Treatments used in complementary and alternative medicine

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Pharmacovigilance in complementary and alternative medicine Pharmacovigilance in complementary and alternative medicine has attracted much attention worldwide. The awareness of the need for surveillance of adverse reactions to natural health products has stimulated the implementation of a reporting system for suspected adverse reaction in Italy [1C]. From April 2002 to March 2007, 233 spontaneous reports of suspected adverse reactions to natural health products were collected. A large proportion of the suspected adverse reactions were serious: hospitalization was reported in 35% of cases; 6% reported life-threatening clinical events, and there were two fatal events. Most of the reported cases involved herbal products (66%); 21 reports were associated with 27 homeopathic preparations, most of which contained a mixture of substances; 14 reports attributed the suspected reactions to products containing propolis. A review in China has shown that traditional Chinese medicine (TCM) led to several adverse drug reactions during the past few years and that pharmacovigilance in TCM remains problematic, although great efforts have been made to improve it [2R]. In order to report adverse effects of interventions in randomized controlled trials Side Effects of Drugs, Annual 33 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/B978-0-444-53741-6.00048-9 # 2011 Elsevier B.V. All rights reserved.

transparently, it has been suggested that Consolidated Standards of Reporting Trials (CONSORT) for TCM should include background information on adverse reactions to each intervention, specific outcome assessments of adverse effects, and interpretation of the occurrence of adverse reactions in a structural report [3R]. In South India, a pharmacist-coordinated program has been initiated to improve the reporting of adverse reactions to complementary and alternative medicines [4C].

ASIAN HERBAL MEDICINES [SED-15, 1609; SEDA-32, 879]

Ling yang gan mao capsule Immunologic Ling yang gan mao capsule is a commonly used over-the-counter Chinese herbal mixture for the treatment of colds and flu. It contains Cornu Saigae Tataricae (antelope horn, ling yang jiao), Fructus Arctii (achene of great burdock, niu bang zi), glycine max (fermented soybean, dan dou chi), Flos Lonicerae Japonicae (honeysuckle flower, jin yin hua), Herba Schizonepetae (fineleaf schizonepeta herb, jing jie), Fructus Forsythiae (lian qiao), Herba Lophatheri (dan zhu ye), Radix Platycodonis (platycodon root, jie geng), Oleum Menthae (peppermint oil, bo he you), and 989

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Radix Glycyrrhizae (liquorice root, gan cao). An allergic reaction has been reported to Ling yang gan mao capsule [5A].

Cortex Dictamnus dasycarpus (bai xian pi) and Radix Sophora flavescens (ku shen), is commonly used to treat hematochezia, anal bulge, and constipation caused by hemorrhoids. The State Food and Drug Administration of China (SFDA) has received several reports of adverse reactions to Zhi xue capsule in recent years [7A, 8S]. Up to September 2008, 35 cases of adverse reactions associated with Zhi xue capsule had been reported, of which 21 were associated with abnormal liver function, cholestatic hepatitis, and drug-induced liver damage. After withdrawal and symptomatic treatment, there was full recovery in eight cases, and the rest improved markedly.

• A 62-year-old woman took Ling yang gan mao capsule three times in 2 days to treat a cold. She gradually developed increasing numbness, distension and itching of the lips, pain in the palms, swollen fingers, and erythema and itching in the hands. After she took cyproheptadine, triprolidine, and dexamethasone her symptoms gradually disappeared.

Shen ling bai zhu san Skin Shen ling bai shu san, an over-thecounter Chinese herbal formula that is commonly used to help digestion, consists of 10 herbs: Radix Ginseng (ren shen), Poria (fu ling), Rhizoma Atractylodis macrocephalae (bai zhu), Tuber Dioscores opposita (shan yao), Semen Lablab album (bai bian dou), Semen Nelumbo nucifere (lian zi), Semen Coicis (yi yi ren), Fructus Amomi xanthioidis (sha ren), Radix Platycodonis (jie geng), and Radix Glycyrrhizae (gan cao). It has been reported to cause erythema multiforme [6A]. • A 5-month-old girl developed swollen red skin around her eyes and mouth 1 day after taking three doses of Shen ling bai zhu san. After stopping the medication, her skin lesion worsened and spread to the whole body, with erythema multiforme and exfoliation. She became agitated, and cried and moved restlessly. She was given hydrocortisone, penicillin, promethazine, vitamin C, and calamine lotion, and her skin condition gradually resolved after 1 week. • An 8-month-old boy developed similar symptoms after two doses of the same brand of Shen ling bai zhu san. The skin lesion also included bullae, which was easily ruptured. He made a gradual recovery treatment with hydrocortisone, ceftriaxone, calamine lotion, a sedative, and medications for anaphylaxis.

Zhi xue capsule Liver Zhi xue capsule, a preparation that contains two Chinese medicinal herbs,

K. Chan, H.W. Zhang, and Z.X. Lin

Zhuang gu guan jie wan Liver Zhuang gu guan jie wan is a compound herbal preparation consisting of Rhizoma Cibotii (gou ji), Flos Epimedium brevicornum (yin yang huo), Radix Angelicae biseratae (du huo), Rhizoma Drynariae fortuei (gu sui bu), Radix Dipsaci asperoidis (xu duan), Fructus Psoralea corylifolia (bu gu zhi), Herba Taxilli Chinensis (sang ji sheng), Caulis Spatholobus suberectus Dunn (ji xue teng), Radix Rehmanniae preparata (shu di huang), Radix Aucklandiae (mu xiang), Boswellia carterii (ru xiang), and Commiphora myrrha (mo yao). It is commonly used in the treatment of osteoarthritis and lumbar muscle strains. Since 2001, there have been increasing numbers of reports of adverse reactions to zhuang gu guan jie wan [9S, 10A]. The most common adverse reaction is liver damage, of which 47 cases have been recorded among 158 patients monitored. The other adverse reactions include rashes, pruritus, nausea and vomiting, stomach ache, abdominal pain, diarrhea, and high blood pressure. After drug withdrawal there is good recovery. No drug-related deaths have been reported. It has been speculated that olibanum and myrrh are the main hepatotoxic ingredients in zhuang gu guan jie wan, and Fructus Psoraleae may also have detrimental effects on liver function [11E].

