4.1. Medicinal plants of the family Boraginaceae containing pyrrolizidine alkaloids.
<numbers in (bold) refer to Fig. 8.>
4.1.1. Alkanna tinctoria (L.) Tausch
Alcannet (ger. Alkanna, fr. Orcanette tinctoriale, it. Ancusa), grows in South Europe, Turkey and Egypt and is still today cultivated in these countries. From time immemorial the root of this herb is applied internally as antidiarrheal agent and externally in cases of skin diseases. Due to its intensively purple-colored dyestuffs, called alkannins, the bark of the root is also used for staining cosmetics and foods. Three open-chain alkaloids, 7-angeloylretronecine (32), triangularine (35) and dihydroxytriangularine (25), were isolated from the bark of the root in a total concentration of 0.25 to 0.3% . The drug should however no longer be administered internally. Prior to staining of foods, e.g. of lemonades, alkaloids should previously be eliminated.
4.1.2. Anchusa officinalis L.
Common bugloss (ger. Ochsenzunge, fr. Buglosse officinale), is widely distributed in Europe. The aerial parts of the plant are occasionally applied externally with contused injuries, ulcus cruris, sciatica, as compresses with diseases of a joint and of the adjacent bones, internally as a mild expectorant. The total alkaloid content of the dried drug is ca. 0. 12%. Besides the nontoxic alkaloids laburnine (1) and acetyl-laburnine (2) it contains the toxic alkaloids intermedine (4), lycopsamine (5) and 7-acetyllycopsamine (7) [68-70]. Common bugloss should no longer be used as medicinal plant.
4.1.3. Borago officinalis L.
Borage (ger. Boretsch, fr. Bourache, it. Boragine) is a native plant. It is distributed all over Europe from Denmark to Spain and North Africa. It is cultivated in North America. Borage herb and flowers are not only used as salade and spice but also in folk medicine as depuratives, prophylactics against inflammation of the chest and peritoneum, in cases of rheumarthritis, cough and throat diseases as well as phlebitis.
Besides the toxic alkaloids intermedine (4), lycopsamine (5) and their 7-acetyl derivatives (6, 7) these materials contain in very small amounts the slightly toxic amabiline (17), supinine (18) and the nontoxic thesinine (3). The total alkaloid amount is less than 0.001% relative to the dry weight [71, 72]. The <German> Federal Health Administration (BGA) does not regard a use of the claimed fields of applications as justified . On the other hand, there are no objections against an occasional consumption as a spice.
4.1.4. Cynoglossum officinale L.
Common bugloss, common hounds tongue, Beggar's-lice, (ger. Hundszunge, fr. Cynoglosse officinale, it. Cinoglosa) is widely distributed in Europe. In folk medicine the flowering herb and the roots are applied externally in cases of injuries and sprainings, internally as antidiarrheal and a mucolytic agent. Common bugloss contains the alkaloids heliosupine (19), the N-oxide of the latter, 12-acetylheliosupine (20), echinatine (23), and 7-angeloylheliotridine (36) [74, 75]. The alkaloids found by Mankov et al. and Sykulska et al. by paper chromatography (cynoglossophine, viridiflorine, lasiocarpine, heliotrine and platyphylline) could not be confirmed [76-81]. Since the total content of alkaloids varying from 0.7 to 1.5% is very high neither the drug nor preparations there of should be administered. The BGA considers a therapeutic application no longer justified .
4.1.5. Heliotropium arborescens L, (syn. H. corymbosum) Ruiz. et Pav.
Garden heliotrope, (ger. Vanille-Heliotrop, Vanille-Sonnenwendkraut, fr. Fleur des Dames, it. Eliotropio) grows in Peru and Ecuador. In Europa it is cultivated as fragrant ornamental plant. In medicine it is also applied in homeopathy in cases of laryngitis and displacement of the uterus. In an older study it was claimed on the basis of a TLC comparison that the drug contained the alkaloid lasiocarpine (21) .
A more recent investigation revealed, however, that the plant does not contain lasiocarpine (21) but indicine (28) and 12-acetylindicine (29), respectively the N-oxides of the two compounds in a total concentration of 0.007% in leaves and of 0.01% in roots . Since PA-containing homeopathic preparations may be used for human purposes externally from D4 on and internally from D6 on there are no objections concerning applications of the indicated limiting doses in human medicine .
4.1.6. Lithospermum officinale L.
Gromwell, Stone-seed (ger. Steinsame, fr. Grémil officinal, it. Miglio des Sole) is widely distributed in Europe. In folk medicine it is used as antipyretic and gout remedy as well as in cases of urolithic and intestinal complaints. Fresh plant extracts are supposed to display an anticonceptive effect . From the seeds of the gromwell the alkaloids lithosenine (26) and 12-acetyllithosenine (27) could be isolated in a total concentration of 0.003% . The plant or the seed thereof should, if possible, no longer be used.
4.1.7. Myosotis scorpioides L. (syn. M. palustris (L.) Hill)
True forget-me-not, (ger. Vergissmeinnicht, fr. Myosotis des Marais) is a widespread plant in Europe. In folk medicine it is used internally as a sedative and tonic, externally in eye baths. In the dried plant the alkaloids myoscorpine (11), scorpioidine (15), 7-acetylscorpioidine (16), and symphytine (12) were detected in a total content of 0.08% [88, 89]. In any case the application of forget-me-not is considered obsolete.
