Ž .Fitoterapia 71 2000 S58]S65

Phytotherapy and quality of herbalmedicines

Raffaele Capassoa, Angelo A. Izzob, Luisa Pintob,Teresa Bifulcob, Carmen Vitobellob, Nicola Mascoloa,U

aDepartment of Pharmaceutical Sciences, Via Ponte Don Melillo, 84084 Fisciano Salerno, ItalybDepartment of Experimental Pharmacology, Uni ersity of Naples ‘Federico II’

Via D. Montesano 49, 80131 Napoli, Italy

Abstract

The extensive use of plants as medicines has pointed out that herbal medicines are not assafe as frequently claimed. Therefore, it can be harmful to take herbal medicines withoutbeing aware of their potential adverse effects. A comprehensive surveillance system formonitoring the adverse effects of herbal medicines is now essential. Also knowledge of thecorrelation existing between the marker compounds and other ingredients that occur inplants is a necessary requirement for ensuring the efficacy and quality of the herbalmedicines. Q 2000 Elsevier Science B.V. All rights reserved.

Keywords: Herbal medicine; Toxicity; Standardisation; Efficacy

1. Introduction

The sale of herbal medicines has increased considerably over the last 10 years inthe industrialised countries. This growing trend to use herbal medicines to treat a

Žwide range of problems from insomnia, anxiety, obesity, bronchial asthma, consti-pation, gingivitis, Vincent’s infection, eczema and varicosity to immunodeficiency

. Ž .syndrome has been promoted by: i the development of new diseases, with severeŽ .complications, for which there is still no appropriate treatment; ii the belief thatŽ .herbal remedies are innocuous, in contrast to conventional drugs; iii the idea that

U Corresponding author. Tel.: q39-089-964-382; fax: q39-81-7486-403.Ž .E-mail address: mascolo@unina.it N. Mascolo .

0367-326Xr00r$ - see front matter Q 2000 Elsevier Science B.V. All rights reserved.Ž .PII: S 0 3 6 7 - 3 2 6 X 0 0 0 0 1 7 3 - 8

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Table 1Wild and cultivated medicinal plants: advantages and disadvantages

Factor considered Plant

Wild Cultivated

Availability Decreasing IncreasingAgronomic manipulation No YesAdulteration Likely Relatively safeBotanical identification Not always reliable Not questionableFluctuation of supply Unstable Constant qualityGenetic improvement No YesQuality control Poor HighPost-harvest handling Poor Usually good

Ž .what is natural can only be good; iv the special attention that ecologicalŽ .movements give to herbal medicines in Western countries; and v the belief that

w xherbal medicines are naturally superior to synthetic drugs 1]3 . Another factorcan be found in the progress achieved in the field of production and conservationof herbal medicines. Today the possibility of cultivating medicinal plants, sometimesgenetically improved, enables to introduce on the market plants which are rich indesirable active compounds.

Ž .Apart from the advantages which cultivation can offer Table 1 , the develop-ment of modern methods of processing and preserving the raw material of

Ž .medicinal plants dehydration through drying in vacuum packs, liyophilisation, etc.helps to maintain their quality for a longer time. However, a vast number of herbalmedicines used in Western countries have not been submitted to rigorous scientifictesting and their quality is extremely variable. In addition, the components of theseherbal medicines are not rigorously substantiated. Thus, instances of efficacy andtoxicity have recently surfaced with several commercially available herbal medicines,

w xchallenging the effectiveness and safety reputation of phytotherapy 4]6 .

2. Toxicity of herbal medicines and importance of the pharmacovigilance

The potential toxicity of herbal medicines is not new. In several countries, likeAsia and Africa, where herbal medicines are commonly used, it is well known thatsome plants must be used with caution because they may be toxic for liverŽ . Ž .pyrrolizidine alkaloids, apiole, safrole, lignans, etc. , kidney terpenes, saponins ,

Ž . w xskin sesquiterpene lactones, furanocumarins, etc. and other tissues 7]13 . It isŽalso known that many plants produce toxic substances viscotoxins, lectins,

