Reviews 1017 Clinical Aspects of Aconitum Preparations* Authors Chi-Jung Tai1,3 #, Mohamed El-Shazly1, 2 #, Tung-Ying Wu4, Kun-Tai Lee5, 6, Dezső Csupor 7, Judit Hohmann7, Fang-Rong Chang1, 8,9, 10, Yang-Chang Wu1,4, 11,12 Affiliations The affiliations are listed at the end of the article Key words Abstract tion has changed with the application of new l" Aconitum ! technologies for the accurate analysis of its toxic l" Ranunculaceae Aconite species have played an important role in components and the development of efficient de- l" fuzi human history. Aconitum species have been used toxification protocols. Some Asian countries l" monkshood worldwide as poisons as well as remedies. Their started small clinical trials to evaluate the potency l" traditional Chinese medicine l" Ayurvedic medicine potential in targeting several ailments such as and safety of different marketed aconite prepara- pain, rheumatism, and lethargy has been recog- tions. The current review summarizes therapeu- nized by Western, Chinese, and Indian health care tic uses of aconite preparations in China, Taiwan, practitioners. Aconite use in herbal preparations India, and Japan. It also highlights clinical trial re- has declined, especially in Europe and the United sults with special emphasis on their limitations. States, in the first half of the twentieth century Modern drugs and pharmacopoeial preparations due to several reported toxicity cases. The situa- derived from aconite are also discussed. received March 16, 2015 revised May 14, 2015 accepted May 17, 2015 Introduction Rchb. [6]. Several isoquinoline alkaloids and phe- Bibliography ! nethylamine derivatives have also been isolated, DOI http://dx.doi.org/ Aconitum, also known as monkshood, wolfʼs bane, such as higenamine from A. japonicum, magno- 10.1055/s-0035-1546183 or devilʼs helmet, has been widely used in folk florine from A. vulparia and A. napellus, coryneine Published online July 10, 2015 medicine in China, India, and certain parts of Eu- from A. carmichaelii, and N-methyl adrenaline Planta Med 2015; 81: 1017–1028 © Georg Thieme rope [1–4]. The genus Aconitum (Ranunculaceae) from A. nasutum Fisch. ex Rchb. [6]. Lipo-alka- Verlag KG Stuttgart · New York · comprises 300 species distributed all over the loids including lipoaconitines, lipomesaconitines, ISSN 0032‑0943 world [5]. The most common species are Aconi- lipodeoxyaconitines, and lipohypaconitines were Correspondence tum carmichaelii Deb. and Aconitum kusnezoffii also isolated [7,8]. Fang-Rong Chang Rchb. in China, Aconitum japonicum Thunb. in Ja- The efficacy of Aconitum sp. in resolving critical Graduate Institute of Natural pan, Aconitum napellus L. in Europe, Aconitum fer- clinical conditions has been proven by doctors Products College of Pharmacy ox Wall. ex Ser. in India, and Aconitum novebora- practicing traditional Chinese medicine (TCM) Kaohsiung Medical University cense A. Gray ex Coville in the United States [5]. and Ayurvedic medicine for centuries. However, 100, Shih-Chuan 1st Rd. Several classes of secondary metabolites, espe- the long history of Aconitum sp. misuse in homi- Kaohsiung 80708 Taiwan cially alkaloids, have been isolated from different cide cases has shaken the faith in the potential safe Phone: + 88673121101 Aconitum sp. [6]. The type of the isolated major al- application of this herb in therapy [9,10]. The re- ext. 2162 kaloids may vary depending on the species such cent developments in analytical techniques which Fax: + 88673114773 [email protected] as aconitine, hypaconitine, and mesaconitine can identify and determine the concentrations of from A. carmichaelii, aconitine from A. napellus, toxic compounds in herbal products with impres- Correspondence hypaconitine from A. septentrionale Koelle, mesa- sive accuracy and reliability have rekindled the in- Yang-Chang Wu School of Pharmacy conitine from A. kusnezoffii, bikhaconitine from terest in Aconitum preparations [1,5,6, 11,12]. College of Pharmacy A. ferox, talatisamine from A. kongboense Lauener, A plethora of studies have focused on developing China Medical University atisine from A. anthora L., and A. heterophyllum accurate, feasible, and fast analytical techniques No. 91 Hsueh-Shih Road Taichung 40402 Wall. ex Royle, and lycaconitine from A. vulparia to determine the alkaloidal content in each acon- Taiwan Phone: + 886422053366 ext. 1012 Fax:+886422060248 * Dedicated to Professor Dr. Dr. h.c. mult. Adolf Nahrstedt # These authors contributed equally to this work. [email protected] on the occasion of his 75th birthday. Tai, C-J et al. Clinical Aspects of… Planta Med 2015; 81: 1017–1028 1018 Reviews Table 1 Famous formulas with Fuzi. Formula Ingredients Fuzi dosage Sini Tang Aconitum carmichaelii (Raw Fuzi), Zingiber officinale (Ganjiang), and Glycyrrhiza uralensis (roasted Gancao, 1 piece (15–30 g) licorice) Bai Tong Tang Allium fitulosum L. (white stem of shallot), Zingiber officinale (Ganjiang), and Aconitum carmichaelii (Raw Fuzi) 1 piece (15–20 g) Fuzi Lizhong Tang Aconitum carmichaelii (Processed Fuzi), Panax ginseng (ginseng), Zingiber officinale (Ganjiang), Atractylodes 1 piece (15–20 g) macrocephala Koidz. (Bai Zhu), Glycyrrhiza uralensis (roasted Gancao, licorice) Ma Huang Fuzi Hsi Hsin Ephedra sinica (Ma Huang), Aconitum carmichaelii (Processed Fuzi), and Asarum sieboldii (His Hsin) 1 piece (15–20 g) Tang Jen Wu Tang Poria cocos F.A. Wolf. (Fu Ling), Paeonia lactiflora Pallas. (Shaoyao, Chinese peony), Zingiber officinale (fresh 1 piece (15–20 g) ginger), Atractylodes macrocephala Koidz. (Bai Zhu), and Aconitum carmichaelii (Processed Fuzi) Fuzi Tang Aconitum carmichaelii (Processed Fuzi), Poria cocos F.A. Wolf. (Fu Ling), Panax ginseng (ginseng), Atractylodes 2 pieces (30–40 g) macrocephala Koidz. (Bai Zhu), and Paeonia lactiflora Pallas. (Shaoyao, Chinese peony) Ma Huang Fuzi Gancao Ephedra sinica (Ma Huang), Aconitum carmichaelii (Processed Fuzi), Glycyrrhiza uralensis (roasted Gancao, 1 piece (15–20 g) Tang licorice) Gui Zhi plus Fuzi Tang Ramulus Cinnamomi, Cinnamomum cassia (Gui Zhi), Paeonia lactiflora Pallas. (Shaoyao, Chinese peony), 1 piece (15–20 g) Glycyrrhiza uralensis (roasted Gancao, licorice), Zingiber officinale (fresh ginger), Ziziphus jujuba Mill. (jujube), Aconitum carmichaelii (Processed Fuzi) ite preparation using trivial analytical equipment available in al- jing resulted in impressive results. Spreading this knowledge to most all analytical laboratories [13–18]. Also, the biological ef- the rest of the world started in the nineteenth century with the fects of different Aconitum sp. in vitro and in vivo have been surge of migration waves from China to Western countries [30]. studied in depth, revealing the molecular targets of each major Many TCM practitioners found that Aconitum played an impor- component [19–21]. Recently, studies reporting the clinical ap- tant role in the history of Western civilization as a lethal herb plications of different Aconitum preparations have revealed and as a medication. Through combining knowledge accumu- promising results in terms of safety and efficacy [22,23]. Howev- lated over centuries from Eastern and Western civilizations, er, an overview summarizing clinical studies on Aconitum sp., TCM practitioners started to advocate the use of Aconitum which can help in further developments, is still lacking. This re- against several ailments. Hai-Ha Ni (1954–2012) in the USA, Bu- view aims to provide a comprehensive summary of the clinical Tao Chang (1942–2012) in Taiwan, Chin-An Zheng (1824–1911) applications of Aconitum preparations. To fully understand the in China, and other prominent TCM physicians introduced differ- potential of this herb in therapy, a short introduction on the clin- ent therapeutic regimens containing Fuzi. Aconitum was pre- ical use of Aconitum sp. throughout history based on reliable his- scribed for its cardiotonic, antiarrhythmic, analgesic, anti-epilep- torical records is presented. tiform, anticancer and antimicrobial activities [3]. In order to maximize the clinical effects, some followers of Chin-An Zheng recommended the use of raw or processed Fuzi in a dose as high Traditional Chinese Medicine as 60–120 g, which was 4–8 times the dosage recommended by ! previous practitioners. However, the pros and cons of high doses Aconitum was first introduced in Shennong Ben Cao Jing, which is of Fuzi were not investigated. the earliest Chinese herbs book and might be written around the Practitioners have differentiated in their recommendations be- era of Qin to Western Han Dynasties (221–200 BC) [24,25]. Aco- tween raw and processed Fuzi. In general, raw Fuzi was adminis- nitum preparations, including Fuzi (aconiti radix lateralis prae- trated in more critical conditions, while the processed prepara- parata), Wutou (chuan wu, aconiti radix praeparata), and Caowu tion was used to increase circulation and energy [5]. Recent sci- (A. kusnezoffii), have been recommended for cold limbs, painful entific studies showed that the toxicity of raw Fuzi is reduced by knees, walking difficulties, chronic wounds, poor circulation, processing due to the hydrolysis of the ester group of the diester- spasms, and different tumors [3]. diterpenoid alkaloids (aconitine, mesaconitine, and hypaconi- The applications of Aconitum were advocated in Shang Han Lun, tine) (l" Fig. 1) [4]. Initially, the acetyl group is hydrolyzed and in which was written by Zhang Zhongjing, one of the most re- the second step, the benzoyl group is hydrolyzed (l" Fig. 2) [17]. spected TCM physicians