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INJECTABLE FORMULATIONS OF CHINESE MEDICINES

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pneumonia, and acute tonsillitis. It has been associated with acute renal failure, and the SFDA has issued warnings on its clinical use [14A, 15A, 16S].

Ci wu jia injection Skin Allergic skin reactions have been reported to be associated with the use of ci wu jia injection [12A]. • A 40-year-old woman with vertebrobasilar insufficiency was given an intravenous infusion of ci wu jia 250 ml for vertigo after an injection of xue sai tong (Panax notoginsenosides as the main ingredients) in isotonic saline 250 ml. Nearly 40 minutes into the infusion she developed a pruritic maculopapular rash from the neck to the chest, and then spreading all over the body. The rash resolved with oral cetirizine hydrochloride 10 mg, intravenous dexamethasone sodium phosphate 5 mg, and intravenous calcium gluconate 20 ml.

Ku die zi injection Immunologic Ku die zi injection is made from Herba Ixertis Sonchifoliae, which is believed to improve blood circulation and is generally used to treat coronary heart disease and angina pectoris in China. However, it has been reported to cause serious allergic reactions [13A]. • A 65-year-old woman with coronary heart disease and unstable angina pectoris was treated with an intravenous infusion of Ku die zi injection 40 ml in 5% dextrose. On the third day of the treatment, she suddenly developed shivering, cold limbs, and palpitation. The infusion was stopped immediately, and she gradually recovered after a combination treatment of dexamethasone, promethazine, and bromisoval and procaine injection.

Lian bi zhi injection Urinary tract Lian bi zhi injection is a sterilized fluid that contains andrographolide sodium bisulfate, which has antibacterial and anti-inflammatory effects and is commonly used to treat bacillary dysentery,

Shu xue ning injection Immunologic Shu xue ning injection is a sterilized fluid made from Ginkgo biloba leaves, with total flavonol glycosides and ginkgolides as the main active principles. It is generally used in China for the treatment of ischemic cardiovascular and cerebrovascular diseases. Eight cases of adverse effects have been reported. Allergic reactions, such as urticaria, bronchospasm, macular rashes, palpitation, nausea, and chest distension, were observed in six cases after an intravenous infusion of Shu xue ning injection [17A, 18A]. Two cases of anaphylactic shock were observed 2–3 minutes into the infusion, and the patients gradually recovered after treatment [19A, 20A].

Xing nao jing injection Immunologic Xing nao jing injection, a sterilized aqueous extract of Calculus bovis (niu huang), Moschus (she xiang), Dry Obalanopsaromatica Gwaertn. (bing pian), and Fructus Gardeniae (zhi zi), is commonly used in China to treat coma in stroke or traumatic injuries. It has been reported to cause serious allergic reactions [21A]. • A 73-year-old man developed shivering and spasm 25 minutes into an intravenous infusion of Xing nao jing injection 20 ml in isotonic saline 250 ml for cerebral infarction. The infusion was stopped immediately. He gradually recovered 40 minutes later after receiving oxygen, adrenaline, and promethazine. • A 62-year-old man was given Xing nao jing injection 30 ml in 5% dextrose 250 ml. About 10 minutes into the infusion, he developed chest distension, shortness of breath, a flushed complexion, a tachycardia, and a raised blood pressure. The infusion was stopped immediately. After receiving oxygen, dexamethasone, and promethazine he made an uneventful recovery.

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Zedoray tumeric oil and glucose injection

gastrointestinal complaints in 0.1% of patients. A crossover study reported no difference in the occurrence of adverse events between black cohosh and placebo, without providing further details. In two uncontrolled trials there were bleeding episodes in 59 women (36 spotting, eight mild bleeding, nine moderate bleeding, and six major bleeding) and in four women respectively. In three postmarketing surveillance studies involving 5405 patients, adverse events included stiff limbs, gastric pain, allergic reactions, breast tenderness, bleeding, and gastrointestinal complaints. Case reports included liver damage, seizures, muscle damage, and pseudolymphoma. Of all these effects, hepatotoxicity was most often reported.

Zedoray tumeric oil and glucose injection is an oil/water lipid emulsion made from the naphtha of Rhizoma Curcumae aeruginosae, Rhizoma Curcumae Kwangsiensis (or Rhizoma Curcumae Wenyujin) and is commonly used to treat virus infections. It has been reported to cause adverse effects such as allergic reactions, rashes, dyspnea, and even anaphylactic shock, and the SFDA has issued warnings on its clinical use [22S, 23A].

INDIAN MEDICINES Kadda Drug contamination In India, a 39-year-old man with jaundice developed vomiting and severe abdominal pain after consuming 10–15 ml of kadda (in local language) every morning on an empty stomach for 10 days [24A]. Lead poisoning was confirmed when the blood lead concentration was measured. A combination of chelation therapy and nutritional supplements reduced the body lead burden. The original syrup had been consumed and could not be tested for lead content.

