Constituents

Alkaloids, up to about 3%, but widely varying; the major alkaloid is (–)-ephedrine (Fig. 16.1), together with many others. These include (+)-pseudoephedrine, norephedrine, norpseudoephedrine, ephedroxane, N-methylephedrine, maokonine, transtorine and the ephedradines A–D. Other components are catechin derivatives, and diterpenes, including ephedrannin A and mahuannin A, have been isolated from other species of Ephedra.

Fig. 16.1

Therapeutic uses and available evidence

Ephedra has been used since ancient times in China for asthma and hay fever, as a bronchodilator, sympathomimetic, CNS and cardiac stimulant. Herbalists also use it to treat enuresis, allergies, narcolepsy and other disorders, and anti-inflammatory activity has been observed in extracts. Ephedrine is used in the form of elixirs and nasal drops, and has an additional use as a heart rate accelerator in the treatment of some types of bradycardia. Pseudoephedrine, the D-isomer of ephedrine produced by chemical synthesis, is usually the compound of choice for isolated alkaloid preparations. Ephedra herb, ephedrine and pseudoephedrine are all the subject of European Pharmacopoeia (Eur. Ph.) monographs. Ephedra herb is used as an anti-allergic agent; this is supported by evidence that it induces immunoglobulin A in Peyer’s patches and blocks complement activation by both the classical and alternative pathways.

Toxicological risks

The herb has been abused as a slimming aid, and an ergogenic aid in sports and athletics, but this is dangerous (Fleming 2008). For example, hypertension and other cardiovascular events, and a case of exacerbation of hepatitis, have been noted with high doses. The absorption of ephedrine and pseudoephedrine is slower after ingestion of the herb than for isolated alkaloid preparations, and the other constituents, the ephedradins, mahuannins and maokonine, are mildly hypotensive; but both the herb and the isolated alkaloids should be avoided by hypertensive patients as well as in cases of thyrotoxicosis, narrow-angle glaucoma and urinary retention. Therapeutic doses of the herb are calculated to deliver up to 30 mg of the alkaloids, calculated as ephedrine.

Toxicological risks

Camphor has been in use for many years; however, ‘camphorated oil’ was recently taken off the market since, in large quantities, camphor may be absorbed through the skin causing systemic toxicity. Overdose causes vomiting, convulsions and palpitations, and can be fatal. However, when used externally in therapeutic doses it is generally well tolerated.

Constituents

The oil contains 1,8-cineole (eucalyptol; see Fig. 16.4) as the major component, with terpineol, α-pinene, p-cymene and small amounts of ledol, aromadendrene and viridoflorol, aldehydes, ketones and alcohols.

Fig. 16.4

Therapeutic uses and available evidence

The oil is antiseptic, antispasmodic, expectorant, stimulant and insect repellent. It is a traditional Australian Aboriginal remedy for coughs, colds and bronchitis. It may be taken internally in small doses (0.05–0.2 ml), as an ingredient of cough mixtures, sweets and pastilles, or as an inhalation; it is applied externally in the form of a liniment, ointment or ‘vapour rub’. The leaf extract and oil have well-defined antiseptic effects against a variety of bacteria and yeasts. The oil is also insect-repellent and larvicidal, and is used in pharmaceutical products for these properties as well as for its antiseptic and flavouring properties in dentifrices and cosmetics. It is widely used in Menthol and Eucalyptus Inhalation BP for steam inhalation as a decongestant. Eucalyptus oil is irritant and, although safe as an inhalation, caution should be exercised when taken internally as fatalities have been reported.

Constituents

Butterbur contains sesquiterpene lactones (eremophinolides), including a series of petasins and isopetasins, neopetasin, petasalbin, furanopetasin, petasinolides A and B, and flavonoids including isoquercetin glycosides. However, toxic pyrrolizidine alkaloids (senecionine, integerrimine, senkirkine, petasitine and neopetasitine) may be present, usually in higher concentrations in the root.

