, and blood pressure) and total MRS-II score, while reproductive stage differed significantly with more postmenopausal women treated with CR (83%) than MHT (55%) (p = 0.038). Median follow-up time was 12 months. In both groups, metabolic serum parameters and body weight did not change over the follow-up period, while total and MRS-II subscores improved. CONCLUSION: Menopausal symptoms improved significantly in both groups (MHT and CR), while serum metabolic parameters and body weight did not change in MHT- or CR-treated women.

No Clinically Relevant Interactions of St. John's Wort Extract Ze 117 Low in Hyperforin With Cytochrome P450 Enzymes and P-glycoprotein.

Hypericum perforatum L. (St. John's wort) is used to treat mild-to-moderate depression. Its potential safety risks are pharmacokinetic drug interactions via cytochrome P450 (CYP) enzymes and P-glycoprotein, presumably caused by hyperforin. In a phase I, open-label, nonrandomized, single-sequence study, the low-hyperforin Hypericum extract Ze 117 was investigated using a drug cocktail in 20 healthy volunteers. No pharmacokinetic interactions of Ze 117 were observed for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, and P-glycoprotein. Area under the curve (AUC) and peak plasma concentration (Cmax ) of the used probe drugs showed 90% confidence intervals (CIs) of the geometric mean ratios of the drugs taken together with Ze 117 vs. probe drug alone, well within the predefined bioequivalence range of 80-125%. Though Ze 117 did not induce dextromethorphan metabolism by CYP2D6, it weakly increased dextromethorphan AUC ratio (mean 147.99, 95% CI 126.32-173.39) but not the corresponding metabolic ratio. Ze 117 does not show clinically relevant pharmacokinetic interactions with important CYPs and P-glycoprotein.

Effects of a fixed herbal drug combination (Ze 185) to an experimental acute stress setting in healthy men - An explorative randomized placebo-controlled double-blind study.

BACKGROUND: Considering the negative effects of stress on health, there is a growing interest in stress-reducing interventions. The present study examines the effects of a fixed combination of valerian, passion flower, lemon balm, and butterbur extracts (Ze 185) on biological and affective responses to a standardized psychosocial stress paradigm. PURPOSE: The aim of the present study was to investigate the efficacy of Ze 185 on cortisol and anxiety stress responses to acute psychosocial stress in healthy subjects. STUDY DESIGN: This study was a randomized, placebo-controlled, double blind study with 3 parallel groups. METHODS: 72 healthy male participants were randomized to 3 groups (Ze 185, placebo or no treatment) during 4 days prior to a standardized psychosocial stress paradigm. Principle outcomes were salivary cortisol and self-reported anxiety responses to stress assessed at the fourth day. RESULTS: The stress paradigm induced significant and large cortisol and self-reported anxiety responses. Groups did not differ significantly in their salivary cortisol response to stress, but participants in the Ze 185 condition showed significantly attenuated responses in self-reported anxiety in comparison to placebo (F(3, 41) = 3.33, p = 0.03) and no treatment (F(3, 43) = 2.77, p = 0.05). CONCLUSION: The results show that Ze 185 significantly attenuated the subjective emotional stress response during an acute stress situation, without affecting biological stress responses. Given that a circumscribed biological stress response is to be considered as an adaptive mechanism, Ze 185 reduces self-reported anxiety response to stress without affecting assumingly adaptive biological stress responses.

Anti-inflammatory effects of the petasin phyto drug Ze339 are mediated by inhibition of the STAT pathway.

Ze339, an herbal extract from Petasites hybridus leaves is effective in treatment of allergic rhinitis by inhibition of a local production of IL-8 and eicosanoid LTB4 in allergen-challenged patients. However, the mechanism of action and anti-inflammatory potential in virally induced exacerbation of the upper airways is unknown. This study investigates the anti-inflammatory mechanisms of Ze339 on primary human nasal epithelial cells (HNECs) upon viral, bacterial and pro-inflammatory triggers. To investigate the influence of viral and bacterial infections on the airways, HNECs were stimulated with viral mimics, bacterial toll-like-receptor (TLR)-ligands or cytokines, in presence or absence of Ze339. The study uncovers Ze339 modulated changes in pro-inflammatory mediators and decreased neutrophil chemotaxis as well as a reduction of the nuclear translocation and phosphorylation of STAT molecules. Taken together, this study suggests that phyto drug Ze339 specifically targets STAT-signalling pathways in HNECs and has high potential as a broad anti-inflammatory drug that exceeds current indication. © 2016 BioFactors, 43(3):388-399, 2017.

