ARTICLE IN PRESS Phytomedicine 14 (2007) SVI 9–17 www.elsevier.de/phymed REVIEW Fascinating metabolic pools of Pelargonium sidoides and Pelargonium reniforme, traditional and phytomedicinal sources of the herbal medicine Umckaloabos Herbert Kolodziej Institut für Pharmazie, Pharmazeutische Biologie, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany Abstract The metabolic pools of Pelargonium sidoides DC and Pelargonium reniforme CURT, associated with the origin of the herbal medicine Umckaloabos, exhibit remarkable diversity and complexity. They comprise a variety of phenolic and polyphenolic compounds, a notable wealth of highly oxygenated simple coumarins and a number of miscellaneous uncommon metabolites. Noteworthy, the roots of both species express conspicuously distinct coumarin variations that facilitate their identiﬁcation. Of the range of coumarins identiﬁed the titled species shared the ubiquitous scopoletin and the unique members 6,7,8-trihydroxycoumarin and 8-hydroxy-5,6,7-trimethoxycoumarin merely. Furthermore, the current data on the coumarin proﬁles suggest the occurrence of coumarin sulphates and coumarin glycosides to be apparently conﬁned to P. sidoides, while the occurrence of conventional proanthocyanidins was a common chemical feature. An unprecedented diterpene, designated as reniformin, was encountered in the roots of P. reniforme, possessing a novel diterpene skeleton linked to a unique p-oxyphenethansulfonic moiety. Coumarins were less abundant in the aerial parts of both species. These were rich in ﬂavonoids and hydrolysable tannins including a unique series of O-galloyl-C-glucosylﬂavones (P. sidoides and P. reniforme) and novel ellagitannins with a 1C4 glucopyranose core in P. reniforme, trivially named pelargoniins, accompanied by the new 4-allyl-2,5-dimethoxyphenol-1-b-Dglucoside. These Pelargoniums have thus represented an attractive source of fascinating secondary metabolites. A proprietary extract of the roots of P. sidoides, EPss 7630, has been developed from this traditional herbal medicine and introduced into modern phytotherapy in Europe. Structural examination of EPss 7630 constituents showed excellent agreement of the proﬁle with that of P. sidoides. r 2006 Elsevier GmbH. All rights reserved. Keywords: Pelargonium sidoides; Pelargonium reniforme; EPss 7630; Coumarins; Phenols Introduction The genus Pelargonium (Geraniaceae) comprises approximately 270 distinct species of perennial small shrubs of which about 80% occur in southern Africa with the centre of diversity in the Cape Province (Van der Walt and Vorster, 1988). Although Pelargoniums Tel.: +49 30 83 85 37 31; fax: +49 30 83 85 37 29. E-mail address: firstname.lastname@example.org. 0944-7113/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2006.11.021 have a long tradition as ornamental and medicinal plants (Lis-Balchin, 2002), limited chemical sampling of members of this genus produced mainly common organic acids, derivatives of cinnamic acid, ﬂavonoids, tannins, some coumarins and phytosterols (Hegnauer, 1966, 1989; Williams and Harborne, 2002). With the exception of the detection of the unique alkaloids (epi)elaeocarpidin in hybrids (Lis-Balchin et al., 1996), all recent papers deal with these types of secondary products. Owing to the persistent interest in perfumery, ARTICLE IN PRESS 10 H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17 reﬂected by numerous papers on ‘Geranium oil’ (P. graveolens, hybrids and other Pelargonium species!) (Van der Walt and Vorster, 1981; Kaiser, 1984; Van der Walt and Demarne, 1988), essential oils of distinct Pelargonium species, have been the subject of detailed studies (Demarne and van der Walt, 1990, 1992, 1993; Demarne et al., 1993). Initial chemical investigation of Pelargonium reniforme/Pelargonium sidoides was prompted by the discovery of a herbal medicine for the treatment of tuberculosis. The English