SPECIFIC PLANTS Actaea racemosa (Ranunculaceae, black cohosh; formerly Cimicifuga racemosa) Systematic reviews There has been a systematic review of adverse reactions to black cohosh as reported in 13 clinical trials, three postmarketing surveillance studies, four case series, and eight single case reports [25M]. Three studies reported no serious adverse events. In one trial one of 21 patients had joint pain in the hands. Another trial reported

K. Chan, H.W. Zhang, and Z.X. Lin

Liver Cases of liver damage associated with black cohosh continue to appear [26c, 27c]. The hepatotoxic effects of black cohosh have been analysed by the Dietary Supplement Information Expert Committee of the US Pharmacopeia's Council of Experts. Reports were obtained from diverse sources, including the European Medicines Agency [28S]. There were 30 reports, all of which were considered to be possibly associated with the plant, using Naranjo's algorithm. The Expert Committee proposed that black cohosh products should be labeled with a cautionary statement. This is a change from a previous in 2002, which required no such statement. Meanwhile, other national regulatory authorities have issued similar warnings [29S, 30S, 31S, 32S]. In contrast, in a prospective study of 87 postmenopausal women who took a dry extract of black cohosh 40 mg/day for 12 months total hepatic blood flow, assessed by color Doppler ultrasound, was unaffected as were prothrombin time and concentration, serum albumin and bilirubin concentrations, and gamma-glutamyltransferase, alkaline phosphatase, and aminotransferase activities [33c]. However, these results do not rule out an incidence of hepatotoxicity of up to 3.4%. The use of a causality algorithm in four subjects with liver disease suggested that it was not related to the black cohosh that they had taken [34c]. Another group with the same first authors used the same methods in nine patients, in whom they judged that

Treatments used in complementary and alternative medicine

causality was excluded (n ¼ 4) or unlikely (n ¼ 4) and possible in only one case [35c]. Pursuing the same theme, the same group analysed data from 69 reported cases of liver disease in patients taking black cohosh, using the same method [36c]. They considered that causality had been excluded or was unlikely, unrelated, or unassessable in 68 cases; in the other case causality was possible. A major problem with these analyses was that in general the cases were poorly documented. Furthermore, the drawbacks of causality algorithms are well known [37M].

Agauria salicifolia (Ericaceae) See Rhododendron spp. below

Allium sativum (Liliaceae, garlic bulb) Hematologic A renal hematoma after extracorporeal shock-wave lithotripsy was attributed to the antiplatelet action of a garlic extract that the patient was taking [38A]. The authors suggested that herbal medications, such as garlic, ginkgo, and ginseng, should be withdrawn for up to 15 days before urological surgery or shock-wave lithotripsy, in order to minimize the risk of bleeding. Gastrointestinal A 60-year-old woman had severe sustained chest pain due to bullous necrosis of the esophagus when a piece of raw garlic measuring 2.7  1.5 cm impacted and had to be removed at endoscopy [39A]. Skin The application of fresh garlic to the skin can cause erythema and blistering (“garlic burns”), as has been reported in three young people in whom topical garlic was used as an analgesic by naturopaths; they all felt a burning sensation in the area, but did not remove the bandage, even when the burning sensation became severe [40cr]. The risks of garlic burns depend on various factors, such as the concentration,

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freshness of the garlic, duration of exposure, the area of application, the preexisting skin condition, and individual reactivity [41r].

Artemisia vulgaris (Asteraceae, mugwort, moxa) Tumorigenicity The formation of a basal cell carcinoma on a burn scar has been reported after repeated exposure to moxa cautery for 10 years, with occasional accidental burns [42A]. Malignant degeneration can occur in long-standing burn scars, and the authors proposed that moxa had encouraged the formation of the tumor in this case.

Camellia sinensis (Theaceae; green tea) Liver See Garcinia gambogia below.

Crataegus orientalis (Rosaceae, Anatolian hawthorn) Urinary tract Crataegus orientalis contains flavonoids and oligomeric procyanthins as its main active constituents. A multisystem hypersensitivity reaction and progressive acute renal failure has been associated with consumption of this plant [43A]. • A 68-year-old man developed weakness, fatigue, difficulty in breathing, reduced urine output, and epistaxis after eating 1 or 2 kg of raw Crataegus orientalis and drinking five cups of tea made from its leaves. He developed acute renal failure with moderate metabolic acidosis and fluid overload and hemodialysis was performed. A renal biopsy showed acute tubulointerstitial nephritis.

Cynomorium songaricum Rupr. (Cynomoriaceae) Urinary tract Cynomorium songaricum (also called Herba cynomorii) is commonly

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used to treat kidney disorders in traditional Chinese medicine. A high oral dose has been associated with acute renal insufficiency [44A].

perforation of 2–3 cm in the anterocaudal part of the septal cartilage. The right inferior and middle conchae were hypertrophic, and the remaining parts of the septum were deviated to the left. In another case, a 22-year-old man developed a headache, shortness of breath, and a sore throat 1.5 hours after aspirating an unknown amount of the undiluted juice of Ecballium elaterium intranasally [47A]. He responded to oxygen, methylprednisolone 1 g intravenously, and adrenaline 2 mg subcutaneously.

• A 49-year-old woman developed nausea and vomiting after self-administering a decoction made by boiling 100–150 g of Cynomorium songaricum for about 30 minutes. She developed acute renal failure after 7 days and required hemodialysis.

