Toxicity of Herbal Constituents PDF

162 Chapter 10 Toxicity of herbal constituents Most toxic effects of herbal medicines are due to the which confer no apparent health benefit, and herbs poor quality of the product. Fo...

162 Chapter 10 Toxicity of herbal constituents Most toxic effects of herbal medicines are due to the which confer no apparent health benefit, and herbs poor quality of the product. For example, herbal med- containing them should be avoided. Allergic reactions icines may be adulterated with synthetic medicines can be elicited by any drug, and idiosyncratic and other compounds, or there may be problems in responses by definition cannot be foreseen; these are the production of such herbal medicines. However, certainly not restricted to plant medicines, although some toxic compounds, including the pyrrolizidine some plant families (e.g. Asteraceae, Ranunculaceae) alkaloids and aristolochic acids, still pose potential are notorious for their allergenicity. serious risks for a few plant-derived products. This chapter is not about toxic plants as such (see Nelson et al 2006), but about those plants used as her- PYRROLIZIDINE ALKALOIDS bal medicines and in therapy. Most common herbal remedies are fairly safe in clinical use; not because These have only been reported in the plant families they are ‘natural’, but because the long history of Boraginaceae, Asteraceae, Leguminosae, Apocyna- use has uncovered some of the adverse effects. ceae, Ranunculaceae and Scrophulariaceae, and Traditional use is not always a reliable indication of not in all species. Medicinal herbs that may be safety, since toxicity which results only from chronic affected include comfrey (Symphytum spp.), butter- use, or manifests after a long interval between taking bur (Petasites hybridus (L.) P. Gaertn., B. Mey. & the medicine and the onset of a reaction, may make the Scherb.), alkanet (Alkanna tinctoria Tausch, Boragi- connection difficult. Many patients do not consider naceae), coltsfoot (Tussilago farfara) and hemp phytomedicines to be ‘drugs’, therefore an association agrimony (Eupatorium cannabinum L., Asteraceae). may not have been made between the remedy and an Not all pyrrolizidine alkaloids are toxic, only those that adverse reaction, so even though a herb has been used are unsaturated at the 1,2-position (e.g. senecionine; for hundreds of years there may remain cause for vig- Fig. 10.1). These are liver toxins and can produce ilance. Knowledge of the chemistry and metabolism veno-occlusive disease of the hepatic vein as well of the constituents of a herb can help to predict toxicity as being hepatocarcinogenic, and their effects are problems. cumulative. Several documented clinical examples As with all medicines, side effects and interactions can be found in the literature. Although highly toxic, with other drugs are possible; but these are a conse- they are chemically rather labile and may, therefore, quence of the therapeutic use of the herb and an assess- not present the serious risk originally thought, at least ment of the usual risk:benefit ratio should be made. in herbal medicines that have undergone a lengthy Problems produced by misidentification, variations process involving heat. For example, when six in composition, which may cause overdose or under- commercial samples of comfrey leaf were tested, dose, and contamination with microorganisms, pesti- none of these alkaloids were detectable. However, in cides or heavy metals are quality issues; however, fresh plant material, and also root samples, they there are a number of known toxic constituents, may be present in significant amounts. The total © 2012 Elsevier Ltd. All rights reserved.  Chapter 10 Toxicity of herbal constituents 163 H CH3 OH been found substituted for Stephania tetrandra S. CH3 Moore. Herbs containing these substances must H3C not be used. The disastrous consequences of using O O them have been a wake-up call for the regulatory O O authorities and the herbal industry. On the other hand, in many regions of the world species from the genus are widely used as local and traditional N medicines especially in the treatment of gastroin- Senecionine testinal complaints like diarrhoea, of snake bites and poisoning, and of gynaecological conditions, Fig. 10.1 including the treatment of sexually transmitted recommended maximum dose of these alkaloids is diseases (STDs) such as syphilis and gonorrhoea less than 1 mg daily for less than 6 weeks per year. If (Heinrich et al 2009; Nortier et al 2000). herbal products, which may contain these, are to be employed (and some are very useful, e.g. butterbur and coltsfoot; see Chapter 16), the content must be ACONITINE AND CONTROVERSIAL estimated and, if necessary, the alkaloids