Therapeutic uses and available evidence

Butterbur is traditionally used as a remedy for asthma, colds, headaches and urinary tract disorders. It is used as an antihistamine for seasonal allergic rhinitis, and a recent randomized, double-blind comparative study using 125 patients over 2 weeks of treatment showed that butterbur extract is as potent as cetirizine. The anti-inflammatory activity is due mainly to the petasin content. Extracts inhibit leukotriene synthesis and are spasmolytic, and reduce allergic airway inflammation and AHR by inhibiting the production of the Th2 cytokines IL-4 and IL-5, and RANTES (Brattström et al 2010), thus supporting its use in asthma. Use as prophylactic treatment for migraine has also been suggested but further evidence of efficacy is needed (Agosti et al 2006). The usual dose is an extract equivalent to 5–7 g of herb or root. Internal use is not recommended unless the alkaloids are present in negligible amounts or have been removed from preparations, as is the case with the commercially available product, which is a ‘special extract’. Maximum intake of the alkaloids should be less than 1 μg daily for fewer than 6 weeks per year.

Constituents

Key active principles are furanocoumarins, the most important being khellin (Fig. 16.5), together with visnagin, visnadin and khellol glucoside.

Fig. 16.5

Therapeutic uses and available evidence

Khellin, visnadin and visnagin are vasodilators, with calcium channel blocking and spasmolytic activity. Khellin was the starting material for the development of several important semi-synthetic derivatives such as sodium cromoglycate, which is widely used as a prophylactic treatment for asthma, hay fever and other allergic conditions, often in the form of an inhaler or eyedrops. It was also the basis for the development of nifedipine (a calcium channel antagonist and vasodilator) used in heart disease, and amiodarone, a cardiac antiarrhythmic.

Constituents

All contain the phenolic glycosides salicin (salicyl alcohol glucoside), populin (benzoyl salicin) and a volatile oil containing α-caryophyllene, with cineole, bisabolene and farnesene. Flavonoids (pinocembrin and pinobanksin) and, in P. nigra at least, lignans, based on isolariciresinol, have been isolated.

Therapeutic uses and available evidence

Balm of Gilead is an expectorant, stimulant, antipyretic and analgesic. It is a common ingredient of herbal cough mixtures, and also ointments used for rheumatic and other muscular pains. The phenolic glycosides (e.g. salicin) and the volatile oil constituents have antiseptic and expectorant activity. Little evidence is available for efficacy, but the drug has a long history of traditional use. The bark of poplar species is used in a similar way to willow bark, as an antirheumatic.

Balm of Gilead is generally non-toxic, except for patients who are allergic to salicylates. If excessive amounts of these drugs are taken, adverse effects such as stomach upset and tinnitus are possible, due to the salicylate content.

Constituents

The active principle is the volatile oil, which has the major constituent thymol, with lesser amounts of carvacrol, 1,8-cineole, borneol, thymol methyl ether and α-pinene. However, the flavonoids (apigenin, luteolin, thymonin, etc.) and the polyphenolic acids (labiatic, rosmarinic and caffeic) are expected to contribute to the anti-inflammatory and antimicrobial effects.

Therapeutic uses and available evidence

Thyme, and oil of thyme, are carminative, antiseptic, antitussive, expectorant and spasmolytic, and, as such, are used for coughs, bronchitis, sinusitis, whooping cough and similar respiratory complaints. Most of the activity is thought to be due to the thymol, which is expectorant and highly antiseptic. Thymol and carvacrol are spasmolytic and the flavonoid fraction has a potent effect on the smooth muscle of guinea pig trachea and ileum. Thymol (Fig. 24.1) is a popular ingredient of mouthwashes and dentifrices because of its antiseptic and deodorant properties. The oil may be taken internally in small doses of up to 0.3 ml, unless for use in a mouthwash, which is not intended to be swallowed in significant amounts.

Thymol is irritant, and toxic in overdose, and should be used with care.

