History

Gentian, possibly not derived from the species now official, was known to Dioskurides and Pliny. The drug was commonly employed during the Middle Ages.

Collection and preparation

When the plants are 2–5 years old, the turf is carefully stripped around each and the rhizomes and roots are dug up. This usually takes place from May to October, collection in the autumn being more difficult on account of the hardness of the soil, although possibly preferable from the medicinal point of view. There is no UK demand for ‘white’ or unfermented gentian, the commercialdrug consisting of ‘red’ or fermented gentian. The method of preparing this varies somewhat in different districts. Usually, the drug is made into heaps, which are allowed to lie on the hillside for some time and may even be covered with earth. After it is washed and cut into suitable lengths the drug is dried, first in the open air and then in sheds. Prepared in this way the drug becomes much darker in colour, loses some of its bitterness and acquires a very distinctive odour.

Macroscopical characters

The plant has a cylindrical rhizome which may attain a diameter of 4 cm and give off roots more than 1 m in length. The crown bears 1–4 aerial stems. The fresh root is whitish and fleshy internally and practically odourless.

The commercial drug consists of simple or branched, cylindrical pieces up to 20 cm long and 1–3 cm diameter. The outer surface is covered with a yellowish-brown cork. The rhizomes are usually of larger diameter than the roots and frequently bear one or more apical buds and encircling leaf scars. On drying, the rhizomes wrinkle transversely, whereas the roots wrinkle longitudinally. The drug is brittle when perfectly dry, but readily absorbs moisture from the air and becomes very tough. It has a characteristic odour and a sweet taste, which later becomes bitter.

Microscopical characters

A transverse section shows an orange–brown bark separated by a darker cambium line from the porous, very indistinctly radiate wood. Only the rhizomes show a pith. More detailed examination shows about 4–6 rows of thin-walled cork cells between which and the cambium is a somewhat thick-walled phelloderm and wide zone of brown, thin-walled parenchyma containing oil globules and minute needles of calcium oxalate. Small groups of soft phloem are seen but phloem fibres are absent.

Examination of the wood and pith shows abundant parenchyma having similar cell contents to those of the bark. The vessels occur either isolated or in small groups and show mainly reticulate or scalariform thickening; a few spiral and annular vessels occur. Groups of soft phloem (‘phloem islands’, ‘interxylary phloem’) occur in the xylem. The drug contains very little starch and no sclerenchymatous cells or fibres.

Allied drugs

The roots of other species of Gentiana (e.g. G. purpurea, G. pannonica and G. punctata) have been imported. They appear to have similar medicinal properties to the official drug but are usually of smaller size. In India the roots of G. kurroa and Picrorhiza kurroa are used as gentian substitutes under the name of ‘kathi roots’. G. kurroa, however is now considered to be a threatened species and shoot multiplication and root formation in in vitro cultures have been studied for its possible propagation. Similarly, work in Japan has focused on the mass production of G. triflora plants by the cultivation of tissue segments in artificial media in the presence of growth hormones. The BP/EP includes a TLC test to differentiate between the official drug and related species.

Adulterants

Adulteration, probably due to careless collection, sometimes occurs. The rhizomes of Rumex alpinus, which give the test for anthraquinone derivatives, have been reported; also a dangerous but easily detected admixture with the rhizomes of Veratrum album.

Constituents

Gentian contains bitter glycosides, alkaloids, yellow colouring matters, sugars, pectin and fixed oil.

The seco-iridoid gentiopicroside (also known as gentiopicrin and gentiamarin; formula see Fig. 24.1) is the principal constituent and was isolated from fresh gentian root in 1862. It occurs to the extent of about 2% and on hydrolysis yields a lactone (gentiogenin) and glucose. A biphenolic acid ester of gentiopicroside, amarogentin, which occurs in small amount (0.025 to 0.05%) has a bitterness value some 5000 times greater than that of gentiopicroside and is therefore an important constituent of the root; other bitters isolated are sweroside and swertiamarin. The isoprenoid gentiolactone has been separated into its enantiomers (Fig. 24.1) by HPLC involving a chiral column (R. Kakuda et al., Chem. Pharm. Bull., 2003, 51, 885) and the same group of workers (J. Toriumi et al., Chem. Pharm. Bull., 2003, 51, 89) has reported on new triterpenes in addition to α-amyrin, β-amyrin and lupeol.