should be CLAIMS ABOUT ‘DETOXIFICATION’ removed before use. Aconitum species (Ranunculaceae) are widely distrib- uted throughout the northern hemisphere and have ARISTOLOCHIC ACID been used medicinally for centuries. They provide a fascinating example of a highly toxic botanical drug, Most species of birthwort (Aristolochia, known as which, according to claims made by some practi- snakeroot) and related genera including Asarum, tioners, can be detoxified by means of its method of all from the family Aristolochiaceae, contain aristo- preparation. The tubers and roots of Aconitum species lochic acid and aristolactams. Aristolochia has been such as Aconitum kusnezoffii Reichb. and Aconitum found as an ingredient in a slimming formula along japonicum Thunb. are commonly used in Traditional with dexfenfluramine and in Europe, since the mid Chinese Medicine in the treatment of conditions 1990s, more than one hundred cases of nephropa- including syncope, rheumatic fever, painful joints, thy caused by the systemic and long term use of gastroenteritis, diarrhoea, oedema, bronchial asthma, Chinese snakeroot (Aristolochia fangchi Y.C. Wu various types of tumour and even some endocrinal ex L.D. Chow & S.M. Hwang), mainly in these disorders like irregular menstruation. However, the weight-loss preparations, has highlighted the risk cardio- and neurotoxicity of this drug is potentially of using preparations which contain aristolochic lethal, and the improper use of Aconitum in China, acids. Aristolochic acid A (Fig. 10.2) is nephrotoxic India, Japan and some other countries still results in and has been responsible for several deaths from a high risk of severe intoxication Singhuber et al 2009. renal failure. Aristolochia and other species contain- Based upon the regulations stipulated by the State ing these compounds are banned from sale in Food and Drug Administration of China (SFDA), Europe and the USA, but may still be present in only the processed (i.e. ‘detoxified’) tubers and roots imported Chinese medicines, and A. fangchi has of Aconitum are allowed to be administered orally or adopted as raw materials for pharmaceutical manu- O CO2H facturing. To date, more than 70 traditional and mod- ern techniques are applied for processing Aconitum O NO2 roots for medicinal use. In China, only two assays are accepted for the quantitative determination of the alkaloid content in Aconitum species in the Chinese Pharmacopoeia 2005, and these allow a maximum of OCH3 0.15% and 0.20% respectively of alkaloids, calculated as aconitine. Botanical drugs which are below this Aristolochic acid A threshold can be used medicinally in China but this Fig. 10.2 position is not accepted in Europe. 164 Fundamentals of Pharmacognosy and Phytotherapy MONOTERPENES AND DITERPENE ESTERS PHENYLPROPANOIDS The phorbol, daphnane and ingenol esters are Most mono- and sesquiterpenes found in essential oils found in plants of the Euphorbiaceae and Thyme- are fairly safe, apart from causing irritation when used liaceae. Some are highly pro-inflammatory and undiluted and allergic reactions in susceptible indivi- are known to activate protein kinase C, as well as duals. However, some have been shown to be carcino- having tumour-promoting (co-carcinogenic) activ- genic, for example safrole (from Sassafras bark) and ity. The most important is tetradecanoyl phorbol b-asarone (from Acorus calamus L.) (Fig. 10.3). They acetate (formerly known as phorbol myristate acet- do not appear to give cause for concern when present ate; Fig. 10.5), which is an important biochemical in minute amounts in other oils. Methysticin, from probe used in pharmacological research. Some nutmeg, is toxic in large doses, and has been postulated of these plants were formerly used as drastic as being a metabolic precursor of the psychoactive purgatives (e.g. croton oil, from Croton tiglium drug methylene dioxymethamphetamine. Thujone L., Euphorbiaceae) but should now be avoided in (Fig. 10.3), which is present in wormwood (Artemisia herbal products. absinthium L.) and in the liqueur absinthe, is also toxic and hallucinogenic in large doses. PLANT LECTINS AND AGGLUTININS SESQUITERPENE LACTONES Castor beans, which are used to produce castor oil for These compounds are present in many Asteraceae use in medicines and cosmetics, contain a toxic lectin, plants, and are often responsible for the biological ricin. This is denatured during manufacture of the oil, activity of the herb. Some are cytotoxic and some are but the oil, and the seed cake remaining (which is used highly allergenic, which can cause problems if misi- as animal feed), should not be used without heat pro- dentification occurs of, for example, mayweed cessing. Pokeweed (Phytolacca americana