Pharmaceutical Chemistry Journal
Vol. 42, No. 10, 2008
MEDICINAL PLANTS CHEMICAL COMPOSITION OF LICHENS AND THEIR MEDICAL APPLICATIONS A. P. Podterob1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 10, pp. 32 – 38, October, 2008. Original article submitted October 3, 2006.
Some 700 substances with identified structures are currently known in lichens. About 200 of these are depsides, whose molecules consist of 2 – 4 hydroxybenzoic acid residues linked by ester groups. More than 100 compounds are depsidones, which have an additional ether bond between aromatic rings. Many substances extracted from lichens have antimicrobial actions. The best known are usnic acid, an antibiotic with a phenol structure. Its sodium salt is used for treating wounds, burns, fissures, etc. The search for synthetic analogs of the unique lichen antibiotics is relevant. This article presents the structures of a number of lichen compounds (41 structures), along with a brief description of methods of extracting these substances and their properties. Progress in the cultivation of lichens and their mycobionts is discussed, as this presents the possibility of the large-scale use of their chemical components for pharmaceutical purposes. Thus, lichens long used in folk medicine are now potential sources of pharmacologically active substances.
Lichens are a unique and relatively poorly studied group of lower plants/symbionts, in which the fungus (the mycobiont) to some extent parasitizes the alga (the photobiont). Lichen mycobionts form four subdivisions: Ascomycotina (98% of lichens), Basidiomycotina, Deuteromycotina and Mastigomycotina. The photobionts are prokaryotes of eight genera (Nostoc, Gleocapsa, Scytonema, Stigonema, Chroococcus, Hyella, Calothrix, and Dichotrix) and algae of three divisions (green – Chlorophyta; yellow-green – Xanthophyta; and brown – Phaeophyta). Almost half of lichen species include the green alga Trebouxia. The lichen body (thallus, blastema) is a crumbly material – a supple mass consisting of fine fungal filaments (hyphae) occupying 90 – 95% of the volume of the thallus, whose individual filaments or layers contain algal cells [1, 2]. Lichens have long had a number of practical applications, including as sources of medicinal substances [3, 4]. The widest medicinal use has been made of the so-called “Iceland moss,” Cetraria islandica [3, 5 – 8]. The first reference to the medicinal uses of this lichen was in 1673 [9]. A quite large body of experimental data has now been accumulated on the chemical structure, properties [10 – 21], and biological actions [22 – 25] of many lichen substances. 1
Recent years have seen progress in the cultivation of lichens and their mycobionts, demonstrating the possibility of the large-scale production of lichen substances for pharmaceutical purposes [10, 26 – 29]. Among lichen-derived medicinal substances, the agents Binan (sodium usnate) [4, 30], Evosin [31], Cetris, and several others [8] should be noted. This review mainly addresses progress made in the last two decades in studies of the structure and properties of biologically active lichen substances and their applications; data on the elemental chemical compositions of lichens are also presented.
TABLE 1. Mean Chemical Element Contents of Lichens, mg/kg Dry Weight.
Belarus State University, Minsk, Belarus.
Element
Content
Element
Content
N P K Na Ca Mg Si S
8470 770 3330 815 3600 820 3770 870
CI Fe Mn Zn Cu B Mo Co
100 1050 89 40 8.4 4.0 0.39 0.48
582 0091-150X/08/4210-0582 © 2008 Springer Science+Business Media, Inc.
Chemical Composition of Lichens and Their Medical Applications
583 Lichen substances
Chemical Elements A review [32] included a Table showing the average content of 16 chemical elements in lichens, based on Russian and foreign reports. The sample set for each element ranged from several tens to several hundreds of data items (Table 1). In general, as compared with higher plants (mosses, ferns, grasses, legumes, the Chenopodiaceae, the Cruciferae, the Compositae, the Polygonaceae), lichens accumulate more Fe and Zn and less N, P, K, Na, Ca, Mg, S, Cl, B, and Mo. Lichens and higher plants contain essentially similar quantities of Mn, Cu, and Co. A characteristic of lichens is the increased ash content of silicon oxide. Table 2 presents ash analysis results for a number of lichen species [3]. Organic Compounds Lichen substances can arbitrarily be divided into two groups: primary and secondary (Scheme 1). Primary lichen substances have structural functions and roles in cellular metabolism. These are mainly the same substances as in other plants. The roles of secondary lichen substances ultimately remain unclear. More than 250 such substances were known about 30 years ago, of which 75 were specific lichen substances (mainly lichen acids). The roles of secondary lichen substances are ultimately unclear. They are probably antibiotics (acids), or involved in photosynthesis (atranorin), or act as light filters, i.e., to protect the photobiont from extreme radiation (parietin), or facilitate the transfer of carbohydrates from the photobiont to the mycobiont, or have roles in degrading the mineral substrate [2]. According to Huneck in Germany and Yoshimura in Japan, the authors of a contemporary manuscript on the identification of lichen substances, a total of 700 substances with known structures have been found in lichens [10]. Review of lichen substances shows that the most numerous classes are depsides and depsidones, whose structures will be considered further. The chemical composition of the medicinally used lichen Cetraria islandica has been studied in some detail [8].