Datura stramonium (Solanaceae, Jimson weed, thorn apple, angel's trumpet) Nervous system Datura stramonium has been traditionally used in North America, East Asia, and Africa to treat asthma, chronic bronchitis, arthritis, and pain. All parts of the plant contain poisonous alkaloids, including atropine, hyoscyamine, and hyoscine (scopolamine). The highest concentration of anticholinergic alkaloids is present in the seeds (equivalent to 0.1 mg of atropine per seed). Adverse anticholinergic effects can occur [45A]. • Two elderly women developed agitation, confusion, urinary retention, dry mouth, and dilated pupils within 3 hours of taking the dried seeds of Datura stramonium. They recovered completely after symptomatic treatment for 5 days.

Ecballium elaterium (Cucurbitaceae, squirting cucumber) Ear, nose, and throat A 42-year-old man had a perforation of the nasal septum after using nasal drops prepared from Ecballium elaterium [46A]. Within minutes of using the drops, he started to have a burning sensation in the nose and the pharynx, followed by a watery and then a purulent discharge from the nose. After 2 months of regular use he reported not being able to breathe through the nose with excessive crusting. There was a

K. Chan, H.W. Zhang, and Z.X. Lin

Ephedra See Chapter 13.

Garcinia gambogia (Clusiacaeae; brindleberry, gamboge) Liver In recent years, there have been many reports of hepatotoxicity associated with herbal products used for weight reduction. These products, which are sold as dietary supplements, do not usually undergo safety tests before they are marketed [48R]. Proprietary formulations such as Hydroxycut (MuscleTech Research and Development, Inc; Iovate Health Sciences Research, Oakville, Ontario, Canada) and Exilis (Fusion Health Products, Houston, Texas) contain mixtures of ingredients, including Garcinia gambogia. Hydroxycut is said to contain Garcinia gambogia, L-carnitine, chromium picolinate, and guaraná extract; some preparations have also contained MaHuang extract. Exilis is said to contain Garcinia gambogia, Gymnema Sylvestre, calcium, L-carnitine fumarate, chitosan, green tea extract, conjugated linoleic acid, magnesium chelate, and white kidney bean extract. The US Food and Drug Administration (FDA) has issued warnings that Hydroxycut products should not be used [49S], because of the possibility of liver damage, of which there have been several reports [50A, 51A, 52A, 53A, 54A, 55Ar, 56cr, 57r]. In one case an interaction with montelukast was postulated [58A].

Treatments used in complementary and alternative medicine

There has been a review of eight patients who developed liver injury after taking Hydroxycut; all were hospitalized, and three required liver transplantation [59cr]. Nine other cases with adequate clinical information were obtained from the FDA MedWatch database, including one fatal case of acute liver failure. The usual symptoms were jaundice, fatigue, nausea, vomiting, and abdominal pain. Most patients had hepatocellular liver damage. Exilis has also been associated with fulminant hepatic failure [60A]. • A 25-year-old man presented to a walk-in clinic with tea-colored urine and fatigue. He had taken Exilis for less than 3 weeks, and after taking it for 1 week he had developed nausea, vomiting, aches, and fever. His serum aspartate aminotransferase, alanine aminotransferase, and total bilirubin were 1394 U/l, 2362 U/l, and 180 mmol/l (10.5 mg/dl) respectively. He underwent cadaveric liver transplantation.

The principal hepatotoxic ingredient of Garcinia gambogia is thought to be hydroxycitric acid. However, it has been pointed out that 14 different formulations of Hydroxycut have been marketed, that only eight contained hydroxycitric acid, and that products of this sort contain numerous ingredients [61r]. For example, green tea (Camellia sinensis), present in some of these formulations, has also been associated with hepatotoxicity [SEDA-28, 575; 62A, 63A, 64A, 65c, 66C].

Ginkgo biloba (Ginkgoaceae, maidenhair) Placebo-controlled studies An adequately powered placebo-controlled trial of the effect of Ginkgo biloba in the primary prevention of dementia included over 3000 volunteers aged 75 years and over [67C]. They were randomized to twice daily doses of either Ginkgo biloba extract 120 mg or placebo and were followed for a median of 6.1 years. The extract had no effect on the incidence of dementia. The adverse

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events profiles for Ginkgo and placebo were similar and there was no statistically significant difference in the rate of serious adverse events. The rates of major bleeding did not differ between the groups, nor in individuals who combined the study drug with regular aspirin. There were twice as many hemorrhagic strokes in the Ginkgo group, but the number of cases was too low (16 versus eight) to reach significance. Drug–drug interactions Antiplatelet and anticoagulant drugs A systematic review of the potential interaction of Ginkgo biloba with antiplatelet or anticoagulant drugs has shown that concerns about the safety of Ginkgo when used in combination with anticoagulants or antiplatelet drugs are not supported by the currently available evidence [68M]. The author also pointed to the discrepancy between controlled trials of the EGb 761 extract, which has consistently been found to have no significant effect on hemostasis and case reports of episodes of bleeding with Ginkgo, which have rarely implicated this well-defined extract. Efavirenz Virological failure in a 47-yearold HIV-infected patient who had taken antiretroviral drug therapy for 10 years was associated with falling efavirenz plasma concentrations after he started to take Ginkgo biloba [69A].

