Fitoterapia 71 2000.

S58S65

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. 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 from insomnia, anxiety, obesity, bronchial asthma, consti-
pation, gingivitis, Vincents infection, eczema and varicosity to immunodeficiency
syndrome. has been promoted by: i. the development of new diseases, with severe
complications, for which there is still no appropriate treatment; ii. the belief that
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.
E-mail address: mascolo@unina.it N. Mascolo..

0367-326Xr00r$ - see front matter 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 3 6 7 - 3 2 6 X 0 0 . 0 0 1 7 3 - 8
 R. Capasso et al. r Fitoterapia 71 (2000) S58S65 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; iv. the special attention that ecological
movements give to herbal medicines in Western countries; and v. the belief that
herbal medicines are naturally superior to synthetic drugs w13x. 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 Table 1., the develop-
ment of modern methods of processing and preserving the raw material of
medicinal plants dehydration 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 w46x.

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
pyrrolizidine alkaloids, apiole, safrole, lignans, etc.., kidney terpenes, saponins.,
skin sesquiterpene lactones, furanocumarins, etc.. and other tissues w713x. It is
also known that many plants produce toxic substances viscotoxins, 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 Table 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) S58S65

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 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 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 pharmacovigilance..
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 age, 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 i.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 quercetin, 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 atropine, 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 CNS.. 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) S58S65 S61

Table 2
Adverse effects that may occur with some herbal medicines

Herbal drug Adverse effects, toxicity Constituent responsible

Plant.

Agnus-castus Allergic reactions; headache, Viticin?

Vitex agnus castus L.. increase in menstrual flow
Alfa alfa Systemic lupus erythematous Canavanine
Medicago sati a L.. syndrome
Aloe Abdominal discomfort, Antraquinones
A. barbadensis, A. ferox, etc.. melanosis coli
Angelica Photodermatitis Furanocoumarins
Angelica archangelica L..
Aniseed Contact dermatitis Anethole
Pimpinella anisum L..
Arnica Gastroenteritis; dermatitis Helenalin, Sesquiterpene
Arnica montana L.. lactones
Artichoke Allergic contact; dermatitis Sesquiterpene lactones
Cynara scolymus L.. cynaropicrin.
Blueflag Nausea; vomiting Furfural?
Iris ersicolor L..
Bogbean Vomiting, diarrhoea Coumarin derivatives?
Menyanthes trifoliata L..
Boldo Renal irritation Volatile oil ascaridole.
Peumus boldus Mol..
Broom Tachycardia Sparteine
Cytisus scoparius L..
Buchu Gastrointestinal and renal Volatile oil pulegone.
Barosma betulina Bart Wendl.. irritation
Calamus Depression, hepatic and heart Volatile oil -asarone.
Acorus calamus L.. abnormalities
Capsicum Allergie alveolitis Capsaicinoids
C. annum L ., C. frutescens L.,
C. pubescens, Ruiz et Paron, etc..
Cassia Allergic reactions Cinnamaldehyde
Cinnamomum cassia Blume.
Cereus Nausea, vomiting, ?
Cereus grandiflorus Mill.. diarrhoea
Chamomile german Allergic reactions; Sesquiterpene lactones
Matricaria recutita L.. vomiting anthecotulid.; anthemic acid
Chamomile roman Allergic reactions, Sesquiterpene lactones nobilin.
Anthemis nobilis L.. vomiting anthemic acid
Chaporral Acute hepatitis Lignans?
Larrea tridentata Coville.
Cohash, black Nausea, vomiting ?
Cimicifuga racemosa Nutt..
Coltsfoot Hepatic disturbances Pirrolizidine alkaloids
Tussilago farfara L.. senkirkine.
Comfrey Hepatotoxity Pyrrolizidine alkaloids
Symphytum officinale L..
Cornsilk Allergic reactions ?
Zea mays L..
S62 R. Capasso et al. r Fitoterapia 71 (2000) S58S65

Table 2 Continued.

Herbal drug Adverse effects, toxicity Constituent responsible

Plant.

Cowslip Allergic reactions Quinones primin.

