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Treatments used in complementary and alternative medicine
K. Chan and T.X. Lin
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Treatments used in complementary and alternative medicine
GENERAL Susceptibility factors HIV infection In a cross-sectional study of the use of complementary and alternative medicines in 682 participants with HIV infection among the 47% ever-users, vitamins/minerals (81%), meditation/yoga (36%), massage (31%), marijuana (30%), dietary supplements (24%), and herbal medicines (19%) were the most commonly used (1C). Users were less likely to be poorly educated, more likely to be unemployed, more likely to have been taking antiretroviral drugs for longer, and more likely to have objective, action-requiring adverse effects.
HERBAL MEDICINES
(SED-15, 1609; SEDA-27, 512; SEDA-28, 573; SEDA-29, 583)
Observational studies In an audit of 100 patients admitted to a UK hospital for acute medical emergencies, 24 were taking herbal remedies (a total of 40 products); the most popular product was garlic (2cA). Of these 24 patients 20 were also taking prescription medications and 11 were taking herbal remedies that have either documented toxicity or known interactions with Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03148-1 r 2009 Elsevier B.V. All rights reserved.
prescription drugs. However, the use of a herbal preparation was documented in the case notes in only one case. In a 5-month survey on the use of phytomedicines by 1063 patients, based on a prestructured questionnaire, in the out patient department of an urban university general hospital in Italy, of the 1044 women who completed the interview 491 (47%) reported taking at least one herbal com pound (3R). Of these 491 patients, 272 (55%) consumed only one phytomedicine, while 219 (45%) also took traditional drugs. Adverse effects were reported by 47 (9.6%), including: gastrointestinal (due to dandelion, propolis, and fennel); cardiovas cular (after liquorice, ginseng, and green tea); dermatological (after propolis, thyme, arnica, and passion-flower); and neurological (after guaraná and liquorice). Conventional medicines that were taken simultaneously and were potentially involved in adverse effects were antihypertensive drugs, benzo diazepines, non-steroidal anti-inflammatory drugs, antibiotics, and oral contraceptives. In five cases adverse effects were sufficiently serious to justify admission to hospital. In 29/ 47 cases the adverse effect was not commu nicated to the doctor. The authors confirmed previous observations (4R) that consumers of herbal remedies act differently with regard to reporting an adverse reaction (serious or minor) to their physician, and that many adverse manifestations to herbal remedies are not monitored. Perioperative events in 601 patients undergoing major elective surgery who had taken traditional Chinese herbal medicines presurgically have been studied in a teaching
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746 hospital in Hong Kong (5CA). Of these patients, 483 (80%) had taken self-pre scribed herbal medicines and 47 (8%) had taken herbal medicines prescribed by practi tioners of traditional Chinese medicine in the 2 weeks before surgery. The crude incidences of any combined end-points of preoperative, intraoperative, and post operative events were 23% (19–26%), 74% (71–78%), and 63% (59–66%), respectively. Compared with non-users, patients who took traditional Chinese herbal medicines by prescription were more likely to have a preoperative event. The authors presented four case reports to highlight the effect of traditional Chinese herbal medicines by prescription on preoperative prolongation of the activated partial thromboplastin time and hypokalemia. In contrast, there was no significant association between the use of any type of traditional Chinese herbal medicines and the occurrence of either intraoperative or postoperative events. They emphasized that the use of traditional Chinese herbal medicines by prescription near the time of surgery should be discour aged, because of the increased risk of adverse events in the preoperative period. Gastrointestinal Number Ten is a dietary supplement that contains rhubarb, ginger, astragalus, red sage, and turmeric. It has been used to reduce food intake and cause weight loss in a pilot study in 24 healthy women aged 18–60 years, body mass index 25–35 kg/m2, who were taking no long-term medications, but was ineffective (6c). Doserelated loose stools was the main adverse effect, which was not surprising, as Number Ten was found to contain sennosides, known laxatives, and gallic acid, which causes weight loss in rodents. Liver Xiao-chai-hu-tang (syo-saiko-to in Japanese), a herbal remedy (consisting of bupleurum root, pinellia tuber, scutellaria root, jubube fruit, ginseng root, glycyrrhiza root, and ginger root), widely used in China for treatment of respiratory, hepa tobiliary, and gastrointestinal diseases, particularly among patients with chronic liver disease, has been reported to cause acute hepatitis (7A).
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A 52-year-old woman developed weakness,
fatigue, and tea-colored urine after repeated consumption of a decoction of xiao-chai-hu-tang for 1.5 months. Laboratory studies showed acute hepatitis and all markers of viral hepatitis were negative. Liver biopsy showed a picture of acute hepatocellular hepatitis. The symptoms improved after withdrawal of the drug, and liver biochemical tests normalized 2 months later.
This case report reminds us of the possibility of hepatotoxic effects of herbs, even from some that are claimed to have hepatoprotective effects. Hepatotoxicity has also been attributed to traditional medicines in patients with hepa titis B infection (8c). In a pilot study to review the clinical course of drug-induced liver damage in a Singapore tertiary hospital 29 patients were identified, of whom 15 had consumed traditional Chinese medicines and 4 had taken antituberculosis drugs (9c). Drug contamination Legislation to control the quality of traditional Chinese medicines was implemented in Hong Kong in 1989, since when proprietary Chinese medicines have been recalled by government bodies after inspection of products available on the market (10S). This information can be used as an alert when these products are re distributed to other regions. Heavy metals Heavy metals, such as lead, can cause anemia, kidney failure, and adverse effects on the nervous system, gastrointestinal system, and cardiovascular system. The public have been advised not to purchase contaminated products with the brand names listed in Table 1 and to stop using them or to dispose of the product or surrender it to the Pharmaceutical Service of Department of Health, as the lead content of the products concerned exceeded the maximum permitted limit. Microbial counts The Department of Health in Hong Kong has ordered the immediate recall of 17 proprietary Chinese medicines after laboratory tests showed that the total bacterial count exceeded the maximum permitted limit for registration of such medicines in both Hong Kong and Macau (Table 1). Some of these products are intended for pediatric use.
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Table 1. Herbal preparations contaminated with lead or with excess bacterial counts Preparations containing lead Chung San Brand Po Ling Brand (production batch numbers 040607 and Fung Sen Brand 050607) Golden Ship Brand Tin Fung Brand Green Leaf Brand Wintex Tong Brand Proprietary Chinese medicines recalled after laboratory tests showed that the total bacterial count exceeded the maximum permitted limit Bao Zhu Brand Bo Ying Pills Chu Pai Chut Lee San Bao Zhu Brand Chut Lee San Chu Pai Hou Tsao San Bao Zhu Brand Hou Tsao San Hou Tsao San Bo Ying Pills Hung Win Bo Ying Pills Chi Chun Tang Chu Pai Bo Ying Dan Kui Hua Chut Lee San Bird’s Nest & Pearl Chi Chun Tang Chu Pai Chut Lee San Po Wo Tong Ging Fung San Chi Chun Tang Chu Pai Hou Tsao San Po Wo Tong Hou Tsao San Chi Chun Tang Pearl Bat Po Keng Foong Po Wo Tong Wui Chun Tan for Children Powder Xian Cao Tang Chu Pai Hou Tsao San
Pharmaceutical drugs Adulteration of herbal medicines with pharmaceutical drugs continues to be reported.
NSAIDs The Department of Health of Hong Kong has urged members of the public not to buy or take two brands of proprietary Chinese medicines containing NSAIDs (11S): Chuifong Toukuwan and Nan Lien Chui fong Toukuwan, which were marketed for treatment of rheumatoid arthritis and contained diclofenac; Jin Feng Brand Gallinaci Bak Foong Pills, Baozhitang Gallinaci Pai Feng Pills, Pujitang Gallinaci Pai Feng Pill, Jinbei Brand Gallinaci Pai Feng Pills, and Tongjitang Gallinaci Pai Feng Pills; all contained diclofenac and paracetamol.
Sibutramine Adulteration of a herbal medicine with sibutramine has been reported (12A). A young healthy woman took a Chinese
herbal medicine called LiDa Dai Dai Hua Jiao Nang and on the second day developed a severe headache, vertigo, and numbness. She stopped taking it and the symptoms disap peared within 2 days. Sibutramine was identi fied in her urine sample and the capsules each contained 27.4 mg of sibutramine base, about
twice the amount of the highest single dosage form available on the market in Germany.
Drug–drug interactions Multiple interac tions can occur if a patient is taking several different herbal preparations (2Ac). A 77-year-old lady developed epigastric pain
and hematemesis. Her clotting was normal. After identical symptoms 4 months before, a gastroscopy had shown a large sliding intrathoracic hiatus hernia with severe eso phagitis. She had been given lansoprazole 30 mg/day. She had also taken garlic, St John’s wort, feverfew, Echinacea, and ginseng. The herbal remedies were withdrawn.