L.), which is (Anthemis cotula) for one of the chamomiles (Anthemis sometimes used as an anti-inflammatory herb, con- nobilis L. or Matricaria recutita L.). Anthecotulide tains phytoagglutinins called pokeweed mitogens. (Fig. 10.4) is one such allergen and is present in These have been known to cause gastrointestinal several species of the Asteraceae (the daisy family, upset when taken in the fresh herb, but as they are Compositae). heat-labile they may denature on processing. They are also used as biochemical tools in immunology research, for example in blood grouping, erythrocyte CH3 H3C polyagglutination, and lymphocyte subpopulation O studies. OCH3 O H3CO O OCH3 H3C CH3 Safrole β-Asarone Thujone O O Fig. 10.3 H3C(CH2)12 O O CH3 H3C CH3 O H OH H3C H CH3 O H O HO O OH Anthecotulide Tetradecanoyl phorbol acetate (TPA) Fig. 10.4 Fig. 10.5  Chapter 10 Toxicity of herbal constituents 165 OH FURANOCOUMARINS OH Some furanocoumarins (e.g. psoralen, xanthotoxin and imperatorin), which are found in giant hogweed (Heracleum mantegazzianum Sommier & Levier) and Urushiol other umbelliferous plants, as well as in some citrus peels, are phototoxic and produce photodermatitis Fig. 10.7 and rashes on contact. They have a minor legitimate use in PUVA therapy (psoralen plus UV-A radiation) in the treatment of psoriasis, but this is an uncommon severe contact dermatitis. This is a major problem therapy used only in specialist hospital clinics. These in the USA, but less so in Europe where the plants compounds are known to form adducts with DNA, are not native. The anacardic acids, which are as shown in Fig. 10.6. found in the liquor surrounding the cashew nut (Anacardium occidentale L.), are less toxic. The ginkgo- lic acids are reputed to cause allergic reactions; how- URUSHIOL DERIVATIVES ever, they are present in the Ginkgo biloba seed more than in the leaf, which is the medicinal part. Ginkgo The urushiols (Fig. 10.7), anacardic acids and gink- rarely causes this sort of reaction so in practice it is golic acids are phenolic compounds with a long not regarded as a health hazard. side-chain. The uroshiols are found in poison The examples above are not comprehensive but ivy (Toxicodendron radicans (L.) Kuntze) and poison highlight some core problems and how this can be con- oak [T. quercifolium (Michx.) Greene] and cause trolled with appropriate pharmaceutical measures. H O H O N Thymine in DNA N O N H O N H Thymine in DNA O O O O H H N O N O O N O OCH3 O N O OCH3 H Xanthotoxin H Diadduct Fig. 10.6 References Heinrich, M., Chan, J., Wanke, S., Nelson, L.S., Shih, R.D., Balick, M., with the use of a Chinese herb Neinhuis, Ch., Simmonds, M.S.S., 2006. Handbook of poisonous and (Aristolochia fangchi). N. Engl. J. 2009. Local uses of Aristolochia injurious plants, second ed. NY Med. 342, 1686–1692. species and content of and Springer Heidelberg, The New Singhuber, J., Zhu, M., Prinz, S., aristolochic acid 1 and 2 – a global York Botanical Garden. Kopp, K., 2009. Aconitum in assessment based on bibliographic Nortier, J.L., Martinez, M.C., traditional Chinese medicine – a sources. J. Ethnopharmacol. 125, Schmeiser, H.H., et al., 2000. valuable drug or an unpredictable 108–144. Urothelial carcinoma associated risk? J. Ethnopharmacol. 126, 18–30. 166 Chapter 11 What makes phytomedicines unique? Phytomedicines have particular attributes, which are Phytomedicines often take a while to produce a not encountered when using synthetic drugs or sin- measurable improvement and appear to have a gle compounds. Although many natural products cumulative effect; for this reason, long-term ther- have been isolated and are used therapeutically as apy is routine. This is not a unique property of nat- single ingredients, for example most alkaloids (mor- ural products but is also found in conventional phine, hyoscine), cardiac glycosides (digoxin), antic- medicines (e.g. the antidepressants, where several ancer agents (paclitaxel, vincristine) and other highly weeks of treatment may be necessary before a clin- potent drugs. Many more are used in the form of her- ical improvement is seen). The use of drug combi- bal remedies or phytomedicines. Either the whole nations is also not confined to herbal products; for herb or an extract of the plant is prepared, and example, cancer chemotherapy and the treatment may be combined with other herbs or extracts. of HIV and hypertension routinely use drug Also, there is a continuum between products combinations. In addition, although many phyto- which are a (health) food and those which are a medicines may have been characterized phyto- potent herbal medicine (called the food–medicine chemically, their mechanism of action is still interface). In the area of food research, considerable