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FEATURE By WENDELL L. COMBEST, Ph.D., Associate Professor of Pharmacology, Department of Biopharmaceutical Sciences, Shenandoah University School of Pharmacy, Winchester, VA. lack cohosh (Cimicifuga racemosa), of the family Ranunculaceae, is a hardy perennial indigenous to the eastern U.S. but widely cultivated as an attractive garden ornamental. The plant can grow to a height of 8 feet. It has large, irregular, tooth-edged leaves and a flower stalk supporting tall plumes of fragrant white flowers, which bloom from June through September. It prefers rich sandy soil, and is most often found growing in woodland habitats. The name “cohosh” is derived from an Algonquian word meaning “rough,” which describes the knotty texture of the rhizome.1 The rhizomes are dark brownish-black in colour, hence the name black cohosh. The roots and rhizome – which have a bitter, acrid taste – are the medicinally useful part of the plant. The Latin name Cimicifuga means “bug-repellent,” reflecting one of its popular uses. There are 15 species comprising the genus Cimicifuga, and various species in Europe are referred to by the common name “bugbane” for its purported insect-repelling activity. B CHEMICAL COMPOSITION AND ACTIVE CONSTITUENTS benefit of black cohosh is in the treatment of postmenopausal symptoms. Eight clinical trials have been published since the early 1980s; most of the studies have been carried out in Germany. The German Commission E approves black cohosh for “premenstrual discomfort, dysmenorrhea, or menopausal neurovegetative ailments.” One of the first studies involved 36 postmenopausal women treated with Remifemin (an alcoholic extract of black cohosh roots).4 Remifemin is a brand-name product (manufactured by Schaper and Brummer in German) and is standardized to contain triterpene glycoside, usually 1 mg of 27-deoxyacteine per tablet. Treatment for 12 weeks resulted in a decrease in menopausal symptoms, with no reported side effects. These results were supported by a similar study published the next year.5 This 12-week study of 50 postmenopausal women assessed symptoms utilizing the Profile of Mood States (POMS) and Clinical Global Impression Scale (CGI). Remifemin treatment resulted in a significant improvement in both the POMS and CGI scales. The only side effect noted was mild gastrointestinal disturbances in four patients. This popular native American herb is used worldwide to treat menopausal symptoms. The rhizomes and roots contain triterpene glycosides actein, cimicifugoside, and 27deoxyactein, which are considered the main active constituents.2 Eight newly described glycosides have recently been isolated and characterized from the Japanese species Cimicifuga simplex.3 Other constituents include the alkaloid n-methylcytisine along with many other related quinolizidine alkaloids, the isoflavone formononetin, and the phenolic acids isoferulic and salicylic acids, as well as various tannins. Several studies have compared Remifemin to conventional treatment of menopausal symptoms with various forms of estrogen or diazepam (Valuim). One study compared the efficacy of Remifemin in treating menopausal symptoms to hormone treatment or therapy with a psychotropic drug in 60 patients.6 Remifemin (two 1 mg tablets twice daily), conjugated estro- MEDICINAL USES AND PHARMACOLOGY gens (Premarin, 0.625 mg/day) or diazepam (Valium, 2 Native Americans used the roots and rhizomes for a variety of ailments, including menstrual cramps and pain associated with labour and delivery. Eclectic physicians in the U.S during the 1800s used black cohosh to treat uterine difficulties, stimulate menstrual flow, and reduce discomforts during labour. It was one of the main ingredients in Lydia Pinkham’s Vegetable Compound, which was one of the most popular patent remedies for “women’s complaints” during this period. Black cohosh has been used in Germany since the mid-1950s for treatment of menopausal symptoms. Clinical Studies: The strongest evidence for a clinical mg/day) was given for three months. Remifemin was found 10 to be more effective than Premarin or Valium in relieving the depressive mood and anxiety associated with menopause. These results were further supported in a study involving 80 patients who were treated for 12 weeks with either Remifemin (8 mg daily), conjugated estrogens (0.625 mg daily) or placebo.7 Remifemin was more effective in reducing anxiety, atrophic vaginitis, and the frequency of hot flashes. In another clinical trial, 60 women who had hysterectomies with at least one remaining ovary were given either estriol (1 mg COMMUNICATION NOVEMBER/DECEMBER 2000 daily), conjugated estrogens (1.25 mg daily), estrogen-gesta- in ovariectomized rats. Extracts from two Cimicifuga species daily).8 (Cimicifuga heracleifolia and Cimicifuga dahoric) have been gen (Trisequens, 1 tablet daily), or Remifemin (8 mg Menopausal symptoms, such as hot flashes and nervousness, used extensively as antipyretic, analgesic, and anti-inflamma- were significantly reduced by all treatments, with no differ- tory agents in Japanese oral medicine. Ferulic