Symphytum officinale (PROSEA)

Plant Resources of South-East Asia Introduction

List of species

Symphytum officinale L.

Protologue: Sp. pl. 1: 136 (1753).

Family: Boraginaceae

Chromosome number: 2n= 24, (26, about 36), 40, 48, (54), 56

Synonyms

• Symphytum consolida Gueldenst. (1787),
• Symphytum uliginosum A. Kern. (1868).

Vernacular names

• Common comfrey, consound, knitbone (En).
• Grande consoude, oreille de vache (Fr)
• Indonesia: komring.

Origin and geographic distribution

S. officinale is widely distributed in Europe, rare in the south and naturalized in the north. It has long been naturalized in North America, and cultivated in several Mediterranean (Turkey, Egypt), Asian (Japan) and South-East Asian countries (Indonesia, the Philippines).

Uses

All parts of S. officinale are medicinally used in its area of natural distribution, and the flowers, leaves and rhizomes are official in several European pharmacopoeia. The fresh leaves are widely poulticed on bruises and sprains, burns, wounds and cuts, insect bites, sore joints, pulled tendons, broken bones, dry skin, itch, redness and swellings. An infusion of the leaves has been used as a mouthwash and gargle for gum problems, pharyngitis, pneumonia and angina. As a tea, it was used for gastritis and gastro-intestinal ulcers, as well as rheumatism, bronchitis, scrofula, calcium deficiency, pleuritis, leucorrhoea, as a vulnerary, demulcent, anti-inflammatory, astringent, expectorant and also as a general cleanser.

However, internal use of S. officinale preparations is no longer recommended, due to the presence of the extremely hepatotoxic pyrrolizidine alkaloids. As a result of their cumulative effect, liver damage has been known to occur from extended ingestion as a herbal tea. For this reason pyrrolizidine alkaloid-containing plants, including S. officinale, are now forbidden by law to be used as internal herbal remedies in many European countries.

An infusion of the flowers, which contain much mucilage, is used for coughs and to soothe the intestine in diarrhoea and dysentery. In Japan, it is taken to tone the muscles, as a tonic.

The fresh rhizomes are widely used for healing wounds. The wound-healing properties are partially due to the presence of allantoin, which stimulates cell proliferation, and is biologically active for dandruff, in addition to being an anti-inflammatory, antipeptic, antipsoriac, anti-ulcer, immunostimulant, and a vulnerary. The presence of much mucilage has made S. officinale a powerful healing agent in gastric and duodenal ulcers, hernia, chronic varicose ulcers and ulcerative colitis.

In the Philippines, where S. officinale is mainly cultivated as a medicinal for human use, a decoction of the leaves is also used in veterinary medicine, as a drench for pigs to treat fevers. It has also been used to treat rickets, arthritis and rheumatism in dogs. For livestock, the bruised fresh rhizomes have been recommended as a treatment for internal haemorrhaging, ulcers, arthritis, broken bones and rheumatism.

In the western Highlands of Papua New Guinea, a decoction of the leaves of S. peregrinum Lebed. (probably a misidentification of S. × uplandicum Nyman) is reported to be taken as a sedative and for nervous complaints, upset stomach and externally for ulcers and boils.

In Malaysia, the cultivation of the temperate species S. tuberosum L. and S. asperum Lepech. (synonym S. asperrimum J. Donn ex Sims) as fodder plants has failed. Both have medicinal uses similar to those of S. officinale.

S. officinale is also grown as an ornamental in the temperate region, and several cultivars exist, e.g. cv. Rubrum with red flowers and a compact growth habit.

Production and international trade

Most S. officinale is cultivated in Europe and the United States. In 2001, in the United States, about 120 g of dried leaf fetched US$ 3.25 and 120 g of dried rhizome fetched US$ 4.75. The industrial manufacture of extracts virtually free of the alkaloids is nowadays possible.

