Chinese Journal of

Natural Chinese Journal of Natural Medicines 2014, 12(10): 0721−0729 Medicines

doi: 10.3724/SP.J.1009.2014.00721

Oplopanax elatus (Nakai) Nakai: chemistry, traditional use and pharmacology Alexander N. Shikov1*, Olga N. Pozharitskaya1, Valery G. Makarov1, YANG Wen-Zhi2, GUO De-An2

1 Saint-Petersburg Institute of Pharmacy,188663, Kuzmolovo P 245, Russia; 2 Shanghai Research Center for TCM Modernization, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China Available online October 2014

[ABSTRACT] Oplopanax elatus (Nakai) Nakai, a member of the ancient angiosperm plant family Araliaceae, is used for the treatment of different disorders in the medicine systems of China, Russia, and Korea, and was designated in Russia as a classical adaptogen. Despite extensive studies of classical adaptogens, there are comparatively few reports concerning the chemical composition and pharmacological effects of O. elatus in English. The plant is a potential source of saponins, flavonoids, anthraquinones, terpenes, and other active compounds. Experimental studies and clinical applications have indicated that O. elatus possesses a number of pharmacological activities, including adaptogenic, anti-convulsant, anti-diabetic, anti-fungal, anti-inflam- matory, anti-oxidant, blood pressure modulating, and reproductive function effects. In this review, the chemistry, safety, and therapeutic potential of O. elatus are summarized and highlighted to encourage the further development of this plant.

[KEY WORDS] Oplopanax elatus; Chemistry; Safety; Adaptogen; Asthenia; Diabetes; Physical and mental fatigue [CLC Number] R28 [Document code] A [Article ID] 2095-6975(2014)10-0721-09

Introduction Inflorescence axillary 7−18 cm long, peduncles 2.5−6 cm, densely covered with long rust-colored hairs and prickles; The genus Oplopanax (Torr. & A. Gray) Miq. is a umbels small, 9−13 mm across, in oblong raceme or a slightly member of the ancient angiosperm plant family Araliaceae, branching panicle at tips of main and lateral axes; fruit and consists of three species: Oplopanax horridus (Sm.) yellow-red, 7−12 mm long [5-6]. The plant is endangered in Miq., Oplopanax japonicus Nakai, and Oplopanax elatus Russia due to intense uncontrolled harvesting, and is included (Nakai) Nakai. O. horridus is distributed throughout the in the Red Book of the Russian Federation [7]. The roots are Pacific Northwest of North America [1], while O. japonicus collected in September- October after ripening of the fruits [8]. is endemic to Japan [2]. Compared with the extensive research on other familiar Oplopanax elatus (syn. Echinopanax elatus Nakai) is adaptogenic plants of the Araliaceae, such as Ginseng, Eleuther commonly known in Russia as Zamanikha (Заманиха) and as ococcus and Aralia, there is comparatively little known about Ci shen (刺参) in China. It is mainly distributed in Russia, in the chemical composition and pharmacological effects of O. the south of Primorye, while outside of Russia it grows in the elatus in English. The plant has been well-studied in Russia and northern part of the Korean Peninsula, and in the temperate China. However, many of the scientific articles were never regions of Northern China [2-4]. It is a deciduous shrub with a translated into English, and as a result a significant amount of spiny stem of about 1 m (rarely to 2−3 m) heigh, with large information obtained and collected by scientists was not palmately compound leaves, and a long creeping rhizome. available to the international community. In this review, the chemistry, safety, and therapeutic potential of O. elatus are highlighted with the aim for the [Received on] 03-Mar.-2014 further development of plant-based medicines. The information [*Corresponding author] Alexander N. Shikov: Tel: +7-812-3225605, Fax: +7-812-6032433, E-mail: [email protected] regarding the chemistry, safety, effectiveness, and These authors have no any conflict of interest to declare. pharmacological effects of O. elatus was systematically

