[P-101]
ARE HERBAL REMEDIES SAFE FOR GENERAL USE?

Silva DOBRIĈ, Vesna KILIBARDA, Dubravko BOKONJIĈ and
Viktorija DRAGOJEVIĈ-SIMIĈ
National Poison Control Center, Military Medical Academy, Crnotravska 17, 11000 Belgrade, FR Yugoslavia

ABSTRACT

Traditional herbal remedies are used by many patients for selfhealing because they enjoy a reputation as natural products with significant biological potency, which are safer than conventional medicines. Over the past two decades, however, many reports dealing with adverse effects or toxicity of herbal products have been published. Analysis of these reports has been shown that herbal remedies may cause serious gastrointestinal, haematological, cardiac, renal and nervous system adverse reactions and interact with standard drug therapy. In general, both physicians and patients have lack of awareness regarding hazards of herbal products. Physicians should ask patients about use of herbal preparations when a drug history is taken, especially when they have unusual symptoms and signs. On the other hand, people should be educated about rational use of herbal remedies. It means, among other things, not to stop their use, but their abuse.


INTRODUCTION

Traditional herbal remedies are used by many patients for selfhealing. The potential risk of toxicity with herbal products is increased because they are not categorised as drugs (many of them are sold in health food stores and are designed as dietary supplements) and are, therefore, not subjected to standard tests for safety and effectiveness or good manufacturing practice standards that ensure quality control. Many herbal products are imported from foreign countries and often, like some domestic ones, do not have the active or inactive ingredients listed on the package labelling. Besides, many patients use herbal medicines along with standard drug therapy. Since a number of herbal preparations possess one or more pharmacologically active principles it is reasonably to suspect that many of these agents can interact pharmacodynamically and/or pharmacokinetically with prescription and over-the-counter pharmaceuticals. Recently, many reports dealing with adverse effects or toxicity of herbal products have been published.

In this review we present the characteristic examples of herbal products toxicity and their possible interactions with standard drugs and give some recommendations for overcoming this problem


Haematological adverse effects (1,2)
Medicinal plant or herbal product
Suspected
active principle
Adverse effects
Tonka beans (Dipteryx odoratum Will.)
Melilot (Melilotus officinalis L.)
Woodruff (Galium odoratum L.)
coumarin Haemorrhagic diathesis, prolonged protrombine time
Hops (Humulus lupulus L.) lupuline Intravascular haemolysis
Medicago sativa L. canavanine Splenomegalia, pancytopenia

Gastrointestinal adverse effects (3-7)
Medicinal plant or herbal product
Suspected
active principle
Adverse effects
Poke root (Phytolaca americana L.)
triterpene saponins
Gastroenteritis,
bloody diarrhea 
Senna (Casia acutifolia Del.; Casia angustifolia Vahl.)
Buckthorn (Hipthothea rhamnoides)
anthraquinones
Severe watery diarrhea
Comfrey (Symphytum officinale L.)
Groundsel (Senecio vulgaris L.)
Gordolobo (Senecio longilobus L.)
Mate (Ilex paraguayensis St. Hil.)
T'u-san-chi (Gynura segetum)
pyrrolizidine alkaloids
Hepatic venoocclusive disease, hepatic failure
Comfrey (Symphytum officinale L.)
Sassafras (Sassafras albidum)
pyrrolizidine
alkaloids (?)
safrole
Hepatocarcinogenicity
Viscum album L
viscotoxines; alkaloids (?)
Hepatitis
Valeriana officinalis L.
?
Acute hepatitis
Germander (Teucrium chamaedrys L.)
?
Acute hepatitis

Cardiac adverse effects (3,9)
Medicinal plant or herbal product
Suspected
active principle
Adverse effects
Digitalis purpurea L.
Convallaria majalis L.
Urginea maritima L.
Thevetia nereifolia Juss.
Nerium oleander L.
Cardiac glycosides (digoxin, digitoxin, convallotoxin, thevetin, thevetoxin oleadrin, etc.) Malignant arrythmias,
cardiac arrest
Glycyrrhiza glabra L.
?
Oedema and hypertension due to sodium and water retention; hypokalaemia, ventricular fibrillation

Autonomic and CNS adverse effects (3,8)
Medicinal plant or herbal product
Suspected
active principle
Adverse effects
Mandrake (Mandragora officinarym L.)
Thorn apple (Datura sp.)
Lobelia (Lobelia inflata L.)
Burdock root (Arctium minus Hill.; Arctium Lappa L.)
atropine, scopolamine, hyosciamine,
lobeline
Anticholinergic effects (dry mouth, blurred vision, dilated pupils, distended bladder, disorientation, dellirium)
Ephedra nevadensis (a constituent of mormon tea)
Rauwolfia serpentina Benth. (a constituent of snakeroot tea)
Yohimbe bark (Corynanthe yohimbe K. Schum)
ephedrine,
reserpine,
yohimbine
CNS excitation or depression
Piper methysticum Forst. (Kavakava tea) methisticin CNS intoxication
ataxia, deafness, hallucination, blurred vision
Khat (Catha edulis Forsk). khatine, khatinone Amphetamine-like effect
Sage (Salvia officinalis L.) 
Hyssopus officinalis L.
thujone, camphor,
pinocamphone
Convulsions