Gamma-linolenic acid levels correlate with clinical efficacy of evening primrose oil in patients with atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) has been related to a deficiency of delta-6-desaturase, an enzyme responsible for the conversion of linoleic acid to gamma-linolenic acid (GLA). Evening primrose oil (EPO) contains high amounts of GLA. Therefore, this study investigated whether EPO supplementation results in an increase in plasma GLA and its metabolite dihomo-gamma-linolenic acid (DGLA) correlating with clinical improvement of AD, assessed by the SCORing Atopic Dermatitis (SCORAD) index. METHODS: The open study included 21 patients with AD. EPO (4-6 g) was administered daily for 12 weeks. Before treatment, and 4 and 12 weeks after initiation of EPO supplementation, objective SCORAD was assessed and plasma concentrations of GLA and DGLA were determined by gas chromatography. RESULTS: A significant increase in plasma GLA and DGLA levels and a decrease in the objective SCORAD were observed 4 and 12 weeks after initiation of EPO treatment. In the per-protocol population (n = 14), a significant inverse correlation between the changes in plasma GLA levels and SCORAD was found (P = 0.008). CONCLUSION: The clinical disease activity under EPO treatment correlates with the individual increase in plasma GLA levels. Thus, the results of this pilot study indicate that an increase in plasma GLA might be used as predictive parameter for responsiveness of AD to EPO therapy.

The effect of a Cimicifuga racemosa extracts Ze 450 in the treatment of climacteric complaints--an observational study.

BACKGROUND: Root extracts of Cimicifuga racemosa (L.) Nutt. have been successfully used in the treatment of climacteric complaints. METHOD: In this observational study, Cimicifuga racemosa (CR) extract Ze 450 was studied in 442 unselected ambulatory female outpatients with menopausal complaints under daily practice conditions. Physicians were suggested to treat patients for the first 3 months with 13 mg/d CR (high dose, HD) and to continue over additional 6 months either with this treatment or to switch to 6.5mg/d CR (low dose, LD). The choice of treatment and its dose, however, was fully at the discretion of the physician. RESULTS: After 3-months treatment with HD, symptom severity (Kupperman Menopause Index, KMI) decreased significantly (p<0.001) from baseline values. Continuation of treatment with HD or LD decreased total KMI and its sub-item scores further (HD, LD: p<0.001). However, more patients (84.9%) responded to HD than to LD (78.4%) and showed an improvement of symptoms (p=0.011). CONCLUSION: This observational study demonstrated that treatment with CR in unselected patients with climacteric complaints under the conditions of daily practice resulted in a significant improvement of menopausal symptoms assessed by the total KMI score and its sub-item scores with an effect size similar to that in a previous randomized, controlled clinical trial.

Dose-dependent efficacy of the Vitex agnus castus extract Ze 440 in patients suffering from premenstrual syndrome.

BACKGROUND: Preparations of Vitex agnus castus L. (VAC) have been shown to be effective to treat irregular menstrual cycles, cyclical mastalgia and symptoms of the premenstrual syndrome (PMS). However, the dose-effect relationship for the treatment of PMS has not yet been established. This study aimed to investigate the clinical effects of three different doses of the VAC extract Ze 440 in comparison to placebo in patients suffering from PMS. METHODS: In a multicenter, double-blind, placebo-controlled, parallel-group study, 162 female patients with PMS (18-45 years) were randomized to either placebo or different doses of Ze 440 (8, 20 and 30 mg) over three menstrual cycles. PMS symptoms' severity was assessed by patients using visual analog scales (VAS) for the symptoms irritability, mood alteration, anger, headache, bloating and breast fullness. RESULTS: Each of the treatments was well tolerated. Improvement in the total symptom score (TSS) in the 20mg group was significantly higher than in the placebo and 8 mg treatment group. The higher dose of 30 mg, on the other hand, did not significantly decrease symptom severity compared to the 20mg treatment, providing a rational for the usage of 20mg. Corresponding results were observed with the single PMS symptom scores. CONCLUSION: This study demonstrated that the VAC extract Ze 440 was effective in relieving symptoms of PMS, when applied in a dose of 20mg. Therefore, for patients suffering from PMS, 20mg Ze 440 should be the preferred daily dose.