.cyanogenetic glycosides, etc. which discourage consumption by animals. Herbalpreparations may come from plants that are not eaten by other mammals. There-fore, we should not be surprised if particular risks of toxicity are associated with

Ž .the use of herbs which contain potentially toxic constituents Table 2 . A potentialrisk to human health is also presented by the contemporaneous use of multiple

( )R. Capasso et al. r Fitoterapia 71 2000 S58]S65S60

w xherbal products and conventional medicines 2,3 . Herbal medicines can be alsopotentially toxic when they delay or replace a more effective form of conventionaltreatment or when they compromise the efficacy of conventional medicines.Furthermore, from the collection of medicinal plants to their consumption asherbal remedies adulteration andror contamination of commercial products may

Ž .occur Table 3 .Unfortunately, the safety of herbal remedies is of particular importance since

most of these products are self-prescribed and patients usually do not inform theirdoctors that herbal medicines are taken. Many of these products are also sold asdietary supplements but scientific information about their safe and effective use ishard to find because limited toxicological data are available on herbal remedies

w xand the support of rigorous clinical studies is lacking 14 .More research in this area is needed. Of particular concern is the effort to find

out effects, very rare but severe, which could be unobserved for their gravity or fortheir scarce specificity. To prevent such risks, system of collections of information

Ž .must be created pharmacovigilance .Certain herbal medicines can reduce or potentiate the efficacy of a concurrently

used conventional medicine. Therefore, more studies on the interaction betweenherbal and conventional medicines would certainly be welcome. The objective is tofind out adverse effects that could appear occasionally from unusual pharmacologi-cal associations or from the influence of factors regarding the medicine andror the

Ž . w xpatient age, sex, pathophysiological conditions, genetic characters 15,16 .

3. Standardisation and efficacy of herbal medicines

It is now well known that the therapeutic efficacy of herbal medicines is notŽ .influenced by a single group of compounds i.e. alkaloids in belladonna . There-

fore, the chemical analysis should not be confined to a single product but extendedto several groups of constituents in order to obtain a characterisation as completeas possible.

For example, belladonna, the dried leaves of Atropa belladonna, contains pro-Ž .pane alkaloids, flavonoids quercetin, kaempferol, glucosidic flavones , chlorogenic

acid and other compounds which may modify the bioavailability and efficacy of thew xactive constituents 3 . The alkaloids L-hyoscyamine, L-scopolamine, apoatropine,

Ž .belladonnine and their derivatives atropine, tropine show, to different degree,antimuscarinic activity. However, the tropane alkaloids can also react as antihis-

Ž .taminic and as effectors of the central nervous system CNS . So, also scopolaminew xhas a greater effect than atropine as an antispasmodic 17 . It is clear that the

spasmolytic activity of belladonna depends on the interactions which occur amongpropane alkaloids. These constituents can vary greatly as a result of genetic factors,climate, soil quality and other external factors; as a consequence the spasmolyticactivity of different preparations of belladonna cannot be predicted accurately onlyfrom knowledge of either the hyoscyamine content or the total alkaloid concentra-tion. When plant constituents other than alkaloids are considered, flavonoids

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Table 2Adverse effects that may occur with some herbal medicines

Herbal drug Adverse effects, toxicity Constituent responsibleŽ .Plant

Agnus-castus Allergic reactions; headache, Viticin?Ž .Vitex agnus castus L. increase in menstrual flow

Alfa alfa Systemic lupus erythematous CanavanineŽ .Medicago sati a L. syndrome

Aloe Abdominal discomfort, AntraquinonesŽ .A. barbadensis, A. ferox, etc. melanosis coli

Angelica Photodermatitis FuranocoumarinsŽ .Angelica archangelica L.

Aniseed Contact dermatitis AnetholeŽ .Pimpinella anisum L.

Arnica Gastroenteritis; dermatitis Helenalin, SesquiterpeneŽ .Arnica montana L. lactones

Artichoke Allergic contact; dermatitis Sesquiterpene lactonesŽ . Ž .Cynara scolymus L. cynaropicrin

Blueflag Nausea; vomiting Furfural?Ž .Iris ¨ersicolor L.