Hypericum perforatum (Clusiaceae, St John's wort) Drug–drug interactions Finasteride The effects of St John's wort on finasteride and its metabolites, hydroxyfinasteride and carboxyfinasteride, have been studied in 12 men, in whom finasteride 5 mg was administered directly into the intestine via a catheter before and after 14 days of treatment with St John's wort 300 mg bd [70c]. St John's wort significantly reduced the Cmax, the AUC0!24h, and the half-life of finasteride; the kinetics of carboxyfinasteride were also significantly altered.

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Morinda citrifolia (Rubiaceae)

25 patients with ischemic strokes in a randomized, open, controlled study [75c]. The results suggested that co-administration of Panax ginseng did not affect the pharmacological action of warfarin.

Liver Hepatotoxicity related to the consumption of noni juice, prepared from the fruits of Morinda citrifolia, has again been reported [71R]. • A 43-year-old white man with a glioblastoma underwent surgery and was scheduled for radiation and chemotherapy. After drinking noni juice 20 ml bd for 2 weeks, he developed raised aminotransferases in routine prechemotherapy blood tests. The aminotransferases returned to normal as soon as he stopped drinking noni juice.

The hepatotoxic potential of noni fruit juice has been assessed in in vitro tests in the HepG2 cell line of human liver cells and in subchronic oral toxicity tests in rats [72E]. Freeze-dried filtered noni fruit puree did not alter the viability of HepG2 cells or cause neutral lipid accumulation and phospholipidosis and there were no changes in liver function tests in the rats. The authors therefore suggested that consumption of noni fruit juice is unlikely to cause adverse liver reactions.

Panax ginseng (Araliaceae, Asian ginseng) Drug–drug interactions Gefitinib It has been reported in Korea that the use of complementary herbal medicines caused gefitinib treatment failure [73r]. • A 36-year-old woman with a stage IV adenocarcinoma of the lung was given oral gefitinib 250 mg/day as the first-line chemotherapy. Within 9 weeks she became progressively short of breath. She had simultaneously taken multiple complementary herbal medicines including ginseng, Fomes fomentarius, Inonotus obliquus, Phellinus linteus, and selenium along with gefitinib without notifying her physician. After all the complementary herbal medicines were withdrawn, her symptoms improved significantly.

Previous studies have suggested that ginseng may increase the clearance of gefitinib by inducing the activity of CYP3A4 [74E]. Warfarin The interaction between warfarin and Panax ginseng has been investigated in

K. Chan, H.W. Zhang, and Z.X. Lin

Panax notoginseng (Araliaceae) Sanqi pian, a tablet made from Panax notoginseng, is a widely used traditional Chinese medicinal herb. It is commonly used to treat bleeding disorders and traumatic injuries and has been associated with anaphylactic shock [76A]. • A 20-year-old man developed limb weakness, chills, cold sweats, and shortness of breath about 30 minutes after taking two tablets of Sanqi pian. He was given oxygen, dexamethasone, and promethazine, and made a complete recovery.

Panax quinquefolius (Araliaceae, American ginseng) Drug–drug interactions Indinavir In 13 healthy volunteers American ginseng had no effect on the pharmacokinetics of indinavir 800 mg tds [77c]. Warfarin In a randomized, controlled trial in healthy volunteers, American ginseng reduced the effect of warfarin [78c].

Rhododendron spp. (Ericaceae, rhododendron) Cardiotoxicity of “mad honey” Certain species of rhododendron contain grayanotoxins (andromedotoxins), which open sodium channels. In the heart this effect can trigger the Bezold–Jarisch reflex and cause bradycardia, heart block, asystole, and hypotension [79R].

Treatments used in complementary and alternative medicine

Case reports There have been several reports of these complications in people who have eaten honey prepared by bees from Rhododendron luteum, Rhododendron mucronulatum, Rhododendron ponticum, or Castanea sativa [80A–95A]; myocardial infarction has also been reported [96A]. In the eastern Black Sea region of Turkey, where most cases have been reported, such honey is called “bitter honey” or “mad honey”, which is often used as a household remedy for various conditions, including stomach pains, bowel disorders, hypertension, and erectile dysfunction [97R]. Because of variations in the plant content of grayanotoxins, poisoning with honey made in the spring is more severe [97r]. However, honey poisoning is rarely fatal and the effects generally last for no more than 24 hours. This type of poisoning is thought to have been described by Xenophon 2400 years ago [98R]. In one case poisoning from Rhododendron simsii occurred when a baby's grandmother prepared a decoction of this plant in milk [99A]. Poisoning from eating rhododendrons has also been reported in animals such as sheep and goats [100R]. Other Ericaceae can do likewise, as has been reported in a series of cases of poisoning with Agauria salicifolia from Reunion Island [101c]and a case from the Mascarene Islands, where a 28-year-old woman mistakenly drank a herbal tea made with leaves of Agauria salicifolia and developed symptoms characteristic of grayanotoxin intoxication, with vomiting, hypotension, and bradycardia. [102Ar]. Case series In a retrospective series of 19 patients poisoned by “mad honey”, all had nausea, vomiting, sweating, dizziness, and weakness several hours after ingestion [103c]. There was hypotension in 15, sinus bradycardia in 15, and complete atrioventricular block in four. The hypotension and conduction disorders resolved with atropine treatment, resulting in complete recovery within 24 hours. In 66 patients symptoms that occurred several hours after the ingestion of small amounts of “mad honey” included nausea,