Dose-Dependent Effects of the Cimicifuga racemosa Extract Ze 450 in the Treatment of Climacteric Complaints: A Randomized, Placebo-Controlled Study.

Extracts from Cimicifuga racemosa (CR, synonym Actaea racemosa) have shown efficacy in trials in women with menopausal symptoms. Yet, dose dependency remains unclear. Therefore, 180 female outpatients with climacteric complaints were treated for 12 weeks in a randomized, double-blind, placebo-controlled, 3-armed trial (CR extract Ze 450 in 6.5 mg or 13.0 mg, or placebo). Primary outcome was the difference in menopausal symptoms (vasomotor, psychological, and somatic), assessed by the Kupperman Menopausal Index between baseline and week 12. Secondary efficacy variables were patients' self-assessments of general quality of life (QoL), responder rates, and safety. Compared to placebo, patients receiving Ze 450 showed a significant reduction in the severity of menopausal symptoms in a dose-dependent manner from baseline to endpoint (mean absolute differences 17.0 (95% CI 14.65-19.35) score points, P < 0.0001 for 13.0 mg; mean absolute differences 8.47 (95% CI 5.55-11.39) score points, P = 0.0003 for 6.5 mg). QoL and responder rates corresponded with the main endpoint. Changes in menopausal symptoms and QoL were inversely correlated. Reported adverse events and clinical laboratory testing did not raise safety concerns. The CR extract Ze 450 is an effective and well-tolerated nonhormonal alternative to hormone treatment for symptom relief in menopausal women.

Petasol butenoate complex (Ze 339) relieves allergic rhinitis-induced nasal obstruction more effectively than desloratadine.

BACKGROUND: Allergic rhinitis symptoms of itching, sneezing, rhinorrhea, and nasal obstruction significantly decrease patients' quality of life. Compared with histamine and leukotriene receptor antagonists, the petasol butenoate complex Ze 339 displays pharmacologically distinct properties. In vitro it inhibits the biosynthesis of leukotrienes and mediator release from activated eosinophils. OBJECTIVE: This study aimed to assess the efficacy and mode of action of Ze 339, desloratadine, and placebo on allergic rhinitis symptoms, nasal airflow, and local mediator levels after unilateral nasal allergen provocation. METHODS: In this double-blind, randomized, crossover study 18 subjects with allergic rhinitis to grass pollen received Ze 339, desloratadine, and placebo for 5 days before nasal allergen challenge with grass pollen extract. Rhinomanometry, symptom assessment, and local inflammatory mediator measurement were performed during the 24 hours after allergen challenge. RESULTS: With Ze 339, the patient's time to recovery (5.4 ± 1.6 hours) from nasal obstruction after allergen challenge (time for return to 90% of baseline value ± SEM) was significantly shorter than with placebo (9.1 ± 2.3 hours, P = .035) and desloratadine (10.7 ± 2.5 hours, P = .022). Likewise, Ze 339's standardized symptom assessment for nasal obstruction (3.2 ± 1.3 hours) showed significantly faster relief (time for return to baseline value ± SEM compared with placebo, 8.3 ± 2.4 hours; P = .027) and desloratadine (4.5 ± 1.2 hours, P = .030). One interesting finding was that Ze 339 significantly reduced IL-8 and leukotriene B(4) levels in nasal secretions before challenge. CONCLUSION: When compared with desloratadine and placebo, Ze 339 shows better efficacy in relieving nasal obstruction symptoms and inhibiting critical components of the chemokine network and as such represents a novel symptomatic and possible prophylactic treatment for allergic rhinitis.