acid (FA) and ences noted between the various therapies. Remifemin’s isoferulic acid (IFA) were found to be active anti-inflamma- ability to improve menopausal symptoms was compared to tory compounds in methanol extracts of the roots of these previous therapy with estrogen replacement or psychoactive species.14 These compounds were found to inhibit interleukin- drugs in 629 female patients.9 Remifemin treatment for 6 – 8 8 production in response to influenza virus infections in vitro weeks improved menopausal symptoms in more than 80% of and in vivo. The in vitro studies were done in a murine women. The only side effect reported was mild GI distress in macrophage cell line infected with influenza virus. The in 7% of the patients. One study examined the effectiveness of vivo study involved injecting mice with the influenza virus Remifemin in 50 women who had discontinued estrogen with and without prior oral administration (5 Remifemin was administered for 6 mg/mouse/day) of Cimicifuga extracts, 0.5 mg/mouse/day months. Effectiveness was evaluated by a gynecologist as of FA, or 0.125 mg/mouse/day of IFA. The three treatments very good in 21 patients and good in 20 patients, with little reduced IL-8 levels in bronchoalveolar lavage obtained two effect seen in 9 patients. days after infection. These results indicate that at least two replacement therapy.10 A double-blind trial in 10 postmenopausal women, in which half were treated with Remifemin (8 mg daily) for 8 weeks, resulted in significant improvements in menopausal components in Cimicifuga may be responsible for the extract’s analgesic and anti-inflammatory activity. Limited data is available for additional effects of black symptoms for those receiving Remifemin.11 Blood levels of cohosh root extracts. The steroidal triterpene derivative action luteinizing hormone (LH), but not follicle stimulating was shown to lower blood pressure in rabbits and cats, but hormone (FSH), were significantly reduced in the treatment not dogs.15 This hypotensive effect has not been demonstrated group. Many of the symptoms of menopause are believed to in humans. Root extracts from Cimicifuga foetida and result from elevated blood levels of LH. Cimicifuga heraclefolia species were recently shown to inhibit Animal and In Vitro Studies: The effects of an orally parathyroid hormone-induced bone reabsorption in tissue administered ethanolic extract of black cohosh rhizomes on culture and in ovariectomized rats.16 Isopropanolic extracts of uterine growth in immature mice and on vaginal cornification Cimicifuga racemosa were shown to inhibit the proliferation in ovariectomized rats were investigated.12 Results revealed of estrogen-dependent breast cancer cell lines in a dose- no signs of estrogenic growth of uterine or vaginal tissues. dependent manner.17 This study suggests that the beneficial effects of black cohosh SIDE EFFECTS AND TOXICITY are not due to a classic estrogen trophic effect in these tissues. The FDA lists black cohosh as an herb of “undefined In another study, lipophilic extracts of black cohosh roots safety.” The German Commission E notes no contraindica- were subjected to gel-exclusion chromatography, with various tions, with occasional gastric upsets likely due to the high fractions tested for their ability to reduce LH secretion in tannin content. Because of the lack of long-term toxicity stud- ovariectomized rats and to compete with 17-b-estradiol bind- ies, its use is recommended for no more than six months. ing sites in uterine tissue.11 Several fractions had LH-reducing Black cohosh is contraindicated in pregnancy, and large doses activity, whereas others were able to compete for the estrogen could result in miscarriage.18 No reports of adverse effects on receptor. The results of this study suggest the presence of lactation or in nursing children have been made. No drug multiple constituents in black cohosh roots that could act interactions have been noted. Remifemin has often been used synergistically to bring about a coordinated pharmacological in conjunction with estrogen replacement therapy, with no response. reported adverse effects. The above study supports an earlier investigation of chromatographically separated fractions from methanol extracts of black cohosh rhizomes.13 At least three fractions were found that could either decrease LH blood levels in ovariectomized rats or compete with estrogen in an in vitro estrogen receptor assay. One of the isolated fractions was further characterized and found to include the isoflavon formononetine. Isolated formononetine was shown to be a competitor for estrogen in the receptor assay, but failed to decrease LH levels COMMUNICATION NOVEMBER/DECEMBER 2000 DOSAGE FORMS AND RECOMMENDATIONS All clinical studies (mostly Germany-based) have utilized the alcoholic extract of Cimicifuga racemosa Remifemin. Nearly 10 million one-month supplies of Remifemin were sold in Australia, Germany, and the United States in 1996.20 Clinical trial results indicate that dosages of 4-8 mg per day were effective in reducing many of the symptoms of menopause. ■ References available on request to MSP. 11