The yellow colour of fermented gentian root is due to xanthones (Chapter 21) and includes gentisin (also known as gentiamarin) (Fig. 21.16), isogentisin and gentioside (a 3β-primeverosidoisogentisin). Gentian also contains gentisic acid (2,5-dihydroxybenzoic acid) and about 0.03% of the alkaloids gentianine and gentialutine, which may be artefacts of the preparation process.

The bitter principles of G. lutea and G. purpurea have been assayed by HPLC and separated preparatively by overpressure layer chromatography. The official BP bitterness value of the root should be not less than 10 000 when determined by comparison with quinine (200 000).

Gentian is rich in sugars, which include the trisaccharide gentianose, the disaccharides gentiobiose and sucrose. During the fermentationprocess these are partially hydrolysed into glucose and fructose. If fermentation is allowed to proceed too far, the hexose sugars are converted into alcohol and carbon dioxide. Gentian should yield 33–40% of water-soluble extractive (BP not less than 33%), but highly fermented root yields much less.

For references to the chemical composition and to the seasonal variations in the content of secondary metabolites, in the aerial parts of G. lutea, see N. Menkovic× et al., Planta Medica, 2000, 66, 178.

Three monoamine oxidase inhibitors have been located in the bark (H. Haraguchi et al., Phytochemistry, 2004, 65, 2255).

Uses

Gentian is used as a bitter tonic. In traditional medicine it has been employed to treat various gastrointestinal conditions, as an anti-inflammatory and wound-healing agent. It is also reported to have choleretic, antioxidative, hepatoprotective and antifungal activities (see A. Mathew et al., Pharm. Biol., 2004, 42, 8).

Constituents

The constituents appear similar for both species and include the iridoid aucubin and derivatives (Fig. 24.1), flavonoids, e.g. apigenin and luteolin (see Table 21.5), sugars, mucilage and various organic acids. The BP/EP requires a minimum of 1.5% of total o-dihydroxycinnamic acid derivatives expressed as acteoside and detects contamination of the drug with Digitalis lanata leaves by TLC.

Uses

Traditional uses of plantain depend on its stated expectorant, diuretic and antihaemorrhagic properties.

Cultivation, collection and preparation

Valerian-growing in England has now ceased. Much drug is still produced in Europe, particularly in Holland; trials carried out in 1971–74 at Poznán on light soil showed that propagation by sowing seed, as distinct from the more laborious planting of seedlings, is fully justified.

History

The word ‘Valeriana’ is first met with in writings of the ninth and tenth centuries. The drug is mentioned in Anglo-Saxon works of the eleventh century, and was much esteemed not only for its medicinal properties, but also as a spice and perfume. Spikenard ointment, which was used by the Romans and has long been used in the East, was prepared from young shoots of Nardostachys jatamansi.

Macroscopical characters

The drug consists of yellowish-brown rhizomes, stolons and roots. The rhizomes are erect, 2–4 cm long and 1–2.5 cm wide, and may be entire or sliced. The roots, which are up to 10 cm long and 2 mm diameter, are more or less matted and broken. In some samples of the drug they almost completely envelop the rhizome, while in others they are mainly separated from it. The drug breaks with a short and horny fracture and is whitish or yellowish internally. The development of the characteristic odour during drying and storage results from a breakdown of the unstable valepotriates and the hydrolysis of esters of the oil to give isovaleric acid as a product, see below. The taste is camphoraceous and slightly bitter.

Microscopical characters

A transverse section of the rhizome shows a thin periderm, a large parenchymatous cortex which is rich in starch and an endodermis containing globules of volatile oil. Within a ring of collateral vascular bundles lies a large pith containing scattered groups of sclerenchymatous cells.

A transverse section of a root shows an epidermis bearing papillae and root hairs, and an exodermis containing globules of oil. The cortex and pith, the latter well-developed in old roots, contain starch. The starch is present mainly in compound grains with two to four components, measuring 3–20 μm diameter.

Constituents

The drug yields about 0.5–1.0% of volatile oil. This contains esters (bornyl isovalerate, bornyl acetate (c. 13.0%), bornyl formate, eugenyl isovalerate, isoeugenyl isovalerate), alcohols, eugenol, terpenes and sesquiterpenes (e.g. valerenal, c. 12%). The latter comprise various acids, esters, alcohols and a ketone (faurinone) some of which are illustrated in the formulae shown (Fig. 24.2).

Fig. 24.2 Some constituents of valerian.

Also present in the drug are epoxy-iridoid esters called vale-potriates: for example valtrate, didrovaltrate, acevaltrate, and isovaleroyloxyhydroxydidrovaltrate (see formulae).