4.1.8. Symphytum asperum Lepech
Prickly comfrey, Consound. (ger. Rauher Beinwell, fr. Consoud èpineux), growing in Caucasia is cultivated and used as medicinal and useful plant in the southern parts of Russia and in Central Europe like S. officinale and S. x uplandicum. In the dried leaves the total alkaloid content amounts up to 0.13%, in the dried roots up to 0.14 to 0.37%. In these the alkaloids resp. the N-oxides of intermedine (4) and lycopsamine (5), the 7-acetyl derivatives of the latter two alkaloids (6, 7) symlandine (9), symviridine (10), myoscorpine (11). symphytine (12) as well as the major alkaloid echimidine (13) typical of S. asperum were detected [90, 91]. The presence of the alkaloids asperumine, lasiocarpine, echiumine, makrotomine, and rousorine found in the older studies of Manko et al. by means of paper chromatography could not be confirmed [92-95]. Prickly comfrey should no longer be used for medicinal purposes.
4.1.9. Symphytum caucasicum Bieb.
Caucasian comfrey (ger. Kaukasischer Beinwell, fr. Consoud de Caucase) grows in Caucasia and is used there and in the European part of Russia as folk medicine. In these areas it plays nearly the same important role as S. officinale in Central Europe. In the seventieth it was repeatedly studied by Manko et al. who found a total content of 0.48% of PAs.
Among these the following alkaloids were detected by means of paper and thin-layer chromatography: the N-oxide of echimidine (13), asperumine, echinatine, and lasiocarpine [96-97]. Since the latter three alkaloids have not been found so far in other species of the genus Symphytum further investigations of S. caucasicum are required. Owing to its high alkaloid content an internal intake of this comfrey as a medicinal plant is not recommendable.
4.1.10. Symphytum officinale L. (syn. S. consolida (L.))
Comfrey, Common Comfrey (ger. Beinwell, Wallwurz, fr. Consoude officinale, it. Consolida maggiore), is widespread in Europe. The area of distribution extends from Denmark to Central Russia. Both leaves and roots are used externally in cases of fractures, contused injuries, sprainings, contusions strains, thrombophlebitis, mastitis, hematoma in the form of extracts, ointments, compress pastes, etc., internally as infusions and extracts in cases of gastro-intestinal diseases an respiratory tract diseases. For vegetarians numerous recipe are offered for the preparation of comfrey salade, spinach soufflés, soupes, bread, rolls, and root beverages [98-100].
In dried leaves 0.02 to 0.18 and in the roots 0.25 to 0.29% alkaloids resp. their N-oxides were detected. The alkaloid include intermedine (4), lycopsamine (5), their 7-acetyl derivatives (6, 7), symlandine (9), symviridine (10), myoscorpine (11), and symphytine (12) [101-109]. The presence of the alkaloids (echinatine, heliosupine N-oxide, heliotrine, lasiocarpine, and viridiflorine) isolated and characterized by a Russian and Polish working group by means of paper chromatography could not be confirmed [110-113].
A possible risk associated with the consumption of Symphytum in humans was repeatedly reported [114-117] and in medical literature several cases of intoxication attributed to Symphytum and comfrey are described [118-127]. In animal tests acute toxic effects were detected in rats and goat [128-130].
Rats given for a longer period root drug or a mixture of the alkaloids intermedine and lycopsamine, that are also contained in the comfrey, showed insuloma tumors of the pancreas, liver adenomas, hemangioendothelial sarcomata, and tumors of the bladder.
In the long-term test with the root drug carcinogenicity could be attributed to the main alkaloid symphytine [128, 129]. Moreover, administration of the total alkaloid extract resulted in a mutagenic effect [131, 132]. In view of the risks associated with the alkaloid content neither the leaves nor the root should be used internally. However, under certain conditions there are no objections to an external use provided the skin is intact. In a study on the percutaneous absorption of alkaloids from an alcoholic plant extract that had been applied to the skin of rats 0.08 to 0.41% alkaloid N-oxides wen detected in the urine even after two days . For therapeutic purposes the BGA permits ointments and other preparation with 5 to 20% of dried drug to be applied externally, the daily administered dose being not allowed to contain more than 10 mg of alkaloids including their N-oxides . These requirements are met by the application of species of very low alkaloid content .
4.1.11. Symphytum tuberosum L.
Tuberous comfrey (ger. Knoten-Beinwell, fr. Consoud tubereuse), grows in South-East Europe. Its allantoin content is very high; besides, it contains symlandine (9), echimidine (13) and anadoline (14) respectively the N-oxides of these alkaloids in a total concentration of only 0.02% [136-138].
Tuberous comfrey is recommended for medicinal purposes as an alternative to the other comfrey species .
4.1.12. Symphytum x uplandicum Nyman (syn. S. peregrinum Ledeb.)
Russian comfrey (ger. Russischer Beinwell, fr. Consoud de Russe), is a hybrid generated from Symphytum officinale L. and S. asperum Lepech. It originates in Caucasia and has become widespread in Central Europe, England, Canada, USA, Australia, New Zealand, Japan, Kenia and South Africa. Under the designation of Russian comfrey it is not only cultivated as medicinal plant but also on a large scale as vegetable, fodder-and fertilizer plant. Roots and leaves contain intermedine (4), lycopsamine (5), the 7-acetyl derivatives (6, 7) of these alkaloids, uplandicine (8), symlandine (9), symviridine (10), myoscorpine (11), symphytine (12), the major alkaloid echimidine (13), and the N-oxides of these compounds in different concentrations. A total alkaloid content of ca. 0.2% was found in the dried aerial parts [90, 91, 139, 140]. Russian comfrey should no longer be used for medicinal purposes.
Medicinal plants in Europe containing pyrrolizidine alkaloids was written by Prof. Dr. E. Röder and published in the journal "Pharmazie" 50 (1995), pages 83-98.