[Herb-drugs interactions]. / Wechselwirkungen mit Phytopharmaka.

Herbal therapeutics are increasingly associated with herb drug interactions. The vast majority of the purported cases is unsubstantiated and misinterpreted. Pharmacological and clinical studies should only be demanded in cases of reliable evidence. First steps to be taken by manufacturers of herbal drugs should be in vitro studies with metabolizing systems like CYP and P-gp. Manufacturers of drugs that are metabolized by modulated systems should be requested to conduct drug specific interaction studies as necessary.

Inhibitory effect of an isopropanolic extract of black cohosh on the invasiveness of MDA-mB 231 human breast cancer cells.

BACKGROUND: The isopropanolic extract of black cohosh (iCR)b has recently been reported to exert antiproliferative and apoptosis-inducing effects on estrogen receptor-positive MCF-7, as well as estrogen receptor-negative MDA-MB 231 human breast cancer cells. To broaden observations, the anti-invasive effects of iCR and its two major fractions triterpene glycosides (TTG) and cinnamic acid esters (CAE) were tested in highly invasive MDA-MB 231 cells. MATERIALS AND METHODS: The effect of drugs upon the invasive potential of MDA-MB231 cells was studied in BD Biocoat Matrigel invasion chambers over a period of 24 h. RESULTS: The suppression of invasion reached 51.8% at 77.4 microg/ml of iCR, an extract concentration where 89% of MDA-MB231 cells were viable. TTG and CAE reduced cell invasion by 34% and 25.5%, respectively, at a dose of 5 microg/ml. The motility of cells was only moderately reduced. CONCLUSION: In this study iCR was found to suppress tumor cell invasion without affecting cell viability. This result together with the antiproliferative and apoptosis-inducing effect of iCR suggest its use as a secure agent in postmenopausal hormone replacement therapy with additional chemopreventive activity.

Coadministration of the aromatase inhibitor formestane and an isopropanolic extract of black cohosh in a rat model of chemically induced mammary carcinoma.

Non-steroidal as well as steroidal aromatase inhibitors are currently being discussed as alternatives to tamoxifen in the first-line treatment of patients with hormone-dependent breast cancer. Many of these women are in a postmenopausal state and additionally troubled by climacteric complaints. Naturally occurring symptoms like hot flushes and night sweats can be triggered or augmented by anti-hormonal drugs. At the aromatase molecule, steroidal inhibitors like exemestane and formestane compete with the hormonal precursors for the substrate binding site and inactivate the enzyme irreversibly. An isopropanolic extract of the rootstock of black cohosh (iCR), which is a common comedication of aromatase inhibitors in breast cancer patients suffering from climacteric symptoms, contains triterpene glycosides and cinnamic acid esters, both of which possess structural similarities to steroids. We therefore tested a high dose of iCR, guaranteeing an effective uptake of 60 mg herbal substance per kg body weight and shown to influence rat bone and uterus, for putative interactions with two low dosing regimens of 3.5 mg or 5.0 mg formestane per animal and day. We chose a rat model of chemically induced breast cancer and evaluated tumor growth and serum estrogen levels. Compared to a tumor area of 1400 mm2 after 21 days of unopposed tumor growth, formestane treatment, irrespective of concomitant black cohosh application, significantly reduced neoplastic growth by 50%. Formestane also significantly reduced serum estrogen levels, an effect which was also not abolished by iCR. Therefore, in this experimental setting, when challenging two low doses of formestane with a high dose of iCR, our data do not raise concerns against combining aromatase inhibitors with black cohosh.

Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms.

