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Fitoterapia 71 Ž2000.

S58᎐S65

Phytotherapy and quality of herbal


medicines
Raffaele Capassoa, Angelo A. Izzob, Luisa Pintob,
U
Teresa Bifulcob, Carmen Vitobellob, Nicola Mascoloa,
a
Department of Pharmaceutical Sciences, Via Ponte Don Melillo, 84084 Fisciano Salerno, Italy
b
Department 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 as
safe as frequently claimed. Therefore, it can be harmful to take herbal medicines without
being aware of their potential adverse effects. A comprehensive surveillance system for
monitoring the adverse effects of herbal medicines is now essential. Also knowledge of the
correlation existing between the marker compounds and other ingredients that occur in
plants is a necessary requirement for ensuring the efficacy and quality of the herbal
medicines. 䊚 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 in
the industrialised countries. This growing trend to use herbal medicines to treat a
wide range of problems Žfrom insomnia, anxiety, obesity, bronchial asthma, consti-
pation, gingivitis, Vincent’s infection, eczema and varicosity to immunodeficiency
syndrome. has been promoted by: Ži. the development of new diseases, with severe
complications, for which there is still no appropriate treatment; Žii. the belief that
herbal remedies are innocuous, in contrast to conventional drugs; Žiii. the idea that

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

0367-326Xr00r$ - see front matter 䊚 2000 Elsevier Science B.V. All rights reserved.
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R. Capasso et al. r Fitoterapia 71 (2000) S58᎐S65 S59

Table 1
Wild and cultivated medicinal plants: advantages and disadvantages

Factor considered Plant


Wild Cultivated

Availability Decreasing Increasing


Agronomic manipulation No Yes
Adulteration Likely Relatively safe
Botanical identification Not always reliable Not questionable
Fluctuation of supply Unstable Constant quality
Genetic improvement No Yes
Quality control Poor High
Post-harvest handling Poor Usually good

what is natural can only be good; Živ. the special attention that ecological
movements give to herbal medicines in Western countries; and Žv. the belief that
herbal medicines are naturally superior to synthetic drugs w1᎐3x. Another factor
can be found in the progress achieved in the field of production and conservation
of herbal medicines. Today the possibility of cultivating medicinal plants, sometimes
genetically improved, enables to introduce on the market plants which are rich in
desirable active compounds.
Apart from the advantages which cultivation can offer ŽTable 1., the develop-
ment of modern methods of processing and preserving the raw material of
medicinal plants Ždehydration through drying in vacuum packs, liyophilisation, etc..
helps to maintain their quality for a longer time. However, a vast number of herbal
medicines used in Western countries have not been submitted to rigorous scientific
testing and their quality is extremely variable. In addition, the components of these
herbal medicines are not rigorously substantiated. Thus, instances of efficacy and
toxicity have recently surfaced with several commercially available herbal medicines,
challenging the effectiveness and safety reputation of phytotherapy w4᎐6x.

2. Toxicity of herbal medicines and importance of the pharmacovigilance

The potential toxicity of herbal medicines is not new. In several countries, like
Asia and Africa, where herbal medicines are commonly used, it is well known that
some plants must be used with caution because they may be toxic for liver
Žpyrrolizidine alkaloids, apiole, safrole, lignans, etc.., kidney Žterpenes, saponins.,
skin Žsesquiterpene lactones, furanocumarins, etc.. and other tissues w7᎐13x. It is
also known that many plants produce toxic substances Žviscotoxins, lectins,
cyanogenetic glycosides, etc.. which discourage consumption by animals. Herbal
preparations 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
the use of herbs which contain potentially toxic constituents ŽTable 2.. A potential
risk to human health is also presented by the contemporaneous use of multiple
S60 R. Capasso et al. r Fitoterapia 71 (2000) S58᎐S65

herbal products and conventional medicines w2,3x. Herbal medicines can be also
potentially toxic when they delay or replace a more effective form of conventional
treatment or when they compromise the efficacy of conventional medicines.
Furthermore, from the collection of medicinal plants to their consumption as
herbal remedies adulteration andror contamination of commercial products may
occur ŽTable 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 their
doctors that herbal medicines are taken. Many of these products are also sold as
dietary supplements but scientific information about their safe and effective use is
hard to find because limited toxicological data are available on herbal remedies
and the support of rigorous clinical studies is lacking w14x.
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 for
their scarce specificity. To prevent such risks, system of collections of information
must be created Žpharmacovigilance..
Certain herbal medicines can reduce or potentiate the efficacy of a concurrently
used conventional medicine. Therefore, more studies on the interaction between
herbal and conventional medicines would certainly be welcome. The objective is to
find out adverse effects that could appear occasionally from unusual pharmacologi-
cal associations or from the influence of factors regarding the medicine andror the
patient Žage, sex, pathophysiological conditions, genetic characters . w15,16x.