– 721 – Alexander N. Shikov, et al. / Chin J Nat Med, 2014, 12(10): 721−729 collected from the scientific literature through library catalogs, Wang and Xu [17]. The structure elucidation of these new the online service E-library.ru, and, in addition, saponins was mainly based on NMR analysis and selective Medline/Pubmed, Scopus, CNKI (www.cnki.net), Wanfang hydrolysis reactions. Med Online (www.WanFangData.com), VIP (www.cqvip.com), Flavonoids Web of Science, www.fips.ru, and the Espacenet patent databases. Flavonoids are also known to be present in O. elatus, and Soviet scholars reported that the flavonoids occupy 0.9% of Chemical Constituents the roots of O. elatus [11]. Wang and Xu [21] first isolated two Essential oils flavonol O-glycosides from the leaves, and they were Essential oils are the major anti-fungal ingredients of O. identified as the 3-O-biosides of kaempferol and quercetin, elatus. Wu et al [9] used supercritical fluid extraction (SFE) and respectively (Fig. 1). gas chromatography-mass spectrometry (GC-MS) analysis to Anthraquinones study the chemical composition of the essential oils in the The stems and roots of O. elatus were reported to contain [22] roots and rhizomes of O. elatus. A total of nineteen, volatile anthraquinones (Fig. 1). Xu and Liang isolated four ingredients were characterized. They also found a significant anthraquinone derivatives, identified as chrysophanol, physcion, difference in the essential oils extracted by SFE and steam emodin, and aloe-emodin based on NMR analysis. These distillation. SFE was capable of extracting abundant enols, anthraquinones were obtained from O. elatus for the first time, aldehydes, and olefinic aldehydes, whereas a high abundance of and also for the first time in a species of the Araliaceae. In addition, [23] aldehydes, terpenes, and esters were obtained by the traditional Wang et al obtained rhein from the stems of O. elatus. steam distillation method. Zhang et al [10] studied the Other metabolites composition of the volatile oils in the stems of O. elatus by Other constituents, such as phenolic acids, organic acids, steam-distillation extraction and GC-MS and GC-IR analyses. oligosaccharides, sterols and their glycosides, polyacetylenes, The stem contained 3.1% of the oil, and thirty-two compounds and trace elements, have also been reported from O. elatus. [24] were identified, including twenty-five first reported from this As part of a continuing study, Xu and Liang isolated plant. Of these, α-pinene, octanal, 6, 6-dimethyl- syringin, β-sitosterol, stigmasterol, stigmasterol-3-O-β-D-glu- 2-methylene-norpinane, and 5-methyl hexanal were the four copyranoside VI, sitosterol-3-O-β-Dglucopyranoside, behenic most abundant volatile ingredients. The essential oils were acid, and tetracosanoic acid from the stems of O. elatus. [23] reported to contain quite different chemical ingredients Wang et al recently isolated another two phenolic acids depending on the parts of O. elatus that were analyzed. The (3-O-caffeoyl quinic acid and 1-O-caffeoyl quinic acid), as [25] growing environment was another crucial factor that led to the well as sucrose and glucose, from the stems. Liu and Wu variable content of the essential oils of O. elatus [10]. performed a phytochemical study on the roots of O. elatus, Saponins which yielded L-rhamnose, together with sucrose, syringin, The roots and rhizomes of O. elatus contained 6.9% of crude β-sitosterol, daucosterol, and n-heptacosanol. steroid saponins, which were separated into six components using Two new polyacetylenes, oploxynes A (9, 10-epoxyhep- silica gel thin-layer chromatography, however, no references on tadeca-4, 6-diyne-3, 8-diol) and B (10-methoxyheptadeca-4, the isolation of saponins from the roots were reported [11]. 6-diyne-3, 8, 9-triol), as well as the known oplopandiol and Saponins, also known as cirenshenosides or falcarindiol were isolated by Yang et al. from the stem of O. [26] cirensenosides, are a large category of plant secondary elatus . Oplopandiol and falcarindiol, together with (Z, metabolites in O. elatus. Wang and co-workers have E)-nerolidol were identified by on-line solid-phase extraction [27] performed systematic studies focusing on the saponins coupled with HPLC in the root bark of O. elatus . [28] occurring in the leaves of O. elatus. The total saponin content Dou et al conducted a phytochemical study on the in the leaves was 3.32% based on a developed colorimetric roots and stems of O. elatus which resulted in the isolation of method [12]. Twenty-one cirenshenosides (Fig. 1), comprising seven compounds, comprising four lignans and three the newly-reported glycosides A-D, cirenshenosides I-V, and phenylpropanoids. Of these, two new lignans were elucidated three known saponins, were isolated from O. elatus leaves by as 3, 3'-dimethoxy-4, 9, 9'-trihydroxy-4', 7-epoxy-5'8-lignan-4, Wang et al [13-21]. Interestingly, the structures of the saponins 9-bis-O-β-D-glucopyranoside and 5-methoxylariciresinol-4- isolated from the leaves of O. elatus are: i) pentacyclic O-β-D-glucopyranoside. These compounds were isolated triterpene glycosides involving an oleanane or lupane skeleton; from a 60% EtOH extract. [29] ii) different orientations of the 3-OH on the oleanane and Liu et al determined the contents of eight trace elements lupane skeletons; iii) a tri-saccharide glycosyl portion (Cu, Fe, Zn, Mn, Cr, Sr, Al, and Ag) in O. elatus and P. ginseng Glc(6,1)Glc(4,1)Rha glycosylated at C-28 through an ester by their atomic absorption spectrum. The total content of the bond (except for cirenshenoside P); and iv) variation of the determined elements in the stems of O. elatus was slightly higher oxidation level of C-23 as CH3, CH2OH, CHO, and COOH. It than those in the roots. For these two species, Fe, Zn, and Mn is noted that cirensenoside S reported in the literature by Wang occupied the largest portion, and of these, Mn was more abundant et al [16] has the same structure as cirenshenoside U reported by in O. elatus, while Zn was at a higher level in P. ginseng.