OBJECTIVE: Several clinical studies suggest that black cohosh may be effective in climacteric complaints. However, evidence of its efficacy based on current quality standards has been limited. METHODS: This randomized, multicenter, double-blind clinical trial compared the efficacy and tolerability of the isopropanolic black cohosh extract in the treatment of climacteric complaints compared with placebo. A total of 304 patients were randomly allocated to receive tablets corresponding to 40 mg drug or matching placebo daily for 12 weeks. The primary efficacy measure was the change from baseline on the Menopause Rating Scale I; secondary measures included changes in its subscores and safety variables. RESULTS: Patient groups did not differ in baseline characteristics. The isopropanolic black cohosh extract was more effective than placebo (P < .001) depending on time from symptom onset (P = .014) and follicle-stimulating hormone level (P = .011). The effect size was 0.03 to 0.05 Menopause Rating Scale units which is similar to recent hormone replacement therapy study results (0.036 Menopause Rating Scale units) and may therefore be considered clinically relevant. Women in the early climacteric phase benefited more than in the late phase. The hot flush subscore was the most effective measure of the isopropanolic black cohosh extract's efficacy. There were no relevant group differences in adverse events, laboratory findings, or tolerability. CONCLUSION: This isopropanolic extract of black cohosh root stock is effective in relieving climacteric symptoms, especially in early climacteric women.

Apoptosis of human prostate androgen-dependent and -independent carcinoma cells induced by an isopropanolic extract of black cohosh involves degradation of cytokeratin (CK) 18.

BACKGROUND: The inhibitory effects of black cohosh extracts (Cimicifuga syn. Actaea racemosa L.) on the proliferation of human breast cancer cells were reported recently. In this study, we turned examined another hormone-dependent, epidemiologically important tumor disease, prostate cancer. The cell growth inhibitory effect of an isopropanolic extract of black cohosh (iCR) on androgen-sensitive LNCaP and androgen-insensitive PC-3 and DU 145 prostate cancer cells was investigated. MATERIALS AND METHODS: The cytotoxic effect of the extract was determined by WST-1 assay. Apoptosis was determined by the appearance of apoptotic morphology, annexin V-FITC adherence and caspase activation. Cytokeratin (CK) 18 degradation was identified with M30 monoclonal antibody. RESULTS: Regardless of their hormone sensitivity, the growth of prostate cancer cells was significantly and dose-dependently down-regulated by iCR. The drug concentration producing 50% cell growth inhibition in all cell lines after 72h lay between 37.1 and 62.7 microg/ml. Increases in the level of M30 antigen of approximately 1.8-, 5.9- and 5.3-fold over untreated controls were observed in black cohosh-treated PC-3, DU 145 and LNCaP cells, respectively, with the induction of apoptosis being dose- and time-dependent. CONCLUSION: Black cohosh extract kills human hormone-responsive or-unresponsive prostate cancer cells by induction of apoptosis and activation of caspases. This finding suggests that the cell's hormone responsive status is not an important determinant of the response to the extract and that iCR extract may represent a novel therapeutic approach for the treatment of prostate cancer.

Evaluation of cell death caused by triterpene glycosides and phenolic substances from Cimicifuga racemosa extract in human MCF-7 breast cancer cells.

We previously reported that the antiproliferative effect of an isopropanolic-aqueous extract of black cohosh (iCR) on MCF-7 estrogen-responsive breast cancer cell line was due to the induction of apoptosis. Here we address the question to what extent apoptosis induction can be ascribed to one of the two major fractions of iCR, the triterpene glycosides (TTG) or the cinnamic acid esters (CAE). Furthermore, as black cohosh is routinely administered orally, we studied whether its pharmacological effects would withstand simulated liver metabolism. The antiproliferative activity of TTG and CAE as well as of rat liver microsomal S9 fraction-pretreated iCR on MCF-7 cells were investigated by WST-1 assay. The features of cell death induced were tested for apoptosis by flow cytometry (light scatter characteristics, Annexin V binding). Irrespective of S9-pretreatment, 72 h iCR treatment induced a dose-dependent down regulation of cell proliferation with the same IC50 of 55.3 microg/ml dry residue which corresponds to 19.3 microg/ml TTG and 2.7 microg/ml CAE. The degree of apoptotic MCF-7 cells was also comparable. Both, isolated TTG and CAE fractions inhibited cell growth, the IC50 being 59.3 microg/ml and 26.1 microg/ml, respectively. Interestingly, whereas IC50 and apoptosis induction correspond well for the whole extract, TTG and CAE fractions induced apoptosis at concentrations (25 and 5 microg/ml) well below those required for significant growth inhibition. Observation of this study firstly showed that the cell death induced by iCR withstood a metabolic activation system. In addition, TTG and CAE compounds significantly contributed to its apoptotic effect, CAE being the more potent inhibitor of proliferation and apoptosis inducer.

