Muscle damage induced by black cohosh (Cimicifuga racemosa).
Extracts of black cohosh (Cimicifuga racemosa) are commonly used for the treatment of symptoms associated with menopause. Adverse events with black cohosh are rare, mild and reversible. A few number of serious adverse events, including hepatic and circulatory conditions, have been also reported, but without a clear causality relationship. We report the case of a woman with severe asthenia and very high blood levels of creatine phosphokinase and lactate dehydrogenase. The patient referred to take a dietary supplement derived from black cohosh for ameliorating menopause vasomotor symptoms. To exclude a possible involvement of this product, the patient was suggested to discontinue this therapy. After suspicion the patient showed a progressive normalization of biochemical parameters and improvement of clinical symptoms.
We can hypothesise a causative role for black cohosh in the muscle damage observed in this patient. Factors suggesting an association between black cohosh and the observed myopathy included the temporal relationship between use of herbal product and asthenia and the absence of other identified causative factors. Rechallenge with the suspected agent was inadvisable for ethic reasons because of the risk of a serious relapse. This is the first time that asthenia associated with high muscle enzymes serum levels by black cohosh has been reported. In our opinion, this report is of interest because of the widespread diffusion of use of black cohosh as an alternative medicine for relief from menopausal symptoms.
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Keywords: Black cohosh; Cimicifuga racemosa; Menopause; Asthenia; Muscle enzyme
Hormone replacement therapy is commonly used for the treatment of symptoms associated with menopause and to prevent osteoporosis. Owing to the appearance of adverse affects, such as cardiovascular diseases and the increased risks of endometrial or breast cancer, many menopausal women are actively seeking alternative treatments. About 80% of women aged 45-60 reported the use of non-prescription therapies, such as botanical dietary supplements, for the management of peri- and post-menopausal symptoms (Kaufert et al. 1997; Dantas, 1999; Glazier et al., 2001; Mahady et al., 2003). As to herbal therapies, extracts of black cohosh (BC; Cimicifuga racemosa) are one of the most commonly used. BC is an indigenous Eastern-North American plant, whose constituents include salicylic, tannic and phenolic acids, phytosterols, alkaloids, crystalline alcohols, the diterpenoid fukinolic acid, triterpenoid glycosides (actein and cimifugoside) and the isoflavone formononetin (Dantas, 1999). The mechanism by which BC may exert its effects is unclear. Although an estrogen-like action of BC has been suggested (Kang et al., 2002), recent results suggest that BC capability to reduce some climateric disorders (e.g. vasomotor symptoms and psychic complaints) associated to menopause is very likely due to components acting at central level (Borrelli et al., 2003; Burdette et al., 2003; Jarry et al., 2003; Winterhoff et al., 2003).
Few is known about the biological activity of pure components present in BC (Einbond et al., 2004). Actein, 27-deoxyactein and cimiracemoside A (the most abundant triterpene glycosides contained in extracts of BC rhizomes) are able to inhibit growth of human breast cancer cells, by inducing cell cycle arrest at G1; also cycloartane glycosides inhibit the growth of human oral squamous cell carcinoma cells. Furthermore, several compounds with antioxidant activity, such as methyl caffeate, have been isolated from BC, but none of these compounds are cytotoxic. Finally, fukinolic acid inhibits the activity of neutrophil elastase and belongs also to the class of phytoestrogens.
Data from clinical studies and spontaneous reporting programs suggest that adverse events with BC are rare (5.4%), mild and reversible. The most common adverse reactions are nausea, vomiting, headaches, dizziness, mastalgia, weight gain and rashes (Mahady et al., 2002; Dog et al., 2003); however a few number of serious adverse events, including hepatic and circulatory conditions, have been also reported, but without a clear causality relationship (Whiting et al., 2002; Huntley and Ernst, 2003; Lontos et al., 2002).