Garlic, feverfew, and ginseng all inhibit platelet aggregation and could have increased the risk of bleeding in this case, particularly since they were taken in com bination. An interaction between lansopra zole and St John’s wort may also have contributed, since lansoprazole is metabo lized by CYP2C19, which is induced by St John’s wort. In a cross-sectional survey of the use of herbal medicines that might interfere with the effects of antiplatelet drugs or antic oagulants among 250 patients, 106 (42%) were taking herbs, of whom 76 (72%) had been using them for the past 12 months (13C). Overall, almost 31% were taking one
748 or more herbal medicines that are thought to interact with antiplatelet drugs or antic oagulants: ginseng (Panax ginseng), garlic (Allium sativum), and ginkgo (Ginkgo biloba). A large proportion of respondents involved in potential drug–herb interaction were elderly (63%). However, more than 90% of herbal users did not disclose the use of herbal medicines to their health profes sionals.
ANTHROPOSOPHIC MEDICINES Patient-reported and physician-assessed adverse drug reactions to anthroposophic medications for chronic diseases have been prospectively assessed over 2 years in 662 consecutive outpatients aged 1–75 years in 131 German medical practices (14C). Con firmed adverse reactions to any anthropo sophic medication occurred in 2.2% of medications (21 of 949) and 3.0% of users (20 of 662); there was one adverse reaction per 382 patient-months of use. The origins of the medicines were mineral (n ¼ 77, 8.1%), botanical (n ¼ 397, 42%), zoological (n ¼ 74, 7.8%), chemically defined (n ¼ 100, 11%), and mixed (n ¼ 301, 32%). There were 1861 adverse events, of which the most frequent were non-specific (513 of 1861 events, 28%), including mus culoskeletal (17%), respiratory (8.2%), and digestive problems (6.6%). There were no serious adverse events attributable to any medication. Of the 1861 reported adverse events, 284 (15%) in 29 patients were suspected by the physician or the patient to be an adverse reaction to a non-medication therapy. Of these, 20 had confirmed reac tions to 21 anthroposophic medications: local reactions to topical application (n ¼ 6), systemic hypersensitivity (n ¼ 1), and aggravation of pre-existing symptoms (n ¼ 13). In 10 patients the medication was withdrawn because of an adverse reaction; 2 patients had reactions of severe intensity. All the reactions resolved after withdrawal; none was serious.
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SPECIFIC PLANTS Aconitum spp. (Ranunculaceae) The Hospital Authority Toxicology Refer ence Laboratory, Princess Margaret Hospital, Hong Kong, confirmed 10 cases of aconite poisoning from March 2004 to May 2006 (15c). In 4 of these 10 cases, the aconite herb was not listed in the written prescription. The authors reported four cases to highlight the problem of “hidden” aconite poisoning. They reported that yunaconitine, a newly identified alkaloid, was detected by HLPC-MS in all four cases. It is not one of the common toxins (aconitine, hypaconitine, and mesaconitine) seen in aconite poisoning. The diagnosis would have been missed in these four cases if laboratory screening for yunaconitine had not been included. The presence of yunaconitine sug gests that the mix-up occurred in aconitum species of Yunnan origin. The frequent occurrence of “hidden” aconite poisoning has public health significance for the community in Hong Kong. This mistaken substitution with aconite herbs can occur randomly and result in severe poisoning. It also highlights the importance of quality assurance in herbs with low margins of safety. Efforts should be made to enhance the safety of herbs through the promotion of Good Agricultural Practice and Good Manufacturing Practice (16R,17R). A 20-year-old man took a decoction of a
prescribed mixture of 17 Chinese medicinal materials for low back pain and developed sudden weakness, sweating, vomiting, and shortness of breath. He had impaired con sciousness, circulatory failure, a systolic blood pressure of 70 mmHg, and ventricular tachy cardia. Cardioversion was attempted unsuc cessfully. Amiodarone was given immediately but the cardiac dysrhythmia was refractory to standard therapy. During bouts of ventricular tachycardia his pulse became imperceptible. Following prolonged cardiopulmonary resus citation, aggressive supportive management, and temporary pacing, he recovered fully. He had taken a similar decoction 2 months before the event without problem and a Chinese medicine pharmacist found that it did not include any cardiotoxic herbs. Leftover herbal
Treatments used in complementary and alternative medicine broth and a urine sample collected on the day of admission were screened for common toxins and yunaconitine was found in both samples; its source was a mystery. A 27-year-old woman developed chest dis comfort, dizziness, numbness, and weakness 1 hour after taking a decoction of Chinese herbal medicines containing 19 components. She was unwell. Her blood pressure was 95/ 73 mmHg and her pulse rate 55 per minute because of sinus bradycardia with first-degree heart block. Her symptoms resolved comple tely in 24 hours with supportive therapy alone. This patient had enjoyed good health and had no history of cardiac disease. The herbal remnants were examined and one item did not match any of the prescribed herbs but appeared to be a piece of aconitum rootstock. Yunaconitine was detected in both the leftover herbal broth and the patient’s urine. A 51-year-old woman, with a history of optic neuritis, suddenly developed neck rigidity, dizziness, numbness of the extremities, and weakness 2 hours after taking a bowl of herbal decoction that contained 15 herbs. She had taken the same herbal mixture before without problems. Her blood pressure was 105/ 63 mmHg and her pulse rate 63 per minute in sinus rhythm. The hypotension responded to fluid therapy. Routine laboratory investiga tions were unremarkable. Her symptoms resolved spontaneously the next day. Leftover herbal decoction and a urine specimen were analyzed and yunaconitine was found in both. A 45-year-old woman became ill 1 hour after taking a herbal broth containing 11 ingredients for a menstrual problem. She had tongue numbness, nausea, dizziness, and generalized weakness. Her blood pressure was 91/ 44 mmHg and her pulse rate 58 per minute, with a junctional bradycardia. Her symptoms improved with supportive treatment. Leftover herbal broth and a urine sample collected on the day of admission were analyzed and yunaconitine was found in both.
Aconite has also been implicated in a case of murder (18A).
Cimicifuga racemosa (Ranunculaceae, black cohosh) Liver Black cohosh has been linked to fulminant hepatic failure that required liver transplantation (19A). Musculoskeletal Muscle damage has been attributed to black cohosh (20A). A 54-year-old woman took a herbal product
derived from black cohosh (Remifemins) for
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menopausal vasomotor symptoms. She took one tablet bd for 1 year, stopped taking it, and then started taking it again 2 months later. Each tablet contains 20 mg of dried rhizome and root extracts, standardized to contain 1 mg of 27 deoxyactein. After 2 months she started to feel weak. She had increased activities of creatine kinase (247 U/l; reference range 24–170) and lactate dehydrogenase (987 U/l; 230–460). The black cohosh was withdrawn and her symptoms improved within 10 days; the enzyme activities fell and were normal after 20 days.
There may have been very mild muscle damage in this case, but the increases in enzymes were much less than one usually sees in cases of rhabdomyolysis. Pregnancy and lactation The use of black cohosh in pregnancy and lactation has been reviewed. There is weak evidence based on theory and expert opinion that black cohosh has the following effects during pregnancy: labor-inducing effects, hormo nal effects, emmenagogue properties, and anovulatory effects (21A). The authors concluded that black cohosh should be used with caution during pregnancy.
Citrus aurantium (Rutaceae, bitter orange) (SED-15, 3087; SEDA29, 586)
After the US marketing ban of Ephedracontaining supplements in April 2004, many manufacturers used C. aurantium instead and marketed the products as “ephedra-free” supplements. However, extracts of C. aurantium contain synephr ine, an alpha-adrenoceptor agonist. In the 2004 California Behavioral Risk Factor Surveillance Survey, 70 of 4140 respon dents reported having taken a dietary supplement containing C. aurantium during 2003 (22S). Compared with non-users, they were more likely to be single, aged 18–34 years, and Hispanic and to have a heavier body mass index. Five users reported adverse events that they attributed to the supplement. Between March 1, 2004 and October 31, 2006, Health Canada received 21 domestic reports of adverse reactions suspected of being associated with C. aurantium (22S).
750 Of these, 15 reports were of cardiovascular adverse reactions, 10 of which were serious and included 1 report of myocardial infrac tion. According to Health Canada, synephr ine found in bitter orange can have serious adverse effects on heart rate and blood pressure; these effects are significantly potentiated by caffeine. Synephrine is found in various natural health products that are promoted for weight loss. Health Canada has cautioned that the following people may be particularly at risk of adverse reactions from synephrine-contain ing products: those with heart conditions, central ner vous system disorders, diabetes mellitus, enlarged prostate, glaucoma, hyperten sion, pheochromocytoma, thyroid disease, or known risk factors for cardiovascular disease; those taking caffeine-containing pro ducts, monoamine oxidase inhibitors, thyroid hormones, or medications to control blood pressure or heart rate; underweight people. Immunologic Eosinophilic gastroenteritis has been linked to citrus fruit allergy (23Ar).
