Symphytum-alkaloids

Fig. 3.6. HPLC separation of some Symphytum alkaloids Column MN-Nucleosil C18 10 urn (300x4 mm ID), mobile phase methanol - water (45 55), flow rate 2 ml/min, detection UV 220 nm. Peaks 1, echimidine N-oxide 2, symphytine N-oxide. (Reproduced with permission from ref. 18, by courtesy of Hippokrates Verlag)...

Quinolizidine alkaloids (QA) are thought to be typical natural products of many Leguminosae (1-3) but a few isolated occurrences have been reported also in unrelated families, e.g. Chenopodiaceae ( 1 ), Berberidaceae ( ), Papaveraceae ( ), Scrophulariaceae ( ), Santalaceae ( ), Solanaceae ( ), and Ranunculaceae (J ). These observations could indicate that the genes for QA biosynthesis are probably not restricted to the Leguminosae but are widely distributed in the plant kingdom however, they are only rarely expressed in the other families. We could support this belief by recent experiments using plant cell suspension cultures. A short-term and transientQA formation could be detected after induction even in "QA-free" species, such as Daucus, Spinacia, Conium, and Symphytum (6). 

Comfrey (Symphytum officinale) Uses Topical treatment of wounds, bruises, sprains, inflammation Action Multiple chemical components, allantoin promotes cell division, rosmarinic acid has anti-inflammatory effects, tannin possesses astringent effects, mucilage is a demulcent w/ anti-inflammatory properties, pyrrolizidine alkaloids cause hepatotox Available forms Topical application w/ 5—20% of herb applied on intact skin for up to 10 d Contra Do not take orally d/t hepatotox, do not use if PRG or w/ lactation Notes/SE N/V, exfoliative dermatitis w/ topical use Interactions T Risk of hepatotox W/ ingestion of borage, golden ragwort, hemp, Petasites EMS None... 

Pyrrolizidine alkaloids have a wide distribution, but are characteristic of certain genera of the Boraginaceae (e.g. Heliotropium, Cynoglossum, and Symphytum), the Compositae/Asteraceae (e.g. Senecio) and the Leguminosae/Fabaceae (e.g. Crotalaria). The pyrrolizidine bases rarely occur in the free form, but are generally found as esters with rare mono- or di-basic acids, the necic acids. Thus, senecionine (Figure 6.18) from Senecio species is a diester of retronecine with senecic acid. Inspection of the ten-carbon skeleton... 

Russian comfrey (Symphytum x uplandicum Nyman) is widely recommended as a medicinal herb and an item of human diet. A previous investigation of this species led to the isolation of three alkaloids which were not fully characterized (cf. Vol. 7, p. 57). Culvenor and co-workers have separated eight pyrrolizidine alkaloids from the leaves of this perennial plant by counter-current distribution.21 The known alkaloids echimidine (51), symphytine (52), lycopsamine (53), and intermedine (54) were present. In addition, four new alkaloids, i.e. 7-acetyl-lycopsamine (55), 7-acetylintermedine (56), symlandine (57), and uplandicine (58), were characterized by spectroscopic methods, and by hydrolysis. The total alkaloidal extract caused chronic hepatotoxic effects in rats, and the authors... 

Comfrey Symphytum species Leaves and roots Internal digestive aid, topical for wound healing Pyrrolizidine alkaloids, hepatotoxicity Avoid internal ingestion topical use should be limited to 4-6 weeks... 

There are no drugs based on the pyrrolizidine alkaloids of the Asteraceae (e.g., Senecio and Symphytum) and Boraginaceae (Crotolaria). However, these alkaloids pose a great threat to human and animal health because of their potential for inadvertent consumption. In the case of 1,2-dehydro derivatives, such as senecio-nine, ingestion leads to non-reversible hepatotoxicity. Pyrrolizidine nucleus formation from two units of ornithine is shown (Fig. 24). 

Symphytum officinale (black wort, boneset, bruise wort, comfrey, knitback, knitbone, slippery root) contains pyrrolizidine alkaloids, such as lasiocarpine and symphytine, and their N-oxides, and has repeatedly been associated with hepatotoxicity. 

Pyirolizidine alkaloids Symphytum officinale n-CeHi4 EtOH -MeOH 0.05% TEA (5 5 5 5) HSCCC... 

Cai et al. first used a chloroform-0.07 M sodium phosphate buffer (pH 6.4-6.5) solvent system for the separation of matrine and oxymatrine from Sophora flavescens, atropine, scopolamine, and hyoscyamine from Datura mete L. by HSCCC. Cooper et al. successfully used chloroform-0.2 M potassium phosphate buffer with an optimum pH value of each at 5.0, 5.6, 6.0, and 7.4 for the separation of pyrrolizidine alkaloids from various sources of Senecio douglasii var. longilobus, Trichodesma incanum, Symphytum spp. and Amsinckia tessellata, respectively. 