Major Charles Henry Stevens who has been heavily suffering from this respiratory disease travelled to South Africa for a cure and had the believe that he has been restored to health by decoctions of a root material given by a traditional healer (Bladt, 1977; Helmstädter, 1996). The true botanical nature of this herbal medicine was debated for many years until 1974 when its origin was claimed to be P. reniforme (Bladt, 1974, 1977; Wagner and Bladt, 1975). Current evidence points to erroneous identiﬁcation of the plant material in the earlier investigation and suggests P. sidoides as plant origin (vide infra) (Kolodziej and Kayser, 1998). However, it should be stressed that chemical studies have not been carried out on distinct plant extracts of either Pelargonium species. With botanically deﬁned plant materials available through cultivation, studies on the individual patterns of constituents of each Pelargonium species were permitted for the ﬁrst time. It should be noted that the plant material of P. reniforme studied conformed with ssp. reniforme. Although current interest focuses on the composition of root metabolites, this communication also includes the fascinating metabolic pools of the aerial parts in view of the hitherto limited information on the chemical constituents of Pelargoniums and their various traditional uses. In addition, extended knowledge of the chemical proﬁle of both species may provide a clue for the detection of key compounds in terms of their pharmacological proﬁles. Due to the indicated taxonomic ambiguity, this report represents a summary of the compositional studies of the titled Pelargonium species mainly carried out in our research group. Structures depicted represent unusual and typical metabolites. Pelargonium reniforme CURT The pink-ﬂowered P. reniforme is an attractive erect shrublet, developing from a tuberous rootstock. The zygomorphous ﬂower heads are borne on tall slender stalks. Each ﬂower has ﬁve lanceolate petals, with two distinctive stripes on the upper two petals. The reniform leaves are a characteristic feature of this species that is reﬂected in its botanical name ‘‘reniforme’’ (Van der Walt and Vorster, 1983, 1988). Noteworthy is that the two subspecies of P. reniforme not only differ morphologically, but also in area of distribution (Dreyer et al., 1995). P. reniforme ssp. reniforme is conﬁned to the region at Port Elizabeth where it is fairly widespread at low altitudes. All the material extending in the coastal districts further north and south and in inland areas is apparently represented by the ssp. velutinum. The only notably morphological difference between the two subspecies lies in the shape and arrangement of leaves and in the length of petioles; ssp. velutinum shows reniform to predominantly cordate leaves and conspicuously longer petioles, reminiscent of those of P. sidoides (vide infra). The aqueous acetone and methanol extracts of the roots of P. reniforme afforded a total of 24 various metabolites including ten simple phenolic acids, six coumarins, four ﬂavonoids, two ﬂavan-3-ols with associated proanthocyanidins, one phytosterol and an unprecedented diterpen, reniformin (Table 1). With the exception of gallic acid and its methyl ester, all these metabolites have been encountered in relatively low yields. The presence of catechin and gallocatechin in the roots of P. reniforme has only been qualitatively demonstrated by TLC as trace compounds. In contrast, structurally related oligomeric and polymeric proanthocyanidins occurred in exceptionally high concentrations with the indicated ﬂavanyl entities as chain extender units. An illustrative structure of these complex molecules is presented as depicted in formula ‘proanthocyanidin’. Our systematic examination of root extracts has revealed a remarkable series of highly oxygenated simple coumarins as characteristic constituents of P. reniforme (Lattè