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Ephedra See Chapter 13.
Ginkgo biloba (Ginkgoaceae; maidenhair tree) (SED-15, 1507; SEDA-28, 576; SEDA-29, 587; SEDA-30, 553)
Skin Acute generalized exanthematous pustulosis (AGEP), which is commonly caused by systemic antibacterial drugs, has been attributed to G. biloba (24A). A 45-year-old man developed a symmetrical
maculopapular eruption on his limbs. Within 2 days the rash generalized to involve the face. Disseminated non-follicular small pustules on erythematous skin were predominant. The palms, soles, and mucous membranes were spared. His temperature was 38.81C. The rash had developed 48 hours after starting oral G. biloba treatment for tinnitus. He denied previously having taken G. biloba and was not taking any other medications. He reported no previous adverse drug reactions and no history of psoriasis. A skin biopsy showed neutrophil-containing spongiotic pustules in the epidermis and a mixed cellular infiltrate with edema in the papillary dermis, consistent with AGEP. The rash cleared within 10 days after withdrawal of G. biloba.
A 46-year-old man developed non-bloody
loose stools 16 times a day associated with abdominal cramping and nausea but no vomiting. Ten years before he had had urticaria and wheezing, but no gastrointestinal symptoms, after taking lemons or grapefruit followed by exercise, and had avoided citrus fruits since then. A CT scan of the abdomen showed colonic, ileal, and duodenal wall thickening. Colonoscopy showed terminal ileitis and pancolonic reduced vascular mark ings, suggesting chronic inflammation. Histol ogy showed acute colitis and ileitis with eosinophil infiltration. Specific IgE against the following foods was found; lemon, grapefruit, tomato, carrot, potato, coconut, banana, pars ley, yeast, garlic, onion, hazelnut, peanut, sesame, and corn. He responded to non enteric-coated budesonide and mesalazine. Montelukast was added when the peripheral eosinophilia persisted and prednisolone when he had a recurrence 1 year later.
The authors diagnosed eosinophilic gastro enteritis, which they classified into four types, in three of which food allergies are common.
Pregnancy and lactation The use of ginkgo in pregnancy and lactation has been reviewed (25M). There is weak evidence from animal and in vitro studies that ginkgo has antiplatelet activity and might therefore prolong bleeding time during labor. There is also weak evidence that it may be an emmenagogue. The authors concluded that ginkgo should be used with caution during pregnancy, particularly around the time of labor. Its safety during lactation is unknown and it should be avoided. Drug contamination In a study of human placental blood a factor that affected human neutrophils and their adherence was discovered and turned out to be colchicine (26c). Significant concentrations of colchicine (49–763 mg/l) were then found in the placental blood of patients who had used non-prescription herbal dietary supplements during pregnancy,
Treatments used in complementary and alternative medicine
and colchicine was found in commercial preparations of G. biloba. Drug overdose Poisoning with ginkgo nuts has been reported in a child (27A). A 2-year-old boy took about 50 ginkgo nuts
and 4 hours later started vomiting and had an afebrile generalized tonic seizure. There was a large volume of ginkgo nuts in the vomitus. He was given diazepam 0.4 mg/kg and pyridoxal phosphate 8 mg/kg intravenously and recov ered. Sleep electroencephalography 12 hours after admission showed irregular spikes and high-voltage slow waves in the left central, parietal, occipital, and posterior temporal regions; 6 months later electroencephalogra phy was normal.
Drug–drug interactions The possible interactions of G. biloba extract with several commonly used drugs have been investi gated in a number of pharmacokinetic studies. In healthy subjects there was no interaction with diclofenac (28c), metformin (29c), ticlopidine (30c), or warfarin (31c). For tolbutamide the data were not consistent (27c,32c) and for midazolam there was a slight reduction in clearance (31c). Aspirin In a double-blind, double-dummy study in 50 healthy men (aged 20–44 years) aspirin alone (500 mg/day for 7 days) prolonged bleeding time and altered plate let aggregation; the addition of an extract of G. biloba, EGb 761, had no additional significant effect (33C). Cilostazol Co-administration of G. biloba with either cilostazol or clopidogrel did not enhance ex vivo antiplatelet activity compared with individual agents in a pharmacodynamic interaction study in male volunteers. How ever, there was significant potentiation of the prolongation of the bleeding time with the combination of cilostazol+G. biloba com pared with the two drugs individually (34c).
Glycyrrhiza spp. (Fabaceae, liquorice or liquorice root) (SED-15, 1311; SEDA-24, 538; SEDA-25, 569; SEDA-26, 531)
Endocrine Extracts of liquorice and glycyrrhizin, its principal component, have
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extensive use in foods, tobacco, and in both traditional and herbal medicines (35R). It is estimated that consumption of liquorice and glycyrrhizin by the US public ranges from 0.027 to 3.6 mg/kg/day of glycyrrhizin. Both products have been approved for use in foods by most national and supranational regulatory agencies. Glycyrrhizinates inhibit 11-hydroxysteroid dehydrogenase, the enzyme responsible for inactivating cortisol. As a result, continuous high exposure to glycyrrhizin compounds can produce mineralocorticoid-like effects in both animals and humans. The effects may be greater in men than in women (36c) and are reversible. Pseudoaldosteronism occurred in a 77-year-old Japanese man who took two Chinese herbal medicines containing gly cyrrhizin (Arejin for chronic allergic rhinitis and Daiokanzo-to as a laxative). The condition became manifest only when he developed symptoms related to hypokale mia when his dosage of enalapril was reduced (37A). In a study of the effects of liquorice in nine healthy women aged 22–26 years during the luteal phase of the menstrual cycle after 2 months consumption of 3.5 g/day of a commercial preparation of licorice (containing 7.6%, w/w, of glycyr rhizic acid), plasma renin activity, aldosterone, cortisol, serum parathyroid hormone (PTH), 1,25-dihydroxycolecalci ferol (1,25OHD), 25-hydroxycolecalciferol (25OHD), estradiol, FHS, LH, alkaline phosphatase, calcium, phosphate, and crea tinine, urinary calcium and phosphate, and mineralometry were measured (38c). PTH, 25OHD, and urinary calcium increased significantly from baseline after 2 months of therapy, while 1,25OHD and alkaline phosphatase did not change. All these parameters returned to pretreatment values 1 month after withdrawal of licorice. Plasma rennin activity and aldosterone were depressed during therapy, but blood pres sure and plasma cortisol were unchanged. The effects of liquorice on calcium metabo lism are probably mediated by several components of the root, which have aldos terone-like, estrogen-like, and antiandrogen activity.
752 Mutagenicity and teratogenicity Various studies have shown that glycyrrhizin is neither teratogenic nor mutagenic, and that it may even have antigenotoxic properties under certain conditions (34R).
Harpagophytum procumbens (Passifloraceae, Devil’s claw) The effect of Devil’s claw in osteoarthritis has been studied in a meta-analysis of 14 pub lished clinical trials (39M). Many of the published trials lacked important methodolo gical quality criteria, although the data from the higher-quality studies suggested that Devil’s claw reduces pain. Devil’s claw appears to be associated with minor risks relative to NSAIDs. However, the clinical evidence to date cannot provide a definitive answer to its claimed efficacy and safety. Further better designed clinical investigations are warranted.
Hydroxycut Hydroxycut formerly contained ma huang, an Ephedra-type alkaloid. However, since restrictions on the use of Ephedra as a dietary supplement were introduced in 2004, it has been reformulated as a caffeine-based Ephedra-free preparation. A 42-year-old man, previously healthy, developed malignant hypertension and hypertensive retinopathy while taking Hydroxycut (40A). Given the lack of investigative studies in regard to their safety and efficacy, judicious care should be taken with the use of all herbal supple ments, including those designated as Ephedra-free.
Morinda citrifolia (Rubiaceae, noni) (SED-15, 3085; SEDA-30, 554) Liver Noni, a Polynesian herbal remedy, is a tropical fruit that has been implicated in liver damage (41A). A 24-year-old woman with multiple sclerosis
drank noni juice for 4 weeks and developed a mildly raised bilirubin concentration and
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serum transaminase activity after treatment with interferon beta-1a for 6 weeks. Interferon was withdrawn because of the possibility of drug-induced hepatitis, after exclusion of viral hepatitis due to hepatitis A–E. One week later she developed severe icterus, greatly raised bilirubin and transaminases, and a reduced prothrombin time, indicating impaired liver function with a suspicion of incipient acute liver failure. There was no evidence of hepatotoxic viruses, alcoholic hepatitis, Budd–Chiari syndrome, hemochromatosis, or Wilson’s disease. Fine-needle aspiration biopsy of the liver ruled out autoimmune hepatitis but showed signs of drug-induced toxicity. After withdrawal of the noni juice, her transaminase activities fell and were in the reference range within 1 month.