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vomiting, salivation, dizziness, weakness, hypotension, bradycardia, and syncope [104c]. All had hypotension and most had bradycardia. These features resolved completely in 24 hours with intravenous fluids and atropine; none died. In a review of 47 patients who had ingested “mad honey” 0.5–9 (mean 2.8) hours before presentation, the heart rate was 30–77 (mean 47) per minute and the systolic blood pressure was 50–140 (mean 47) mmHg [105c]. Cardiac rhythms on arrival were sinus bradycardia (n ¼ 37), nodal rhythm (6), sinus rhythm (3), and complete atrioventricular block (1). All were given atropine 0.5–2 mg. In a prospective study of 42 patients (33 men; median age 49 years) who had been hospitalized with “mad honey” intoxication, all had nausea, vomiting, dizziness, fainting, and sweating; five had syncope [106c]. The mean blood pressure was 73/52 mmHg and the mean heart rate 38/minute; 18 had sinus bradycardia, 15 had complete atrioventricular block, and nine had nodal rhythm. None needed temporary pacing and all were discharged without complications. In 33 patients (30 men, median age 52 years) the most common effects of poisoning with “mad honey” were sinus bradycardia (91%), nausea and vomiting (82%), and dizziness (79%); average heart rate was 55/minute and mean blood pressure was 78/46 mmHg [107c]. In seven cases of grayanotoxin poisoning due to consumption of wild honey that was brought from the Himalayan belt of Nepal, most had blurring of vision, diplopia, and nausea and vomiting; two had cardiac effects [108c]. Chronic mad honey intoxication syndrome has also been described in a prospective evaluation of 173 patients with bradycardia or atrioventricular conduction abnormalities; in five cases there was a history of ingestion of non-commercial honey made by different amateur beekeepers in the eastern Back Sea region of Turkey [109c]. When they stopped taking the honey there was prompt normalization of conduction and significant symptomatic improvement.

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Although most cases of poisoning are accidental, in a few cases deliberate selfpoisoning has occurred. In 21 patients (18 men) with acute grayanotoxin poisoning, enhancement of sexual performance was the reason for the would-be therapeutic use of “mad honey” [110c].

Uncaria tomentosa (Rubiacaeae, cat's claw)

Incidence This type of poisoning is said to be rare, but the incidence is not known. In one report 69 published reports were reviewed [111M]. Management Muscarinic M2 receptors in the vagus are involved in the cardiotoxicity of grayanotoxin [112AE, 113AE], and bradycardia and heart block in these cases respond to atropine, as in toxicity with veratrum alkaloids. However, temporary pacing may sometimes be required [114Ar].

Tripterygium wilfordii Hook. f. (Celastraceae, bittersweet) Skin Tripterygium wilfordii, also called Lei-gong-teng in Chinese (literally meaning “thunder vine god”), is a common herb used in traditional Chinese medicine for the treatment of many autoimmune disorders. The multiglycosides derived from this plant have been made into tablet form as over-the-counter herbal products in China. Lei-Gong-Teng Multiglycosides tablets have immunodepressant and anti-inflammatory effects, and are widely used to treat rheumatoid arthritis, nephrotic syndrome, and some systemic autoimmune diseases. However, it has been reported to cause skin pigmentation [115A]. • A 35-year-old woman with nephrotic syndrome developed brown to dark pigmented spots on the face after taking Lei-Gong-Teng Multiglycosides tablets 20 mg tds for 20 days. She stopped taking the medication for about 1 month, and the pigmentation gradually disappeared.

K. Chan, H.W. Zhang, and Z.X. Lin

Drug–drug interactions HIV protease inhibitors In a 45-year-old HIV-positive woman with cirrhosis due to hepatitis C infection, the serum trough concentrations of atazanavir, ritonavir, and saquinavir increased when she took cat's claw (Uncaria tomentosa), perhaps because of inhibition of CYP3A4 [116A]. The respective concentrations with and without cat's claw were 0.30 and 1.22 mg/l (atazanavir), 0.92 and 6.13 mg/l (ritonavir), and 0.64 and 3.4 mg/l (saquinavir).

Vaccinium macrocarpon (Ericaceae, cranberry) Drug–drug interactions Warfarin The possible effects of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin have been investigated in an open, three-treatment, randomized, crossover trial in 12 healthy men [117c]. They took a single oral dose of warfarin 25 mg alone or after 2 weeks of pretreatment with either garlic or cranberry. Pretreatment with cranberry significantly increased the area under the INR versus time curve by 30% compared with warfarin alone. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (but not CYP2C9) genotype-dependent interactions with warfarin. Co-administration of warfarin and cranberry requires careful monitoring.

ANIMAL DRUGS Carp gallbladder Urinary tract Fish gallbladder has long been used as a folk remedy in China, and its consumption has been linked to acute renal failure [118A].

Treatments used in complementary and alternative medicine • A 67-year-old woman developed nausea and epigastric pain 2 hours after taking grass carp gallbladder stewed with honey. She also had raised alanine aminotransferase activity after 8 hours. On day 3 she developed oliguria, and hemodialysis was performed on day 5, following which she gradually recovered and was discharged on day 26.

Toad extract (Chan Su) Toad extract, obtained from the secretions of the salivary and skin glands of Chinese toads, is commonly used in Chinese medicine. It contains bufotenine and a series of bufadienolides that are structurally similar to cardiac glycosides [119E]. • A 24-year-old man collapsed and died soon after an intravenous injection of 35–40 ml of what was thought to be ecstasy [120A]. MDMA was not detected in toxicological analyses, but a low concentration of bufotenine was identified instead. In addition, resibufogenin, cinobufagin, and bufalin, which are bufadienolides present in toad venom, were found in the injected material.