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Fig. 1 The saponins, flavonoids, and anthraquinones reported in Oplopanax elatus. S1: Glc(6, 1)Glc(4,1)Rha; S2: Glc(6,1)Glc; S3: Glc(2,1)Glc

variety of ailments, such as asthenia, depressive states [33], Pharmacology diabetes, cough, rheumatism, gastro-intestinal disorders, and [34] Ethnopharmacology wounds . In Russian medicine and traditional Chinese medicine, O. Adaptogenic effects elatus is regarded to possess similar actions to Panax ginseng. The term "adaptogens" (phytoadaptogens), and the In China, Russia, and Korea it is used for the treatment of concept of these plant-derived substances as compounds that chronic fatigue syndrome [30]. In Chinese medicine, it has would increase "the state of non-specific resistance" under been used for treating neurasthenic, hypopiesis, conditions of stress, was formalized in the USSR between schizophrenia, cardiovascular diseases, diabetes mellitus and 1950 and 1960. An adaptogen must: produce a non-specific rheumatism. It also possesses antifungal, fever-relieving, response, i.e. increase the power of resistance against multiple pain-relieving, and anti-aging activities [31]. The stem of O. (physical, chemical, or biological) stressors; have a elatus has been traditionally used in China as an analgesic normalizing effect, irrespective of the nature of the pathology medicine to treat arthritis [32]. and be non-toxic; be innocuous and not influence normal [35-36] In Korea, it has been traditionally used for treating a body functions more than required . According to the