The toxic pyrrolizidine alkaloids are a large group of related compounds which occur in plants, mainly in species of Crotalaria, Senecio, Heliotropium, Trichodesma, Symphytum and Echium and are poisonous (Brown, 2003 Orech et al., 2005). 

Betz JM, Eppley RM, Taylor WC, et al Determination of pyrrolizidine alkaloids in commercial comfrey products (Symphytum sp.). 1 Pharm Sci 83 649-653,1994... 

Comfrey is a perennial herb used for the prevention of kidney stones nourishing and repairing bone and muscle and for the treatment of injuries such as burns and bruises. In Australia, comfrey is classified as a poison and its sales have been restricted in several regions. Many different commercial forms of comfrey are marketed, including oral and external products. Commercial comfrey is usually derived from the leaves or roots of Symphytum officinale (common comfrey). However, some products are also derived from Russian comfrey. Russian comfrey contains a very toxic pyrrolizidine alkaloid, echimidine, which is not found in common comfrey. However, common comfrey contains other hepatotoxic alkaloids, namely 7-acetylintermedine, 7-acetyllycopsamine and symphytine. The metabolites of these alkaloids are very toxic to the liver. Ridker et al. documented hepatic venocclusive disease associated with consumption of comfrey root. Long-term smdies in animals have also confirmed the carcinogenicity of comfrey in animal models. ... 

Commercial comfrey is usually derived from the leaves or roots of Symphytum officinale (common comfrey) (USP, 1998). However, some products are derived from Symphytum x uplandicum Nyman (Russian comfrey) or Symphytum asperum Lepech (prickly comfrey), which appear to be more toxic than common comfrey (Anonymous, 1998). Russian comfrey and prickly comfrey contain a very toxic pyrrolizidine alkaloid (PA) called echimidine that common comfrey does not contain (Tyler, 1994). Although common comfrey does not contain echimidine, it does contain other hepatotoxic PAs. These alkaloids include 7-acetylintermedine, 7-acetyllycopsamine, their unacetylated precursors, and symphytine (Tyler, 1993). 

Brauchli J, Luthy J, Zweifel U, Schlatter C. Pyrrolizidine alkaloids from Symphytum officinale L. and their percutaneous absorption in rats. Experientia 1982 38 1085-7. 

The level of alkaloids in Symphytum officinale (comfrey) at various stages of plant development has been investigated. The alkaloid content appears to be greatest in the aerial parts during flowering and in the roots at the end of fruit formation. The alkaloids identified include lasiocarpine and heliosupine N-oxide in the aerial parts, and viridiflorine, echinatine, and heliosupine IV-oxide in the roots.23... 

Three new alkaloids [(35)-(37)J were present in this mixture, together with symphytine (38). The structure (35) for 7-acetyl-scorpioidine was established by spectroscopic data, by hydrogen-olysis of (35) to give 7-acetylretronecanol, and by alkaline hydrolysis of (35) to yield retronecine (1), acetic, tiglic, and (2S,3S)-viridifloric acids. Scorpioidine (35) was also separated and gave (35) on acetylation. An epimer of scorpioidine, anadoline (39), was previously isolated from two Symphytum species (cf. 

This technique has now been extended for use on h.p.l.c., and the alkaloids from comfrey (Symphytum spp.) were separated. Diastereoisomeric pyrrolizidine alkaloid monoesters containing a vicinal diol were previously separated as their borate complexes (cf. Vol. 12, p. 62). Related diastereoisomeric alkaloids have... 

A number of recent studies of the pyrrolizidine alkaloids in various Symphytum species have succeeded in characterizing twelve mono- and di-ester alkaloids of retronecine and hellotridine (31, 95-104). We have examined twelve samples each of comfrey root and leaf sold as herbs in the U.S. As determined by nmr, the total alkaloid content of the leaf samples was < 0.005% the roots, on the other hand, contained from 0.14-0.42% (130). Examination of the root alkaloid mixture by capillary gc-ms after derivatization allowed identification of seven alkaloids (Figures 4 and 7) in all of the samples the first four peaks, lycopsamine, intermedlne, and their 7-acetyl derivatives, accounted for 75% or more of the total alkaloids. The same seven alkaloids have been found in Russian comfrey, a cross between Symphytum officinale and asperum, sometimes called Symphytum X uplandIcum (31,96,104). 

Comfrey Symphytum officinale Anti-inflammatory gastritis diarrhea Hepatic veno-occlusive disease possible teratogen/carcinogen. (Note many other plants also contain hepatotoxic pyrrolizidine alkaloids-see Table 11-46). 

Comfrey Symphytum officinaie 1,3 Irritant tannin and hepatotoxic pyrrolizidine alkaloids... 

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