Valerian also contains alkaloids (0.05–0.1% in the dried root); no structures have been assigned to those (e.g. chatinine and valerine) described in the older literature. Two quaternary alkaloids with a monoterpene structure and which are not identical with those previously isolated have been reported; they are similar to skytanthine and related alkaloids, which occur in widely separated families.

Seasonal variations in the constituents of valerian raised in the Netherlands have been reported. Thus the accumulation of valerenic acid and its derivatives together with valepotriates reached a maximum in February to March whereas the volatile oil remained essentially constant during the period of study. Strains producing 0.9% essential oil and a high content of valerenic acid and derivatives (0.5%) were recognizable (R. Bos et al., Planta Medica, 1998, 64, 143). For the clinical significance of such strains see ‘Action and uses’.

Thirteen valepotriates have been identified in the suspension root culture of V. officinalis; root differentiation promotes production. A new iridoid diester, not present in untransformed roots, has been reported in hairy root cultures of var. sambucifolia which also produce various kessane derivatives, tentatively identified as kessyl alcohol and acetate. (F. Grünicher et al., Phytochemistry, 1995, 38, 103; 40, 142).

Quality control

The pharmacopoeia requires a minimum volatile oil content of 0.5% for the whole drug and 0.3% for the cut drug. There is a minimum requirement for sesquiterpenic acids of 0.17% calculated as valerenic acid and maximum values for total ash (12.0%) and ash insoluble in hydrochlaoric acid (5.0%). Stem bases are limited to 5.0%.

Allied drugs

Indian valerian, which is official in the Indian Pharmacopoeia, consists of the dried rhizome and roots of Valeriana wallichii. It is collected in the Himalayas. The drug consists of yellowish-brown rhizomes, 4–8 cm long and up to 1 cm thick, and a very variable amount of roots up to 7 cm long and 1–2 mm thick. The rhizomes are unbranched and somewhat flattened dorsiventrally. The upper surface bears leaf scars and the lower surface roots or root scars. The rhizome breaks with a short fracture, and the horny interior shows a small dark bark, a well-marked cambium, about 12–15 light-coloured xylem bundles and a dark pith and medullary rays. The odour is valerianaceous and the taste bitter and camphoraceous. The drug contains valepotriates and about 0.3–1.0% of volatile oil containing esters of isovalerenic and formic acids.

Centranthus ruber root (Valerianaceae) also contains a number of the valepotriates of valerian.

Japanese valerian or kesso is obtained from Valeriana angustifolia. It yields as much as 8% of volatile oil, which is, however, not identical with the oil in the European drug.

Action and uses

Valerian is used as a carminative, and as an antispasmodic in hysteria and other nervous disorders. It is often prescribed with bromides or other sedatives. Considerable quantities of valerian are used by the perfumery industry.

Previously, one problem with valerian preparations was their unreliability of action and this undoubtedly arose from both the unstable nature of the active constituents and the genetic variability of the plant material. The situation was not helped by the lack of success in ascetaining the identity of the sedative components. The volatile oil did not appear to account for the entire action of the drug and the alkaloids were also ruled out in this respect. Subsequent characterization and demonstration of activity in the group of compounds termed valepotriates in the late 1960s and early 1970s appeared in part to resolve the situation and interest turned to these compounds. Nevertheless, it had previously been demonstrated that two sesquiterpene components of the oil, valerenic acid and valeranone, were physiologically active. Further, a related species Nardostachys jatamansi, which is used in Asia for the treatment of nervous diseases, was shown to contain valeranone but lacked valepotriates. In 1978 the pharmacological properties of valeranone were confirmed and Japanese workers concluded that the sedative properties of Japanese valerian could be ascribed to this group of compounds. When, therefore, reports on the cytotoxicity of valtrate and didrovaltrate appeared in 1981 and 1982 (although no side-effects of oral administration of valerian in man have been reported), attention switched to races and species of valerian, as well as selective preparations of the drug, which lacked these compounds.

Description

The drug consists of mainly transverse, often fan-shaped slices of the tuberous root with a reddish-brown to dark brown, longitudinally wrinkled, cork. Seen in transverse section the vascular bundles are arranged in radial rows. It is odourless but has a very bitter taste.

Microscopical features of the root include thin-walled yellowish-brown cork cells, thin-walled cells of cortical parenchyma which may contain reddish-brown contents, needles and crystals of calcium oxalate together with the vascular elements. Starch grains are absent.