Several animal and human studies have shown that high doses of noni juice (up to 750 ml/day), many times greater than in any case reports, have not caused liver damage, as judged by liver function tests and histology (42r). The anthraquinones in noni juice, identified as causative agents in case reports, are of the wrong type and quantity to be of toxicological relevance. In reply the authors of the paper stated that it was not possible to rule out idiosyncratic noni-induced hepatotoxicity. This type of drug reaction is not doserelated in the therapeutic range of doses, is not reproducible in healthy volunteers or in animals, and can present with immu noallergic features.
Piper methysticum (Piperaceae; kava kava) (SED-15, 2837; SEDA-28, 578; SEDA-30, 554)
The effects of kava kava have been reviewed (43R). Its chief adverse effects are a dermopathy and liver damage. The efficacy and safety of kava kava (P. methysticum) have been analyzed in three double-blind, randomized, placebocontrolled trials in generalized anxiety dis order in 64 adult outpatients, including one study with an active comparator (venlafax ine) (44M). Since the study designs were comparable, the kava and placebo data were then pooled for further efficacy and safety analyses. There were no significant
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differences between the groups in any of the trials. In the pooled analyses, kava had no effects, while there was a significant effect in favor of placebo in participants with higher anxiety at baseline. There was no evidence of hepatotoxicity with kava.
PLANT TOXINS Anthraquinones Anthraquinones are found in rhubarb root, senna leaf and pod, Cascara sagrada, buckhorn, and aloe, all common components of herbal slimming regimens. Anthraquinones have several biological effects and adverse effects have been reported. The root contains a complex mixture of 2–5% anthraquinone derivatives (anthranoids), of which most are present as glycosides. After ingestion, colo nic bacteria metabolize the anthraquinone glycosides to anthranols, which are absorbed to a moderate degree and are excreted in the bile, saliva, milk, and urine. Rhubarb root has mainly been used traditionally for its laxative properties and in short-term ther apy. Since 1996 the Federal Institute for Drugs and Medical Devices in Germany has recommended that anthraquinone-contain ing laxatives should not be used continuously for periods exceeding 1–2 weeks. Urinary tract Acute renal failure has been associated with anthraquinones (45A). A 23-year-old woman developed acute renal
failure with hypocellular interstitial fibrosis after prolonged use of a proprietary Chinese herbal slimming pill that contained anthraqui none derivatives, extracted from rhubarb. The renal damage was probably aggravated by concomitant use of diclofenac. Her renal function recovered after withdrawal of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later.
Although a causal relation between the anthraquinone-containing agents and renal damage remains to be proven, phytother apy-associated interstitial nephropathy
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should be considered in patients who present with unexplained renal failure.
AROMATHERPY Aromatherapy uses essential oils created by distilling various plant-derived chemicals to create a concentration as great as 100 times. It should be used with caution. Aromatherapy preferences and complications in 3000 otolar yngology patients have been studied (46M). Among these patients, 1.67% had some form of complication induced by essential oils used in aromatherapy, including skin eruptions, respiratory distress, and other symptoms. Some patients (0.93%) refused aromatherapy because of individual preference and unplea sant smell. People should follow instructions at all times and should never use these oils for an extended period or overuse them.
CUPPING Skin Cupping, the therapeutic application of heated cups to the skin, is an East Asian and Oriental tradition, still in use in many cultures. Alcohol-soaked cotton in the cup is ignited and the cup immediately pressed tightly against the skin. The procedure usually lasts 5–20 minutes. The vacuum created during cupping breaks superficial capillaries and can cause circular erythema, edema, ecchymoses, purpura, burns, keloid, and factitious panniculitis. A 57-year-old woman with a tender red patch on
her lower back reported that cupping had been performed 2 weeks before to relieve back pain (47A). However, the cup had been held on her skin for over 40 minutes. She experienced intense pain soon after the procedure, and bullae and crusting developed over the area during the following week. There was a 50-mm, circular, red patch on the right lumbar area, with several uniform intact vesicles, serous exudation, and crusting on the surface. Routine laboratory parameters were normal, except for a raised white blood cell count (14 109 per liter) and fasting blood glucose (9.28 mmol/l). Wet dressings and an antibiotic ointment led to complete resolution of the crusts and vesicles within 10 days.
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References 1. Dhalla S, Chan KJ, Montaner JSG, Hogg RS. Complementary and alternative med icine use in British Columbia—a survey of HIV positive people. Compl Ther Clin Pract 2006;12:242–8. 2. Constable S, Ham A, Pirmohamed M. Herbal medicines and acute medical emer gency admissions to hospital. Br J Clin Pharmacol 2007;63(2):247–8. 3. Cuzzolin L, Zaffani S, Benoni G. Safety implications regarding use of phytomedi cines. Eur J Clin Pharmacol 2006;62:37–42. 4. Barnes J, Mills SY, Abbot NC, Willoughby M, Ernst E. Different standards for reporting ADRs to herbal remedies and conven tional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol 1998;45:496–500. 5. Lee A, Chiu PT, Aun ST, Angel SC, Lau BSN, Gin T. Incidence and risk of adverse perioperative events among surgical patients taking traditional Chinese herbal medicines. Anesthesiology 2006;105: 454–61. 6. Greenway FL, Martin CK, Kai-yuen W, Nofzger J, Rood JC, Yu Y, Amen RJ. Safety and efficacy of NT, an herbal supplement, in treating human obesity. Int J Obes 2006;30:1737–41. 7. Hsu L-H, Huang Y-S, Tsay S-H, Chang F-Y, Lee S-D. Acute hepatitis induced by Chinese hepatoprotective herb, xiao-chai hu-tang. J Chin Med Assoc 2006;69(2): 86–8. 8. Yuen M-F, Tam S, Fung J, Wong DK-H, Wong BC-Y, Lai C-L. Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study. Aliment Pharmacol Ther 2006;24:1179–86. 9. Wai CT. Presentation of drug-induced liver injury in Singapore. Singapore Med J 2006; 47(2):116–20. 10. Chinese Medicine Council of Hong Kong. http://www.cmchk.org.hk/pcm/eng/index.htm. 11. Department of Health. The Government of the Hong Kong Special Administrative Region. Recall of proprietary Chinese medicines with Western drug ingredient;
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9 June 2006, http://www.dh.gov.hk/english/ press/2006/060609.html. Jung J, Hermanns-Clausen M, Weinmann W. Anorectic sibutramine detected in a Chinese herbal drug for weight loss. Forensic Sci Int 2006;161(2–3):221–2. Saw JT, Baharia MB, Ang HH, Lim YH. Potential drug–herb interaction with antiplatelet/anticoagulant drugs. Compl Ther Clin Pract 2006;12:236–41. Hamre HJ, Witt CM, Glockmann A, Troger W, Willich SN, Kiene H. Use and safety of anthroposophic medications in chronic disease: a 2-year prospective ana lysis. Drug Saf 2006;29(12):1173–89. Poon WT, Lai CK, Ching CK, Tse KY, So YC, Chan YC, Hau LM, Mark TWL, Chan YW. Aconite poisoning in camouflage. Hong Kong Med J 2006;12:456–9. Chan K. Chinese medicinal materials and their interface with Western medical concepts. J Ethnopharmacol 2005;96:1–18. Chan K. Some aspects of toxic contami nants in herbal medicines. Chemosphere 2003;52:1361–71. Ohno Y. Experimental approach to murder by aconite poisoning from the viewpoint of medicolegal toxicology. Nihon Hoigaku Zasshi 2006;60(2):101–9. Lynch CR, Folkers ME, Huston WR. Fulminant hepatic failure associated with the use of black cohosh: a case report. Liver Transpl 2006;12(6):989–92. Minciullo PL, Saija A, Patafi M, Marotta G, Ferlazzo B, Gangemi S. Muscle damage induced by black cohosh (Cimicifuga racemosa). Phytomedicine 2006;13(1–2):115–8. Dugoua JJ, Seely D, Perri D, Koren G, Mills E. Safety and efficacy of black cohosh (Cimicifuga racemosa) during pregnancy and lactation. Can J Clin Pharmacol 2006; 13(3):e257–61. Anonymous. Citrus aurantium (bitter orange). Reports of adverse cardiovascular effects. WHO Pharm Newslett 2007;3:4. Kumar A, Teuber SS, Naguwa S, Prindi ville T, Gershwin ME. Eosinophilic gastroenteritis and citrus-induced urticaria. Clin Rev Allergy Immunol 2006;30(1):61–70.