Properties

All parts of S. officinale contain allantoin (0.5-1.7%, mostly in the leaves), mucilage (29%), triterpene saponins, choline, asparagine, tannins (8-9% in the aerial parts, 4-6% in the rhizomes), silicic acid (4%), and pyrrolizidine alkaloids (0.003-0.2% in the leaves, especially the young ones, 0.2-0.4% in the rhizomes). The major pyrrolizidine alkaloids are intermedine, lycopsamine, 7-acetyllycopsamine and 7-acetylintermedine, followed by echimidine, echinatin, lasiocarpine, symphytine, (and minor isomers symlandine, symveridine), echiumine, myoscorpine and heliosupine. The minor compounds do not occur in all specimens analyzed and they are even often absent in dried leaves. The leaves also contain the phenolic acids rosmarinic-, chlorogenic-, caffeic- and lithospermic-acid. The aerial parts also contain the toxic alkaloid symphytocynoglossine and a toxic gluco-alkaloid, consolidine, which can paralyze the central nervous system. Consolicine, the aglycone, occurs in the free state and is said to be three times stronger than consolidine. The protein content of S. officinale may be as high as 36%, including the amino acid methionine, which helps in wound healing and in the formation of epithelian tissue.

The triterpenoid saponin symphytoxide A is reported from the rhizomes.

Many pyrrolizidine alkaloids (PAs) are toxic and several have been shown to be hepatotoxic, pneumotoxic, carcinogenic and mutagenic. The presence in the molecule of a 1,2-unsaturated retronecine skeleton, together with an esterification at the C9-hydroxy group, is a prerequisite for the toxic effects, as is found in more than 80% of the naturally occurring PAs. In man, PAs can cause obstruction of the hepatic venous system which leads to hepato-necrosis. Human poisoning most often results from ingesting contaminated foods (milk, honey), or when PA-containing plants are used for internal medicinal purposes. In the past, S. officinale has been used freely in herbal teas. The most common disease associated with consumption of pyrrolizidine alkaloids in man is veno-occlusive disease (a form of Budd-Chiari syndrome). Clinical manifestations include abdominal pain, ascitis, hepatomegaly and raised serum transaminase levels. Prognosis is often poor with death rates of 20-30% being reported. No alkaloid-free rhizomes were found in more than 300 samples from over 150 different natural habitats in Germany. The alkaloid concentrations varied from 0.05-0.6%. The PAs are not distributed uniformly within the plants, but are concentrated in the underground parts, especially at the extreme exodermis and in the centre of the rhizome, in light young roots and in hairy roots. These PA concentrations were a 100-fold higher than those of the aerial parts. For external application, S. officinale-containing preparations were positively evaluated for use in case of contusions, strains and spraining. Absorption of PAs through the skin is negligible, therefore their application is considered safe.

Many PAs are not palatable and livestock avoid eating them if other forages are available. There are large differences in susceptibility to pyrrolizidine alkaloids in different animals; pigs are most susceptible, followed by horses and cattle, goats, and finally sheep. Common clinical signs of toxicity are jaundiced skin, rough unkempt appearance, diarrhoea, prolapsed rectum, oedema of tissues of the digestive tract, dullness, photosensitization and abnormal behaviour.

In the literature, S. officinale is reported to have anti-inflammatory, analgesic and tissue regenerating properties. The percutaneous efficacy of an ointment of comfrey extract (4 treatments per day for 8 days) was investigated in a double-blind, multi-centre, randomized, placebo-controlled group comparison study in Germany using patients suffering from unilateral acute ankle sprains. Compared to the placebo, the active treatment was clearly superior regarding the reduction of pain and ankle oedema. Statistically significant differences between active treatment and placebo were also shown for ankle mobility (neutral zero method), and global efficacy. No adverse drug reactions were reported.