unknown, which makes isolation of one constitu- efforts have been put into understanding the bene- ent impossible. fits of a ‘balanced diet’ and thus a diet which is composed of a complex combination of mixtures. However, in medicines research in general and spe- cifically in research on herbal medicines systematic PROPERTIES OF MIXTURES research has only been developed since the start of this century (Williamson 2001). Herbal practitioners have always argued that the Generally, highly toxic drugs are used as single effects of combinations of ingredients, such as entities since the dose needs to be very precise, those found in herbal medicines, contribute to the but the natural mixture found in a plant extract efficacy of phytomedicines, but until recently there may have benefits conferred by some form of inter- has been little evidence to demonstrate that this is action between the components. Conversely, there the case. In the absence of direct (i.e. clinical) evi- may be toxic ingredients present that do not contri- dence to demonstrate that combination effects are bute to the therapeutic efficacy and which are, there- taking place, indirect evidence may be useful, for fore, undesirable. If the toxic component is also one example, instances where it appears that the dose of the active principles, then the usual assessment of of supposed active constituents, calculated on the risk:benefit profile applies, but quite often the toxic basis of the amount of a known constituent, is too compound serves no useful purpose and must low to have an effect, but clinical and pharmacolo- either be removed or some form of limit test applied. gical evidence has shown that the preparation is in Some examples are discussed in Chapter 10. fact effective. This is the case with willow bark, © 2012 Elsevier Ltd. All rights reserved.  Chapter 11 What makes phytomedicines unique? 167 which will be discussed later. In general, synergis- l Multiple compounds affecting multiple related tic and other interactions within herbal mixtures targets: these are not necessarily interactions, but are considered to be positive, enabling lower doses the result of a number of constituents acting in of potent compounds to be used and reducing the different ways; however, interactions could incidence and severity of side effects. The proper- certainly also be taking place. There may be cases ties of mixtures described below apply to all types where the effect of one compound cancels out the of combinations between two or more drugs, effect of another by antagonism and this would whether of herbal or synthetic origin. They also not be known unless fractionation of an extract apply to drug interactions, which are also a form before testing had been carried out. of synergistic, antagonistic or additive effect, and Several or all of these mechanisms may be taking place the mechanisms of interaction are the same. The at the same time, and the overall effect is, therefore, the body does not know or care where a therapeutic result of a complex interaction between different com- agent originated; it deals with them all in the same ponents of a mixture and different targets which may way, and with the same mechanisms and the same all be relevant in the treatment of a particular condition. enzymes! There may be unwanted interactions in or between phytomedicines, such as the presence of high levels of tannins in a herbal drug, which may complex with SYNERGISTIC, MULTI-FACTORIAL and inhibit the absorption of proteins and alkaloids. AND POLYVALENT EFFECTS As with conventional medicines, interactions may be mediated via the induction or inhibition of cytochrome Synergy and other forms of interaction between the P450 enzymes or P-glycoprotein, and these are dis- constituents of herbal extracts is expected, and cussed below. It must also be remembered that herbal- widely cited as a fundamental tenet of phytother- ists use preparations and mixtures not necessarily apy, but it is still poorly documented, despite a great intended to target a particular enzyme or biochemical deal of interest. Interactions may result in enhance- system. The use of phytomedicines has been described ment of a therapeutic effect, reduction of toxicity or as the ‘herbal shotgun’ approach, as opposed to the ‘sil- preservation of stability. Synergy is a specific type of ver bullet’ method of conventional medicine. This interaction, and needs to be proven experimentally; approach would not only encompass synergy in a however, although it may take place, it actually herb, but would even include routine practices such may not be the most important type of interaction as adding a laxative to a formula for haemorrhoids. occurring in herbal mixtures. Not only