Treatments used in complementary and alternative medicine 24. Pennisi RS. Acute generalized exanthema tous pustulosis induced by the herbal remedy Ginkgo biloba. Med J Aust 2006;184(11): 583–4. 25. Dugoua JJ, Mills E, Perri D, Koren G. Safety and efficacy of ginkgo (Ginkgo biloba) during pregnancy and lactation. Can J Clin Pharmacol 2006;13(3):e277–84. 26. Petty HR, Fernando M, Kindzelskii AL, Zarewych BN, Ksebati MB, Hryhorczuk LM, Mobashery S. Identification of colchi cine in placental blood from patients using herbal medicines. Chem Res Toxicol 2001; 14(9):1254–8. 27. Dugoua JJ, Mills E, Perri D, Koren G. Safety and efficacy of ginkgo (Ginkgo biloba) during pregnancy and lactation. Can J Clin Pharmacol 2006;13(3): e277–84. 28. Mohutsky MA, Anderson GD, Miller JW, Elmer GW. Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo. Am J Ther 2006;13:24–31. 29. Kudolo GB, Wang W, Javors M, Blodgett J. The effect of the ingestion of Ginkgo biloba extract (EGb 761) on the pharma cokinetics of metformin in non-diabetic and type 2 diabetic subjects—a double blind placebo-controlled, crossover study. Clin Nutr 2006;25:606–16. 30. Lu WJ, Huang JD, Lai ML. The effects of ergoloid mesylates and Ginkgo biloba on the pharmacokinetics of ticlopidine. J Clin Pharmacol 2006;46:628–34. 31. Jiang X, Blair EY, McLachlan AJ. Inves tigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic–pharmacody namic modeling approach. J Clin Pharma col 2006;46:1370–8. 32. Uchida S, Yamada H, Li XD, Maruyama S, Ohmori Y, Oki T, Watanabe H, Umegaki K, ohaski K, Yamada S. Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J Clin Pharmacol 2006;46:1290–8. 33. Wolf HR. Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation and bleeding when added to acetylsalicylic acid 500 mg daily? Drugs R D 2006;7(3):163–72.
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34. Aruna D, Naidu MJ. Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects. Br J Clin Pharmacol 2007;63: 333–8. 35. Isbrucker RA, Burdock GA. Risk and safety assessment on the consumption of licorice root its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul Toxicol Pharmacol 2006;46:167–92. 36. Sigurjonsdottir HA, Axelson M, Johanns son G, Manhem K, Nyström E, Wallerstedt S. The liquorice effect on the RAAS differs between the genders. Blood Press 2006;15 (3):169–72. 37. Iida R, Otsuka Y, Matsumoto K, Kuriyama S, Hosoya T. Pseudoaldosteronism due to the concurrent use of two herbal medicines containing glycyrrhizin: interaction of gly cyrrhizin with angiotensin-converting enzyme inhibitor. Clin Exp Nephrol 2006; 10:131–5. 38. Mattarello MJ, Benedini S, Fiore C, Camozzi V, Sartorato P, Luisetto G, Armanini D. Effect of licorice on PTH levels in healthy women. Steroids 2006;71:403–8. 39. Brien S, Lewith GT, McGregor G. Devil’s claw (Harpagophytum procumbens) as a treatment for osteoarthritis: a review of efficacy and safety. J Altern Complement Med 2006;12(10):981–93. 40. Willis SL, Moawad FJ, Hartzell JD, Iglesias M, Jackson W. Hypertensive retinopathy associated with use of the Ephedra-free weight-loss herbal supplement Hydroxycut. Med Gen Med 2006;8(3):82. 41. Yüce B, Gülberg V, Diebold J, Gerbes AL. Hepatitis induced by noni juice from Morinda citrifolia: a rare cause of hepato toxicity or the tip of the iceberg? Digestion 2006;73:167–70. 42. West BJ. Hepatotoxicity from interferonbeta, not noni juice. Digestion 2006;74(1): 47–8. 43. Gounder R. Kava consumption and its health effects. Pac Health Dialog 2006;13 (2):131–5. 44. Connor KM, Payne V, Davidson JRT. Kava in generalized anxiety disorder: three placebo-controlled trials. Int Clin Psycho pharmacol 2006;21:249–53.
756 45. Kwan TH, Tang MKH, Lai CK, Poon WT, Chan YW, Au TC. Acute renal failure associated with prolonged intake of slim ming pills containing anthraquinones. Hong Kong Med J 2006;12(5):394–7. 46. Yoo K-M. Statistical analysis of aromather apy preferences and complications for 3000
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otolaryngology patients. Int J Aromather 2006;16:181–5. 47. Tuncez F, Bagci Y, Kurtipek GS, Erkek E. Suction bullae as a complication of pro longed cupping. Clin Exp Dermatol 2006;31: 281–305.
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GENERAL Susceptibility factors HIV infection In a cross-sectional study of the use of complementary and alternative medicines in 682 participants with HIV infection among the 47% ever-users, vitamins/minerals (81%), meditation/yoga (36%), massage (31%), marijuana (30%), dietary supplements (24%), and herbal medicines (19%) were the most commonly used (1C). Users were less likely to be poorly educated, more likely to be unemployed, more likely to have been taking antiretroviral drugs for longer, and more likely to have objective, action-requiring adverse effects.
HERBAL MEDICINES
(SED-15, 1609; SEDA-27, 512; SEDA-28, 573; SEDA-29, 583)
Observational studies In an audit of 100 patients admitted to a UK hospital for acute medical emergencies, 24 were taking herbal remedies (a total of 40 products); the most popular product was garlic (2cA). Of these 24 patients 20 were also taking prescription medications and 11 were taking herbal remedies that have either documented toxicity or known interactions with Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03148-1 r 2009 Elsevier B.V. All rights reserved.
prescription drugs. However, the use of a herbal preparation was documented in the case notes in only one case. In a 5-month survey on the use of phytomedicines by 1063 patients, based on a prestructured questionnaire, in the out patient department of an urban university general hospital in Italy, of the 1044 women who completed the interview 491 (47%) reported taking at least one herbal com pound (3R). Of these 491 patients, 272 (55%) consumed only one phytomedicine, while 219 (45%) also took traditional drugs. Adverse effects were reported by 47 (9.6%), including: gastrointestinal (due to dandelion, propolis, and fennel); cardiovas cular (after liquorice, ginseng, and green tea); dermatological (after propolis, thyme, arnica, and passion-flower); and neurological (after guaraná and liquorice). Conventional medicines that were taken simultaneously and were potentially involved in adverse effects were antihypertensive drugs, benzo diazepines, non-steroidal anti-inflammatory drugs, antibiotics, and oral contraceptives. In five cases adverse effects were sufficiently serious to justify admission to hospital. In 29/ 47 cases the adverse effect was not commu nicated to the doctor. The authors confirmed previous observations (4R) that consumers of herbal remedies act differently with regard to reporting an adverse reaction (serious or minor) to their physician, and that many adverse manifestations to herbal remedies are not monitored. Perioperative events in 601 patients undergoing major elective surgery who had taken traditional Chinese herbal medicines presurgically have been studied in a teaching
745
746 hospital in Hong Kong (5CA). Of these patients, 483 (80%) had taken self-pre scribed herbal medicines and 47 (8%) had taken herbal medicines prescribed by practi tioners of traditional Chinese medicine in the 2 weeks before surgery. The crude incidences of any combined end-points of preoperative, intraoperative, and post operative events were 23% (19–26%), 74% (71–78%), and 63% (59–66%), respectively. Compared with non-users, patients who took traditional Chinese herbal medicines by prescription were more likely to have a preoperative event. The authors presented four case reports to highlight the effect of traditional Chinese herbal medicines by prescription on preoperative prolongation of the activated partial thromboplastin time and hypokalemia. In contrast, there was no significant association between the use of any type of traditional Chinese herbal medicines and the occurrence of either intraoperative or postoperative events. They emphasized that the use of traditional Chinese herbal medicines by prescription near the time of surgery should be discour aged, because of the increased risk of adverse events in the preoperative period. Gastrointestinal Number Ten is a dietary supplement that contains rhubarb, ginger, astragalus, red sage, and turmeric. It has been used to reduce food intake and cause weight loss in a pilot study in 24 healthy women aged 18–60 years, body mass index 25–35 kg/m2, who were taking no long-term medications, but was ineffective (6c). Doserelated loose stools was the main adverse effect, which was not surprising, as Number Ten was found to contain sennosides, known laxatives, and gallic acid, which causes weight loss in rodents. Liver Xiao-chai-hu-tang (syo-saiko-to in Japanese), a herbal remedy (consisting of bupleurum root, pinellia tuber, scutellaria root, jubube fruit, ginseng root, glycyrrhiza root, and ginger root), widely used in China for treatment of respiratory, hepa tobiliary, and gastrointestinal diseases, particularly among patients with chronic liver disease, has been reported to cause acute hepatitis (7A).