Influence of marketed herbal menopause preparations on MCF-7 cell proliferation.

OBJECTIVE: Given the increasing use of alternative menopause treatments, we evaluated the effect of several herbal preparations used for menopause relief on the proliferation of estrogen-sensitive breast cancer cells (MCF-7) as a means of assessing appropriateness for use in women at risk for estrogen-sensitive breast cancer. DESIGN: An MCF-7 cell culture model, as described previously, was used to evaluate the estrogen-agonist and -antagonist activity of commercially available herbal menopause preparations containing red clover, soy, black cohosh, or a combination of herbs. Each test substance was evaluated for cytotoxic effects before conducting the proliferation assays. RESULTS: Commercially available products containing soy, red clover, and herbal combinations induced an increase in the MCF-7 proliferation rates, indicating an estrogen-agonistic activity in the absence of estradiol. In contrast, an isopropanolic black cohosh extract (Remifemin Menopause) did not stimulate MCF-7 growth and exerted inhibitory effects on cellular proliferation. None of the tested products enhanced estradiol-induced cell proliferation. The black cohosh preparation and one of the herbal combinations exhibited strong estrogen-antagonistic effects. CONCLUSIONS: The lack of proliferative effects of isopropanolic black cohosh extract on estrogen-sensitive breast cancer cells in vitro suggests a favorable safety profile for use in women with a history of breast cancer. Alternatively, preparations containing red clover, soy, and combinations of various herbal ingredients may induce cell proliferation, suggesting that such herbal preparations should be used with caution in the treatment of menopause symptoms in women at risk for, or with a history of, estrogen-sensitive breast cancer.

Concomitant administration of an isopropanolic extract of black cohosh and tamoxifen in the in vivo tumor model of implanted RUCA-I rat endometrial adenocarcinoma cells.

Black cohosh is a well known herbal remedy of long traditional use against menopausal complaints. Recently published studies on postmenopausal hormone replacement with synthetic substances associated severe negative side effects with an increase in duration of administration. The subsequent popularity of alternative treatments, often herbal drugs, made investigations into the safety of these preparations more pressing. Until now, black cohosh demonstrated no estrogen-agonistic activity in mammary cells, neither in animal model nor in cell culture, i.e., no gene transcription or cell proliferation was induced. Here we tested for the influence of a standardized isopropanolic extract of black cohosh on an animal model of endometrial cancer. Ectopic growth of the primary tumor as well as the incidence and localization of metastases were examined, partly in the setting of a combination treatment with tamoxifen. In contrast to the endometrial estrogen agonist tamoxifen, black cohosh did not further growth or metastasizing potential of the primary tumor. Absence of detectable supportive or antagonistic effects between both treatments most probable come from the relatively high tamoxifen dose.

Influence of peroral application of a herbal immunomodulator on the antibody production of Peyer's patches cells.

The influence of the peroral administration of the macromolecular components of a herbal immunomodulator isolated from an aqueous-ethanolic extract of the mixed herbal drugs Thujae summitates, Baptisiae tinctoriae radix, Echinaceae purpureae radix and Echinaceae pallidae radix on the function of Peyer's patches cells was investigated in mice. Peyer's patches cells isolated from mice which had received oral administration of the macromolecular fraction of the plant extract developed a significantly enhanced plaque-forming cell (PFC) response to sheep red blood cells after incubation with these cells in the presence of lipopolysaccharide or the extract fraction for 7 days in vitro. These results show that after oral administration of the herbal immunomodulator, the immunologically active macromolecules can contact the cells of the gut-associated lymphoid tissue and modulate the mucosal immune response.

Effects of an isopropanolic extract of Cimicifuga racemosa on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis.