Bogbean Vomiting, diarrhoea Coumarin derivatives?Ž .Menyanthes trifoliata L.

Ž .Boldo Renal irritation Volatile oil ascaridoleŽ .Peumus boldus Mol.

Broom Tachycardia SparteineŽ .Cytisus scoparius L.

Ž .Buchu Gastrointestinal and renal Volatile oil pulegoneŽ .Barosma betulina Bart Wendl. irritation

Ž .Calamus Depression, hepatic and heart Volatile oil b-asaroneŽ .Acorus calamus L. abnormalities

Capsicum Allergie alveolitis CapsaicinoidsŽC. annum L ., C. frutescens L.,

.C. pubescens, Ruiz et Paron, etc.Cassia Allergic reactions CinnamaldehydeŽ .Cinnamomum cassia Blume

Cereus Nausea, vomiting, ?Ž .Cereus grandiflorus Mill. diarrhoea

Chamomile german Allergic reactions; Sesquiterpene lactonesŽ . Ž .Matricaria recutita L. vomiting anthecotulid ; anthemic acid

Ž .Chamomile roman Allergic reactions, Sesquiterpene lactones nobilinŽ .Anthemis nobilis L. vomiting anthemic acid

Chaporral Acute hepatitis Lignans?Ž .Larrea tridentata Coville

Cohash, black Nausea, vomiting ?Ž .Cimicifuga racemosa Nutt.

Coltsfoot Hepatic disturbances Pirrolizidine alkaloidsŽ . Ž .Tussilago farfara L. senkirkine

Comfrey Hepatotoxity Pyrrolizidine alkaloidsŽ .Symphytum officinale L.

Cornsilk Allergic reactions ?Ž .Zea mays L.

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Ž .Table 2 Continued

Herbal drug Adverse effects, toxicity Constituent responsibleŽ .Plant

Ž .Cowslip Allergic reactions Quinones priminŽ .Primula ¨eris L.

Damiana Convulsions Cyanogenetic glycosidesŽ .Teernera diffusa Willd.

Dandelion Contact allergic reactions Sesquiterpene lactonesŽ .Taraxacum officinale Weber

Devil’s clow Headache, anorexia, ?Ž .Harpagophytum procumbens DC. loss of taste

Elder Nausea, vomiting, diarrhoea Cyanogenic glygosidesŽ .Sambucus nigra L.

Elecamp2ane Allergic contact dermatitis Sesquiterpene lactonesŽ .Inula helenium L.

Evening primrose Nausea, laxation, headache ?Ž .Oenothera biennis L.

Fever few Gastrointestinal disturbances, Sesquiterpene lactonesŽ .Tanacetum parthenium L. hypersensitivity reactions

Fucus Hyperthyroidism IodineŽ .Fucus ¨esiculosus L.

Fumitory Raised intraocular pressure and ?Ž .Fumaria officinalis L. oedema

Garlic Nausea, vomiting, diarrhoea, Sulphur containing compoundsŽ .Allium sati um L. contact dermatitis

Ginkgo Gastrointestinal upset, ?Ž .Ginkgo biloba L. headache

Ginseng Hypertension, diarrhoea, ?Ž .Panax ginseng Meyer insomnia, vaginal bleeding, skin

eruptions, nervousnessGuaiacum Contact dermatitis ResinŽ .Guaiacum officinale L.

Hawthorn Nausea, sweating, rash on the ?Ž .Crataegus monogyna Jacq. hands

Hops Allergic reactions MyrceneŽ .Humulus lupulus L.

Horse- chestnut Hepatic injury AescinŽ .Aesculus hippocastanum L.

Hydrocotyle Pruritus, photosensitisations Terpenoids?Ž .Centella asiatica L.

Ispaghula Flatulence, abdominal ?Ž .Plantago o¨ata Forsk. distention, intestinal

obstructionLiquorice Hypertension, sodium chloride GlycyrrhizinŽ .Glycyrrhiza glabra L. and water retention,

hypokalaemia, weight gainLobelia Nausea, vomiting, diarrhoea LobelineŽ .Lobelia inflata L.

