ethnopharmacologic investigation on tropane-containing drugs in chinese solanaceous plants
TRANSCRIPT
Journal of Ethnophannacoiogy, 8 (1983) 1-18 Elsevier Scientific Publishers Ireland Ltd.
Review Paper
ETHNOPHARMACOLOGIC INVESTIGATION ON TROPANE- CONTAINING DRUGS IN CHINESE SOLANACEOUS PLANTS
XIAO PEIGEN (HSIAO, PEI-KEN) and HE LIYI
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing (China)
(Accepted September 15, 1982)
Summary
The role of tropane-containing drugs derived from Solanaceae has long been recognized. This report deals with Chinese solanaceous plants, includ- ing historic, botanical, phytochemical, pharmacological and clinical aspects. Our investigation revealed that this kind of drug is constantly being confirmed to be of true therapeutic value; however, further studies are in order.
Introduction
The tropane alkaloids esterified with tropic acid have so far been found to be restricted to the solanaceous plants(Romeike, 1978). Many of these alkal- oids (atropine, scopolamine, etc.) and plants containing these bases (Atropa, Scopolia, Daturu, Hyoscyamus, etc.) have shown marked physiological activities, they have long been recognized to play a distinctive role both in health care and in culture (Schultes, 1979; Mehra, 1979).
In China, not only are tropane-containing plants abundant, but also vast experience of using this type of drug has been accumulated. In addition, much research has been carried out in China on this subject in recent years.
This paper deals with an interdisciplinary investigation covering historic, botanical, phytochemical, pharmacological and clinical aspects of tropane- containing drugs derived from Chinese solanaceous plants.
0378-8741/83/$05.70 @ 1983 Elsevier Scientific Publishers Ireland Ltd Published and Printed in Ireland
2
Occurrence of tropane alkaloids in Chinese solanaceous plants
Based on our previous work (Xiao et al., 1973), those plants featured with high-incidence of tropane-alkaloids belonged to the Tribe Solaneae - Sub- tribe Hyoscyaminae and Subtribe Mandragorinae, as well as Tribe Datu- reae (Wettstein, 1895). Thus 121 samples representing 7 genera, 15 species from these categories were collected and analysed quantitively for their individual alkaloids.
Material and methods
Plant material
Plant materials were collected by Xiao and his colleagues from different localities as shown in Table 1.
The identification of plants was carried out by Xiao. Herbarium speci- mens listed in this report are deposited in the herbarium at the Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, China.
Chemicals
All the authentic samples were secured by isolation from Scopolia tan- gutica, and identified by means of IR, NMR and MS in our Institute.
Extraction of plant sample
One gram of the powdered sample was macerated with 20.0 ml chloroform and 0.3 ml 25% N&OH in a glass-stoppered flask overnight. A lo-ml aliquot of the filtrate was evaporated and the residue dissolved in 1.0 ml chloroform.
Identification of plant extract
Thin-layer chromatography was carried out on the resulting solution on a silica gel G plate (10 cm x 15 cm) with chloroform/methanol/ammonium hydroxide (85: 15:0.7, by vol.) as the developing solvent. Tropine, cusco- hygrine, (-)-6P-hydroxy-hyoscyamine (I), hyoscyamine (II), apoatropine, daturamine (III) and scopolamine (IV) (Fig. 1) were separated with Rf values of 0.04, 0.12, 0.23, 0.34, 0.77, 0.85 and 0.92, respectively. The spots were stained with modified Dragendorff reagent. The plate was then covered immediately with a glass plate of the same size and sealed and put aside for 1 h to allow the spots to become stable before their areas were scanned with a Shimadzu Dual-Wave-length TLC Scanner CS-910 under the following conditions: lamp, tungsten; wave-length, As 540 nm, ha 650 nm; scan mode, linear; determination mode, reflective; scan speed,
I II
III IV
Fig. 1. Structures of (-)-6P-hydroxy-hyoscyamine O), hyoscyamine (II), daturamine (III) and scopolamine (IV).