A potential bone-sparing effect of Rhizoma actaeae (= cimicifugae) racemosae (black cohosh) was evaluated in ovariectomized Sprague-Dawley rats. The rats were ovariectomized at 12 weeks of age (body weight, 219-226 g) and placed on a soy-free diet 6 days after surgery. Animals were randomly assigned the following groups: control (n = 10), soy-free diet only; RAL (n = 10), soy-free diet plus raloxifene 3 mg/kg intragastrically; and REM (n = 10), soy-free diet supplemented with an isopropanolic black cohosh extract (Remifemin) with a daily intake of 4500 micro g triterpeneglycosides. Urinary levels of pyridinoline (PYR) and deoxypyridinoline (DPY), specific markers for bone loss, were measured at baseline and at weekly intervals. At the end of the study, the animals were killed and bone loss was determined by volumetric bone mineral density (BMD) measurements and peripheral quantitative computed tomography (pQCT). Mechanical resistance to fracture was also determined. Results demonstrated that an isopropanolic extract of black cohosh significantly diminished the urinary content of PYR and DPY and the morphometric correlates of bone loss associated with ovariectomy in rats. Reversal of the effects of ovariectomy on bone loss began 2-5 weeks after the start of treatment and continued through at least 7 weeks. Results similar in quality and magnitude were obtained in the group treated with raloxifene, a known selective estrogen receptor modulator (SERM). Because extracts of black cohosh are already recognized as safe and effective in the treatment of certain gynecological disorders, a longer-term clinical trial of this herbal remedy for the treatment of osteoporosis is warranted.

Esberitox N as supportive therapy when providing standard antibiotic treatment in subjects with a severe bacterial infection (acute exacerbation of chronic bronchitis). A multicentric, prospective, double-blind, placebo-controlled study.

53 patients with planned antibiotic therapy for the treatment of acute exacerbation of chronic bronchitis as an example of a severe bacterial infection requiring antibiotics were included in a prospective, multicentre, double-blind, placebo-controlled study. The chronic bronchitis was staged by forced expiratory volume of the 1st second (FEV(1)) measured in the infection-free interval prior to the current episode and had to be between 35 and 75% for the predicted value. Patients were randomly assigned to receive newer macrolide antibiotics plus either Esberitox N or placebo. Antibiotic therapy was administered according to generally accepted guidelines and Esberitox N or placebo was given for 28 days. The baseline-adjusted means for FEV(1) (%) on day 10 were 68.7 points for the Esberitox N group and 59.2 points for the placebo group (p = 0.0303). For FEV(1) the difference between the two treatment groups was 267 ml (p = 0.0499). The time to half maximal improvement was 5.7 days in the Esberitox N group compared to 12.8 days in the placebo group. The treatment was well tolerated; no serious adverse events were documented. In conclusion, comedication of antibiotics with Esberitox N in subjects with acute exacerbation of chronic bronchitis seems to be of benefit for the patient. Apparently, therapy with Esberitox N leads to a faster recovery from this severe bacterial infection, possibly via preventing an impairment of the host's immune system which might otherwise occur as a consequence of aggressive antimicrobial therapeutics.

Influence of Cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells.

Hormone replacement therapy, which is a common menopausal treatment, is contraindicated in women with breast cancers due to concerns regarding the potential for breast cell proliferation. As such, there is a need for alternative methods for treating menopausal symptoms. To determine the influence of one such alternative, black cohosh (Cimicifuga racemosa [CR]), on estrogen-dependent mammary cancers, we conducted an in vitro investigation of the effect of an isopropanolic CR-extract on the proliferation of estrogen receptor-positive breast cancer cells. The experiments were performed using the human breast adenocarcinoma (MCF-7) cell test system, an established in vitro model for estrogen-dependent tumors. The influence of CR-extract on the proliferation of the MCF-7 cells was determined by measuring the incorporation of radioactively labeled thymidine. Under estrogen-deprived conditions, the CR-extract (10(-3)-10(-5) dilutions) significantly inhibited MCF-7 cell proliferation. Additionally, application of the CR-extract inhibited estrogen-induced proliferation of MCF-7 cells. Moreover, the proliferation-inhibiting effect of tamoxifen was enhanced by the CR-extract. Such data that suggest a non-estrogenic, or estrogen-antagonistic effect of CR on human breast cancer cells lead to the conclusion that CR treatment may be a safe, natural remedy for menopausal symptoms in breast cancer.

Effect of oral application of an immunomodulating plant extract on Influenza virus type A infection in mice.