Secondary
Primary Chitin (in hyphal walls) Lichenin Isolichenin Hemicellulose Pectins Disaccharides Polyalcohols Amino acids Vitamins Enzymes Pigments (in algal chromophores: chlorophylls a and b, b- and g-carotenes, xanthophylls, etc.
Usually 0.1 – 2% of air-dried weight, sometimes up to ~2 – 5%: atranorin (1.2%) fumarprotocetraric acid (0.5 – 1.5%) gyrophoric acid (1 – 4%) salicylic acid (4 – 6%) usnic acid (0.2 – 4%) lecanoric acid (up to 36% of dry weight in colored Parmelia, etc.)
SCHEME 1. Approximate composition of lichen substances (from [2]).
idues. Lichenans and isolichenans are branched D-glucans whose chains (D-glucose residues) are linked by 1 ® 3 and 1 ® 4 bonds. The difference is that lichenans consist of b-D-glucose residues while isolichenans consist of a-D-glucose residues [11]. It is important to note that the polysaccharide fractions of lichens have antitumor activity [12]. The carbohydrate contents of different lichen species are shown in Table 3. This shows that the greatest lichenin content is found in Cetraria islandica. Carotenoids Carotenoids, along with other plant pigments (chlorophylls and phycobilins), are known [33] to function as receptors of light energy. Carotenoids also perform a protective function – they prevent the degradation of chlorophyll by molecular oxygen. Most carotenoids have long (18 carbon atoms) polyisoprenoid chains, whose terminals bear unsaturated substituted cyclohexene rings. Some carotenoids have been found to have antimutagenic activity (b-carotene). Chromatographic methods were used to study the carotenoids of 33 lichen species from Antarctica [13]. The total carotenoid content varied from 23.25 to 123.5 mg/g dry
Polysaccharides Studies reported in [9] established that boiling of Cetraria islandica with water resulted in the formation of large quantities of a sticky gelatinous product termed “moss starch” or lichenin. “Moss starch” is now known to consist of at least two fractions with different solubilities: a lichenan fraction insoluble in cold but soluble in boiling water (lichenin), and an isolichenin fraction soluble in cold water. Given the multidispersity of these fractions, it is preferable to refer to lichenans and isolichenans. After extraction with boiling water, subsequent extraction with aqueous alkali yields a mixture of heteropolysaccharides consisting of D-mannose, D-galactose, D-glucose, and hexuronic acid res-
TABLE 2. Ash Composition of Some Lichen Species. Ash content, % Components
Cetraria cucullata
Cladonia rangiferina
Cladonia alpestris
Alectoria ochroleuca
SiO2 Fe2O3 + Al2O3 CaO MgO K2O P2O5 Cl
43.32 20.90 1.27 3.84 11.02 7.87 1.97
78.37 9.72 0.55 4.56 3.38 2.81 0.12
84.10 7.58 0.47 1.15 1.79 2.91 0.19
31.54 25.30 1.68 11.28 10.90 11.51 0.93
584
A. P. Podterob
weight. Fifteen lichen species from the Anatolian peninsula (Asia Minor) yielded 24 carotenoids [14]: a-carotene
zeaxanthine
b-carotene
lutein epoxide
b-citraurine capsochrome
e-carotene
antheraxanthine
6-epoxide
b-cryptoxanthine violaxanthine Lutein flavoxanthine 3-epilitein auroxanthine
mutatoxanthine echinenone
lycopene-5
4-hydroxyechine none cantaxanthine
bixin heteroxanthine
astaxanthine neoxanthine