et al., 2000). Apart from the widely distributed disubstituted scopoletin, all the coumarins possess triand tetrasubstituted oxygenation patterns on the aromatic nucleus, oxygenation patterns that are very rarely found in the plant kingdom (Murray, 1997). Amongst these notable structural variants, 6,7,8-trihydroxycoumarin and 8-hydroxy-5,6,7-trimethoxycoumarin represent novel metabolites of the above class of secondary products. It should be noted that the natural occurrence of the former coumarin has recently been demonstrated in P. sidoides (Table 1 and Fig. 1). The heterogeneity of metabolites in P. reniforme root extracts was further demonstrated by the characterization of an unprecedented diterpen ester, linked to the hydroxy group of p-hydroxyphenethansulfonic acid which, in turn, presents an unusual natural acyl moiety (unpublished). This unique metabolite, designated as reniformin, was apparently accompanied by analogous compounds. Low quantities and their decomposition excluded the isolation and structural assessment of additional fascinating analogues with a view to evaluate their biological activities. ARTICLE IN PRESS H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17 Table 1. 11 Constituents of the root material of P. reniforme, P. sidoides and EPss 7630 P. reniforme P. sidoides EPss 7630 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Coumarin glycosides Magnolioside Isofraxoside Umckalin-7-b-D-glucoside + + + + Coumarin sulfates 5,6-Dimethoxycoumarin-7-sulfate 6,7-Dihydroxycoumarin-8-sulfate 6-Hydroxy-5,7-dimethoxycoumarin-8-sulfate 8-Hydroxy-5,7-dimethoxycoumarin-6-sulfate + + + + Compound Phenolic acids, phenylpropanoids and derivatives Gallic acid Gallic acid methyl ester p-Hydroxybenzoic acid Protocatechuic acid Vanillic acid Caffeic acid Ferulic acid p-Coumaric acid p-Coumaraldehyde Shikimic acid Shikimic acid 3-O-gallate Coumarins 6,7-Dioxygenation 7-Hydroxy-6-methoxycoumarin (Scopoletin) 5,6,7-Trioxygenation 7-Hydroxy-5,6-dimethoxycoumarin (Umckalin) 7-Acetoxy-5,6-dimethoxycoumarin 5,6,7-Trimethoxycoumarin 6-Hydroxy-5,7-dimethoxycoumarin (Fraxinol) 5,6-Dihydroxy-7-methoxycoumarin (Isofraxetin) 6,7,8-Trioxygenation 6,7,8-Trihydroxycoumarin 6,8-Dihydroxy-7-methoxycoumarin 8-Hydroxy-6,7-dimethoxycoumarin (Fraxidin) 7,8-Dihydroxy-6-methoxycoumarin (Fraxetin) 5,6,7,8-Tetraoxygenation 6,8-Dihydroxy-5,7-dimethoxycoumarin 5,6,7,8-Tetramethoxycoumarin (Artelin) 8-Hydroxy-5,6,7-trimethoxycoumarin + + + + + + Flavonoids Kaempferol-3-O-b-D-glucoside Kaempferol-3-O-b-D-galactoside Quercetin-3-O-b-D-glucoside Myricetin-3-O-b-D-glucoside + + + + Flavan-3-ols/Proanthocyanidins Afzelechin Catechin Gallocatechin Proanthocyanidins + + + + Miscellaneous Reniformin b-Sitosterol b-Sitosterol-3-O-b-D-glucoside + + + + + + + + + ARTICLE IN PRESS 12 H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17 In contrast to the roots, the aerial parts of P. reniforme have not been the subject of chemical studies, which may be attributed, at least in part, to less relevant therapeutic uses. Benzoic and cinnamic acid derivatives, ﬂavonoids and tannins are the principal phenolic substances found in the aerial parts of P. reniforme (Table 2). That these plant parts again represented an R1 H OCH3 OCH3 OCH3 OCH3 OH H H H H OCH3 OCH3 OCH3 H H OCH3 coumarin Scopoletin Umckalin 7-Acetoxy-5,6-dimethoxycoumarin 5,6,7-Trimethoxcoumarin Fraxinol Isofraxetin 6,7,8-Trihydroxycoumarin 6,8-Dihydroxy-7-methoxycoumarin Fraxidin Fraxetin 6,8-Dihydroxy-5,7-dimethoxycoumarin Artelin 8-Hydroxy-5,6,7-trimethoxycoumarin Magnolioside Fraxetin-7-ß-D.glucoside Umckalin-7-ß-D-glucoside R4 R 3 8 7 R2 6 O O 5 Rv1 attractive metabolic pool was demonstrated by the isolation of a wealth of new and rarely found secondary products. For example, the occurrence of glycerol-1gallate has hitherto been shown only in Mallotus japonicus (Euphorbiaceae) (Saijo et al., 1990) and in a Rheum species (Polygonaceae) (Nonaka and Nishioka, 1983), while that of (a,b)-3,4-di-O-galloylglucopyranoside R2 OCH3 OCH3 OCH3 OCH3 OH R3 OH OH OAc OCH3 OCH3 OH OCH3 OH OH OH OCH3 OCH3 OCH3 OCH3 OH OH OCH3 OCH3 OCH3 OCH3 OCH3 OGlc OCH3 OCH3 OGlc OCH3 OGlc R4 H H H H H H OH OH OH OH OH OCH3 OH H OH H HO HO HO CH2OH HO O O RO galloyl CO O RO O HO OH HO OH glcerol-1-gallate OH O HO OH (α,ß)-3,4-di-O-galloylglucoside salidroside-6“-gallate HOH2C OH HO O OH O O O O HO OH HO OH HO HO OH C O O C H2 C O-galloyl HO O C H 2C O-galloyl O OH O O HO C O OH OH OH O C C O O H2 C O-galloyl O O O-galloyl O O O HO O HOC O C O C O HOOC OH HO HO OH O HO C O C O HO HO O O corilagin HO OH isostrictinin (R = galloyl) OH C O O O OH HO OH HO O O HO OH C O HO OH strictinin (R = galloyl) OH HO O O C OR HO OH HO OH O H 2C C O O phyllanthusiin E (R = H) methyl ester ( R = CH3) OH O C O HO HO O brevifolin carboxylic acid HO OH O C-O-CH2 HO ROOC OR O HO HOOC O HO HO HO OH HO OH O OH OH O phyllanthusiin C pelargoniin A Fig. 1. O OH OH OH pelargoniin E ARTICLE IN PRESS H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17 CH2OH OH CH2OH O-galloyl O O C O C O O C OH OH OH HO O HO OH HOOC OHC HO O O HO O HO C O C O HOOC O-galloyl O O O O CH2OH OH O-galloyl OH O 13 OH OH O O pelargoniin B pelargoniin C pelargoniin D H H3CO CH3 OH C OGlc HO H OCH3 O OGlc HO OH OH cyclolariciresinol2a-ß-D-glucoside 4,6-dihydroxyacetophenone2-O-ß-D-glucoside OH OH HO HO O R HO OH R OH HO HO HO HO O R O galloyl-O HO OH OH OH HO O O R OH O galloyl-O OH OH OH OH O OH OH HO O n OH O R OH OH 2“-O-galloyl-isovitexin (R = H) 2”-O-galloyl-isoorientin (R = OH) 2“-O-galloyl-vitexin (R=H) 2”-O-galloyl-orientin (R = OH) HOH2C CH3 proanthocyanidin (R=H or OH) CH3 O O SO3H reniformin Fig. 1. (Continued) is conﬁned to Macaranga tamarius (Euphorbiaceae) (Lin et al., 1990) and that of salidroside-600 -gallate to Quercus phillyraeoides (Fagaceae) (Nonaka et al., 1989) and Q. stenophylla (Nonaka et al., 1982). On the other hand, gallic acid butyl ester represents a new natural product (Lattè, 1999). This species thus provided a remarkable broad range of O-galloylated compounds. As regards ﬂavonoids, the extracts afforded a complex mixture of ﬂavonols, ﬂavanones, dihydroﬂavonols and ﬂavones. Noteworthy is the presence of a unique series of 200 -Ogalloyl derivatives of orientin, isoorientin, vitexin and isovetixin, respectively, representing the ﬁrst described ARTICLE IN PRESS 14 Table 2. sidoides H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17 Constituents of the aerial parts of P. reniforme, P. Compound P. reniforme Phenolic acids, phenylpropanoids and derivatives Gallic acid + Gallic acid methyl ester + Gallic acid ethyl ester + Gallic acid butyl ester + Shikimic acid 3-O-gallate + Shikimic acid 3,5-di-O-gallate + p-Hydroxyphenylethanol + p-Hydroxyphenyl acetic acid + p-Hydroxybenzyl alcohol + Protocatechuic acid p-Coumaric acid + p-Coumaroyl-4-O-b-D-glucoside + Glycerol-1-gallate + Glucogallin + (a,b)-3,4-Di-O+ galloylglucopyranoside Salidroside-600 -O-gallate + Coumarins Scopoletin Umckalin 6,8-Dihydroxy-5,7dimethoxycoumarin Fraxetin Fraxetin-7-b-D-glucoside Magnolioside 6,7-Dihydroxycoumarin-8sulfate Flavonoids Kaempferol 7-O-b-D-glucoside Kaempferol 3-O-b-D-rutinoside Quercetin Quercetin 3-O-b-D-rutinoside Quercetin 7-O-b-D-glucoside Dihydrokaempferol Dihydrokaempferol 3-O-b-Dglucoside Dihydroquercetin (Taxifolin) Taxifolin-7-O-b-D-glucoside Taxifolin-3-O-b-D-glucoside Naringenin 7-O-b-D-glucoside Luteolin 7-O-b-D-glucoside Vitexin Vitexin 200 -O-gallate Orientin Orientin 200 -O-gallate Isovitexin Isovitexin 200 -O-gallate Isoorientin Isoorientin 200 -O-gallate Epigallocatechin-3-O-gallate Hydrolysable tannins Brevifolin carboxyclic acid Phyllantusiin E + + + + + + + + + + + + + + + + + + + + + + + + + + + + Compound P. reniforme Phyllantusiin E O-methyl ester Strictinin Isostrictinin Corilagin Isocorilagin Phyllantusiin C