40 mm/min; chart speed, 20 mm/min; sensitivity, x2; slit width, 0.5 X 10 mm. The results were calculated by comparison with standards spotted on the same plate (Table 1).
Tropane-containing drugs
Twelve tropane-containing drugs have so far been used in Chinese herbal medicine. These drugs, listed following the original plants, are grouped according to the family classification offered by von Wettstein (1895): Solaneae Hyoscyaminae: “Tsang-ch’ieh” (Scopolia tangutica and S. lurida), “San-fen-San” (S. acutangulus), “Ch’i-li-san” (S. carniolicoides), “T’ien-pung- tzu” (Atropanthe sinensis), “Ai-lang-tang” (Przewalskia tangutica), “Tien- hsien-tzu” (Hyoscyamus niger), “Pao-nang-ts’ao” (Physochlaina physaloides), “Hua-shan-shen” (P. infundibularis), “Hsi-tsang Pao-nang-ts’ao” (P. praealta); Solaneae Mandrogorinaei “Ch’ieh shen” (Mandragora caulescens), “Chinghai Ch’ieh shen (M. chinghaiensis). Datureae “Yang- chin hua” (Datura metel and D. innoxia).
In recent years, a lot of research has been done in China on these drugs covering botany, phytochemistry, pharmacology and clinical evaluation. In the following sections an introduction to the current knowledge of these drugs is given.
Solaneae Hyoscyaminae
Scopolia Tsang Ch’ieh: this drug is derived from the roots of “Shan-lang-tang”
Scopolia tangutica Maxim. (Anisodus tanguticus (Maxim.) Pascher) or
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33
“Ling-tang-tzu” S. lurida Dunal (Anisodus luridus Link et Otto; S. str- amonifolia Semenova). It has been commonly used in Tibetan traditional medicine (“Tangchom Nagbo”) as analgesic, anesthetic, antispasmodic and to reduce swellings, for the treatment of ulcers, acute or chronic gastro- enteritis, gastroneurosis and pains due to biliary ascariasis or cholelithiasis.
Chemically, S. tangutica contains hyoscyamine, (-)-6P-hydroxy-hyoscy- amine (anisodamine), scopolamine, daturamine (anisodine) and cuscohygrine (Xie et al., 1975a,b). The occurrence of the first four alkaloids in S. tan- gutica is far from being fixed or uniform, the ratios of positive to negative results in 161 individual samples were: hyoscyamine 112:49; (-)-SD- hydroxy-hyoscyamine 154: 7; scopolamine 64:97; daturamine 31; 130 (Xiao et al., 1973). While S. lurida contains hyoscyamine as its main constituent, minor alkaloids such as scopolamine, cuscohygrine, tropine and apoatropine are sometimes present. Apart from hyoscyamine and scopolamine which are both well-known pharmacologically and clinically, two other tropane al- kaloids, (-)-6fl-hydroxy-hyoscyamine and daturamine have recently been found to have marked therapeutic value in China.
(-)-6P-Hydroxy-hyoscyamine has marked peripheral anticholinergic effects. It can inhibit acetylcholine-induced contraction of the smooth muscle of the isolated ileum and urinary bladder and this antispasmodic activity was comparable in efficacy with that of atropine sulfate, while the in- hibitory action on salivary secretion, the mydriatic action and influence on EEG and other central actions of the (-)-6P-hydroxy-hyoscyamine were about 20 times, 10 times and 6-20 times weaker, respectively, than that of atropine.
The LDW of (-)-6P-hydroxy-hyoscyamine in mice was 350-430 mg/kg i.p. and 123.3 mg/kg i.v., and the minimal lethal dose (MLD) by oral ad- ministration was 1600 mglkg, whereas the comparable figures for atropine were 226 mg/kg (i.p.), 97.7 mg/kg (i.v.) and 700 mg/kg (MLD). All these results indicate that (-)-6/3-hydroxy-hyoscyamine is less toxic than atropine (Department of Pharmacology, Institute of Materia Medica, 1973).