The total quantities were from 20.49 to 81.18 mg/g dry weight. Other substances Secondary lichen substances with acidic properties are of particular interest – lichen acids. Each lichen species has its own set of lichen acids, which overall give qualitative reactions allowing lichen species to be distinguished from each other. The reagents for this purpose are 10% potassium hydroxide solution, saturated calcium hypochlorite solution, ethanolic iodine, benzidine, p-phenylenediamine, etc. [34]. Thus, for example, species differences were identified in the qualitative composition of lichen acids in members of the genus Parmelia [15] in a study of 143 samples of 16 species. Acetone extracts were loaded onto Silufol-UV 254 and Merck chromatography plates. Mobile phases consisted of the following solvent systems: a) toluene:dioxane:glacial acetic acid (180:45:5); b) hexane:diethyl ether:formic acid (120:90:20); and c) toluene:glacial acetic acid (200:30). After the plates were dried, the pigments were detected in visible light, while aromatic substances were detected in UV light at 254 nm. Components were identified in terms of their Rf values. Chemically pure samples of lichen substances were used for comparison. Many species were found to contain atranorin, lecanoric, salicinic, lobaric, and other acids. Usnic acid was seen only in Flavoparmelia caperata. Lichen acids are important not only for identifying lichens, but also
TABLE 3. Carbohydrate Content in Some Lichen Species (from [3]), % of Dry Weight. Carbohydrate content, % Lichen species
Cetraria islandica Cetraria nivalis Alectoria ochroleuca Cladonia alpestris Cladonia mitis Cladonia deformens Peltigera aphthosa Stereocaulon paschale
WaTotal ter-soluHemicell Lichenin Cellulose carbohyble sugulose drates ars
1.9 1.5 1.2 0.3 0.4 0.3 0.4 1.1
50.9 18.8 45.6 2.4 1.6 4.1 4.9 219
25.8 59.7 34.6 73.8 71.6 68.5 35.2 59.8
3.9 3.9 3.7 7.3 6.6 10.8 8.3 8.6
82.5 83.9 85.1 83.8 80.2 83.7 48.8 72.4
as natural antibiotics. The names of a number of lichen substances are given in Table 4. Please insert scheme labeled (A) from R.p. 35. A review [6] summarized results of studies of lichen acids in members of the Parmeliaceae family and isocoumarins (3, 4) first isolated from lichens, a phenanthrene pigment (biruloquinone) (16), a binaphthoquinoid pigment (cuculloquinone) (17), and hydroxymethylanthraquinone pigments: islandicin (11) and cynodontin (12), which are also found in the lower fungi. Isocoumarins, namely a- and b-collatolic acids were present in samples of Asahinea chrysantha from the Ternei region of the Primor’e at levels of 0.30% and 0.23% respectively. However, the Magadan sample of this species contained a- and b-alectoronic acids. The authors suggested that isocoumarins, which are isomeric to depsidones, are the products of their catabolism. The level of
TABLE 4. Some Lichen Substances. No.
Name
1 2
Alectoronic acid depsidone
3
b-Alectoronic acid
4
b-Collactolic acid Fumarprotocetraric acid Caperatic acid Colensoic acid depsidone Lobaric acid Norcaperatic acid Chrysophanol Islandicin Cynodontin Emodin Tetrahydroxymethylanthraquinone Pentahydroxymethylanthraquinone Biruloquinone Cuculloquinone Lecanoric acid Evernic acid Gyrophoric acid Hyascinic acid Ovoic acid Umbilicaric acid Papulosic acid Crustinic acid Losallic acid Tenuiorin Deliseic acid Atranorin Usnic acid Physodic acid Rangiformic acid Glycosides (general formula) Acetylenic acids
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 – 41
Reference
[16]
a-Collatolic acid depsidone
[17]
[4] [4] [4] [18] [19] [20]
Chemical Composition of Lichens and Their Medical Applications OH
COC 5H11
COOH
O
18
O
OH
COO
RO
HO O
OH
O
COOH
CH 2 1: R = H 2: R = CH3
CH2OCOCH=CHCOOH OH
COO
ROOC
6: R = CH3 20 7: R = H
COOH
OH
COO
9
COOH
O
H3CO
C5H11
COOH O
21
OH
HO
O
OH 16
10: 11: 12: 13: 14: 15:
R2 H H OH H OH OH
HO
O HO HO
R3 H H H OH OH OH
OH
CH 3
CH 3
OH
OH
OH
COO
HO
COOH
CH 3
CH 3
CH 3
OH
OCH 3
OH
COO
COO
COOH
CH 3
CH 3
CH 3
OCH 3
OH
OH
O OH OH
O
O HO HO O 17
COO
OH
23 HO
COO
COO
COOH
OH OH
CH3 HO
CH 3
HO COO
OH
CH3
CH3
H3C
OH
OH
HO
CH3