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A 52-year-old woman developed weakness,
fatigue, and tea-colored urine after repeated consumption of a decoction of xiao-chai-hu-tang for 1.5 months. Laboratory studies showed acute hepatitis and all markers of viral hepatitis were negative. Liver biopsy showed a picture of acute hepatocellular hepatitis. The symptoms improved after withdrawal of the drug, and liver biochemical tests normalized 2 months later.
This case report reminds us of the possibility of hepatotoxic effects of herbs, even from some that are claimed to have hepatoprotective effects. Hepatotoxicity has also been attributed to traditional medicines in patients with hepa titis B infection (8c). In a pilot study to review the clinical course of drug-induced liver damage in a Singapore tertiary hospital 29 patients were identified, of whom 15 had consumed traditional Chinese medicines and 4 had taken antituberculosis drugs (9c). Drug contamination Legislation to control the quality of traditional Chinese medicines was implemented in Hong Kong in 1989, since when proprietary Chinese medicines have been recalled by government bodies after inspection of products available on the market (10S). This information can be used as an alert when these products are re distributed to other regions. Heavy metals Heavy metals, such as lead, can cause anemia, kidney failure, and adverse effects on the nervous system, gastrointestinal system, and cardiovascular system. The public have been advised not to purchase contaminated products with the brand names listed in Table 1 and to stop using them or to dispose of the product or surrender it to the Pharmaceutical Service of Department of Health, as the lead content of the products concerned exceeded the maximum permitted limit. Microbial counts The Department of Health in Hong Kong has ordered the immediate recall of 17 proprietary Chinese medicines after laboratory tests showed that the total bacterial count exceeded the maximum permitted limit for registration of such medicines in both Hong Kong and Macau (Table 1). Some of these products are intended for pediatric use.
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Table 1. Herbal preparations contaminated with lead or with excess bacterial counts Preparations containing lead Chung San Brand Po Ling Brand (production batch numbers 040607 and Fung Sen Brand 050607) Golden Ship Brand Tin Fung Brand Green Leaf Brand Wintex Tong Brand Proprietary Chinese medicines recalled after laboratory tests showed that the total bacterial count exceeded the maximum permitted limit Bao Zhu Brand Bo Ying Pills Chu Pai Chut Lee San Bao Zhu Brand Chut Lee San Chu Pai Hou Tsao San Bao Zhu Brand Hou Tsao San Hou Tsao San Bo Ying Pills Hung Win Bo Ying Pills Chi Chun Tang Chu Pai Bo Ying Dan Kui Hua Chut Lee San Bird’s Nest & Pearl Chi Chun Tang Chu Pai Chut Lee San Po Wo Tong Ging Fung San Chi Chun Tang Chu Pai Hou Tsao San Po Wo Tong Hou Tsao San Chi Chun Tang Pearl Bat Po Keng Foong Po Wo Tong Wui Chun Tan for Children Powder Xian Cao Tang Chu Pai Hou Tsao San
Pharmaceutical drugs Adulteration of herbal medicines with pharmaceutical drugs continues to be reported.
NSAIDs The Department of Health of Hong Kong has urged members of the public not to buy or take two brands of proprietary Chinese medicines containing NSAIDs (11S): Chuifong Toukuwan and Nan Lien Chui fong Toukuwan, which were marketed for treatment of rheumatoid arthritis and contained diclofenac; Jin Feng Brand Gallinaci Bak Foong Pills, Baozhitang Gallinaci Pai Feng Pills, Pujitang Gallinaci Pai Feng Pill, Jinbei Brand Gallinaci Pai Feng Pills, and Tongjitang Gallinaci Pai Feng Pills; all contained diclofenac and paracetamol.
Sibutramine Adulteration of a herbal medicine with sibutramine has been reported (12A). A young healthy woman took a Chinese
herbal medicine called LiDa Dai Dai Hua Jiao Nang and on the second day developed a severe headache, vertigo, and numbness. She stopped taking it and the symptoms disap peared within 2 days. Sibutramine was identi fied in her urine sample and the capsules each contained 27.4 mg of sibutramine base, about
twice the amount of the highest single dosage form available on the market in Germany.
Drug–drug interactions Multiple interac tions can occur if a patient is taking several different herbal preparations (2Ac). A 77-year-old lady developed epigastric pain
and hematemesis. Her clotting was normal. After identical symptoms 4 months before, a gastroscopy had shown a large sliding intrathoracic hiatus hernia with severe eso phagitis. She had been given lansoprazole 30 mg/day. She had also taken garlic, St John’s wort, feverfew, Echinacea, and ginseng. The herbal remedies were withdrawn.
Garlic, feverfew, and ginseng all inhibit platelet aggregation and could have increased the risk of bleeding in this case, particularly since they were taken in com bination. An interaction between lansopra zole and St John’s wort may also have contributed, since lansoprazole is metabo lized by CYP2C19, which is induced by St John’s wort. In a cross-sectional survey of the use of herbal medicines that might interfere with the effects of antiplatelet drugs or antic oagulants among 250 patients, 106 (42%) were taking herbs, of whom 76 (72%) had been using them for the past 12 months (13C). Overall, almost 31% were taking one
748 or more herbal medicines that are thought to interact with antiplatelet drugs or antic oagulants: ginseng (Panax ginseng), garlic (Allium sativum), and ginkgo (Ginkgo biloba). A large proportion of respondents involved in potential drug–herb interaction were elderly (63%). However, more than 90% of herbal users did not disclose the use of herbal medicines to their health profes sionals.
ANTHROPOSOPHIC MEDICINES Patient-reported and physician-assessed adverse drug reactions to anthroposophic medications for chronic diseases have been prospectively assessed over 2 years in 662 consecutive outpatients aged 1–75 years in 131 German medical practices (14C). Con firmed adverse reactions to any anthropo sophic medication occurred in 2.2% of medications (21 of 949) and 3.0% of users (20 of 662); there was one adverse reaction per 382 patient-months of use. The origins of the medicines were mineral (n ¼ 77, 8.1%), botanical (n ¼ 397, 42%), zoological (n ¼ 74, 7.8%), chemically defined (n ¼ 100, 11%), and mixed (n ¼ 301, 32%). There were 1861 adverse events, of which the most frequent were non-specific (513 of 1861 events, 28%), including mus culoskeletal (17%), respiratory (8.2%), and digestive problems (6.6%). There were no serious adverse events attributable to any medication. Of the 1861 reported adverse events, 284 (15%) in 29 patients were suspected by the physician or the patient to be an adverse reaction to a non-medication therapy. Of these, 20 had confirmed reac tions to 21 anthroposophic medications: local reactions to topical application (n ¼ 6), systemic hypersensitivity (n ¼ 1), and aggravation of pre-existing symptoms (n ¼ 13). In 10 patients the medication was withdrawn because of an adverse reaction; 2 patients had reactions of severe intensity. All the reactions resolved after withdrawal; none was serious.
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SPECIFIC PLANTS Aconitum spp. (Ranunculaceae) The Hospital Authority Toxicology Refer ence Laboratory, Princess Margaret Hospital, Hong Kong, confirmed 10 cases of aconite poisoning from March 2004 to May 2006 (15c). In 4 of these 10 cases, the aconite herb was not listed in the written prescription. The authors reported four cases to highlight the problem of “hidden” aconite poisoning. They reported that yunaconitine, a newly identified alkaloid, was detected by HLPC-MS in all four cases. It is not one of the common toxins (aconitine, hypaconitine, and mesaconitine) seen in aconite poisoning. The diagnosis would have been missed in these four cases if laboratory screening for yunaconitine had not been included. The presence of yunaconitine sug gests that the mix-up occurred in aconitum species of Yunnan origin. The frequent occurrence of “hidden” aconite poisoning has public health significance for the community in Hong Kong. This mistaken substitution with aconite herbs can occur randomly and result in severe poisoning. It also highlights the importance of quality assurance in herbs with low margins of safety. Efforts should be made to enhance the safety of herbs through the promotion of Good Agricultural Practice and Good Manufacturing Practice (16R,17R). A 20-year-old man took a decoction of a
prescribed mixture of 17 Chinese medicinal materials for low back pain and developed sudden weakness, sweating, vomiting, and shortness of breath. He had impaired con sciousness, circulatory failure, a systolic blood pressure of 70 mmHg, and ventricular tachy cardia. Cardioversion was attempted unsuc cessfully. Amiodarone was given immediately but the cardiac dysrhythmia was refractory to standard therapy. During bouts of ventricular tachycardia his pulse became imperceptible. Following prolonged cardiopulmonary resus citation, aggressive supportive management, and temporary pacing, he recovered fully. He had taken a similar decoction 2 months before the event without problem and a Chinese medicine pharmacist found that it did not include any cardiotoxic herbs. Leftover herbal
Treatments used in complementary and alternative medicine broth and a urine sample collected on the day of admission were screened for common toxins and yunaconitine was found in both samples; its source was a mystery. A 27-year-old woman developed chest dis comfort, dizziness, numbness, and weakness 1 hour after taking a decoction of Chinese herbal medicines containing 19 components. She was unwell. Her blood pressure was 95/ 73 mmHg and her pulse rate 55 per minute because of sinus bradycardia with first-degree heart block. Her symptoms resolved comple tely in 24 hours with supportive therapy alone. This patient had enjoyed good health and had no history of cardiac disease. The herbal remnants were examined and one item did not match any of the prescribed herbs but appeared to be a piece of aconitum rootstock. Yunaconitine was detected in both the leftover herbal broth and the patient’s urine. A 51-year-old woman, with a history of optic neuritis, suddenly developed neck rigidity, dizziness, numbness of the extremities, and weakness 2 hours after taking a bowl of herbal decoction that contained 15 herbs. She had taken the same herbal mixture before without problems. Her blood pressure was 105/ 63 mmHg and her pulse rate 63 per minute in sinus rhythm. The hypotension responded to fluid therapy. Routine laboratory investiga tions were unremarkable. Her symptoms resolved spontaneously the next day. Leftover herbal decoction and a urine specimen were analyzed and yunaconitine was found in both. A 45-year-old woman became ill 1 hour after taking a herbal broth containing 11 ingredients for a menstrual problem. She had tongue numbness, nausea, dizziness, and generalized weakness. Her blood pressure was 91/ 44 mmHg and her pulse rate 58 per minute, with a junctional bradycardia. Her symptoms improved with supportive treatment. Leftover herbal broth and a urine sample collected on the day of admission were analyzed and yunaconitine was found in both.