Pelargoniin A Pelargoniin B Pelargoniin C Pelargoniin D Pelargoniin E + + + + + + + + + + + P. sidoides P. sidoides + + + + + Table 2. (continued ) + + + + + + + + + + Miscellaneous (+)-Cyclolariciresinol-2a-b-Dglucoside 4,6-Dihydroxyacetophenone 2O-b-D-glucoside 4-Allyl-2,5-dimethoxyphenol-1b-D-glucoside + + + O-galloyl derivatives of C-glucosylﬂavones (Latté et al., 2002). Proanthocyanidins were associated with ellagitannins, which were conspicuously absent from the root material. Identiﬁed members of the ellagitannins included strictinin and isostrictinin, composed of a central glucose core, adopting the 4C1 conformation, a b-linked galloyl group at C-1 and a hexahydroydiphenoic (HHDP) moiety, formed by oxidative C–C coupling of two adjacent galloyl groups (Fig. 1). Noteworthy was the co-occurrence of a series of structural variants, similarly based on a 1-O-galloyl-b-Dglucopyranose precursor which itself adopts the less favourable 1C4 conformation. However, the galloyl ester groups at C-3 and C-6 are ideally aligned in an axial position for the feasible coupling in this energetically unfavourable chair conformation. These metabolites included corilagin, its unique a-isomer and a series of corilagin-based ellagitannins such as the rarely found phyllantusiin C (Yoshida et al., 1992b; Liu et al., 1999; Amakura et al., 1999) and ﬁve structurally related unique ellagitannins, designated as pelargoniins A–D (Latté and Kolodziej, 2000) including the recently identiﬁed pelargoniin E (unpublished). A remarkable common structural feature of these analogues is the presence of an oxidized DHHDP entity, bridging the 2,3-position. From their close structural relationship to geraniin, a biogenetic relationship may be postulated, though geraniin itself appears to be conspicuously absent from members of the genus Pelargonium. Generally oxidative coupling of galloyl ester groups via the 4C1 form of the glucopyranose precursor is much more widely encountered in plants than that via the ARTICLE IN PRESS H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17 alternative 1C4 conformation (Haslam, 1998). This is the ﬁrst example of the co-occurrence of ellagitannins with 4 C1 and 1C4 glucose cores demonstrated for plants belonging to Geraniaceae. Up to now, only a few plants of the Euphorbiaceae (Saijo et al., 1989a, b), Melastomataceae (Yoshida et al., 1992a) and Onagraceae (Haddock et al., 1982) have been shown to contain both forms of metabolites. Our detailed chemical study on P. reniforme has also led to the isolation of two structurally closely related lignan glucosides, (+)-isolariciresinol-2a-b-glucopyranoside and an isomer of undeﬁned stereochemistry due to limited sample quantity, the ﬁrst members of this group of secondary products to be reported for the Geraniaceae (Lattè, 1999). Noteworthy is also the detection of 4,6-dihydroxyacetophenone 2-O-b-D-glucopyranoside in that acetophenones being reported to occur only in a limited number of plant families (Singh et al., 1997). Pelargonium sidoides DC In its unadulterated form, this species can readily be distinguished by the cordate shape of the leaves and the dark red, but commonly almost black ﬂowers borne on long, slender stalks (Van der Walt and Vorster, 1988). P. sidoides is predominantly found over large parts of the interior of southern Africa, but also occurs in coastal mountain ranges (Van der Walt and Vorster, 1983, 1988). Compositional studies of the roots of P. sidoides provided a similar picture of a broad metabolic proﬁle as found in P. reniforme, reﬂecting a close botanical relationship between these two species. Again, proanthocyanidins were present in signiﬁcant amounts. Here, the putative precursors afzelechin, catechin and gallocatechin could be successfully isolated. In addition, the root extract of P. sidoides also contained a wealth of highly oxygenated simple coumarins, unique in its composition (Table 2 and Fig. 1). For example, 6,8-dihydroxy-5,7-dimethoxycoumarin and 7-acetoxy-5,6-dimethoxycoumarin represent new natural products; the latter being the ﬁrst natural compound known hitherto within this group possessing an acetoxy function (Kayser and Kolodziej, 1995). As for the exclusive 7-hydroxy-5,6-dimethoxycoumarin (umckalin) and 5,6,7-trimethoxycoumarin, earlier work has documented their natural occurrence by their isolation from P. reniforme (Wagner and Bladt, 1974, 1975), which, however, is subject to taxonomic ambiguity. Noteworthy is also the characterization of three novel coumarin sulphates, obtained from polar fractions (Lattè et al., 2000). This group of analogues has hitherto been restricted to three examples reported from a single plant source, Seseli libanotis (Apiaceae) (Lemmich and 15 Shabana, 1984). In this context it should be noted that 6-hydroxy-5,7-dimethoxycoumarin-8-sulfate and 8-hydroxy-5,7-dimethoxycoumarin-6-sulfate could only be obtained as an inseparable mixture despite extensive chromatographic efforts. Their identiﬁcation not only extends the unique series of naturally occurring coumarin sulphates but also introduces the ﬁrst analogues in which sulfation occurred at a phenolic function. Extensive chromatographic efforts have additionally yielded three coumarin glycosides in traces. In the aerial parts, proanthocyanidins were again associated with members of hydrolysable tannins, as evidenced by the identiﬁcation of brevifolincarboxyclic acid and corilagin. Additional notes concern the very limited occurrence of coumarins, in contrast to the abundance in the roots, the distinct presence of C-glycosyl ﬂavones including members of the exclusive series of 200 -O-galloyl analogues (vide supra) and the new metabolite, 4-allyl-2,5-dimethoxyphenol 1-b-Dglucoside (Gödecke, 2005). The identiﬁcation of 6,7-dihydroxycoumarin-8-sulfate not only extends the range of unique natural coumarin sulphates, but also introduces the ﬁrst member found in the aerial parts (Gödecke et al., 2005). EPss 7630 Following the well-documented therapeutic beneﬁts in infectious conditions of the respiratory tract, a proprietary extract of the roots of P. sidoides, EPss 7630 (exclusively contained in Umckaloabos, marketed by Spitzner Arzneimittel, Ettlingen, Germany), has been developed from this traditional herbal medicine and introduced into modern phytotherapy in Europe, in the Commonwealth of Independent States, in Baltic states and in Mexico. EPss 7630 is a special aqueous ethanolic (11% m/m) extract of P. sidoides. Naturally enough, conditions of the extraction procedure have a signiﬁcant impact on the chemical composition of the ﬁnal product. Therefore, our fundamental structural studies on the titled Pelargonium species were recently extended to this medicinal product. The identiﬁed coumarin pattern is strongly reminiscent of that of P. sidoides (Table 1). Also, the limited range of phenolic acids, as evident from our current data, supports this note. In addition, a considerable proportion of high molecular weight proanthocyanidins was found to occur in EPss 7630. No detailed chemistry has yet been carried out on these polyphenols, their characterization being limited to the production of cyanidin and delphinidin upon treatment with acid. On this basis, (epi)catechin and (epi)gallocatechin were shown to be the chain extender units, while the sequence of constituent units, the mode of interﬂavanyl bondings and the stereochemistry remain to be deﬁned. ARTICLE IN PRESS 16 H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17 Conclusion Initially, P. reniforme has been suggested to form the plant source of a South African originating herbal medicine for the treatment of respiratory diseases such as tuberculosis (Bladt, 1974), but, according to present evidence, erroneous identiﬁcation of the plant material claimed to be P. reniforme is