COO CH3
COOH
28 HO H3COOC
OH
COO
H3CO
OH
COO
OH
27
COOH
COO
HO
COO
CH 3
HO
CH3
26
COOH
O
R1
HO
25
COO
CH 3
CH 3 24
OH
HO
22
R1 H OH OH H H OH
OH
OCH3
H 3C
CH 3 O
CH 3
COO
HO
C5H11
R2
COOH
OH
O
R3
COO
HO
COO
OH O
OH
OH
CO C4H9
H3CO
OH
COH
H3C(H2C)12
C5H11 8
CH 3
CH 3
CH 3
CHO
CH 3
H3CO
CH2CH2COOH
HC
COOH
O
HO
COOH
COC5H11
19 CH 3
COO
HO
CH2 3: R = H 4: R = CH3
COC 5H11
5
OH
C5H11
CH 2
RO
585
COO
OH COOCH3
CH3
CH3
CH3
OH
OH
OH
COO CH3
COO CH3
COOH CH3
CH3 HO
COOH
hydroxymethylanthraquinone pigments in the Parmeliaceae lichens was low, at 10 – 5% to 10 – 3%. The content of biruloquinone in Parmelia birulae was about 10 – 2%. Cuculloquinone, a red pigment isolated from Cetraria cucullata collected in the Ten’kin area of the Magadan region, had an original structure. Data presented in [35] indicate that a pigment identical to cuculloquinone was found in the deep-wa-
ter Holothuria. This pigment was located in the lower part of the lichen, close to the mineral substrate, where it was present mainly as complexes with metals. Subsequent studies showed that polyhydroxynaphthoquinoid pigments were present in the lower bright red tips of the thalli of Cetraria islandica and Flavoparmelia cucullata [35]. These compounds could be extracted from raw material only after treat-
586
A. P. Podterob
ment with acid, as they formed tight non-extractable metal complexes. The author suggested that the role of quinoid pigments, along with depsides and melanins, was related to the adaptation of lichens to harsh living conditions. Studies reported in [17] established the structures of depsides and tridepsides (18 – 28) extracted from lichens of the Umbilicareaceae family: Peltigera aphthosa, Cetrariella delisei, Umbilicaria polyphylla, and Lasallia papulosa. Plant material was treated with acetone at 40°C for 20 min and components were separated by HPLC with UV detection (254 nm). A Beckman Ultrasphere ODS-5 m column (10 ´ 250 mm) was eluted with an ascending methanol gradient at a flow rate of 2 ml/min for 90 min. Chemical structures were studied by NMR and mass spectroscopy. Study compounds were found to be important for the chemotaxonomic characterization of lichens of the Umbilicareaceae family. Atranorin (29) is a common substance in lichens; it is a colorless crystalline substance with a melting temperature of 192 – 194°C. The classical method for extracting atranorin is based on the different solubilities of lichen substances in organic solvents. Atranorin is most soluble in boiling benzene, chloroform, and xylene; it is poorly soluble in boiling ethanol and diethyl ether; it is insoluble in water, cold ethanol, and cold diethyl ether [4]. CH 3 29
COO
HO O=CH
CH 3
OH
COOCH 3 CH 3
OH
Usnic acid (30) is the most widely used lichen acid in medicine; this is a crystalline substance with a yellow color. Usnic acid is optically active and both forms are found in lichens; the melting temperatures and specific rotations of these forms are essentially identical. Usnic acid dissolves well in benzene, chloroform, amyl alcohol, and glacial acetic acid; it is poorly soluble in ethanol, petroleum ether, and diethyl ether; it is insoluble in water. Usnic acid contents in lichens range from 0.2% (Cladonia sylvatica) to 4.0% (Alectoria achroleuca) [4]. OH H3C HO 30
H3C
O COCH3
OH COCH3 O
Physodic acid (31) is a colorless crystalline substance with a melting temperature of 199 – 202°C (with degradation). It has good solubility in ethanol, diethyl ether, and acetone; it is poorly soluble in chloroform and benzene and almost insoluble in water. The physodic acid content of the lichen Pseudevernia furfuracea is 3 – 5% [4].