Aconite has also been implicated in a case of murder (18A).
Cimicifuga racemosa (Ranunculaceae, black cohosh) Liver Black cohosh has been linked to fulminant hepatic failure that required liver transplantation (19A). Musculoskeletal Muscle damage has been attributed to black cohosh (20A). A 54-year-old woman took a herbal product
derived from black cohosh (Remifemins) for
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menopausal vasomotor symptoms. She took one tablet bd for 1 year, stopped taking it, and then started taking it again 2 months later. Each tablet contains 20 mg of dried rhizome and root extracts, standardized to contain 1 mg of 27 deoxyactein. After 2 months she started to feel weak. She had increased activities of creatine kinase (247 U/l; reference range 24–170) and lactate dehydrogenase (987 U/l; 230–460). The black cohosh was withdrawn and her symptoms improved within 10 days; the enzyme activities fell and were normal after 20 days.
There may have been very mild muscle damage in this case, but the increases in enzymes were much less than one usually sees in cases of rhabdomyolysis. Pregnancy and lactation The use of black cohosh in pregnancy and lactation has been reviewed. There is weak evidence based on theory and expert opinion that black cohosh has the following effects during pregnancy: labor-inducing effects, hormo nal effects, emmenagogue properties, and anovulatory effects (21A). The authors concluded that black cohosh should be used with caution during pregnancy.
Citrus aurantium (Rutaceae, bitter orange) (SED-15, 3087; SEDA29, 586)
After the US marketing ban of Ephedracontaining supplements in April 2004, many manufacturers used C. aurantium instead and marketed the products as “ephedra-free” supplements. However, extracts of C. aurantium contain synephr ine, an alpha-adrenoceptor agonist. In the 2004 California Behavioral Risk Factor Surveillance Survey, 70 of 4140 respon dents reported having taken a dietary supplement containing C. aurantium during 2003 (22S). Compared with non-users, they were more likely to be single, aged 18–34 years, and Hispanic and to have a heavier body mass index. Five users reported adverse events that they attributed to the supplement. Between March 1, 2004 and October 31, 2006, Health Canada received 21 domestic reports of adverse reactions suspected of being associated with C. aurantium (22S).
750 Of these, 15 reports were of cardiovascular adverse reactions, 10 of which were serious and included 1 report of myocardial infrac tion. According to Health Canada, synephr ine found in bitter orange can have serious adverse effects on heart rate and blood pressure; these effects are significantly potentiated by caffeine. Synephrine is found in various natural health products that are promoted for weight loss. Health Canada has cautioned that the following people may be particularly at risk of adverse reactions from synephrine-contain ing products: those with heart conditions, central ner vous system disorders, diabetes mellitus, enlarged prostate, glaucoma, hyperten sion, pheochromocytoma, thyroid disease, or known risk factors for cardiovascular disease; those taking caffeine-containing pro ducts, monoamine oxidase inhibitors, thyroid hormones, or medications to control blood pressure or heart rate; underweight people. Immunologic Eosinophilic gastroenteritis has been linked to citrus fruit allergy (23Ar).
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Ephedra See Chapter 13.
Ginkgo biloba (Ginkgoaceae; maidenhair tree) (SED-15, 1507; SEDA-28, 576; SEDA-29, 587; SEDA-30, 553)
Skin Acute generalized exanthematous pustulosis (AGEP), which is commonly caused by systemic antibacterial drugs, has been attributed to G. biloba (24A). A 45-year-old man developed a symmetrical
maculopapular eruption on his limbs. Within 2 days the rash generalized to involve the face. Disseminated non-follicular small pustules on erythematous skin were predominant. The palms, soles, and mucous membranes were spared. His temperature was 38.81C. The rash had developed 48 hours after starting oral G. biloba treatment for tinnitus. He denied previously having taken G. biloba and was not taking any other medications. He reported no previous adverse drug reactions and no history of psoriasis. A skin biopsy showed neutrophil-containing spongiotic pustules in the epidermis and a mixed cellular infiltrate with edema in the papillary dermis, consistent with AGEP. The rash cleared within 10 days after withdrawal of G. biloba.
A 46-year-old man developed non-bloody
loose stools 16 times a day associated with abdominal cramping and nausea but no vomiting. Ten years before he had had urticaria and wheezing, but no gastrointestinal symptoms, after taking lemons or grapefruit followed by exercise, and had avoided citrus fruits since then. A CT scan of the abdomen showed colonic, ileal, and duodenal wall thickening. Colonoscopy showed terminal ileitis and pancolonic reduced vascular mark ings, suggesting chronic inflammation. Histol ogy showed acute colitis and ileitis with eosinophil infiltration. Specific IgE against the following foods was found; lemon, grapefruit, tomato, carrot, potato, coconut, banana, pars ley, yeast, garlic, onion, hazelnut, peanut, sesame, and corn. He responded to non enteric-coated budesonide and mesalazine. Montelukast was added when the peripheral eosinophilia persisted and prednisolone when he had a recurrence 1 year later.
The authors diagnosed eosinophilic gastro enteritis, which they classified into four types, in three of which food allergies are common.
Pregnancy and lactation The use of ginkgo in pregnancy and lactation has been reviewed (25M). There is weak evidence from animal and in vitro studies that ginkgo has antiplatelet activity and might therefore prolong bleeding time during labor. There is also weak evidence that it may be an emmenagogue. The authors concluded that ginkgo should be used with caution during pregnancy, particularly around the time of labor. Its safety during lactation is unknown and it should be avoided. Drug contamination In a study of human placental blood a factor that affected human neutrophils and their adherence was discovered and turned out to be colchicine (26c). Significant concentrations of colchicine (49–763 mg/l) were then found in the placental blood of patients who had used non-prescription herbal dietary supplements during pregnancy,
Treatments used in complementary and alternative medicine
and colchicine was found in commercial preparations of G. biloba. Drug overdose Poisoning with ginkgo nuts has been reported in a child (27A). A 2-year-old boy took about 50 ginkgo nuts
and 4 hours later started vomiting and had an afebrile generalized tonic seizure. There was a large volume of ginkgo nuts in the vomitus. He was given diazepam 0.4 mg/kg and pyridoxal phosphate 8 mg/kg intravenously and recov ered. Sleep electroencephalography 12 hours after admission showed irregular spikes and high-voltage slow waves in the left central, parietal, occipital, and posterior temporal regions; 6 months later electroencephalogra phy was normal.
Drug–drug interactions The possible interactions of G. biloba extract with several commonly used drugs have been investi gated in a number of pharmacokinetic studies. In healthy subjects there was no interaction with diclofenac (28c), metformin (29c), ticlopidine (30c), or warfarin (31c). For tolbutamide the data were not consistent (27c,32c) and for midazolam there was a slight reduction in clearance (31c). Aspirin In a double-blind, double-dummy study in 50 healthy men (aged 20–44 years) aspirin alone (500 mg/day for 7 days) prolonged bleeding time and altered plate let aggregation; the addition of an extract of G. biloba, EGb 761, had no additional significant effect (33C). Cilostazol Co-administration of G. biloba with either cilostazol or clopidogrel did not enhance ex vivo antiplatelet activity compared with individual agents in a pharmacodynamic interaction study in male volunteers. How ever, there was significant potentiation of the prolongation of the bleeding time with the combination of cilostazol+G. biloba com pared with the two drugs individually (34c).