Several extracts and fractions of S. officinale have been evaluated on immunological parameters. For instance, the effect of in vivo stimulation with an aqueous rhizome extract on mouse peritoneal macrophages was investigated. The results showed that these products initially activated the respiratory burst of the cells and later inhibited it, activating the synthesis of catalase, SOD etc., suggesting that macrophages challenged by various ingested antigens destroy them initially through oxygen dependent mechanisms and later through enzymatic digestion in order to retain their epitopes unimpaired. The crude watery extract and its protein fraction were studied for their effect upon the in vivo and in vitro proliferation of Ehrlich ascites cells, EL-4 cell line and of human T lymphocytes and upon the respiratory burst of human PMN granulocytes stimulated via Fc receptors. The results indicate that the crude extract and its proteic fraction stimulate the in vivo proliferation of the studied neoplastic cells and exert an antimitotic effect on in vitro human T lymphocytes stimulated with phyto haemagglutinin. The vegetal preparations have remarkable effects on the respiratory burst of the granulocytes non-stimulated and stimulated via Fc receptors.

A crude extract of adult comfrey leaves only showed a slight analgesic activity, and did not show anti-inflammatory activity in rats. Use was made of Wistar albino rats in which an inflammation was induced through the simultaneous injection of carageenan and prostaglandin E1 in order to evaluate the anti-inflammatory activity of freeze-dried plant extracts. The extract did not inhibit the inflammation, however, but suppressed the leukocyte infiltration during the 3rd and 4th hour of the induced inflammation.

The aqueous extract of the leaves markedly increased the production of prostaglandins (PGF2α, 6-keto-PGF1α) in rat gastric mucosa homogenates.

Two arabino-pyranosides, leontosides A and B, were isolated from the dried rhizomes collected in Turkey. Both compounds were tested for their antibacterial activity against 6 Gram-negative and 6 Gram-positive bacteria. Leontoside A at 100 and 200μg/100μl showed activity against Salmonella typhi, Staphylococcus epidermidis and Streptococcus faecalis. However, leontoside B was only active against Escherichia coli, at 200μg/100μl. In another test, an aqueous extract of the rhizomes inhibited the release of oxygen free radicals by human polymorphonuclear leukocytes (PMNLs) stimulated with either opsonized zymosan or concanavalin A. However, it enhanced the generation and release of OFRs by unstimulated PMNLs. When injected into anaesthetized rats, symphytoxide-A (from the rhizomes) produced a fall in mean arterial blood pressure which was abolished by pre-treatment with atropine (1 mg/kg). In isolated guinea-pig atria, symphytoxide-A produced inhibitory effects on force and rate of contractions while in smooth muscle preparations such as guinea-pig ileum and rat uterus, it induced stimulant responses. All these responses were abolished in the presence of atropine (80 ng/ml), similarly to acetylcholine. In skeletal muscle preparation (frog rectus abdominis) symphytoxide-A produced contractions which were blocked byδ-tubocurarine, similar to those produced by acetylcholine, carbachol or nicotine. These results indicate the mechanism of action of symphytoxide-A to be mediated via the parasympathetic system.

Crushed aerial parts reduced the induction of micronucleated polychromatic erythrocytes by mitomysin C, dimethylnitrosamine and tetracycline, showing that the plant has antimutagenic effects. Heating did not affect its antimutagenic properties. An acetone extract was evaluated for mutagenic activity with the Salmonella/mammalian-microsome mutagenicity test (Ames), using tester strains TA98 and TA100 and in the presence and absence of induced rat liver microsomes. The extract produced toxic responses that were abolished in the presence of the microsomal bioactivation system. Furthermore, an alkaloid fraction was investigated for its chromosome-damaging effect in human lymphocytes in vitro. In concentrations up to 14μg/ml the alkaloids had no effect, in concentrations of 140-1400μg/ml the alkaloids induced sister chromatid exchanges (SCE) as well as chromosome aberrations. The influence of rat liver enzymes (S9) was also tested. The SCE-inducing capacity and the clastogenic effect of Symphytum alkaloids were increased by simultaneous application of S9-mix.