Mate Liver disturbances Xanthine constituents`Ž .Ilex paraguariensis St.-Hill.

Mistletoe Hepatitis Lectins, viscotoxinsŽ .Viscum album L.

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Ž .Table 2 Continued

Herbal drug Adverse effects, toxicity Constituent responsibleŽ .Plant

Nettle Gastric irritation, oedema, ?Ž .Urtica dioica L. oliguria

Plantain Laxative and hypotensive effect ?Ž .Plantago major L.

Rubarb See senna AntraquinonesŽ .Rheum officinale Baill.

Saw palmetto Gastric disturbances ?Ž .Serenoa repens Hook

Senna Abdominal discomfort, loss AntraquinonesŽ .Cassia angustifolia Vahl. of electrolytes and water,

melanosis coli, urine colouredin red

St. John’s wort Photodermatitis HypericinŽ .Hypericum perforatum L.

Yarrow Allergic reactions ?Ž .Achillea millefolium L.

appear to be synergistic with the alkaloids in spasmolytic action, but antagonistic tothe alkaloids in action on urine retention. Chlorogenic acid may be synergistic with

Ž .the alkaloids in antihistaminic activity but antagonistic to alkaloids in CNS Fig. 1 .Therefore, the standardisation of belladonna preparations based on selected marker

Ž .constituents hyoscyamine, total alkaloid content remains questionable from aw xtherapeutic standpoint 18 .

The same problem arises with any other herbal preparation. In fact, in the ipecacŽ .preparations are present alkaloids emetine, cephaline which act synergistically,

but also tannins and anthraquinone constituents which can modify the effect ofalkaloids; in cinchona preparations compounds like chlorogenic acid may actsynergistically with the alkaloids quinine, quinidine and cinchonine, while tanninsand anthraquinones could decrease the absorbability of alkaloids from the intesti-

Table 3Risks contributing to the toxicity of herbal remedies

Žv Presence of potentially toxic constituents apiole, b-asarone, estragole, safrole, pyrrolizidine.alkaloids, lectins, cyanogenetic glycosides, sesquiterpene lactones, etc. in the herbal remedies

v Use of herbal remedies in addition to conventional drugsv Herbal remedies containing numerous plantsv Automedicationv Misidentification of the plantv Inadequate preparation and storage

Žv Presence of contaminants micro-organisms, heavy metals, microbial toxins, pesticides,.fumigation agents, radioactivity, synthetic and animal drug substances

v Adulteration during conditioningv Mislabelling of the final product

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Fig. 1. Constituents of Atropa belladonna and their interactions: q, synergism; y, antagonism.

Ž .nal tract; also the pharmacological effect of ma huang Ephedra sinica prepara-Žtions results from a number of competing actions of alkaloidal ephedrine,

. Žephedradines and non-alkaloidal constituents leucoanthocyanidins and other.flavonoids . The listing could go on and on.

It is also of great importance the appropriate application of herbal medicinew x3,1,19 : the efficacy and harmlessness of herbal medicine depends not only on theremedy and its dosage, but also on consumer-related parameters, such as age,genetics, concomitant diseases and concurrent use of other drugs.

Such findings demonstrate that standardisation is not just an analytical operationŽ .and does not end with the identification and assay of the main active principle s .

Standardisation signifies the body of information necessary to guarantee not only aconstant chemical composition of herbal medicines, but also an equal efficacy.

4. Conclusions

Herbal medicines are becoming popular in developed countries as a result ofdissatisfaction with conventional medicines. There is a wide belief that herbalpreparations, being ‘natural’, are intrinsically harmless. Their effects are generallynot due to their natural origin but rather to the pharmacological characteristicsand dose levels of their active constituents. The chemical analysis of the con-stituents is the most important part of the standardisation. However, herbalmedicines can be potentially toxic if used incorrectly and as substitutes for

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conventional medicines. Toxic effects can be also attributed to several factorsincluding toxicity of constituents, contamination of preparations by pesticides,microorganisms, heavy metals or synthetic drugs. Therefore, both users and doctorsŽ .and practitioners should be enabled to make the best risk-benefit assessmentbefore using any herbal medicine.

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