may two While here we focus on the unique characteristics or more components of a mixture interact with of complex mixtures, novel concepts and approaches each other, but also single constituents may interact in pharmacology show ‘the other side of the coin’. with different pharmacological targets. Thus, the Network pharmacology and systems biology are various interaction mechanisms involved in the used to represent the different types of relationships action of phytomedicines are now mainly referred between biological entities such as genes, proteins, to as multi-factorial effects (also known as polyva- chemical compounds, and transcription factors. In lent action) and may include the following: essence, the single drug single target view is giving l Several compounds affecting a single target, way to a more complex understanding of networks either directly or indirectly: this may include within an organism affected by a medicine and the synergy, the metabolism of one active altered by complexity of the intervention (Pujol et al 2010). the presence of others in the extract, or the bioavailability of a component changed by the MECHANISMS OF INTERACTION presence of another. These are true interactions and may include pharmacokinetic and Interactions can also be classified as: pharmacodynamic interactions l pharmacodynamic: where the effects of one drug l A single compound affecting multiple targets: are altered or added to by the presence of another this is not an interaction between components at the site of action (so-called ‘pharmacological’ of a mixture of course, but it helps to explain interactions) why a particular herbal medicine (or any drug, for l pharmacokinetic: processes involving absorption, that matter) can be used for different purposes distribution, metabolism and excretion. 168 Fundamentals of Pharmacognosy and Phytotherapy An example of both is provided by Ayurveda, where however, have a precise mathematical definition, an ancient combination formula known as ‘Trikatu’ which may depend on the method used to prove contains black pepper (Piper longum). Pepper contains it. Such methods have been discussed extensively the alkaloid piperine, which has many useful pharma- (Berenbaum 1989, Spelman et al 2006, Wagner 2009, cological activities (anti-inflammatory, anti-allergic, Wagner and Ulrich-Merzenich 2009, Williamson digestive), which add to the desired effects of the other 2001) and the isobole method is generally accepted ingredients in the formula. These could be considered as the method of choice. It is independent of the to be pharmacodynamic interactions. However, mechanism of action and applies under most con- piperine is also known to increase the bioavailability ditions; it makes no assumptions as to the behaviour of a number of drugs by enhancing absorption. of each agent and is, therefore, applicable to multi- Piperine modulates the multidrug transporter ple component mixtures. An isobole is an ‘iso-effect’ P-glycoprotein and influences the efflux of other com- curve, in which a combination of ingredients (da,db) pounds, both herbal and synthetic drugs, from cells is represented by a point on a graph, the axes of (Najar et al 2010). P-gp (the ‘permeability protein’) which are the dose axes of the individual agents is a trans-membrane ATP-binding cassette transpor- (Da and Db). If there is no interaction, the isobole ter or pump, which transports various molecules (the line joining the points representing the combi- across intra- and extra-cellular membranes, especially nation to those on the dose axes representing the in the gut, kidney, liver and blood–brain barrier. It individual doses with the same effect as the combi- regulates the distribution and bioavailability of nation) will be a straight line. If synergy is present, many drugs by blocking or facilitating entry into the dose of the combination needed to produce the cells. Thus, increased intestinal expression of P-gp same effect will be less than that for the individual will reduce absorption of drugs that are substrates, components and the curve will be ‘concave up’. The reducing bioavailability, lowering drug plasma opposite applies for antagonism, which produces a concentrations, and, therefore, reducing efficacy. ‘concave down’ isobole, as shown in Fig. 11.1. Inhibition of P-gp will conversely increase plasma It is quite possible to have synergy at one dose com- concentrations, which may lead to enhanced efficacy, bination and antagonism at another, with the same but also, possibly, drug toxicity. Many other natural substances; this would give a complicated isobole products are also known to modulate P-gp, and these with a wave-like or even elliptical appearance. There- include curcumin, quercetin, hesperidin and epigallo- fore, for complex multicomponent mixtures, a method catechin gallate. They affect the bioavailability of not only other herbal components, but also ‘conventional’ 10 drugs, and this is an untapped therapeutic area which remains to be explored. Inhibition of P-gp by non- Antagonism Dose of A (arbitrary units) 8 toxic, common elements of the diet may even help to delay or inhibit resistance to, for example, antibio- tics and anti-cancer drugs. 