– 723 – Alexander N. Shikov, et al. / Chin J Nat Med, 2014, 12(10): 721−729 definition suggested and agreed on at an International pentobarbital, chloral hydrate, and chlorpromazine to Conference on Adaptogens in Gothenburg, Sweden in 1996, pentylenetetrazole-induced and electroconvulsive convulsions the term adaptogen refers to "metabolic regulators which [44]. increase the ability of an organism to adapt to environmental Anti-diabetic effects stressors and prevent damage to the organism by such The anti-diabetic effects of a dealcoholized tincture from stressors" [37]. Since 1997, the term "adaptogen" has been used the roots were evaluated in mice and rats. Oral pretreatment as a functional term by Russian health-regulatory authorities, of alloxan-induced diabetic mice with the tincture (2.5 g·kg−1, and in 1998 this term was allowed as a functional claim for 6 days before alloxan injection) significantly reduced the certain products by the U.S. Food and Drug Administration [36]. pancreatic malondialdehyde (MDA) level by 34%, and O. elatus, among other related Araliaceae plants such as lowered the blood glucose level by 16% compared to control. Panax ginseng C.A.Mey, Aralia mandshurica Rupr. et Oral treatment of mice with the tincture (2.5 g·kg−1, 6 days), Maxim., and Eleutherococcus senticosus Maxim., was starting 48 h after alloxan injection, resulted in a significant designated in Russia as a classical adaptogen [35-38]. increase of glycogen in the liver by 45% compared to control, The swimming time of mice to exhaustion was increased while the glucose level tended to decrease. The blood glucose by 36% compared to control after single dose per oral level in rats with epinephrine-induced hyperglycemia was administration of 5 mL·kg−1 of EtOH (10%) liquid extract decreased by 18% after intragastric administration of a tincture from the roots of O. elatus [39]. An excitation effect of a at the dose of 2.5 g·kg−1 over six days. The elevated blood tincture (10−200 μg) was observed in frogs [40]. The glucose level in rats pretreated with the tincture (2.5 g·kg−1, 6 locomotor activity of mice was significantly increased 15−20 days before alloxan injection) was reduced by 18%, and was min after subcutaneous injection of a tincture (5 mL·kg−1) and accompanied by an increase of glycogen in the liver. A lasted for 30−40 min. However, the stimulating effect of the significant decrease in the plasma glucose level by 16%, and −1 purified glycosides of O. elatus (25−50 mg·kg ) lasted for 2 h in an increase in insulin level by 42%, were observed in [40] mice . alloxan-induced diabetic rats treated with the tincture (2.5 The survival of mice subjected to hypobaric hypoxia and g·kg−1) over six days after alloxan injection [45]. hypoxia with hypercapnia was increased by 42% and 34%, Antifungal effects respectively after intragastric pretreatment with a dealcoho- The antimycotic activity of the essential oil from O. −1 lized tincture from the roots of O. elatus (2.5 g·kg ) over elatus was evaluated in vitro by the serial dilution method on [41] seven days . After seven days of consecutive oral solid nutrient medium. Fungistatic effects were shown against −1 administration, O. elatus root dry extract (2.5 g·kg ) Microsporum gypseum, M. lanosun, Trichophyton gypseum, T. significantly increased the vertical activity of mice by 46% purpureatum, and Epidermophyton floccosum with MIC = [42] and ambulation time . 0.0625% for each species [46]. The essential oil of O. elatus −1 Oral administration of O. elatus EtOH (40%) extract (10 g·kg ) stem demonstrated antifungal activity against Trichophyton to rats caused a marked depletion of adrenal ascorbic acid in rubrum, T. verrucosum, T. tonsurans, T. violaceum, intact rats, while no effect was observed in hypophysec- Microsporum canis, and M. nanum with MIC = tomized rats. The authors suggested that O. elatus has a 0.063%−0.125%, while the minimal fungicidal concentration stimulatory action on the hypophyseal-adrenal system [32]. (MFC) was in the range of 0.125%−0.25%. Linalool and The psycho-stimulating effect of an ethanolic tincture (40%) p-cymene were determined to be the main active constituents was observed in animals after injection of sodium barbiturate. of the essential oil against pathogenic dermatophytes [10]. The sleeping time of animals was decreased by 35% [43]. Anti-inflammatory effects Immediately after injection of 0.15 mg·g−1 of sodium 5, The anti-inflammatory effects of the O. elatus essential oil 5-diethylbarbiturate, the EtOH extract of O. elatus roots was intraperitoneally injected to albino mice at a dose of 0.5 g·kg−1, were studied in the acute paw edema model in rats evoked by and the sleeping time of the animals was decreased by 20% [39]. carrageenan injection into the sub-plantar tissues of the hind Anti-convulsant effects paws. Intraperitoneal injection of an oil emulsion (0.09 mL −1 The vertical activity of mice with pentylenetetrazole- volatile oil/mL emulsion) at 2.2 mL·kg significantly [47] induced seizures was increased by 88%, and the ambulation inhibited edema . The anti-arthritic effect of EtOH (40%) time was increased by 81% after seven days of treatment with extracts of the stem was evaluated in rats with formalin- and O. elatus root dry extract at 2.5 g·kg−1 [42]. dextran-induced paw edema and cotton-pellet induced The essential oil from O. elatus, as a 0.1 mL volatile oil/mL granuloma, respectively. The intragastric administration of the −1 emulsion, injected intraperitoneally at a dose of 0.67 mL·kg−1 extract (10 g·kg ) resulted in a significant inhibition of both could keep the animal quiet, tame, and with an absence of edema and granuloma. However, the extract from O. elatus locomotor activity. When the dose was increased to 2.76 mL·kg−1, had no effect on the bilateral adrenalectomized rats with the the rats were prostrate with drooping eyelids, but they could inflammation induced by dextran [32]. still respond to outside stimuli. The O. elatus essential oil The polyacetylenes oploxynes A, oplopandiol, and emulsion had a good synergistic effect on antagonism with falcarindiol, isolated from the stem, inhibited the formation of