The toxicities of 5 different concentrations of saponin and crude saponin, isolated from S. officinale, and mercaptodimethylether (positive reference) to the snail Physa acuta were determined after exposure for 24 h. The LC₅₀for saponin, crude saponin and mesurol was 11.2, 10.7 and 3.4 ppm, respectively. Topical application of a crude ethanol extract of the leaves produced striking acaricidal effects on engorged Boophilus microplus, including mortality, inhibition of oviposition and inhibition of embryogenesis.

Egg yolk of Leghorn hens given S. officinale leaves was a more intense yellow colour than that of the controls. Chickens given 8% leaves showed no difference in weight gain from the controls but those given 2% decoction in their water showed an increase in weight gain. When up to 80% leaves was given in the feed or 20% in the water some chickens had diarrhoea and there were slight signs of congestion and haemorrhage in internal organs. With 8% comfrey in the diet, calcium and phosphorus balances were positive and bone mineralization was normal.

Adulterations and substitutes

More than 350 pyrrolizidine alkaloids have been identified in over 6 000 plants in the Boraginaceae, Compositae, and Leguminosae.

Description

• A perennial, rough hairy herb, (30-–)50-120 cm tall, stems stout, often branched, tillering; rhizome vertical, fleshy.
• Leaves alternate, simple, ovate-lanceolate to lanceolate, up to 25 cm × 15 cm, apex acuminate, base decurrent into petiole and stem, forming a wing, upper leaves sessile; stipules absent.
• Inflorescence a short terminal scorpioid cyme, many-flowered, bracts absent.
• Flowers bisexual; calyx 5-lobed, lobes lanceolate; corolla tube cylindrical, 12-18 mm long, lobes small, deflexed, purple-violet, dirty pink or white, scales 5 at throat, broadly triangular-lanceolate, papillate, lower marginal papillae shortly cylindrical-conical, upper much smaller and shorter; stamens 5, included, inserted at the middle of the tube, with connective projecting beyond thecae, filaments as wide as anther; ovary superior, 4-locular, style exserted, stigma very small, entire.
• Fruit dry, composed of 4 nutlets, calyx persistent.
• Nutlet ovoid, 5-6 mm long, very smooth, black, shining.
• Seedling with epigeal germination; cotyledons ovoid; first leaves alternate, hairy.

Growth and development

S. officinale can be found flowering and fruiting throughout the year in the tropics. In temperate regions it flowers during spring and summer. Flowers are self-incompatible and are mainly pollinated by bees and bumble-bees.

Other botanical information

Symphytum is native of Eurasia, and comprises 35 species. Morphological and chemotaxonomic studies indicated that S. × uplandicum (2 n = 36 and 40) is a hybrid between S. officinale (2 n = 40 and 48) and S. asperum . The 2 n = 40 cytotype of S. officinale is regarded as conspecific with S. officinale (2 n = 48) and not as its hybrid with S. asperum.

Ecology

S. officinale occurs in its natural distribution area on river banks and damp grassland. It tolerates most soils, and even grows well on heavy clay soils.

Propagation and planting

S. officinale can be propagated by seed, division or through in vitro propagation from root explants. Seeds germinate easily on peat in water or watered loam. Optimal planting is at 70 cm × 70 cm.

In vitro production of active compounds

Primary calluses were induced from roots, petioles, peduncles, stems and leaves cultured on solid Murashige & Skoog (MS) medium with 1.0 mg/l butyric acid (BA) + 0.01-1.0 mg/l indole acetic acid (IAA) or on solid Gamborg B5 medium with 2 mg/l 2,4-D + 1.0 mg/l BA or kinetin. The calluses were further subcultured on B5 medium. Calluses and cell suspension cultures regenerated whole plants on solid MS medium with 1.0 mg/l BA + 0.1 mg/l IAA. Plants regenerated from short-term cultures were identical in morphology and chromosome number to plants from which cultures were initiated. Pyrrolizidine alkaloid production ceased on prolonged subculturing of suspensions, although polyamines, which might act as precursors, were still detectable. Regenerated plants, however, produced the original alkaloids.