evident. For example, the coumarin pattern and here the striking presence of 7-hydroxy-5,6-dimethoxycoumarin (umckalin), typical of P. sidoides, in the previous paper on alleged P. reniforme conﬂicts with current information (vide supra). Independent support for this conjecture is also provided by the geographical origin of the former plant material, i.e. Grahamstown, an area where P. reniforme ssp. velutinum commonly occurs. Thus, it would be of great interest to extend phytochemical studies to this subspecies. Notably, the roots of P. reniforme and P. sidoides express conspicuously distinct coumarin variations, although they contained similarly highly oxygenated simple coumarins based on tri- and tetraoxygenated substitution patterns. Of the identiﬁed coumarins, the two species share the ubiquitous scopoletin, the unique analogues 6,7,8-trihydroxycoumarin and 8-hydroxy-5,6,7-trimethoxycoumarin only that may therefore serve as useful chemical markers. Although the coumarin pools encountered in the two Pelargonium species were very similar, a distinguishing feature appeared to be the presence of a 5,6-dimethoxy arrangement within the group of 5,6,7-trioxygenated members of P. sidoides and an unsubstituted 6-hydroxyl function in that of P. reniforme. Another discriminating chemical character was the distinct occurrence of coumarin sulphates and glucosides in P. sidoides. The concurrent presence of the unique umckalin in both root and aerial parts of P. sidoides may facilitate the identiﬁcation of this species without harvesting roots. With the exception of the characteristic umckalin and 6,7,8-trihydroxycoumarin in the respective species, the remaining coumarins are only present in relatively small amounts. The occurrence of tannins may explain the traditional use of the aerial parts as wound healing agent, which may be attributed, at least in part, to their astringent action. A similar rationale explanation based on the presence of tannins may be provided for the treatment of gastrointestinal disorders such as diarrhoea in traditional medicine. Owing to the high degree of polymerization of proanthocyanidins present in appreciable concentrations, absorption of these tannins from the digestive tract with an intact mucosa is highly unlikely, thereby acting as an effective astringent. For example, the hitherto assumed precipitation of proteins in the epithelial surface of the gut should form a protective layer along the intestinal lumen. Also, some of the beneﬁcial antisecretory effects which tannins exert in these conditions may well follow from their interaction with toxins produced by pathogenic bacteria in the intestine (Hör et al., 1995). Besides, owing to the various reported biological activities of proanthocyanidins (Haslam, 1996, 1998) and their possible impact on the efﬁcacy of EPss 7630, these are the subject of current studies. Coumarins and phenolic compounds including simple phenolic acids and proanthocyanidins are the principal compounds found in the special extract, EPss 7630. Although compositional studies are still in progress, the present data clearly point to a kind of selective extraction, as evident from some ‘missing’ and lowyield occurring substances in this phytotherapeutical product. For example, gallic acid was consistently obtained in fairly high concentrations when the plant material was extracted under more rigorous conditions, whereas it occurred in low amounts in EPss 7630. While the Pelargonium species under study represented attractive sources for a wealth of unusual metabolites, the efﬁcacy of EPss 7630 entails a particularly fascinating account, involving the identiﬁcation of biologically active substances contributing to the hitherto poorly deﬁned underlying active principle. Acknowledgements Sincere appreciation is expressed to Drs. O. Kayser, K.P. Latté, T. Gödecke and M. 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