Constituents

Sage contains a volatile oil, with α- and β-thujone as the major components (usually about 50%), and cineole, borneol, camphor, 2-methyl-3-methylene-5-heptene and others. Spanish sage does not contain thujone; Greek sage contains only small amounts. Diterpene bitters picrosalvin (carnosol), carnosolic acid, abietane derivatives called royleanones, and flavonoids such as salvigenin, genkwanin, luteolin and derivatives are present, together with the polyphenolic acids salvianolic, rosmarinic and caffeic acids.

Therapeutic uses and available evidence

An infusion of sage is used as a gargle or mouthwash for pharyngitis, tonsillitis, sore gums, mouth ulcers and other similar disorders. Sage extracts and oil have been reported to be antimicrobial. The flavonoids and phenolic acid derivatives have antiviral and anti-inflammatory activity. Sage has a reputation for enhancing memory, and there is some clinical trial evidence (Scholey et al 2008), and the fact that it has anticholinesterase activity, to support this use.

Constituents

The active constituents are triterpenoid saponins, the mixture generally known as ‘senegin’. These are based on the aglycones presenegenin, senegenin, hydroxysenegin, polygalacic acid and senegnic acid, including the E- and Z-senegins II, III and IV, E- and Z-senegasaponins a, b and c, and others.

Therapeutic uses and available evidence

Senega is used primarily for chronic bronchitis, catarrh, asthma and croup. The saponins are the active constituents, as with other mucolytic plant drugs, and senega is usually taken orally as an infusion. The saponins also have immunopotentiating activity to protein and viral antigens, and exhibit less toxicity than quillaia saponins. They are anti-inflammatory and antiseptic. Senega extracts, the senegasaponins and the senegins are hypoglycaemic in rodents, the senegasaponins are inhibitors of alcohol absorption, and the senegins also have anticancer and anti-angiogenic effects in vitro (Arai et al 2011). The dose is usually equivalent to 0.5–1 g of the powdered root.

The saponins are irritant and haemolytic, but taken orally do not appear to pose many problems. Nausea and vomiting are the most common side effects and, in view of the other pharmacological actions, care should be taken with senega when given in high doses or to sensitive individuals.

Constituents

The actives are saponins based on oleanolic acid, bayogenin and hederagenin, including the hederosaponins (or hederacosides) B, C and D, and α- and β-hederin, the polyyne falcarinol, and also flavonoids.

Therapeutic uses and available evidence

Ivy extracts are used in preparations for bronchitis and catarrh, as an expectorant. The saponins and sapogenins are the main active ingredients; they are expectorant and antifungal. Few clinical studies have been carried out, and further work is needed (Holzinger and Chenot 2011). One study showed that after 7 days of therapy with dried ivy leaf extract, 95% of patients showed improvement or healing of their symptoms, and it was safe and well-tolerated: the overall incidence of adverse events was 2.1%, mainly gastrointestinal disorders (Fazio et al 2009).

Both the saponin and the flavonoid fractions have spasmolytic effects.

A specific mode of action relevant for respiratory conditions of the saponins has been postulated: hederacoside C (which is converted into α-hederin by esterases) as well as its aglucone hederagenin, acts on G protein-linked β₂-adrenergic receptors of epithelial lung cells, resulting ultimately in an indirect β₂-sympathomimetic effect (Hegener 2004). Ivy extracts are often used in cosmetic preparations to treat cellulite, with some success. Ivy saponins are being widely investigated for their antileishmanial, molluscicidal, antimutagenic, antithrombin and anticlastogenic effects. The usual therapeutic dose as an expectorant is 0.3 g of crude drug, or equivalent.

Like all saponin-containing drugs, ivy can be irritant and allergenic. These effects are also due at least in part to the falcarinol content.

Constituents

The main constituents of the balsam are cinnamic and benzoic acids, their esters such as benzyl benzoate and cinnamyl cinnamate, and esters with resin alcohols, including coniferyl and hydroconiferyl benzoates.