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−1 nitric oxide with IC50 of 1.98, 2.72, and 1.28 μmol·L , No signs of toxicity were observed in mice after acute oral respectively, and inhibited prostaglandin E2 with IC50 of 3.08, administration of EtOH (40%) extracts of stem at a dose of 2.99, and 1.54 μmol·L−1, respectively in lipopolysaccharide 50 g·kg−1 [32]. (LPS)-induced murinemacrophage RAW 264.7 cells [26]. The safety of the 50% EtOH extract of O. elatus stems Anti-oxidant effects was examined in a 14-day repeated-dose toxicity study with To determine the antioxidant activity, the chemical Sprague-Dawley rats. The rats were treated with the extract interaction of O. elatus EtOH root extract with the mediator by gavage at 0, 500, 1 000, and 2 000 mg·kg−1. There were no system K3[Fe(CN6)]/K4[Fe(CN6)] leading to its redox potential significant changes in body and organ weights during the shift by potentiometry, and by a chemiluminescent method in experimental period. The hematological analysis and blood the model system of photooxidation of peptide Gly-Trp using chemistry data revealed no toxic effects from the O. elatus riboflavin as a photosensitizer, were used. The antioxidant EtOH extracts. Pathologically, neither gross abnormalities nor activity was 4 meq/L by potentiometry and 0.5 mg·mL−1 of rutin histopathological changes were observed on comparison equivalents by chemiluminiscence methods, respectively, and between the control and treated rats of both sexes [34]. was equivalent to Echinacea purpurea juice [48]. Clinical data Effects on blood pressure The effect of an oral treatment with the EtOH (40%) The effects of a dealcoholized tincture of O. elatus and tincture of O. elatus was studied in twenty-five patients with the purified glycosides on blood pressure were studied in cats diabetes in an open clinical trial without a control group. All −1 and rabbits. Intravenous injection of the tincture to cats at the patients followed a diet with energy values of 30−40 kcal·kg , doses of 10−50 mg·kg−1 resulted in a slight increase of blood which consisted of 60% carbohydrates, 24% fats, and 16% pressure, while higher doses (100−200 mg·kg−1) induced a proteins. Daily glycosuria was calculated after the first four significant decrease in the arterial blood pressure by 20−30 days, and the individual doses of insulin were calculated and mm Hg, which was evident during the first hour. The effect injected into patients during ten days. On day 11, patients was accompanied with stimulation of breathing. Intravenous were injected with insulin followed with oral administration injection of purified glycosides (20 mg·kg−1) induced a slight of 1.5 mL of tincture. One hour after tincture administration, a decrease of blood pressure in rabbits with a stimulation of significant decrease in blood glucose level was observed in breathing. Low doses of glycosides (10−50 mg·kg−1) did not twenty-four patients, among them the blood glucose level was affect the heart rate of cats in situ. However, an increase in decreased in seven patients by 80%, and in some individuals −1 dose up to 80−100 mg·kg−1 resulted in a significant increase it dropped from 350 to 200 mg·dL . A decrease in cholesterol −1 in amplitude of the heart contractions by 20%−30%, and a level to 160−170 mg·dL was registered in four patients. decrease of heart rate by 5−10 beats/min [40]. More significant therapeutic effects were observed in patients The effect of intravenous injection of cirensenoside (CRS) after six days of treatment, including increased physical on blood pressure was studied in rats. The mean arterial activity, improved appetite, normalization of gastrointestinal pressure dropped slightly after injection of CRS at 10 mg·kg−1, tract function, decreased thirst, diuresis, and glycosuria. In ten however, it was significantly increased after injection of CRS cases, the efficacy was so pronounced that it became possible at higher doses of 30 mg·kg−1 and 100 mg·kg−1. The effect on to reduce the dose of insulin. The blood glucose level was −1 blood pressure was antagonized by tolazoline. The plasma decreased from 350 to 150−200 mg·dL in fifteen patients. A monoamine concentration in the CRS-treated group was significant decrease of daily glycosuria was registered in higher compared with the control [49]. twelve patients. Arterial blood pressure was normalized in Effects on reproductive function twenty-three patients and the heart rate, up to 80−90 To assess whether O. elatus root EtOH (10%) extract beats/min, was increased in sixteen patients. The most affected maturation of the reproductive tract in mice, the pronounced effects were registered in patients with weakness [50] progress toward the first estrous cycle was studied. Female . Positive therapeutic effects of O. elatus on asthenic and pre-pubertal mice were administered orally with the extract at astheno-depressive states (particularly in exogenous a dose of 0.25 mg·kg−1. As a result, progression toward the depression) in psychiatric diseases have been reported. A first estrus was initiated earlier in the treated mice. By day 24, group of patients 20−60 years old was included in a clinical nine of ten treated mice had passed through estrus, thereby trial. Administration of the tincture (1.5−2.0 mL, 2−3 times per completing their first estrous cycle. In contrast, 5 of 10 day) for seven days produced stimulation of the CNS in control mice had reached this point at day 25 [39]. These data patients with asthenia. Subjects reported a decrease of evidenced a stimulating effect of the O. elatus extract on complaints of fatigue, headaches, precordialgia, general maturation of the reproductive tract of female rats. weakness, anxiety, and normalization of the night sleep pattern. Toxicity Patients became energetic and physically more active after The toxicity of O. elatus roots is very low. After acute 2−3 weeks of treatment. These results suggest that O. elatus −1 administration in mice, the LD50 was 14.5 g·kg , and after seven acts in the long term as a stimulant of the cerebral cortex, −1 [39] days of administration of the root the LD100 was 1.0 g·kg . inducing feedback inhibition of the subcortex. It was