CO(CH2)4CH3 CH2 OH
COO
COOH
O
HO
(CH2)4CH3
31
Rangiformic acid (32) is a higher dicarboxylic acid. Its structure was identified by NMR [18]. Rangiformic acid was extracted from the lichen Cladina retipora. CH2COOCH3
HOOC H
C
C
COOH
CH2CH2 H25C12
H
32
Recent studies isolated and identified the structures of new glycosides of lichen acids (33) from nine lichen species growing in the banks of lake Issyk-Kul in Central Asia: Acarospora gobiensis, Cladonia furcata, Lecanora fructulosa, Leptogium saturninum, Peltigera canina, Rhizoplaca peltata, Parmelia camtschadalis, Parmelia tinctina, and Xanthoria elegans [19]. CH2
HOOC
R4O O O
R3O 2
RO
CH3 OR1
(CH2)11
O
O
33
In the molecules of compound (33), one or two R substituents can consist of glucose (it is more rare for both to be glucose residues). The other R groups are hydrogen atoms. Thus, several glycosides can be regarded as oligosaccharide derivatives. Nearly all lichen species growing around lake Issyk-Kul yielded acetylenic acids (34 – 41). Lichens were treated with a mixture of chloroform and methanol (1:1). The extract was fractionated on a Sephadex LH-20 column and by reverse-phase HPLC. The structures of the extracted components were established by 1H and 13C NMR and mass, IR, and UV spectroscopy. Acetylenic acids had structures unusual for natural compounds. They were monobasic higher unsaturated carboxylic acids with several multiple bonds and one or two bromine atoms per molecule. One structure also contained a cyclopropane ring, while another contained oxyrane (ethylene oxide). Acetylenic acids had antimicrobial, cytotoxic, and ichthyotoxic activities and were inhibitors of a number of enzymes. The levels of individual acetylenic acids in lichens were from 0.3 to 13.1 mg/50 g dry weight. Scabrosine esters were isolated from Xanthoparmelia scabrosa, these being epidithiopiperazine diones. Structures were studied by NMR spectroscopy and x-ray structural analysis. The authors demonstrated the cytotoxic activities of the number of esters for P815 mouse mastocytoma cells and MCF7 human breast cells [21].
Chemical Composition of Lichens and Their Medical Applications
COOH 34
Br COOH
35
36
Br
COOH
Br Br
COOH 37
Br Br
38
COOH Br
39 COOH Br Br 40 COOH O
41
Br
OH
COOH
Medical applications The use of lichens in medicine is based on the fact that they contain unique and varied biologically active substances, mainly with antimicrobial actions. Cetraria islandica. The so-called “Iceland moss,” i.e., Cetraria islandica, has received the greatest medical application. Iceland moss has long been used in tuberculosis, chronic bronchitis, and diarrhea, and as a nutrient and a tonic. In the 19th century, this lichen was also regarded as an excellent feed for deer and pigs, and in lean years was used to make bread. Cetraria islandica has been widely used in Iceland for about 200 years. Doctors gave it to patients with exhaustion due to severe diseases [5, 9]. Cetraria islandica is included in the list of medicinal plants of Belarus. Medicinal forms include infusions and teas, as well as usnic acid. The use of these preparations is based on its mucigenous, bactericidal, antiperspirant, and antiemetic actions. Lichen acids (usnic, protolichesterinic, protocetraric, and others, 3 – 5%) suppress the growth of Gram-positive microorganisms and tuberculosis bacilli in humans. Cetraria islandica is used in acute respiratory diseases of the upper respiratory tract, inflammation of the
587
throat and oral cavity, stomach diseases, gastric and duodenal ulcers, reduced acidity, poor digestion and absorption, general emaciation and weakness, and after serious illnesses or operations [6]. Cetraria islandica is also used for the treatment of influenza and catarrhal illnesses. Colleagues at St. Petersburg Chemico-Pharmaceutical Academy have compared the gastric-protective actions of a dry extract (extracted with ethanol) of Cetraria islandica, an extract of one-year shoots of Caragana spinosa, and “sea buckthorn oil.” The activity of the Cetraria islandica extract was significantly greater than the activities of the other agents. The mechanisms of action of the extracts and sea buckthorn oil” were different [22]. The medical uses of Cetraria islandica in medicine were reviewed in [8]. The authors reported therapeutic agents developed in Russia and other countries at the end of the 20th century, based on