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E. Yeşilada 1 ADVERSE EFFECTS AND DRUG INTERACTIONS WITH HERBAL MEDICINES AND SCIENTIFIC EVALUATION OF TOXICITY REPORTS ON HMPs.

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Presentation on theme: "E. Yeşilada 1 ADVERSE EFFECTS AND DRUG INTERACTIONS WITH HERBAL MEDICINES AND SCIENTIFIC EVALUATION OF TOXICITY REPORTS ON HMPs."— Presentation transcript:

1 E. Yeşilada 1 ADVERSE EFFECTS AND DRUG INTERACTIONS WITH HERBAL MEDICINES AND SCIENTIFIC EVALUATION OF TOXICITY REPORTS ON HMPs

2 EACH PLANT IS A MIXTURE OF DOZENS OF COMPONENTS EACH MOLECULE MAY HAVE THERAPEUTICAL or TOXIC or POISONOUS effect Expressions like “HERBALS ARE SAFE ??? or THEY ARE NATURAL THEN NOT TOXIC??? “ are illogical E. Yeşilada 2

3 Paracelsus (16.century) “ Difference between the therapeutic and poisonous effects of a particular compound is dose ” E. Yeşilada 3

4 ( WHO ) Adverse effects of drugs: “ Unwanted or toxic effect observed against a drug when administered in NORMAL DOSAGE for diagnostic purposes, prophylactic or treatment of diseases or to change a physiological response in human ” 4 E. Yeşilada

5 Double-blind clinical studies revealed that; “even through placebo drug administration a wide-range of unwanted/adverse effects may be observed” In 1228 healthy volunteers, percentages of advers effects after placebo drug administration; Single dose administration; 19% Older ages single dose administration; 26% Repeated administration increased the rate to 28% Reported advers effects; headache (7%), lethargy (5%) ve anxiety (4%) etc. Rates may be subjected to change depending on the population and designation of the study 5 E. Yeşilada

6 6

7 Due to the ingredients with toxic effect, high concentration of plant ingredients with potent activity, Falcification/Adulteration: Addition of wrong plant materials Intended/Unintended, Undeclared addition of synthetic active chemicals to strenghten the activity, 7 E. Yeşilada

8 Contamination with toxic materials; Environmental wastes, Heavy metals, Agricultural agents; pesticides, fumigants, veterinary drugs etc., Microbiological contamination, 8 E. Yeşilada

9 Wrong pharmaceutical formulation design; Inappropriate excipients selection etc. Wrong procedures in the preparation of HMP: Insufficient denaturation of toxic ingredients, Extraction of toxic components 9 E. Yeşilada

10 10 Administration in high doses, Long-term administration, Due to a metabolic/physiological deficiency of the patient, Due to personal sensitivity or idiosyncratic reactions, i.e., allergy, irritation etc. II. Risks due to individual factors or sensibility

11 E. Yeşilada 11 Age-dependent increased risks, Interactions with concurrent therapy, Delayed risks; carcinogenity/mutagenity/teratogenity etc., II. Risks due to personal factors or sensibility

12 Commercial competition Slanderous claims 12 E. Yeşilada

13 Multivitamin researchers say "case is closed" after studies find no health benefits 13 E. Yeşilada

14 14

15 E. Yeşilada 15 Are Vitamins realy ineffective?

16 December 2013: CBS News: 16 E. Yeşilada

17 Hypothetical suggestions or warnings are postulated based on the composition of the HMP in some sources were quoted to other documents without notifying as hypothetical, and may be accepted as if it is real by others 17 E. Yeşilada

18 18 E. Yeşilada

19 Plants/ingredients with powerful physiological activity ; - May have a unique physiological/ therapeutical effect in very low doses, - In higher doses may be dangerous or fatal; -Atropine etc. alkaloids [Nightshade- Atropa sp., Henbane- Hyoscyamus sp.], -Cardioactive components, i.e. digitoxine [Foxglove- Digitalis sp. ] Plant/parts containing toxic components should not be used in phytotherapy: 19 E. Yeşilada

20 Care should be given in Excessive usages Long term applications High concentrations/doses E. Yeşilada 20

21 1. Pyrazolidine alkaloids: Hepatic veno-occlusive (HVO) disease Occlusion of the centrolobular veins of the liver, Clinical symptoms in human: abdominal pain, Water-arrest in abdomen, hepatomegaly, Increase in serum transaminases: AST, ALT 21 E. Yeşilada

22 22 Plants with Pyrazolidine derivatives are prohibited/restricted to be used in formulations Coltfoots; öksürükotu (Tussilago farfarae)

23 Senecio sp., kanarya otu, liferoot Senecio scandens (unsaturated pyrazolidine alkaloids) In Traditional Chinese Medicine (Qianbai Biyan Pian); prohibited by EMEA E. Yeşilada 23