– 725 – Alexander N. Shikov, et al. / Chin J Nat Med, 2014, 12(10): 721−729 concluded that O. elatus therapy can be indicated in asthenia 0.25%. A cure rate of 90% on the patients with and depressions of psychogenic etiology (so-called dermatomycoses was obtained, suggesting the potential for “exogenous” depressions), or those related to excessive development into a natural antifungal agent derived from O. fatigue, somatic, and nervous exhaustion [8]. Similar effects elatus essential oils. In addition, O. elatus was used to treat were observed for another classical adaptogen Schisandra chronic rheumatic arthritis [55]. After consecutive chinensis [51]. administration of the capsules (25 mg, twice a day) containing The effect of O. elatus tincture was evaluated in patients an extract of O. elatus stems for a month, patients who suffering from sluggish schizophrenia with astheno-depressive suffered from serious arthralgia exhibited obvious recovery syndrome. As a result, the patients became calmer, more with statistical significance in comparison with the control sociable, and gregarious, and free of emotional tension and group. The total effective rate reached 82.7% for the anxiety. They were less pronounced phenomenon mutism. A treatment group, in contrast to 21.1% for the control group. decrease in fatigue and anxiety was registered in patients with A group of 56 patients (35 females, 21 males), suffering post-traumatic encephalopathia. The most effective O. elatus from multiple sclerosis with asthenia syndrome, were treated tincture application was in the recovery of patients with with a mixture of tinctures of adaptogens: P. ginseng roots post-infection fatigue. However, in subjects with post-contu- (18%−20%), S. chinensis seeds (10%−12%), Aralia elata roots sion asthenia, sexual neurasthenia, after suffering (8%−10%), O. elatus roots (10%−12%), Eleutherococcus encephalomyelitis, weak therapeutic efficacy was observed senticosus roots (18%−20%), Leuzea carthamoides roots [43]. (10%−12%), Rhodiola rosea roots (8%−10%), and deer antler Interesting results were reported concerning an increase extract (10%−12%) [56]. Positive gonadotropic, tonic, of antibiotic therapy efficacy with O. elatus in children. A fortifying, immunomodulating, metabolism-corrective, group of 258 children aged 0 to 14 years suffering from acute reparation, and regeneration enhancing effects were mentioned dysentery caused by Shigella sonnei, S. flexneri, and in all patients after six months. The reduction in the size and enterocolitis of the Proteus etiology were included in a number of demyelinating lesions was registered by MRT in clinical trial. Group 1 (157 patients) were treated with ten female and six male patients. Reduction in the dizziness monomycin and kanamycin in combination with O. elatus incidence was observed in twenty-six female and thirteen tincture (2−3 drops per day) and Group 2 (101 patients) were males. An increase in physical endurance was reported in treated with the antibiotics alone. The synergistic effect of O. sixteen female and ten male subjects. Twenty-eight female elatus with antibiotics was registered after 10−14 days of and twelve males mentioned a decrease in symptoms of treatment. Combination therapy with O. elatus decreased the anorexia nervosa. time of disease course, reduced the frequency of A mixture of forty-five plants, including the roots of O. complications, and promoted early normalization of lysozyme elatus, was patented and recommended for the treatment of activity and lymphocyte blast transformation [52]. patients with mastopathy, benign brain tumors, osteosarcoma, A comparative study of the effect of O. elatus tincture and myoma. Each herb was ground to a powder, and the and some other adaptogens (Eleutherococcus, Aralia, and powders mixed and pressed into tablets (2 g). The tablets Schizandra) on the functional state of helicopter crews is were dipped in alcohol solution with bear bile, dried, and available. The subjects, consisting of 665 pilots, navigators, dipped in aqueous solution of mumie (shilajit), followed by mechanics, and radio-operators, were treated with the drying. Patients were treated with tablets (1-4 per day with a preparations or placebo at a dose of 0.5−2.0 mL, twice a day glass of water) for one year [57]. The total saponins extract of for 10 days, and were tested before a flight and again 1−15 O. elatus leaves (20% of saponins in dry extract) and a min later, and finally, 1 and 3 h after landing. The method for its preparation was proposed by Dou et al [58], and psycho-physiological state of each participant was evaluated it was recommended for anti-cancer therapy. through the application of seven tests, including assessment A mixture of sixty-six plants, including the roots of O. of dynamic tremometry, sensomotor response, and attention elatus, was recommended in a complex therapy for and memory functions. O. elatus tincture prevented, in a insulin-dependent diabetes mellitus, together with a parallel statistically significant manner, the decrease in attention and injection of insulin. A maximal positive effect was recorded memory functions recorded immediately after landing. All for patients under 18 years old [59]. adaptogens were effective in expediting the restoration and O. elatus was referred as a component of traditional elevation of the basal level of the functional state [53]. Chinese medicine composition for improving microcircu- Aimed at developing natural antifungal new drugs, the lation. The composition included 10−30 parts of ground antifungal properties of the essential oils of O. elatus were beetle, 10−30 parts of leech, 10−30 parts of earthworm, evaluated by Fu et al [54]. Results revealed the significant 10−30 parts of scorpion, 10−30 parts of centipede, 10−30 antifungal action of the essential oil. The MIC against parts of stiff silkworm, and 10−30 parts of O. elatus [60]. common pathogenic dermatophytes ranged from Throughout the clinical data published in the form of 0.0625%−0.125%, and the MFC varied between 0.125% and articles in Russian and Chinese scientific journals, proceedings