Taking advantage of the weaker central action, similar spasmolytic action and less side effects than atropine, clinically (-)-S/3 -hydroxy-hyoscyamine has been widely adopted as an emergency measure for septic shock from toxic bacillary dysentery, fulminant epidemic meningitis and hemorrhagic enteritis, resulting in a markedly lower death rate (Department Pediatrics, Peking Friendship Hospital et al., 1973).
Daturamine (= anisodine) showed similar pharmacologic actions as other tropic acid esters of tropane alkaloids. In comparison with atropine, daturamine showed similar efficacy on central anticholi’nergic action, influence on EEG; inhibition of analgesic induced by tremorine and antagonism against arecoline-induced tremor; all these effects were about lo-19 times weaker than scopolamine. On the other hand, the peripheral anticholinergic effect of daturamine, such as antispasmodic activity, was almost the same compared with atropine, but weaker in the mydriatic action and the inhibitory action on salivary secretion (Department of
9
Pharmacology, Institute of Materia Medica, 1975). In addition, daturamine was more effective for the detoxication against organic phosphorus com- pounds; its toxity was less than atropine, (-)-6P-hydroxy-hyoscyamine and scopolamine. It is now being used clinically for the treatment of migraine, diseases of the fundus occuli caused by vascular spasm, detoxication of organic phosphorus pesticides, and in some clinical cases for paralysis caused by various neurological diseases. It is also the main constituent in “Intravenous Combination Anesthesia” (Department of Pharmacology, In- stitute of Materia Medica, 1975). As an anticholinergic, daturamine showed central influences on cerebral acetylcholine release, and the processes of learning and memory of rabbits and mice (Chen et al., 1980). Furthermore, daturamine is easily absorbed from the gastro-intestinal tract without des- truction and quickly excreted in the urine (Department of Pharmacology, Institute of Materia Medica, 1977).
Animal tests and clinical observations have demonstrated that (-)-6/3- hydroxy-hyoscyamine and daturamine improve microcirculation (Depart- ment Pediatrics, Peking Friendship Hospital et al., 1973).
Total synthesis of (t)-6P-hydroxy-hyoscyamine and daturamine was also carried out and they are now being marketed commercially both from natural sources and by synthetic means.
San-fen-San is a native drug used in Yunnan province, originating from the roots of Scopolia acutanguhs C.Y. Wu et C. Chen (Fig. 2). Literally the
Fig. 2. Pieces of drug “San-fan-San”, roots of Scopolia acutangulus C.Y. Wu et C. Chen.
10
drug’s name means that the maximum dosage administrated should be limited to San-fen-San (0.99 g) by weight. It is applied as an anesthetic and analgesic, with the functions to remove “dampness” and eliminate stasis, for the treatment of injuries and pains due to rheumatism or gastro-intestinal spasm.
The drug contains 2.11-3.18% total alkaloids, including hyoscyamine, scopolamine, (-)-6@-hydroxy-hyoscyamine, daturamine and cuscohygrine.
Overdosage of the extract of this drug produces pharmacologic actions resembling those of belladonna intoxication, i.e. dilation of the pupils, dry- ness and later frothing of the mouth, mental disturbances.
Ch’i-E-sun: the drug is derived from the roots of Scopolia carniolicoides C.Y. Wu et C. Chen ex C. Chen et C.L. Chen. One of its vernacular names is “Feng Yao”. Its action causing delirium is also spoken of, being said to produce laughter or dancing movements.
Medically, it functions as hemostatic, anodyne, and promotes granulation, invigorates the blood circulation and eliminates blood stasis and thus is administered for the treatment of bruises, fractures, injuries and pains in the bone and tendons; the powder is taken orally 0.2 g twice a day, or applied externally over the affected area.
Atropanthe T’ien-pung-tzu: this drug consists of the dried roots of Atropanthe sinen-
sis (Hemsl.)Pascher (Scopolia sinensis Hemsl.). Ethnopharmacologically it is used for the treatment of exterior symptom-complex and cold, for rheuma- talgia of joints and muscles, difficulty in bending and stretching of limbs, and even for paralysis. Because of its stronger action, the dosage is restric- ted to only 0.2 g each time.