6 Piperine, along with many other natural com- Additivity pounds, also inhibits both constitutive and induci- 4 ble cytochrome P450 (CYP-450) drug metabolizing enzymes. Inhibition reduces the metabolism (and, Synergism therefore, rate of clearance from the body) of any 2 other substance metabolized by the same enzymes, whether of herbal or other origin, and thus enhances 0 its blood levels. The opposite can occur: CYP enzy- 0 2 4 6 8 10 mes can be induced, enhancing the clearance of any Dose of B (arbitrary units) drug metabolized by the same enzymes. Fig. 11.1 The three types of combination effect for a mixture of an effective agent A and an ineffective MEASURING SYNERGY compound B. If there is no interaction between A and B, the isobole is a straight line parallel to the dose axis of B (additivity). If The general understanding of synergy is that it is an there is a synergistic interaction, an isobole deviating towards effect seen by a combination of substances that is the B axis is seen: i.e. in the presence of B, smaller doses of A are greater than would have been expected from a sufficient to produce the predetermined effect. When there is consideration of individual contributions. It does, antagonism, the isobole deviates away from the B axis.  Chapter 11 What makes phytomedicines unique? 169 using deviation from predictions can be more suitable; than as an isolated compound. Whole extracts of here, predicted responses are plotted and compared liquorice inhibit angiogenesis, granuloma forma- with actual values obtained experimentally. tion and fluid exudation in inflammation, as does There are only a few examples of synergy avail- isoliquiritin, whereas glycyrrhizin and glycyrrheti- able from the literature, mainly because it is so dif- nic acid tend to promote angiogenesis (reviewed ficult to prove it conclusively. To do so would in Williamson 2001). The mechanism of the an- necessitate first testing the individual constituent(s) tiinflammatory effect has recently been further and comparing the activity with an equivalent investigated on both cyclooxygenase (COX) and dose in the mixture. In addition, different dose com- lipoxygenase (LOX) products, using models of binations would be needed to construct the relevant lipopolysaccharide (LPS)-induced prostaglandin E2 isoboles for proof. It is an immense undertaking and (PGE2), calcimycin-induced thromboxane (TXB2), prohibitively expensive in terms of time and money. and leukotriene (LTB4) release, in murine macro- Antagonism is a much easier concept to define, phages and human neutrophil cells. The whole being a reduced effect from that expected, and tends plant extract, and isolated glabridin, inhibited the to be more easily demonstrated regardless of the release of PGE2 and TXB2 (COX products) and LTB4 mathematical derivation. We, therefore, tend to (a LOX product), while isoliquiritigenin exerted an use the term ‘polyvalent action’ to denote a combi- inhibitory effect only against COX products and nation effect, without necessarily qualifying it. This failed to suppress LOX products (Chandrasekaran can apply to either an increased therapeutic effect, a et al 2010). Glycyrrhizin failed to exhibit any inhibi- reduced profile of side effects or, preferably, both. tory effects on both COX and LOX products in this model, although it has previously shown anti- MULTIPLE PHARMACOLOGICAL EFFECTS inflammatory activity by inhibiting the generation IN A SINGLE PLANT of reactive oxygen species by neutrophils. However, glycyrrhizin has also recently been shown to attenu- Ispaghula, Plantago ovata ate LPS-induced acute lung injury by inhibiting cyclooxygenase-2 (COX-2) and inducible nitric Ispaghula, or psyllium husk, is (paradoxically) effec- oxide synthase expression. In this case, the elevated tive in both constipation and diarrhoea. The laxative concentrations of pro-inflammatory cytokines in- effect is achieved principally through its fibre content, terleukin 1b and tumour necrosis factor (TNF)-a but the reason why it is more effective in chronic con- in bronchoalveolar fluid, caused by LPS adminis- stipation than other types of fibre may be due to the tration, were significantly inhibited by glycyrrhizin fact that the seed also contains constituents with gut