Husbandry

S. officinale grows best in open localities, or with partial shade, in a deep, rich soil, at 70 cm intervals. In field trials with plants from root cuttings or seedlings, growth was most vigorous on rich garden soils, or alluvial soils, followed by brown soils, rendzinas and pseudo-podzolic soils.

Diseases and pests

Comfrey rust (Melampsorella symphyti) is the biggest problem in S. officinale. The infection can be reduced by removing the infested leaves. In China, bacteria and mycoplasma-like organisms cause wilt and root rot. S. officinale is a host for the nematode Meloidogyne incognita.

Harvesting

The roots of S. officinale should be harvested at the beginning or end of the growing season, when the allantoin levels are the highest. Leaves and flowers are harvested when needed.

Yield

Dry root yields of S. officinale vary from 5 to 12 t/ha depending on soil type. The highest average allantoin content was found in roots from rendzinas (1.7%) and the lowest in those from pseudo-podzolic soils (0.9%).

Handling after harvest

Harvested plant parts of S. officinale are used fresh or dried in the shade for future use. The roots can also be split down the middle and dried in an oven at 40-60C.

Genetic resources and breeding

S. officinale is widespread and common throughout its natural distribution area. In South-East Asia it is only cultivated on a small scale, and as the plants are probably mainly propagated through division, the genetic base may be small.

There are no known breeding programmes of S. officinale.

Prospects

The possibilities for cultivation of S. officinale in other South-East Asian countries need further investigation, but do not seem very promising. The hepatotoxocity of the pyrrolizidine alkaloids limits application of Symphytum preparations to external applications, for instance in the treatment of contusions, strains and sprains.

Literature

• Gilani, A.H., Aftab, K., Saeed, S.A., Ahmad, V.U., Noorwala, M. & Mohammad, F.V., 1994. Pharmacological characterization of symphytoxide-A, a saponin from Symphytum officinale. Fitoterapia 65(4): 333-339.
• Gutierrez, H.G., 1982. An illustrated manual of Philippine materia medica. Vol. 2. Natural Research Council of the Philippines, Tagig, Metro Manila, the Philippines. pp. 281–-283.
• Huizing, H.J., Pfauth, E.C., Malingre, T.M. & Sietsma, J.H., 1983. Regeneration of plants from tissue- and cell suspension cultures of Symphytum officinale L. and effect of in vitro culture on pyrrolizidine alkaloid production. Plant Cell, Tissue and Organ Culture 2(3): 227-238.
• Koll, R., Buhr, M., Dieter, R., Pabst, H., Predel, H.G., Petrowicz, O., Gianetti, B. & Wagener, S., 2000. Wirksamkeit und Vertraglichkeit von Beinwellwurzel-extrakt (Extr. Rad. Symphyti) bei Sprunggelenks-distorsionen. Ergebnisse einer multizentrischen, randomisierten, placebo-kontrollierten Doppelblindstudie [Efficacy and tolerance of comfrey extract (Extr. Rad. Symphyti) in ankle distortions: results of a multi-centre, randomized, placebo-controlled double-blind study]. Zeitschrift für Phytotherapie 21(3): 127-134.
• Stegelmeier, B.L., Edgar, J.A., Colegate, S.M., Gardner, D.R., Schoch, T.K., Coulombe, R.A. & Molyneux, R.J., 1999. Pyrrolizidine alkaloid plants, metabolism and toxicity. Journal of Natural Toxins 8(1): 95-116.
• Tutin, T.G., Heywood, V.H., Burges, N.A., Moore, D.M., Valentine, D.H., Walters, S.M. & Webb, D.A. (Editors), 1972. Flora Europaea, Vol. 3. Cambridge University Press, Cambridge, United Kingdom. pp. 103-105.

Other selected sources

2, 26, 98, 179, 208, 243, 252, 266, 308, 611, 648, 653, 696, 698, 723, 759, 815, 1065.

Authors

G.H. Schmelzer & S.F.A.J. Horsten