Primula eris L..
Damiana Convulsions Cyanogenetic glycosides
Teernera diffusa Willd..
Dandelion Contact allergic reactions Sesquiterpene lactones
Taraxacum officinale Weber.
Devils clow Headache, anorexia, ?
Harpagophytum procumbens DC.. loss of taste
Elder Nausea, vomiting, diarrhoea Cyanogenic glygosides
Sambucus nigra L..
Elecamp2ane Allergic contact dermatitis Sesquiterpene lactones
Inula helenium L..
Evening primrose Nausea, laxation, headache ?
Oenothera biennis L..
Fever few Gastrointestinal disturbances, Sesquiterpene lactones
Tanacetum parthenium L.. hypersensitivity reactions
Fucus Hyperthyroidism Iodine
Fucus esiculosus L..
Fumitory Raised intraocular pressure and ?
Fumaria officinalis L.. oedema
Garlic Nausea, vomiting, diarrhoea, Sulphur containing compounds
Allium sati um L.. contact dermatitis
Ginkgo Gastrointestinal upset, ?
Ginkgo biloba L.. headache
Ginseng Hypertension, diarrhoea, ?
Panax ginseng Meyer. insomnia, vaginal bleeding, skin
eruptions, nervousness
Guaiacum Contact dermatitis Resin
Guaiacum officinale L..
Hawthorn Nausea, sweating, rash on the ?
Crataegus monogyna Jacq.. hands
Hops Allergic reactions Myrcene
Humulus lupulus L..
Horse- chestnut Hepatic injury Aescin
Aesculus hippocastanum L..
Hydrocotyle Pruritus, photosensitisations Terpenoids?
Centella asiatica L..
Ispaghula Flatulence, abdominal ?
Plantago o ata Forsk.. distention, intestinal
obstruction
Liquorice Hypertension, sodium chloride Glycyrrhizin
Glycyrrhiza glabra L.. and water retention,
hypokalaemia, weight gain
Lobelia Nausea, vomiting, diarrhoea Lobeline
Lobelia inflata L..
Mate ` Liver disturbances Xanthine constituents
Ilex paraguariensis St.-Hill..
Mistletoe Hepatitis Lectins, viscotoxins
Viscum album L..
 R. Capasso et al. r Fitoterapia 71 (2000) S58S65 S63

Table 2 Continued.

Herbal drug Adverse effects, toxicity Constituent responsible

Plant.

Nettle Gastric irritation, oedema, ?

Urtica dioica L.. oliguria
Plantain Laxative and hypotensive effect ?
Plantago major L..
Rubarb See senna Antraquinones
Rheum officinale Baill..
Saw palmetto Gastric disturbances ?
Serenoa repens Hook.
Senna Abdominal discomfort, loss Antraquinones
Cassia angustifolia Vahl.. of electrolytes and water,
melanosis coli, urine coloured
in red
St. Johns wort Photodermatitis Hypericin
Hypericum perforatum L..
Yarrow Allergic reactions ?
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 Fig. 1..
Therefore, the standardisation of belladonna preparations based on selected marker
constituents hyoscyamine, 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 emetine, 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

Presence of potentially toxic constituents apiole, -asarone, estragole, safrole, pyrrolizidine

alkaloids, lectins, cyanogenetic glycosides, sesquiterpene lactones, etc.. in the herbal remedies
Use of herbal remedies in addition to conventional drugs
Herbal remedies containing numerous plants
Automedication
Misidentification of the plant
Inadequate preparation and storage
Presence of contaminants micro-organisms, heavy metals, microbial toxins, pesticides,
fumigation agents, radioactivity, synthetic and animal drug substances .
Adulteration during conditioning
Mislabelling of the final product
S64 R. Capasso et al. r Fitoterapia 71 (2000) S58S65

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

nal tract; also the pharmacological effect of ma huang Ephedra sinica. prepara-
tions results from a number of competing actions of alkaloidal ephedrine,
ephedradines. 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 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 principles..
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) S58S65 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
and practitioners. should be enabled to make the best risk-benefit assessment
before using any herbal medicine.

References
w1x Tyler VE. Herbs of choice. The therapeutic use of phytomedicinals. New York: Pharmaceutical
products Press, 1999.
w2x Shulz V, Hansel R, Tyler VE. Rational phytotherapy. A physicians guide to herbal medicine.
Berlin: Springer-Verlag, 1998.
w3x Capasso F, Grandolini G. Fitofarmacia. Uso razionale delle droghe vegetali. 2nd ed. Milano:
Springer-Verlag Italia, 1999.
w4x Huxtable RJ. Ann Intern Med 1992;117:165.
w5x Carlsson C. Lancet 1990;336:1086.
w6x Gordon DW et al. Chaparral ingestion the broadening spectrum of liver injury caused by
herbal medicines. J Am Med Assoc 1995;273:489490.
w7x Larrey DJ. Hegatology 1997;26:47.
w8x Perharic L, Shaw D, Murray V. Lancet 1993;342:180.
w9x Kaplowitz N. Gastroenterology 1997;113:1408.
w10x DArcy PF. Adverse reactions and interactions with herbal medicines.
w11x Shaw D, Leon C, Kolev S, Murray V. Drug Saf 1997;17:342.
w12x De Smet PAGH. Drug Saf 1993;13:81.
w13x Capobianco DJ, Brazis PW, Fox TP. H Engl J Med 1993;329:1430.
w14x Fossati C, Fanzio G. La Clin Terap 1985;112:249.
w15x De Smet PAGM. In: De Smet PAGM, Kelle K, Hansel R, Chandler RF, editors. Adverse effects
of herbal drugs, vol. 3. Berlin: Springer-Verlag, 1997:113.
w16x Shaw D. J R Soc Med 1998;91:294.
w17x Izaddoost M, Robinson T. In: Craker LE, Simon TE, editors. Synergism and antagonism in the
pharmacology of alkaloidal plants, vol. 2. New York: Food Product Press, 1987:137158.
w18x Bifulco T, Capasso R, Capasso F. Ann Piante Officinali 1999;6:127.
w19x Anderson LA, Phillipson JD. Pharm J 1986;236:303.