Therapeutic uses and available evidence

Balsam of tolu is expectorant, stimulant and antiseptic. It is used in cough mixtures and pastilles, and as a lozenge base. Although there is no modern clinical evidence, many balsams are used for similar purposes and generally agreed to have a useful therapeutic role as expectorants, antiseptics and demulcents. Balsam of tolu is an ingredient in Friar’s balsam, which is used as a steam inhalation and also as a protectant in skin formulations. The antimicrobial activity is due to the benzyl benzoate and benzyl cinnamate content.

Tolu balsam, like many other balsam resins, can cause allergic reactions.

Constituents

Both species contain isoquinoline alkaloids as the active principles, usually about 2–3%. The most important are emetine (Fig. 16.6) and cephaeline, with psychotrine and some others.

Fig. 16.6

Therapeutic uses and available evidence

Ipecac extract is an ingredient of many cough preparations, both elixirs and pastilles, because of its expectorant activity. It is also well known as an emetic and has been employed to induce vomiting in cases of drug overdose, particularly in children. This use is, however, highly controversial (Quang and Woolf 2000). The alkaloids are amoebicidal, but the emetic activity means that they are rarely used for this purpose. There is little clinical evidence for the use of ipecac as an expectorant but it has a long history of traditional use. Ipecacuanha Liquid Extract BP is given at a dose of 0.25–1 ml.

Ipecac causes vomiting in large doses and the alkaloids are cytotoxic.

Constituents

The main constituent is a mucilage composed of acidic polysaccharides, together with flavonoids, triterpenes and sterols. Pyrrolizidine alkaloids, including senkirkine, tussilagine and isotussilagine, may be present in variable amounts, usually very minor (about 0.015%) or absent, depending on source.

Therapeutic uses and available evidence

Coltsfoot is used for pulmonary complaints, irritating or spasmodic coughs, whooping cough, bronchitis, laryngitis and asthma. The polysaccharides are anti-inflammatory and immunostimulating, as well as demulcent, and the flavonoids also have anti-inflammatory and antispasmodic action.

The pyrrolizidine alkaloids are known to cause hepatotoxicity in rats fed daily on high doses, but not on daily low-dose regimens, and appear not to cause damage to human chromosomes in vitro. However, samples containing significant quantities of these alkaloids should not be used.

Constituents

Triterpenes including ursolic and oleanolic acid derivatives, flavonoids (rutin, quercetin, nicotoflorin, hyperoside), and phenolic acids such as chlorogenic acid are the main actives. The flowers contain an essential oil.

Therapeutic uses and available evidence

Elder flowers are used as an infusion or herbal tea, and a mixture with peppermint is a traditional remedy for colds and influenza. They induce perspiration, which is thought to be beneficial in such cases. Recent studies show an in vitro activity against several strains of influenza virus, and a clinical study has also demonstrated a reduction in the duration of flu symptoms for the berries (see Vlachojannis et al 2010 for review). The effect was attributed to an increase in inflammatory cytokine production as well as a direct antiviral action. The usual dose is about 3 g of flowers infused with 150 ml of hot water, but is not critical. Elder flowers are non-toxic and no side effects have been reported. Both the berries and the flowers are used to make cordials which are taken medicinally for their reputed antioxidant and antiviral properties.

Constituents

The flowers contain volatile oil (linalool, germacrene, geraniol, 1,8-cineole, 2-phenyl ethanol and others), flavonoids (hesperidin, quercetin, astralagin, tiliroside), a mucilage of arabinose, galactose and rhamnose polysaccharides, polyphenolics such as chlorogenic and caffeic acids, and GABA (γ-aminobenzoic acid).

Therapeutic uses and available evidence

Linden flowers are used for feverish colds, catarrh, coughs and influenza. They are used as herbal teas to induce diaphoresis (perspiration) like elder and at a similar dose (see above). The polysaccharides are soothing and adhere to epithelial tissue, producing a demulcent effect. The other main use of the flowers is for nervous disorders; the extract is thought to act as an agonist for the peripheral benzodiazepine receptor. There is evidence that components of the aqueous extract of the flowers bind to GABA receptors in rat brain (an effect not due entirely to the GABA content of the extract) and mild sedative effects were confirmed using the elevated maze anxiety test in mice (Anesini 1999). Linden flowers are non-toxic and no side effects have been reported.