Glycyrrhiza spp. (Fabaceae, liquorice or liquorice root) (SED-15, 1311; SEDA-24, 538; SEDA-25, 569; SEDA-26, 531)
Endocrine Extracts of liquorice and glycyrrhizin, its principal component, have
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extensive use in foods, tobacco, and in both traditional and herbal medicines (35R). It is estimated that consumption of liquorice and glycyrrhizin by the US public ranges from 0.027 to 3.6 mg/kg/day of glycyrrhizin. Both products have been approved for use in foods by most national and supranational regulatory agencies. Glycyrrhizinates inhibit 11-hydroxysteroid dehydrogenase, the enzyme responsible for inactivating cortisol. As a result, continuous high exposure to glycyrrhizin compounds can produce mineralocorticoid-like effects in both animals and humans. The effects may be greater in men than in women (36c) and are reversible. Pseudoaldosteronism occurred in a 77-year-old Japanese man who took two Chinese herbal medicines containing gly cyrrhizin (Arejin for chronic allergic rhinitis and Daiokanzo-to as a laxative). The condition became manifest only when he developed symptoms related to hypokale mia when his dosage of enalapril was reduced (37A). In a study of the effects of liquorice in nine healthy women aged 22–26 years during the luteal phase of the menstrual cycle after 2 months consumption of 3.5 g/day of a commercial preparation of licorice (containing 7.6%, w/w, of glycyr rhizic acid), plasma renin activity, aldosterone, cortisol, serum parathyroid hormone (PTH), 1,25-dihydroxycolecalci ferol (1,25OHD), 25-hydroxycolecalciferol (25OHD), estradiol, FHS, LH, alkaline phosphatase, calcium, phosphate, and crea tinine, urinary calcium and phosphate, and mineralometry were measured (38c). PTH, 25OHD, and urinary calcium increased significantly from baseline after 2 months of therapy, while 1,25OHD and alkaline phosphatase did not change. All these parameters returned to pretreatment values 1 month after withdrawal of licorice. Plasma rennin activity and aldosterone were depressed during therapy, but blood pres sure and plasma cortisol were unchanged. The effects of liquorice on calcium metabo lism are probably mediated by several components of the root, which have aldos terone-like, estrogen-like, and antiandrogen activity.
752 Mutagenicity and teratogenicity Various studies have shown that glycyrrhizin is neither teratogenic nor mutagenic, and that it may even have antigenotoxic properties under certain conditions (34R).
Harpagophytum procumbens (Passifloraceae, Devil’s claw) The effect of Devil’s claw in osteoarthritis has been studied in a meta-analysis of 14 pub lished clinical trials (39M). Many of the published trials lacked important methodolo gical quality criteria, although the data from the higher-quality studies suggested that Devil’s claw reduces pain. Devil’s claw appears to be associated with minor risks relative to NSAIDs. However, the clinical evidence to date cannot provide a definitive answer to its claimed efficacy and safety. Further better designed clinical investigations are warranted.
Hydroxycut Hydroxycut formerly contained ma huang, an Ephedra-type alkaloid. However, since restrictions on the use of Ephedra as a dietary supplement were introduced in 2004, it has been reformulated as a caffeine-based Ephedra-free preparation. A 42-year-old man, previously healthy, developed malignant hypertension and hypertensive retinopathy while taking Hydroxycut (40A). Given the lack of investigative studies in regard to their safety and efficacy, judicious care should be taken with the use of all herbal supple ments, including those designated as Ephedra-free.
Morinda citrifolia (Rubiaceae, noni) (SED-15, 3085; SEDA-30, 554) Liver Noni, a Polynesian herbal remedy, is a tropical fruit that has been implicated in liver damage (41A). A 24-year-old woman with multiple sclerosis
drank noni juice for 4 weeks and developed a mildly raised bilirubin concentration and
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serum transaminase activity after treatment with interferon beta-1a for 6 weeks. Interferon was withdrawn because of the possibility of drug-induced hepatitis, after exclusion of viral hepatitis due to hepatitis A–E. One week later she developed severe icterus, greatly raised bilirubin and transaminases, and a reduced prothrombin time, indicating impaired liver function with a suspicion of incipient acute liver failure. There was no evidence of hepatotoxic viruses, alcoholic hepatitis, Budd–Chiari syndrome, hemochromatosis, or Wilson’s disease. Fine-needle aspiration biopsy of the liver ruled out autoimmune hepatitis but showed signs of drug-induced toxicity. After withdrawal of the noni juice, her transaminase activities fell and were in the reference range within 1 month.
Several animal and human studies have shown that high doses of noni juice (up to 750 ml/day), many times greater than in any case reports, have not caused liver damage, as judged by liver function tests and histology (42r). The anthraquinones in noni juice, identified as causative agents in case reports, are of the wrong type and quantity to be of toxicological relevance. In reply the authors of the paper stated that it was not possible to rule out idiosyncratic noni-induced hepatotoxicity. This type of drug reaction is not doserelated in the therapeutic range of doses, is not reproducible in healthy volunteers or in animals, and can present with immu noallergic features.
Piper methysticum (Piperaceae; kava kava) (SED-15, 2837; SEDA-28, 578; SEDA-30, 554)
The effects of kava kava have been reviewed (43R). Its chief adverse effects are a dermopathy and liver damage. The efficacy and safety of kava kava (P. methysticum) have been analyzed in three double-blind, randomized, placebocontrolled trials in generalized anxiety dis order in 64 adult outpatients, including one study with an active comparator (venlafax ine) (44M). Since the study designs were comparable, the kava and placebo data were then pooled for further efficacy and safety analyses. There were no significant
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differences between the groups in any of the trials. In the pooled analyses, kava had no effects, while there was a significant effect in favor of placebo in participants with higher anxiety at baseline. There was no evidence of hepatotoxicity with kava.
PLANT TOXINS Anthraquinones Anthraquinones are found in rhubarb root, senna leaf and pod, Cascara sagrada, buckhorn, and aloe, all common components of herbal slimming regimens. Anthraquinones have several biological effects and adverse effects have been reported. The root contains a complex mixture of 2–5% anthraquinone derivatives (anthranoids), of which most are present as glycosides. After ingestion, colo nic bacteria metabolize the anthraquinone glycosides to anthranols, which are absorbed to a moderate degree and are excreted in the bile, saliva, milk, and urine. Rhubarb root has mainly been used traditionally for its laxative properties and in short-term ther apy. Since 1996 the Federal Institute for Drugs and Medical Devices in Germany has recommended that anthraquinone-contain ing laxatives should not be used continuously for periods exceeding 1–2 weeks. Urinary tract Acute renal failure has been associated with anthraquinones (45A). A 23-year-old woman developed acute renal
failure with hypocellular interstitial fibrosis after prolonged use of a proprietary Chinese herbal slimming pill that contained anthraqui none derivatives, extracted from rhubarb. The renal damage was probably aggravated by concomitant use of diclofenac. Her renal function recovered after withdrawal of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later.
Although a causal relation between the anthraquinone-containing agents and renal damage remains to be proven, phytother apy-associated interstitial nephropathy
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should be considered in patients who present with unexplained renal failure.
AROMATHERPY Aromatherapy uses essential oils created by distilling various plant-derived chemicals to create a concentration as great as 100 times. It should be used with caution. Aromatherapy preferences and complications in 3000 otolar yngology patients have been studied (46M). Among these patients, 1.67% had some form of complication induced by essential oils used in aromatherapy, including skin eruptions, respiratory distress, and other symptoms. Some patients (0.93%) refused aromatherapy because of individual preference and unplea sant smell. People should follow instructions at all times and should never use these oils for an extended period or overuse them.
CUPPING Skin Cupping, the therapeutic application of heated cups to the skin, is an East Asian and Oriental tradition, still in use in many cultures. Alcohol-soaked cotton in the cup is ignited and the cup immediately pressed tightly against the skin. The procedure usually lasts 5–20 minutes. The vacuum created during cupping breaks superficial capillaries and can cause circular erythema, edema, ecchymoses, purpura, burns, keloid, and factitious panniculitis. A 57-year-old woman with a tender red patch on
her lower back reported that cupping had been performed 2 weeks before to relieve back pain (47A). However, the cup had been held on her skin for over 40 minutes. She experienced intense pain soon after the procedure, and bullae and crusting developed over the area during the following week. There was a 50-mm, circular, red patch on the right lumbar area, with several uniform intact vesicles, serous exudation, and crusting on the surface. Routine laboratory parameters were normal, except for a raised white blood cell count (14 109 per liter) and fasting blood glucose (9.28 mmol/l). Wet dressings and an antibiotic ointment led to complete resolution of the crusts and vesicles within 10 days.
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