We report the case of a 54-year-old woman with a severe asthenia. Some days after the appearance of symptoms, the patient underwent, under medical counselling, blood laboratory exams that showed for two times, with a distance of 9 days, high blood levels of creatine phosphokinase (CPK; 237 and 230 Units/l; normal value: 24-170 U/l), lactate dehydrogenase (LDH; 504 and 548 U/l; normal value: 230-460 U/l), total cholesterol (277 and 282 mg/ml; normal value: 120-250 mg/ml) and high density lipoprotein cholesterol (HDL; 110 mg/ml; normal value: 48-75 mg/ml). Owing to the worsening of the symptom, the patient referred to our division. In this circumstance, the woman showed markedly higher levels of LDH (987 U/l) and CPK (247 U/I), and levels of total cholesterol and HDL similar to those previously measured. Other routine biochemical parameters, such as blood cell count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), kidney and thyroid functionality indexes, and erythrocyte sedimentation rate continued to be in the normal range. These same laboratory exams, including muscle enzymes, effectuated by the patient three months before the appearance of asthenia, for a routine control, had shown no alteration. Patient anamnesis and clinical examination were negative for chronic systemic diseases, excepting a uterine fibroma. The patient referred to take a herbal product derived from black cohosh plant (Remifemin[R]; Glaxo Smith Kline) for ameliorating menopause vasomotor symptoms. Each table of Remifemin[R] contains 20 mg of dried rhizome and root extracts, standardized to contain 1 mg of 27-deoxyactein; the approved indication of Remifenin[R] is the treatment of minor climateric symptoms, such as hot flushes, sweating, sleep disturbances and nervous tension. The patient had started to assume this product, under gynaecologist suggestion, after having interrupted a hormone replacement therapy due to the increased growth of a uterine fibrome. The patient had taken one table of Remifemin[R] twice a day for 1 year and then had discontinued the therapy; she had restarted the same therapy 2 months later for the reappearance of menopausal symptoms. Asthenia appeared 2 months later the re-assumption of Remifemin[R]. In concomitance with the appearance of asthenia, the patient had not practiced any type of physical exercises, had not modified her dietary or life habits and had consumed, in addition to Remifemin[R], no other drugs, nutraceuticals or dietary supplements. Before undergoing invasive examinations, such as electromyography and muscle biopsy, and to exclude a possible involvement of Remifemin[R], the patient was suggested to discontinue this therapy. After 10 days the patient showed improvement of symptoms, although blood exams evidenced a further increment in CPK levels (278 U/l) with a significant reduction of LDH (493 U/l) and a mild reduction of total cholesterol (278 mg/ml) levels. Five days later the values of CPK started to decrease (221 U/l) and those of LDH and total cholesterol began to normalise (464 U/l and 203 mg/ml, respectively); furthermore the patient showed complete remission of symptoms. After a week, only CPK value was altered (190 U/l), while LDH and cholesterol levels were normal (402 U/l and 190 mg/ml, respectively). Twenty days later all parameters were normal. Until 3 months after the normalization of muscle enzymes and cholesterol levels, the patient did not presented any alteration in laboratory exams.
BC extracts are widely employed to relieve menopause symptoms. However, in spite of several reports claiming Remifemin[R] levels efficacy for alleviation of menopausal complaints (McKenna et al., 2001), its clinical efficacy has not been convincingly confirmed through rigorous clinical trials (Borrelli and Ernst, 2002). In addition, despite the popularity of this drug, few are known about the metabolism or possible toxicity of many compounds contained in it. For example, BC contains several catechols, such as caffeic and piscidic acids and fukiic acid esters; these cathecols are of particular interest in toxicology because of the possibility that they may be metabolically or chemically activated to electrophiles quinines, whose potential toxicity is well documented. However, formation of quinoid metabolites of black cohosh was demonstrated only in vitro but not in vivo (Johonson and van Breemen, 2003).
We can hypothesise a causative role for BC in the muscle damage observed in this patient. Several clinical features are useful for identifying a myopathy as toxic in nature: lack of preexisting muscle symptoms; delay in onset of symptoms after exposure to a putative toxic substance; lack of any other cause for myopathy; often complete or partial resolution of symptoms after the toxic agent is withdrawn (Sieb and Gillessen, 2003). All these features were true in our case. Another factor suggesting an association between BC and the observed myopathy was the temporal relationship between use of Remifemin[R] and asthenia. Rechallenge with the suspected agent was inadvisable for ethic reasons because of the risk of a serious relapse. Use of the Naranjo ADR probability scale indicates a probable relationship between skin manifestations and Remifemin[R] treatment (Naranjo et al., 1981).
One has to point out that possible risks in the use of over-the-counter products, including dietary plant supplements, may be related to a drug intake at excessive dosage levels or for a too long period (Bergmann, 2003). In this case, the patient assumed the drug for a period very longer that that recommended for Remifenin[R]. In fact, the suggested dose of Remifenin[R] is 2 tablets/day, to be taken for up 6 months continuously. Although used in the traditional medicine for very long period without any report of toxicity or adverse reactions, BC products are considered safe only if they are taken for a limited length of time due to lacking of long-term studies (Huntley and Ernst, 2003). For example, Food & Drug Administration classifies BC as an herb of undefined safety; furthermore the German licensing authority Bundes Gesundheit Amt (BGA) considers BC safe as a hormone replacement therapy, but recommends to limit its use to a 6-month period.
Finally, the side effects of over-the-counter products have to be rare and not severe (Naranjo et al., 1981). Although the main adverse events of BC are rare, mild and reversible, there are some reports about acute liver failure caused by this herbal product, which required urgent liver transplantation and whose pattern of injury was suggestive of an idiosyncratic/immunological reaction (Whiting et al., 2002; Lontos et al., 2002). This is the first time that asthenia associated with high muscle enzymes serum levels (a serious adverse reaction) by BC has been reported. One has to point out that none of biological effects demonstrated for the main components of BC (Einbond et al., 2004) can explain the myopathic effect described in the present report.
In our opinion, this report is of interest because of the widespread diffusion of the of BC as an alternative medicine for relief from menopausal symptoms.
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P.L. Minciullo (a), A. Saija (b), M. Patafi (a), G. Marotta (a), B. Ferlazzo (a), S. Gangemi (a,*)
(a) Department of Human Pathology, Division and School of Allergy and Clinical Immunology, University of Messina, Italy
(b) Department of Farmaco-Biologico, School of Pharmacy, University of Messina, Italy
Received 7 July 2004; accepted 14 September 2004
*Corresponding author. Tel.: +39 090 716070; fax: +39 090 6782336.
E-mail address: firstname.lastname@example.org (S. Gangemi).