Constituents

The main constituents are mucilages, sulphated flavonol glycosides such as gossypin-3-sulphate, hypolaetinglucoside-3′-sulphate and others, and anthocyanins (malvin, the diglucoside of malvidin, and delphinidin).

Therapeutic uses and available evidence

Mallow is a demulcent and pectoral. An infusion is used for colds and coughs, and the mucilage from the leaves is anti-inflammatory with anticomplement activity. Little clinical evidence is available but there is a long tradition of historical use. No adverse effects are known.

Constituents

Both rootstock and leaves are rich in mucilage, consisting of a number of polysaccharides (composed of L-rhamnose, D-galactose, D-galacturonic acid and D-glucuronic acid) and others. It also contains common flavonoids, especially derivatives of kaempferol and quercetin.

Therapeutic uses and available evidence

Both the leaves and root are used internally for coughs and bronchial complaints. Extracts of both are used occasionally for gastric and urinary inflammation in general, and for cystitis. They may be applied externally as a soothing poultice and vulnerary. The mucilages have proven biological activity, including the stimulation of phagocytosis in vitro. Antimicrobial and anti-inflammatory activities have also been documented. Several of the polysaccharides isolated from the roots have been found to have antitussive activity. The most common use of extracts of marshmallow root is in the making of confectionery.

Constituents

The main active components are hydrolysable tannins, (+)-catechin, gallic acid and methyl gallate, including a unique series of O-galloyl-C-glucosylflavones. Flavonoids including myricetin and quercetin-3-O-beta-d-glucoside, coumarins including scopoletin, umckalin, 5,6,7-trimethoxycoumarin and 6,8-dihydroxy-5,7-dimethoxycoumarin, are present in both species. A series of benzopyranones has been isolated from P. sidiodes, and the pelargoniins (a type of ellagitannin) and a diterpene, reniformin, have been found in P. reniforme.

Therapeutic uses and available evidence

In Germany, a standardized extract of Pelargonium sidoides (EPs® 7630, also known as Umckaloabo®) is registered by the Federal Institute for Drugs and Medical Devices (BfArM) for the indication ‘acute bronchitis’ and several randomized, double-blind, placebo-controlled clinical trials support its efficacy in adults and children (Agbabiaka et al 2008). The extract EPs® 7630 has multiple effects which are beneficial in respiratory infections, and include antiviral, antibacterial, immunomodulatory and cytoprotective effects. It also increases the frequency of ciliary beats, thus helping to remove pathogens for the upper respiratory tract, and inhibits the interaction between bacteria and host cells. A recent study has found that EPs® 7630 interferes with the replication of different respiratory viruses including seasonal influenza A virus strains, RSV, human coronavirus, parainfluenza virus and coxsackie virus (Michaelis et al 2011). This extract is also given to athletes to help strengthen the immune system, which can be compromised by extreme exercise, to protect against colds. A study in athletes submitted to intense physical activity found that Pelargonium sidioides increased the production of secretory immunoglobulin A in saliva, and decreased levels of both interleukin-15 and interleukin-6 in serum, suggesting a strong modulating influence on the immune response associated with the upper airway mucosa (Luna et al 2011).

Constituents

Numerous compounds have been identified, but the most pharmacologically relevant ones are not known. All species contain similar types of compounds, although not necessarily the same individual ones. The most important are the caffeic acid derivatives, including echinacoside (Fig. 16.8) (E. pallida root), cichoric acid (E. purpurea aerial parts) and others, and the alkylamides (found throughout the plant in all three species), which are a complex mixture of unsaturated fatty acid derivatives. Some have a diene or diyne structure (with two unsaturated and two triple unsaturated groups) or a tetraene structure (with four unsaturated groups) linked via an esteramide to a (2)-methylpropane or (2)-methylbutane residue.