ACUPUNCTURE Observational studies In a Korean retrospective cross-sectional survey of 1095 subjects who used acupuncture, 75 (6.8%) described negative short-term acupuncture reactions, including feelings of pain in 37 (3.4%), tiredness in 24 (2.2%), and dizziness in nine (0.8%). The only adverse event reported was bleeding in 92 (8.4%) of the participants [121c]. In a German observational study of 503 397 treatments documented between July 2001 and June 2003, physicians recorded at least one adverse effect in 7.8% of all patients, the most frequent being needling pain in 3.9% [122C]. Serious adverse events were reported in 17 cases, the most frequent event being pneumothorax (five cases). Of 6140 patients who received acupuncture, 9.3% reported adverse reactions, and

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a quarter of these were considered to be troublesome. The most frequent adverse reactions were pain, fatigue, and circulatory disturbances. In 20 patients who received acupuncture for acute non-penetrating limb injuries, only minor complications were reported, including local pain at the acupuncture site, light-headedness, sweating and pruritus, erythema, and minor bleeding at the acupuncture site [123c]. In a review of case reports and prospective surveys of adverse events focusing on “Japanese acupuncture”, almost all of the adverse reactions commonly seen in acupuncture practice, such as fatigue, drowsiness, aggravation of existing symptoms, minor bleeding, pain on insertion, and subcutaneous hemorrhage, were mild and transient [124R].

Anecdotal reports Some serious adverse events have also been reported in individual patients who have received acupuncture. • A 52-year-old woman presented with a 3-day history of anorexia and jaundice after receiving acupuncture twice a day for 7 weeks, performed bilaterally at the Zusanli (ST36) acupoint to a depth of 22 mm [125A]. Electrical stimulation was performed, with the stimulation frequency fixed at 5 Hz for 20 minutes. Her aspartate aminotransferase and alanine aminotransferase activities and total bilirubin concentrations were 84 U/l, 109 U/l, and 216 mmol/l respectively She developed pale stools, dark urine, pruritus, pedal edema, and diarrhea during the next 12 days. Her laboratory results continued to worsen. No specific therapy was provided for the severe cholestatic jaundice. Over the next 12 weeks, her symptoms and the laboratory results gradually improved. • A 42-year-old man received acupuncture at the Jiaji (EX-B2, L4 & 5) and Weizhong (BL40) acupoints, with electrical stimulation for about 30 minutes 2 days after a back sprain [126A]. While he was walking from the clinic to a hospital pharmacy, he suddenly felt dizzy, blacked out, and became flustered; he sweated heavily and his face was pale. After receiving oxygen and intravenous dextrose, he made a full recovery. • A 35-year-old woman received conventional acupuncture and stauntoniae injection 2 ml at Jiaji points (EX-B2, C6 & 7) for the treatment of pain and numbness in the right neck

1000 and arm [126A]. After about 3 minutes, she developed dizziness, chest distension, shortness of breath, and a hot flush. Her face was flushed, and her eyelids and mouth were swollen. The needles were removed immediately and she was given intramuscular dexamethasone 10 mg. She then began to lose consciousness and had a blood pressure of 75/55 mmHg. Several minutes after being given oxygen and a series of anti-allergy treatments, she regained consciousness. The swellings on the eyelids and mouth disappeared after 2 days. • A 43-year-old woman suddenly developed a headache, dizziness, and heavy sweating with vomiting during the second acupuncture treatment for low back and leg pain [126A]. The needles were removed immediately and she was helped to lie down. Most of her symptoms resolved but the headache persisted for 2 days. A subarachnoid hemorrhage was later confirmed by CT scan.

Immunologic Allergic reactions to the metal used in acupuncture needles have been reported [127A]. • A 72-year-old man who received acupuncture for neck and shoulder pain developed erythema, pruritus, and swelling on the needling region after the needles had been removed from Jiaji points (EX-B2, C5, 6, & 7), which had been stimulated with electrical pulsation for 30 minutes. The next day he developed mung bean-sized blisters on the needling region. He was found to be allergic to the metal in the needle. Acupuncture was stopped and the blisters disappeared after symptomatic treatment for 1 week. • A 49-year-old woman with cervical spondylopathy developed pruritus at the needling region 1 day after acupuncture at Jiaji points (EX-B2, C5, 4, 5, & 6) with electronic stimulation. She then developed rice grain-sized blisters at the needling region on the third day. She was allergic to the metal in the needle. Acupuncture was discontinued and the blisters disappeared after symptomatic treatment for 5 days.

CHIROPRACTIC Observational studies In a case–control and case-crossover study there was no difference in the risk of vertebrobasilar artery stroke associated with chiropractic care and primary care [128C].