Chemically the drug contains hyoscyamine, scopolamine and cuscohy- grine.
Przewalskia Ai-lung-tang consists of the dried roots or aerial parts of Przewalskia
tangutica Maxim. (Pr. shebbearei (C.B.C. Fischer) Kuang, in sched.) (Fig. 3), which is a monotypic genus endemic to the Qinghai-Tibet plateau. It has been commonly used in Tibetan traditional medicine with the name “Tang- chom Gaabo” and is employed as an analgesic, antispasmodic, detoxicant and to reduce swellings for the alleviation of pains and for treating certain skin diseases when applied externally (Xiao and Xia, 1973).
This drug was recorded in a most famous and complete manual of Tibetan medicine “Rgyud bzhi” (820 A.D.). In the “Coloured Atlas of Tibetan Medicine” (1704 A.D.) which illustrated “Vaidouria-onbo” (end of seven- teenth century) and served as a commentary on “Rgyud-bzhi”, this drug was painted with satisfactory accuracy (Fig. 4).
Chemically it contains tropine, cuscohygrine, (-)-GP-hydroxy-hyoscy- amine, hyoscyamine, apoatropine and scopolamine. We have analysed many
11
Fig. 3. Pmxualskia tangutica Maxim. (this photograph was taken in Tibet in 1979).
Fig. 4. Drawing of “Ai-lang-tang”, Pnewulskiu tangutica Maxim., from Atlas of Tibetan Medicine (1704 A.D.).
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samples of this drug collected from different localities, the results showed high content of hyoscyamine, (-)-6p-hydroxy-hyoscyamine and total al- kaloids, amounting to 1.67382% 0.10-0.68% and 2.06-4.01% in roots, 0.33-2.18%, trace+O.60% and 0.58-2.72% in leaves, 0.60-1.52%, 0.02-0.29% and 0.81-1.88% in stems and 0.162.06%, O-0.14% and 0.262.07% in fruits, respectively (Xiao and He, 1982).
Furthermore, the presence or absence of these alkaloids in 28 samples of Pr. tangutica was also found to be far from uniform; the ratio of posi- tive/negative occurrence of hyoscyamine was 28 : 0, (-)-Gfi-hydroxy-hyoscy- amine 22: 6, scopolamine 23: 5 and daturamine 1: 27.
Geographically this plant grows abundantly at altitudes of 3200-5200 m in the provinces of Kansu, Tsinghai, Szechuan and Tibet autonomous region, and because of its higher tropane-alkaloids content Pr. tangutica would be a good source for the pharmaceutical production of medicaments of this kind.
Hyoscyam us Tien-hsien-tzu is the dried seeds of Hyoscyamus niger L. Another popular
name of this drug is called “Lang-tang-tzu”. Both names suggest that it may elicit a series of delirious and hallucinogenic symptoms.
“Lang-tang” was first recorded and rated as one of the inferior category remedies in the oldest Chinese “Pen ts’ao” (Herbal) “Shen Nung Pents’ao Jing” (22-250 A.D.), from which the following is quoted: “Lang-tang-tze (seeds of Hyoscyamus niger), test bitter, ‘cold’ in property, and used for the treatment of toothache. After administration it may cause strengthening walking, overdosing of this drug may induce mad-walking, continuous use leads one to vitality with light weight, walking like dashed horse, streng- thening the mind and increasing the force.” (Fig. 5).
The drug contains mainly hyoscyamine and scopolamine. It is now being used as spasmolytic, anodyne and sedative for the treatment of pains due to gastralgia and rheumatalgia, also for bronchial asthma.
Physochlaina Hua-shun-shen consists of the dried root of Physochlaina infundubularis
Kuang (Fig. 6). The local people in Shensi and Henan provinces have regarded it as a kind of ginseng and it serves as a general tonic.
Ethnopharmacologically, this drug has a sweet and slightly bitter, hot, astringent taste, so that it is also called “Je-shen” (hot ginseng), used as an antiasthmatic, sedative and for the treatment of chronic bronchitis and asthma, for diarrhea due to deficiency of vital energy with symptoms of cold, to relieve gastric or abdominal pain, for palpitation and insomnia.