3. Standardisation and efficacy of herbal medicines

It is now well known that the therapeutic efficacy of herbal medicines is not
influenced by a single group of compounds Ži.e. alkaloids in belladonna.. There-
fore, the chemical analysis should not be confined to a single product but extended
to several groups of constituents in order to obtain a characterisation as complete
as possible.
For example, belladonna, the dried leaves of Atropa belladonna, contains pro-
pane alkaloids, flavonoids Žquercetin, kaempferol, glucosidic flavones., chlorogenic
acid and other compounds which may modify the bioavailability and efficacy of the
active constituents w3x. The alkaloids L-hyoscyamine, L-scopolamine, apoatropine,
belladonnine and their derivatives Žatropine, tropine. show, to different degree,
antimuscarinic activity. However, the tropane alkaloids can also react as antihis-
taminic and as effectors of the central nervous system ŽCNS.. So, also scopolamine
has a greater effect than atropine as an antispasmodic w17x. It is clear that the
spasmolytic activity of belladonna depends on the interactions which occur among
propane alkaloids. These constituents can vary greatly as a result of genetic factors,
climate, soil quality and other external factors; as a consequence the spasmolytic
activity of different preparations of belladonna cannot be predicted accurately only
from knowledge of either the hyoscyamine content or the total alkaloid concentra-
tion. When plant constituents other than alkaloids are considered, flavonoids
R. Capasso et al. r Fitoterapia 71 (2000) S58᎐S65 S61

Table 2
Adverse effects that may occur with some herbal medicines

Herbal drug Adverse effects, toxicity Constituent responsible


ŽPlant.

Agnus-castus Allergic reactions; headache, Viticin?


Ž Vitex agnus castus L.. increase in menstrual flow
Alfa alfa Systemic lupus erythematous Canavanine
Ž Medicago sati¨ a L.. syndrome
Aloe Abdominal discomfort, Antraquinones
Ž A. barbadensis, A. ferox, etc.. melanosis coli
Angelica Photodermatitis Furanocoumarins
Ž Angelica archangelica L..
Aniseed Contact dermatitis Anethole
Ž Pimpinella anisum L..
Arnica Gastroenteritis; dermatitis Helenalin, Sesquiterpene
Ž Arnica montana L.. lactones
Artichoke Allergic contact; dermatitis Sesquiterpene lactones
Ž Cynara scolymus L.. Žcynaropicrin.
Blueflag Nausea; vomiting Furfural?
Ž Iris ¨ ersicolor L..
Bogbean Vomiting, diarrhoea Coumarin derivatives?
Ž Menyanthes trifoliata L..
Boldo Renal irritation Volatile oil Žascaridole.
Ž Peumus boldus Mol..
Broom Tachycardia Sparteine
Ž Cytisus scoparius L..
Buchu Gastrointestinal and renal Volatile oil Žpulegone.
Ž Barosma betulina Bart Wendl.. irritation
Calamus Depression, hepatic and heart Volatile oil Ž␤-asarone.
Ž Acorus calamus L.. abnormalities
Capsicum Allergie alveolitis Capsaicinoids
Ž C. annum L ., C. frutescens L.,
C. pubescens, Ruiz et Paron, etc..
Cassia Allergic reactions Cinnamaldehyde
Ž Cinnamomum cassia Blume.
Cereus Nausea, vomiting, ?
Ž Cereus grandiflorus Mill.. diarrhoea
Chamomile german Allergic reactions; Sesquiterpene lactones
Ž Matricaria recutita L.. vomiting Žanthecotulid.; anthemic acid
Chamomile roman Allergic reactions, Sesquiterpene lactones Žnobilin.
Ž 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 alkaloids
ŽTussilago farfara L.. Žsenkirkine.
Comfrey Hepatotoxity Pyrrolizidine alkaloids
Ž Symphytum officinale L..
Cornsilk Allergic reactions ?
Ž Zea mays L..
S62 R. Capasso et al. r Fitoterapia 71 (2000) S58᎐S65

Table 2 Ž Continued.

Herbal drug Adverse effects, toxicity Constituent responsible


ŽPlant.

Cowslip Allergic reactions Quinones Žprimin.