The influence of the oral administration of an aqueous-ethanolic extract of a mixture of Thujae occidentalis herba, Baptisiae tinctoriae radix, Echinaceae purpureae radix and Echinaceae pallidae radix, on the course of Influenza A virus infection in Balb/c mice was investigated. The extract was administered to mice via the drinking water for 14 days starting 6 days before intranasal infection with Influenza A virus. The progress of infection was recorded during a time range of 21 days. Parameters for the evaluation of antiviral activity were survival rate and mean day to death. In a further set of experiments infected mice were sacrificed on defined days. Determination of consolidation score and virus titer were performed for each lung. The data show that the oral treatment with the extract induced a statistically significant increase in the survival rate, prolonged the mean survival time and reduced lung consolidation and virus titer. The experiments demonstrate that the plant immunomodulator given 6 days before exposure is a potent inhibitor of Influenza A virus pathology in vivo.

Oral administration of freshly expressed juice of Echinacea purpurea herbs fail to stimulate the nonspecific immune response in healthy young men: results of a double-blind, placebo-controlled crossover study.

Echinacea extracts are widely used in European countries and in the United States as "immune-stimulating" agents. Even though the evidence to stimulate certain components of the nonspecific immune system (phagocytosis, macrophages, and production of cytokines) stems from in vitro experiments or studies after parenteral application, the commercially available Echinacea preparations used as drugs or supplements are for oral use. The aim of the study was to determine whether phagocytic activity and production of cytokines is stimulated by oral application of a commercially available Echinacea preparation. Forty healthy male volunteers (ages 20-40 years) participated in the study. They received either a freshly expressed juice of Echinacea purpurea herbs or placebo juice using a double-blind placebo-controlled crossover design with two treatment periods of 14 days and a wash-out period of 4 weeks in between. Endpoints for immune stimulation: phagocytic activity of polymorphonuclear leukocytes and monocytes measured by flowcytometry, production of tumor necrosis factor alpha (TNF)-alpha and Interleukin (IL)-1beta by LPS-stimulated blood monocytes. Echinacea purpurea herbs did neither enhance phagocytic activity of polymorphonuclear leukocytes nor that of monocytes when compared with placebo. Echinacea purpurea herbs did not influence the production TNF-alpha and IL-1beta by LPS-stimulated monocytes. Unexpectedly, Echinacea purpurea herbs decreased serum ferritin concentration (p = 0.0005). All other laboratory and safety data remained unchanged. The "immune stimulation" by Echinacea purpurea observed in vitro and after parenteral administration are not confirmed in healthy humans after oral intake. Other immunomodulatory effects may explain the benefits of Echinacea preparations in reducing duration and severity of upper-respiratory tract infections found in randomized, double-blind clinical trials.

Lack of promotion of estrogen-dependent mammary gland tumors in vivo by an isopropanolic Cimicifuga racemosa extract.

Cimicifuga racemosa (CR) is widely used in the treatment of menopausal symptoms. Mechanistic studies suggest that unlike hormone-replacement therapy, CR does not stimulate estrogen-receptor positive breast cancer cells. To evaluate CR safety, we performed an in vivo investigation of a clinically tested isopropanolic CR extract. Mammary tumors were induced in Sprague Dawley rats (n = 75) by the application of 7,12-dimethylbenz[a]anthracene. Five to nine weeks later, the animals were ovariectomized, allowed to recover, and administered daily doses of CR extract (0.714, 7.14, or 71.4 mg/kg body weight per day) or control substances (estrogen/positive control: 450 microg/kg/day mestranol; or CR vehicle/negative control). The animals were sacrificed 6 weeks later, and tumor number, size, plasma hormone levels, and the weight of estrogen-sensitive organs were analyzed. In contrast to mestranol treatment, CR treatment did not stimulate cancerous growth. There were no significant differences in tumor number or size between the CR groups and the vehicle control. Likewise, prolactin, follicle-stimulating hormone, and luteinizing hormone levels and organ weights and endometrial proliferation were unaffected. The lack of mammary tumor-stimulating effects of this extract is of great significance in establishing the safety of CR extracts for treatment of menopausal symptoms in women with a history of breast cancer in which hormone-replacement therapy is contraindicated.