Some processing is usually carried out with the aim of reducing toxicity. The fresh raw roots are peeled and boiled with the addition of small amount of other drugs: Glycyrrhiza uralensis (rt), Ophiopogon japonica (rhz), Gar- denia jasminoides (fr) and sugar; and then dried.
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Fig. 5. A part page of Ching Shih Cheng Lei Tu Kuan Pents’ao, showing the drawing of ‘“rien-hsien-tzu”, and describing the properties of this drug. The characters in white on black background are quotations from Shen Nrtng Pmtts’ao Jing (translation see text).
Fig. 6. Drug “Hua-shan-shen”, the dried roots of Physachlaina infundubdsris Kuang.
Chemically Ihe drug contains a coumarin glycoside, fabiatrin, and al- kaloids scopolamine, atropine, (-)-6~-hy~oxy-hyosey~ine, scopoline &nd aposcopolamine (Chen et al., 1981).
The pharmacologic actions were: (1) By the method of motor defence conditioned reflex, oral administrations in rats produced prolongation of the latent period of conditioned reflex, intraperitoneal injection not only prolonged the latent period reflex, but also partly disturbed the differen- tiation; (2) In mice, rats and rabbits, deco&ion of the drug given in- traperitoneally produced a marked reduction in spontaneous activity lasting about 3-6 h. Oral administration in dogs produced sedation; (3) In-
14
traperitoneal injection of the drug in mice potentiated the hypnotic and anaesthetic effect of pentothal, pentobarbital and chloral hydrate and in- hibited the hyperactivity induced by amphetamine and caffeine; (4) The acute LD50 for mice was found to be 43 g/kg when the drug was given intraperitoneally in the form of decoction (Che, 1965). Clinically the drug has been used in tablet or aerosol form, both of which are included in the latest Chinese Pharmacopiea, for the treatment of chronic bronchitis or bronchial asthma.
P’ao-nang-ts’ao is a native drug used in traditional medicine of Mon- golia, derived from the roots of Physochlaina physaloides (L.)G. Don. (Fig. 7). Therapeutically, this drug has the effect of replenishing weakness, warming up the stomach, soothing the mental condition and relieving asthma, and is used for the treatment of diarrhea due to deficiency of vital energy with symptoms of cold, also for cough or asthma caused by excessive phlegm or neurasthenia.
Fig. 7. Whole plant of Physochlaina physaloides (L.) G. Don.
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It contains mainly hyoscyamine, (-)-66-hydroxy-hyoscyamine (Liu and Xie, 1979) and sometimes scopolamine as a minor alkaloid.
Hsi-tsang Pao-nang-ts’ao: the medicamentous parts are dried roots or upperground parts of Physochlaina praealta (Decne.) Miers. In Tibet, this drug has been used as a substitute of “Tsang-ch’ieh” (Scopolia tangutica). In India, the leaves of this plant possess the belladonna-like property of dilat- ing the pupils and are used to cure boils (Sharma and Singh, 1975).
The roots of this plant contain mainly hyoscyamine, cuscohygrine and scopolamine. The upperground parts also contain such alkaloids but with (-)-66-hydroxy-hyoscyamine instead of cuscohygrine.
Solaneae Mandrogorae
Mand rogora Ch’ieh Shen consists of the dried roots of Mandragora caulescens C.B.
Clarke. It has been used in Yunnan and Tibetian traditional medicine. The roots of this plant are similar to that of ginseng in shape and have tonic action for weakness. It is therefore called “Xiang Yang Shen”.
This drug, containing mainly hyoscyamine, has the effect of warming up the stomach and dispelling interior cold, and is used for the treatment of stomach troubles.
Ch’inghai Ch’ieh Shen is derived from the whole plant or roots of Man- drogora chinghaiensis Kuang et A.M. Lu. It is used for the treatment of pains or as a substitute for M. caulescens.