Ž Primula ¨ eris L..
Damiana Convulsions Cyanogenetic glycosides
ŽTeernera diffusa Willd..
Dandelion Contact allergic reactions Sesquiterpene lactones
ŽTaraxacum officinale Weber.
Devil’s clow Headache, anorexia, ?
Ž Harpagophytum procumbens DC.. loss of taste
Elder Nausea, vomiting, diarrhoea Cyanogenic glygosides
Ž Sambucus nigra L..
Elecamp2ane Allergic contact dermatitis Sesquiterpene lactones
Ž Inula helenium L..
Evening primrose Nausea, laxation, headache ?
Ž Oenothera biennis L..
Fever few Gastrointestinal disturbances, Sesquiterpene lactones
ŽTanacetum parthenium L.. hypersensitivity reactions
Fucus Hyperthyroidism Iodine
Ž Fucus ¨ esiculosus L..
Fumitory Raised intraocular pressure and ?
Ž Fumaria officinalis L.. oedema
Garlic Nausea, vomiting, diarrhoea, Sulphur containing compounds
Ž 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, nervousness
Guaiacum Contact dermatitis Resin
Ž Guaiacum officinale L..
Hawthorn Nausea, sweating, rash on the ?
Ž Crataegus monogyna Jacq.. hands
Hops Allergic reactions Myrcene
Ž Humulus lupulus L..
Horse- chestnut Hepatic injury Aescin
Ž Aesculus hippocastanum L..
Hydrocotyle Pruritus, photosensitisations Terpenoids?
Ž Centella asiatica L..
Ispaghula Flatulence, abdominal ?
Ž Plantago o¨ ata Forsk.. distention, intestinal
obstruction
Liquorice Hypertension, sodium chloride Glycyrrhizin
Ž Glycyrrhiza glabra L.. and water retention,
hypokalaemia, weight gain
Lobelia Nausea, vomiting, diarrhoea Lobeline
Ž Lobelia inflata L..
Mate ` Liver disturbances Xanthine constituents
Ž Ilex paraguariensis St.-Hill..
Mistletoe Hepatitis Lectins, viscotoxins
Ž Viscum album L..
R. Capasso et al. r Fitoterapia 71 (2000) S58᎐S65 S63

Table 2 Ž Continued.

Herbal drug Adverse effects, toxicity Constituent responsible


ŽPlant.

Nettle Gastric irritation, oedema, ?


ŽUrtica dioica L.. oliguria
Plantain Laxative and hypotensive effect ?
Ž Plantago major L..
Rubarb See senna Antraquinones
Ž Rheum officinale Baill..
Saw palmetto Gastric disturbances ?
Ž Serenoa repens Hook.
Senna Abdominal discomfort, loss Antraquinones
Ž Cassia angustifolia Vahl.. of electrolytes and water,
melanosis coli, urine coloured
in red
St. John’s wort Photodermatitis Hypericin
Ž Hypericum perforatum L..
Yarrow Allergic reactions ?
Ž Achillea millefolium L..

appear to be synergistic with the alkaloids in spasmolytic action, but antagonistic to


the alkaloids in action on urine retention. Chlorogenic acid may be synergistic with
the alkaloids in antihistaminic activity but antagonistic to alkaloids in CNS ŽFig. 1..
Therefore, the standardisation of belladonna preparations based on selected marker
constituents Žhyoscyamine, total alkaloid content. remains questionable from a
therapeutic standpoint w18x.
The same problem arises with any other herbal preparation. In fact, in the ipecac
preparations are present alkaloids Žemetine, cephaline. which act synergistically,
but also tannins and anthraquinone constituents which can modify the effect of
alkaloids; in cinchona preparations compounds like chlorogenic acid may act
synergistically with the alkaloids quinine, quinidine and cinchonine, while tannins
and anthraquinones could decrease the absorbability of alkaloids from the intesti-

Table 3
Risks contributing to the toxicity of herbal remedies

䢇 Presence of potentially toxic constituents Žapiole, ␤-asarone, estragole, safrole, pyrrolizidine


alkaloids, lectins, cyanogenetic glycosides, sesquiterpene lactones, etc.. in the herbal remedies
䢇 Use of herbal remedies in addition to conventional drugs
䢇 Herbal remedies containing numerous plants
䢇 Automedication
䢇 Misidentification of the plant
䢇 Inadequate preparation and storage
䢇 Presence of contaminants Žmicro-organisms, heavy metals, microbial toxins, pesticides,
fumigation agents, radioactivity, synthetic and animal drug substances .
䢇 Adulteration during conditioning
䢇 Mislabelling of the final product
S64 R. Capasso et al. r Fitoterapia 71 (2000) S58᎐S65

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

nal tract; also the pharmacological effect of ma huang Ž Ephedra sinica. prepara-
tions results from a number of competing actions of alkaloidal Žephedrine,
ephedradines. and non-alkaloidal constituents Žleucoanthocyanidins and other
flavonoids.. The listing could go on and on.
It is also of great importance the appropriate application of herbal medicine
w3,1,19x: the efficacy and harmlessness of herbal medicine depends not only on the
remedy 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 operation
and does not end with the identification and assay of the main active principleŽs..
Standardisation signifies the body of information necessary to guarantee not only a
constant chemical composition of herbal medicines, but also an equal efficacy.

4. Conclusions

Herbal medicines are becoming popular in developed countries as a result of


dissatisfaction with conventional medicines. There is a wide belief that herbal
preparations, being ‘natural’, are intrinsically harmless. Their effects are generally
not due to their natural origin but rather to the pharmacological characteristics
and dose levels of their active constituents. The chemical analysis of the con-
stituents is the most important part of the standardisation. However, herbal
medicines can be potentially toxic if used incorrectly and as substitutes for
R. Capasso et al. r Fitoterapia 71 (2000) S58᎐S65 S65

conventional medicines. Toxic effects can be also attributed to several factors


including toxicity of constituents, contamination of preparations by pesticides,
microorganisms, heavy metals or synthetic drugs. Therefore, both users and doctors
Žand practitioners. should be enabled to make the best risk-benefit assessment
before using any herbal medicine.

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