pre-treatment, as was the concentration of nitric stimulatory properties, mediated partly through cho- oxide (NO) in lung tissues (Ni et al 2011). These exam- linergic activation, which is likely to enhance the laxa- ples illustrate the complexity of the effects involved in tive effect. Interestingly, it also contains gut inhibitory even a single herbal extract, and it may be that this is constituents, which could provide a scientific expla- found much more commonly than has been pre- nation for the traditional use of ispaghula in diar- viously thought. Liquorice has many other benefi- rhoea. In addition to gut stimulatory and inhibitory cial effects, and is still the subject of intensive constituents, ispaghula also contains anti-amoebic research for its potential use as an anticancer, anti- constituents explaining its traditional use in amoebic viral, smooth-muscle relaxant, antipsoriatic and dysentery, thus demonstrating multiple effects, some even memory enhancing agent, and it is likely that supporting and some opposing a particular activity, even more mechanisms and interactions will be in one medicinal plant (Gilani and Rahman 2005). discovered. Liquorice, Glycyrrhiza glabra CLINICAL EXAMPLES OF SYNERGY In Traditional Chinese Medicine (TCM), liquorice AND POLYVALENT ACTION (Glycyrrhiza glabra) is added to many formulae as a synergistic agent, to enhance activity and detoxify, and it demonstrates a number of instances of syner- Ginkgo, Ginkgo biloba gism not only with its own constituents, but also The ginkgolides are known to be platelet-activating with other herbs. For example, blood levels of gly- factor (PAF) antagonists, a mechanism of anti- cyrrhizin are lower, due to reduced absorption, if inflammatory activity, and a synergistic interaction it is taken as part of an extract or mixture rather between ginkgolides A and B has been shown using 170 Fundamentals of Pharmacognosy and Phytotherapy an in vitro platelet aggregation test. A positive inter- threes’ or ‘serial sevens’, which are arithmetic tests action was shown by an isobole curve using a 50% involving subtracting from a random number. mixture of the two. Furthermore, the presence of Although single treatments showed improvements, the other ginkgolides and the ginkgoflavones also the combination produced a significant and sus- had an effect on the overall activity: a mixture of tained improvement, especially in the ‘serial sevens’ ginkgolides A, B and C, at a dose of 100–240 mg, test (Scholey and Kennedy 2002). generated a PAF-antagonizing effect in humans which was equivalent to a dose of 120 mg of a stan- Cannabis, Cannabis sativa dardized ginkgo extract containing only 6–7 mg of ginkgolides, together with bilobalide and flavonol Cannabis has potential as a therapeutic agent in glycosides (Wagner 1999). However, the ginkgo fla- chronic conditions such as rheumatoid arthritis, vones are also anti-inflammatory, the combination HIV infection and multiple sclerosis. Documented being considered additive and possibly synergistic reports of interactions within the herb include the fact in effect as well as increasing blood circulation to that levels of tetrahydrocannabinol (THC) in the brain the brain, and a total ginkgo extract acts as an anti- can be elevated by cannabidiol, and it is known that oxidant activity in brain preparations. Clinical THC taken alone can induce anxiety, which can be studies have shown ginkgo to be effective in attenuated by the presence of cannabidiol in the herb. improving cognitive function as well as the early There is additional evidence to show that the effect of stages of dementia; the preparation used being a the herb is both qualitatively and quantitatively differ- total extract not just the flavonoids. This suggests ent to that of isolated THC (Wilkinson et al 2003). The polyvalent as well as synergistic activity herb extract is a better antispastic agent than THC Ginkgo, taken in combination with other herbs, alone, as measured in an immunogenic model of mul- also shows synergistic-like interactions: a double- tiple sclerosis (Fig. 11.2). The graph shows that the blind, cross-over trial using 20 young, healthy volun- extract acts more rapidly than isolated THC. The rest teers tested ginseng (Panax ginseng) with ginkgo of the extract has no effect in this system, suggesting extract and found it to be more effective in improving that in this case, the effect of THC is enhanced by cognitive function than either alone. Cognitive per- the presence of other compounds in the extract, but formance was assessed in three studies, using ‘serial there is no additive effect. 10 Percentage change in resistance to flexion ± SEM Δ9 Tetrahydrocannabinol (1 mg/kg) Cannabis Extract (5 mg/kg) 0 P