Chemically hyoscyamine and scopolamine are two major alkaloids.
Datureae
Datura Yang-chin hua consists of the dried flowers of Datura mete1 L., “Nan-
yang-chin-hua” is used mainly in the southern part of China, while D. innoxia Mill. as “Pei-yang-chin-hua” is used mainly in the northern part.
It is a traditional Chinese medicament used to relieve cough and asthma for bronchial asthma, also as analgesic to relieve gastralgia and rheuma- talgia. In rural areas, the flowers of Datura are cut into small pieces, mingled with cut tobacco and licorice and made into cigarette form, for the purpose of relieving asthma by smoking.
The drug contains mainly hyoscyamine and scopolamine; the contents of these two alkaloids were, respectively, trace-O.37% and 0.11-0.47% in D. metel, trac+O.14% and 0.17-0.51% in D. innoxia (He and Xiao, 1982).
Recently, Yan-chin-hua has been used in Chinese traditional anesthesia or “Intravenous Combination Anesthesia”, based on ancient general anes- thetics “Ma-fo-tang” (c. 1700 years ago) used by a famous doctor Hua Tuo.
Since the active principle of the anesthetic was identified as scopolamine, the surgical stage of the anesthesia can be reached only if scopolamine is
16
administered in combination with chloropromazine. The synergism of the two drugs can be observed in rats and dogs as well as in monkeys.
Over several hundred thousand cases have been operated under “In- travenous Combination Anesthesia”. Clinical practice has indicated the fol. lowing advantages:
(1) Safety: no fatal accident has ever occurred among the patients anes- thetized.
(2) Simple and convenient in application: no elaborate equipment is required.
(3) After the operation, an injection of physostigmine will awake the patient if necessary.
(4) ‘Intravenous Combination Anesthesia” possesses not only anesthetic but also antishock effects. So, in cases of patients with hypotension or in shock, this ‘Intravenous Combination Anesthesia” is the management of choice in our clinics.
For this reason, the mechanism of the central action on scopolamine was further studied (Department of Pharmacology, Xuzhou Medical College, 1976).
Discussion
Despite the toxic side-effects, almost all species have been used medi- cinally within the tropane-alkaloid containing taxa of the Chinese Solanaceae, viz. Solaneae, Hyoscyaminae and Mandragorinae, and Datu- reae. Besides Atropini Sulfas and Scopolamini Hydrobromidum, which were both widely included in various Pharmacopieas and Chinese Pharmacopiea from the twelve above-mentioned drugs, six of them have already been recorded in the latest Chinese Pharmacopiea, they are: Radix Scopoliae tangutica (for Anisodamini Hydrobromidum), Radix Scopoliae acutanguli, Radix Physochlainae, Radix Przewalskiae tanguticae, Semen Hyoscyami and Flos Daturae. This fact revealed that both these drugs and their chemical constituents possess pronounced physiological properties and maintain an important position in therapy.
Concerning the folklore usages of the drugs, they are most in vogue as analgesic, anesthetic and spasmolytic. In addition, they have functions ac- cording to Chinese traditional medicine such as “warming the spleen and stomach and dispel cold from them”, as well as sedative and antiasthmatic actions, and use as detoxicants to reduce swellings if applied locally. A number of drugs such as Physochlainu infundibularis, P. physaloides and Mandragora caulescens have all been recommended to be a kind of “Shen” (similar to ginseng), and in fact they all exhibited tonic and stimulant actions, beneficial for all forms of debiIity and weakness.
The ethnopharmacologic data mentioned above remind us that the ancient Greeks and Romans considered Mandrake (Mandragora ofiinarum) so potent and valuable in medicine as a panacea and restorative plant.
17
In conclusion, the authors strongly recommend that tropane-containing drugs derived from Solanaceae should be selected as a group of outstanding folklore medicaments worthy of further detailed scientific research. It is very probable that the new discoveries along these avenues of research have yet to be made.
Acknowledgements
Our grateful thanks are due to Profs. Chen Xianyu, Zhang Juntian and Song Weiliang for their valuable help in preparing this manuscript.
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