– 726 – Alexander N. Shikov, et al. / Chin J Nat Med, 2014, 12(10): 721−729 of scientific conferences, and patents, etc., there runs a Clinical Practices in appropriately constructed, blinded clinical consistent theme regarding the effectiveness of O. elatus as a trials. Publications concerning the chemistry of O. elatus are therapeutic agent with anti-diabetic, adaptogenic, quite fragmentary and more research is needed. Overall, there antimicrobial/antifungal, anti-cancer, and anti-inflammatory are number avenues to be explored in further studies on this activities. largely unexamined botanical. Application in officinal medicine of Russia An intensive study of O. elatus was initiated in the References All-Union Institute of Medicinal Plants (Moscow, USSR) in [1] Calway T, Du GJ, Wang CZ, et al. Chemical and pharmacolo- the early 1950s. Since 1955, the EtOH (70%) tincture from the gical studies of Oplopanax horridus, a North American roots and rhizome of O. elatus (1 : 5) has been officially botanical [J]. J Nat Med, 2012, 66 (2): 249-256. approved for therapeutic use in the USSR as a tonic and an [2] Huang WH, Zhang QW, Yuan CS, et al. Chemical constituents anti-diabetic in mild cases of diabetes. The effect of a tincture of the plants from the genus Oplopanax [J]. Chem Biodivers, of the roots is, in general, similar to that of the tincture of 2014, 11 (2): 181-196. ginseng. It is employed primarily to stimulate the central [3] Kholina AB, Nakonechnaya OV, Koren OG, et al. Genetic variation of Oplopanax elatus (Nakai) Nakai (Araliaceae) [J]. nervous system in asthenia conditions and depression. It is also Russ J Genetics, 2010, 46 (5): 555-561. useful in treating impotence, emaciation, hypotension, and [4] Yang JC, Hwang HS, Lee HJ, et al. Distribution of vascular [61] physical and mental fatigue . 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Cite this article as: Alexander N. Shikov, Olga N. Pozharitskaya, Valery G. Makarov, YANG Wen-Zhi, GUO De-An. Oplopanax elatus (Nakai) Nakai: chemistry, traditional use and pharmacology [J]. Chinese Journal of Natural Medicines, 2014, 12(10): 721-729.

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