Fig. 16.8

Therapeutic uses and available evidence

Echinacea preparations are available both as traditional herbal medicinal products used to relieve the symptoms of the common cold and influenza type infections, but also as preparations with a well-established use. There is some evidence in the treatment and prevention of respiratory infections, but more limited evidence for slow healing wounds using topical applications. Clinical evidence for uses as an immunostimulant is available for some of the chemically characterised extracts. Overall a series of meta-analyses showed that Echinacea preparations seem to be efficacious both therapeutically (reducing symptoms and duration) and in terms of prophylaxis against the common cold (Shah et al 2007, Woelkart et al 2008). However, Echinacea preparations tested in clinical trials differ greatly. There is better evidence that preparations based on the aerial parts of E. purpurea might be effective for the early treatment of colds in adults but the results are not fully consistent. A mechanism of action has been postulated by Chicca et al (2009), suggesting that the alkylamides dodeca-2 E,4E,8Z,10Z-tetraenoic acid isobutylamide (A1) and dodeca-2E, 4E-dienoic acid isobutylamide (A2) bind to the cannabinoid-2- (CB2) receptor and are the main anti-inflammatory and immune-modulatory principles, acting in synergy. In addition, alkylamides potently inhibit LPS-induced inflammation in human whole blood and exert modulatory effects on cytokine expression, but these effects are not exclusively related to CB2 binding.

Echinacea appears to be safe, although allergic reactions have been reported. The risk of interactions seems to be very limited (Modarai et al 2007).

Constituents

Triterpenoid saponins, the astragalosides I–VIII, and their acetyl derivatives, agroastragalosides I–IV, astramembranins I and II and others; isoflavones including formononetin and kumatakenin, and polysaccharides known as astrogaloglucans.

Therapeutic uses and available evidence

A number of clinical studies, supported by data from over 1000 patients in China, confirm the use of astragalus as an immunostimulant for use in colds and upper respiratory infections. It is also used prophylactically. In China it is also used as an adjunctive in the treatment of cancer, and appears to potentiate the effects of interferon. It also has antioxidant, hepatoprotective and antiviral activity and is used to enhance cardiovascular function (www.thorne.com 2003). Many animal studies have been carried out, but specific data on toxicity are sparse. In general, astragalus is well tolerated but should probably be avoided in autoimmune diseases.

Constituents

The main actives are diterpenes, known as andrographolides, and consist of andrographolide and its many analogues, including neoandrographolide, isoandrographolide, 14-deoxyandrographolide, 14-deoxy-14,15-dehydroandrographolide, 3,19-isopropylideneandrographolide and 14-acetylandrographolide and many others. Flavonoids and polyphenols such as 7-O-methylwogonin, apigenin, onysilin and 3,4-dicaffeoylquinic acid are also present. An alkaloid, andrographine, and a series of sesquiterpene lactones, paniculides A, B, and C, are also present in the root.

Therapeutic uses and available evidence

Andrographis is most commonly used as an immune stimulant, but is also reputed to possess antihepatotoxic, antimicrobial, antithrombogenic, antiinflammatory and anticancer properties (www.thorne.com 2003). Andrographolide has been shown to have immunostimulatory activity, shown by an increase in proliferation of lymphocytes and production of interleukin-2, and the antiinflammatory activity has been demonstrated by an inhibition of NFĸB, nitric oxide, PGE2, IL-1β, IL-6, LTB4, TXB2 and histamine (Bao et al 2009, Chandrasekaran et al 2010). In one Chilean study, andrographis herb had a significant drying effect on the nasal secretions of cold sufferers who took 1,200 mg of the extract daily for 5 days (Cáceres et al 1999). A systematic review of the literature has suggested the herb alone (or in combination with Eleutherococcus) may be an appropriate treatment for uncomplicated acute upper respiratory tract infection (Poolsup et al 2004).