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In a cross-sectional survey of pediatric chiropractic, chiropractors reported three adverse events per 5438 office visits involving the treatment of 577 children. The parents reported two adverse events from 1735 office visits involving the care of 239 children [129C]. Systematic reviews A systematic review of the reported adverse events of chiropractic procedures has shown that most of the adverse events reported were benign and transient; however, there were reports of complications that were serious or life threatening, such as arterial dissection, myelopathy, vertebral disc extrusion, and epidural hematoma [130M]. The frequency of adverse events was 33–61%, while the frequencies of serious adverse events were 5 strokes/ 100 000 manipulations, 1.46 serious adverse events per 10 000 000 manipulations, and 2.68 deaths per 10 000 000 manipulations. Nervous system Chiropractic has been reported to be associated with a case of quadriparesis [131A]. • A 41-year-old man with chronic neck pain developed weakness of the legs a few hours after undergoing chiropractic manipulation. He recalled hearing a snapping sound during the manipulation and felt tingling and numbness in his arms and legs immediately after. He had no power in the legs, 2/5 in the arms, reduced sensation for light touch over all four limbs, bilateral extensor plantar responses, reduced anal sphincter tone, and urinary retention. He rapidly developed complete quadriparesis. An MRI scan showed a large paracentral C6–C7 disc herniation with marked cord edema. After intravenous injection of methylprednisone and an emergency C6–C7 anterior cervical discectomy and fusion, he had partial improvement, but remained paraplegic 3 months after the incident.

SKIN BRANDING Branding refers to a process whereby thirddegree burns are inflicted on the skin with a hot iron rod or metallic object. Branding uses the phenomenon of counter-irritation, by briefly using moderately intense pain to

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relieve chronic pain. Branding is used by faith healers in some developing countries for therapeutic purposes. Some methods, which are very crude and inhumane, carry a high risk of complications. Four Pakistani patients aged 25–60 years developed severe medical complications after being branded with a red-hot iron rod for various medical reasons [132cr]. The mean duration between the procedure and presentation to the hospital was 6 days. At the time of admission, two had septic shock, one had a cavernous sinus thrombosis, and one had multiple splenic abscesses. All received standard care for wound management and systemic infections. Two eventually died.

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SPA THERAPY Observational studies A postal questionnaire concerning drug prescriptions during spa therapy conducted in France showed that spa therapy was often associated with a reduction in the use of prescribed drugs [133C]. Adverse reactions to spa therapy were rare or usually graded as “unserious” events. However, causality is difficult to establish, justifying the need for specific vigilance.

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[7] Li CR, Xu L, Qiu JM. One case of liver damage caused by zhi xue capsule. Chin J Pharmacovigil 2009; 6(11): 687. [8] State Food and Drug Administration. Chinese Adverse Drug Reaction Information Bulletin 2008; 17. [Notice on the liver damage caused by zhi xue capsule.] http://www. sfda.gov.cn/WS01/CL0304/33571.html. [9] State Food and Drug Administration. Chinese Adverse Drug Reaction Information Bulletin 2008; 16. [Warnings on the liver damage caused by Zhuang gu guan jie wan.] http://www.sda.gov.cn/ WS01/CL0078/32614.html. [10] Song XJ. One case of liver damage caused by zhuang gu guan jie wan. Chin Foreign Med 2009; 28(18): 181. [11] Zhou K, Dai Z, Liu ZB, Tan Y, Hu LM, et al. Experimental study of screening the hepatotoxic medicinal materials in zhuang gu guan jie pill. Chin J Pharmacovigil 2009; 6(11): 641–8. [12] Gong SY, Shi CS. One case of allergic reaction to the Ci Wu Jia injection. Pract Pharma Clin Rem 2008; 11(5): 284. [13] Yuan LY. One case of hypersensitive reactions caused by Chinese medicine preparation of Ku Die Zi injection. Baotou Med 2009; 33(4): 252. [14] Jiang Z, Tan HH, Luo LN. Two cases of acute kidney failure caused by Lian Bi

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medicamentos para perder peso. [Hepatotoxicity induced by herbs and medicines used to induce weight loss.] Gastroenterol Hepatol 2008; 31(7): 447–53. US Food and Drug Administration. FDA warns consumers to stop using Hydroxycut products dietary supplements linked to one death; pose risk of liver injury. 2010. http:// www fda gov/NewsEvents/Newsroom/Press Announcements/ucm149575htm. Stevens T, Qadri A, Zein NN. Two patients with acute liver injury associated with use of the herbal weight-loss supplement Hydroxycut. Ann Intern Med 2005; 142(6): 477–8. Jones FJ, Andrews AH. Acute liver injury associated with the herbal supplement Hydroxycut in a soldier deployed to Iraq. Am J Gastroenterol 2007; 102(10): 2357–8. Shim M, Saab S. Severe hepatotoxicity due to Hydroxycut: a case report. Dig Dis Sci 2009; 54(2): 406–8. Rashid NN, Grant J. Hydroxycut hepatotoxicity. Med J Aust 2010; 192(3): 173–4. Sharma T, Wong L, Tsai N, Wong RD. HydroxycutÒ (herbal weight loss supplement) induced hepatotoxicity: a case report and review of literature. Hawaii Med J 2010; 69(8): 188–90. Chen GC, Ramanathan VS, Law D, Funchain P, Chen GC, French S, Shlopov B, Eysselein V, Chung D, Reicher S, Pham BV. Acute liver injury induced by weight-loss herbal supplements. World J Hepatol 2010; 2(11): 410–5. Dara L, Hewett J, Lim JK. Hydroxycut hepatotoxicity: a case series and review of liver toxicity from herbal weight loss supplements. World J Gastroenterol 2008; 14(45): 6999–7004. Lobb A. Hepatoxicity associated with weight-loss supplements: a case for better post-marketing surveillance. World J Gastroenterol 2009; 15(14): 1786–7. Actis GC, Bugianesi E, Ottobrelli A, Rizzetto M. Fatal liver failure following food supplements during chronic treatment with montelukast. Dig Liver Dis 2007; 39(10): 953–5. Fong TL, Klontz KC, Canas-Coto A, Casper SJ, Durazo FA, Davern TJ 2nd,

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