Other adverse effects (3, 10-12)
Medicinal plant or herbal product
Suspected
active principle
Adverse effects
Aristolochia fangchi L. Aristolochic acid Progressive interstitial fibrosis, renal failure, urothelial carcinoma
Chamomile (Chamomilla recutita & Chamaemelum nobile) Antigens of Compositae family Contact dermatitis, anaphylactic shock
Psoralea carylifolia L. Psoralen, isopsoralen, psoralidin Photosensitivity
Panax ginseng C.A.Meyer Oestrogen hormone-like compounds Gynecomastia, vaginal haemorrhage

Possible interactions between various xenobiotics (including drugs) and active principles of medicinal plants (13-15)

Herbal medicines may interact with conventional drugs both pharmacodynamically and pharmacokinetically. Informations that widely used herbal products such as St. John's wort may induce drug metabolic enzymes from cytochrome P450 (CYP450) family imply a number of possibilities for herbal product-drug interactions. The examples of known data about influence of active principles from plants on drug metabolizing enzymes are given below:
 

Subtype of
CYP-450
Xenobiotics
activated
Xenobiotics
metabolized
Herbal
inducers
Herbal
inhibitors
CYP1A1
benzo[a]pyrene; polycyclic aromatic hydrocarbons 7-ethoxycoumarin;
7-ethoxyresorufin; tacrine;
R-warfarin 8-hydroxylation
cruciferous vegetables 7,8-benzoflavone; apigenin
CYP1A2
acetaminophen; aflatoxin B1 caffeine;
7-ethoxyresorufin; fluoroquinolone; imipramine; phenacetin; theophyline;
tacrine; R-warfarin 6-hydoxylation
cruciferous vegetables;
pseudohypericin; hypericin
7,8-benzoflavone; apigenin;
isosafrole;
apigenin;
CYP2A6
aflatoxin B1;
benzo[a]pyrene; nicotine;
N-nitroso diethylamine
1,3-butadiene;
coumarin
  coumarin
CYP2B6
cyclophosphamideifosfamide benzphetamine;
diazepam
  a-naphthoflavone
CYP3A4
acetaminophen; aflatoxin B1; cyclophosphamideifosfamide alfentanil; amiodarone; carbamazepine; chloropromazine; cyclosporine A; dexamethasone; diazepam; diltiazem; nifedipine; omeprazole; paclitaxel; tamoxifen; terfenadine; verapamil, etc. pseudohypericin; hypericin naringenin;
6,7-dihidroxy-bergamotin

Suggestions for reducing the risk of herbal product adverse effects

For patients

  1. Avoid to take herbs if pregnant or attempting to become pregnant without consultation with medical professionals.

  2. Avoid to take herbs if you are nursing without consultation with medical professionals.

  3. Avoid to give herbs to your baby without consultation with medical professionals.

  4. Avoid to take a large quantity of anyone herbal preparation on a daily basis.

  5. Buy only preparations when the plants are listed on the packet.

  6. Avoid to take anything containing comfrey.

  7. Avoid the use of herbal products with standard drugs without consultation with medical professionals.

  8. Keep herbal products out of the reach of children.

For medical professionals:
  1. Inform your patients that toxicities can occurred even with therapeutically proven herbals.

  2. When take a drug history ask on the use of herbal products.

  3. Report the nearest Poison Control Center or Center for Adverse Drug Effects in case of appearance of adverse reactions to herbal products.

LITERATURE
  1. Hogan R.P. (1983): Hemorrhagic diathesis caused by drinking an herbal tea, JAMA 249, 2679.

  2. Benjamin L.J., Goldstein B.D., Distenfeld A., Troll W. (1977): Production of PNH-like red blood cells by tea, Am. J. Hematol. 2, 245-249.

  3. Ridker P.M. (1987): Toxic effects of herbal teas, Arch. Environ. Health 42, 133-136.

  4. Huxtble R.J. (1992): The myth and beneficent nature: The risks of herbal preparations, Ann. Intern. Med. 117, 165-166.

  5. Harvey J. and Colin-Jones D.G. (1981): Mistletoe hepatitis, Br. Med. J. 282, 186-187.

  6. Larrey D. et al. (1992) : Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity, Ann. Intern. Med. 117, 129-132.

  7. Mac Gregor F.B., Abrnethy V.E., Dahabra S., Cobden I., Hayes P.C. (1989): Hepato-toxicity of herbal remedies, Br. Med. J. 299, 1156-1157.

  8. Millet Y. et al. (1981): Toxicity of some essential plant oils. Clinical and experimental study, Clin. Toxicol. 18, 1485-1498.

  9. Penn R.G. (1988): Adverse reactions to herbal medicines, Aust. Presc. 11, 16-18.

  10. Maurice P.D.L. and Cream J.J. (1989): The dangers of herbalism, Br. Med. J. 299, 1204-1205.

  11. Nortier J.L. et al. (2000): Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi), N. Engl. J. Med. 342, 1686-1692.

  12. Kessler D.A. (2000): Cancer and herbs, N. Engl. J. Med. 342, 1742-1743.

  13. Omiecinski C.J., Remmel R.R. and Hosagrahara P. (1999): Concise review of the cytochrome P450s and their roles in toxicology, Toxicol. Sci. 48, 151-156.

  14. Nebel A., Schneider B.J., Baker R.K. and Kroll D.J. (1999). Potential metabolic interaction between St. John's wort and teophylline, Ann. Pharmacother. 33, 502.

  15. Roby C.A., Anderson G.D., Kantor E., Dryer D.A., Burstein A.H. (1999): St. John's wort: Effect on CYP3A4 activity, Pharmacokin. Drug Disp. 67, 451-457.

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