extracts of Cetraria islandica. Thus, studies in Iceland led to the development of capsules containing extracts of Cetraria islandica with different compositions, used in acute intestinal obstruction, gastric ulcer, respiratory diseases, arthritis, asthma, decreased immune function, and edema. Studies in Germany developed tablets of Cetraria islandica extracts containing polysaccharides and lichen acids, along with pediatric lozenges containing Cetraria islandica for the prophylaxis of coughs and catarrh, with mucolytic actions. A substance for the treatment of mastopathy, “Cetris,” was developed in Russia (Mel’nikova, 1995). Parmelia reticulata (wandering Parmelia). Usnic acid is the main component in the complex of biologically active substances in the wandering Parmelia. Usnic acid is extracted from the wandering Parmelia by boiling in a mixture of acetone and ethanol (with a yield of 0.17%). A modified method for extracting usnic acid, which was simple and economical, was developed (with a yield of 2.5%) [23]. Evernia prunastri (plum Evernia) is a valuable product for perfumery and the pharmaceutical industry [24]. In the mid-20th century, the German investigator Klosa developed a very effective preparation against staphylococci and streptococci – Evosin. The main source of Evosin was the plum Evernia. Evosin is a mixture of evernic and usnic acids, with some substances indifferent for microorganisms [31]. The antifungal activity of acetone extracts of three lichen species, including the plum Evernia [25], were studied recently. The activity of extracts and individual lichen acids against eight species of pathogenic fungi were studied. Sodium usnate is a pale yellow, sparkling crystalline powder, soluble in hot water (1:200), and alcohol (1:20). It is used for the treatment of wounds, burns, skin fissures, etc. It is used as 1% aqueous-alcoholic solution or 0.5% solution in castor oil, and as a solution in glycerol or Canada balsam supplemented with 2% Anestezin. The agent is also used as a powder or a mixture with sulfanilamides (one part sodium usnate with three or five parts Streptocide). It is released as a powder, a 1% solution in ethanol, a 0.5% solution in castor
588
oil with 2% Anestezin, and 0.3% and 0.5% solutions in Canada balsam in vials of 25 and 50 ml [30]. Thus, lichen substances are currently being studied in detail in a number of countries (Russia, Czech Republic, Germany, USA, Japan, Canada, Brazil, Australia, New Zealand, and others). These substances are used in lichen chemotaxonomy (i.e., their classification in terms of chemical features), and they are of interest as natural antibiotics. Knowledge of the structures and functions of unique lichen antibiotics will open paths to the search for their synthetic analogs. REFERENCES 1. N. S. Golubkova, Novosti Sistematiki Nizshikh Rastenii, 29, 84 – 104 (1993). 2. ”The life of plants,” in: Algae. Lichens [in Russian], M. M. Gollerbakh (Ed.), Prosveshchenie, Moscow (1977). 3. A. L. Kursanov and N. N. D’yachenkov, Lichens and their Practical Applications [in Russian], USSR Academy of Sciences Press, Moscow (1945). 4. E. N. Moiseeva, Biochemical Properties of Lichens and their Practical Value [in Russian], USSR Academy of Sciences Press, Moscow, Leningrad (1961). 5. S. E. Zemlinksii, Medicinal Plants of the USSR [in Russian], State Medical Literature Press, Moscow (1958). 6. V. I. Senchilo and Yu. V. Senchilo, Medicinal Plants of Belarus [in Russian], Belarus State University, Minsk (2004). 7. V. D. Onipko, The Treatment of Influenza and Catarrhal Diseases Using Folk Medicine Remedies [in Russian], TOO “Dinamit”, OOO SMIO Press,” St. Petersburg (1997). 8. M. Yu. Safonova, E. I. Sakanyan, and E. E. Lesiovskaya, Rastit. Resursy, 35(2), 106 – 115 (1999). 9. Encyclopedic Dictionary [in Russian], F. A. Brokgauz and I. A. Efron, Typolithography by I. E. Efron, St. Petersburg (1894). 10. S. Huneck and I. Yoshimura, Identification of Lichen Substances, Springer, Berlin (1996). 11. R. P. Gorshkova, E. L. Nazarenko, V. A. Zubkov, et al., Bioorgan. Khim., 23(2), 134 – 138 (1997). 12. E. A. Vainshtein, Novosti Sistematiki Nizshikh Rastenii, 29, 73 – 83 (1993). 13. C. Bazyli, I. Masakane, and U. D. Kumar, Antarct. Rec., 40, 247 – 254 (1996). 14. C. Bazyli, O. Aysen, and O. Sule, Ann. Mus. Goulandris, 10, 53 – 62 (1999).
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