24 2. Furanocoumarins : In: Apiaceae (Parsley, celery), Rutaceae (Bergamot, Orange family), Moraceae (mulberry and Fabaceae (beans) Powerful phototoxic activity ; psoralen, bergapten 24 E. Yeşilada

25 In volatile oils; Bergamot essence is used in perfumes as fixative for a long-lasting scent, Volatile oil contains bergapten, a furanocoumarin, Due to the phototoxic property, increase the sensitivity of skin to sunlight and induce dispersed stains on the skin, in fact burns, This essence was used in some sun-cosmetics for rapid tanning; may induce skin cancer 25 E. Yeşilada Furanocoumarins

26 Sweden; after large amount consumption of CELERY soup a woman sunbathed under UV-light in a Beauty Center suffered from severe burns. U.K.; after taken large amount of a soup containing celery, parsley and wild carrot the patient was subjected to oral photochemotherapy [PUVA; psoralen and UV-A] suffered from severe burns 26 E. Yeşilada

27 Large amount of kantaron (St.John’s wort) consumption may yield photodermatitis only in calves; Not any report has been found in human E. Yeşilada 27 St.John’s wort is used in phytotherapy as an effective antidepressant medicine

28 28 E. Yeşilada

29 29 E. Yeşilada Contact dermatitis; eugenol, L-carvone‘ (mint oil) are the ingredients of toothpaste may induce inflammatory lips in sensitive people, Volatile oil ingredients:

30 Respiratory irritation; We smell the nice fragrance in cosmetics/ lotions/perfumes/soaps etc. without any harmful effect In Aromatherapists and similar professions continuous /repeated inhalation/exposure may develop intolerence/allergic reactions 30 E. Yeşilada

31 Apiol : [in Parsley/maydonoz volatile oil] Abortifacient hepatocarcinogenity: in large amounts and long-term “It is very rare to see such toxicities with spices when it is consumed in rational quantities” E. Yeşilada 31 Volatile oil ingredients: in Spices

32 Camphre/kafur; internally; hepatotoxicity and CNS damage, on skin; neurotoxicity Ointments with camphre (Vicks, etc.) induced hepatotoxicity when applied to the skin of a 2- month old baby in order to reduce the symptoms of catarhh, however, the symptoms recovered as soon as stop application 32 E. Yeşilada Volatile oil ingredients

33 Ma Huang (ephedrine) from Ephedra sinica Bronchodilatator in asthma and similar symptoms (as doping in sports) OTC: Also is used in formulations to loose-weight or to increase energy in x60 times higher doses. December 2003: FDA ( Federal Drug Administration ) prohibited the use of Ephedrin formulations in USA due to the remarkable adrenergic activity; particularly the symptoms of acute hepatit, halucinations and paranoia. 33 E. Yeşilada Alkaloids

34 Anthrasen derivatives laxatives (i.e., aloe, senna/sinameki, cascara, rheum/ravent) Used as laxative/purgative in pharmacotherapy (Pursenid®, Bekunis®, Senecod®, Roha®) Long-term application (over 10 days) increase the risk developping colorectal cancer, 34 E. Yeşilada

35 Kernels/seeds of many edible fruits [ apricot/kayısı, bitter almond/acı badem, cherry/kiraz, sour cherry/vişne, peach/şeftali, pear/armut, prune/erik, apple/elma etc. ]contain cyanogenetic glycosides, 35 E. Yeşilada

36 Cyanogenetic glycosides: Cyanogentic glycosides are used in food as flavour, in therapy as sedative (2-4 gtt). Hydrolysed in the stomach to yield HCN (cyanhydric acid) and absorbed readily from the upper gastro- intestinal system and may induce sudden death due to respiratory collapse (suffocation), Average 50 mg oral HCN or equivalents; apricot kernel in adults or 8-10 in children may induce death. In southeast Anatolia apricot kernels are used as snack after roasted on fire in a pan or in oven until dark color to cleave the toxic principles 36 E. Yeşilada

37 Licorice/Meyan; Licorice extract from roots has been used widespread as beverage “Meyan Şerbeti” in south Anatolia since centuries. Licorice extract/saponins are precious drug components with a wide range of therapeutic effects: antiulcer, antiviral, anti-inflammatory, antihepatotoxic, etc. Have also been added to formulations to increase bioavailability. Long-term application in high doses induced edema and hypertension in cardiac insufficient patients due to the enzyme inactivation in liver, Due to the inactivation of enzyme metabolizing the endogenous ACTH secreted from the upper- kidney glands, ACTH accumulated in the body and induced edema and then induced hypertension in-turn. 37 E. Yeşilada

38 38 E. Yeşilada

39 Botanic identitiy of the plant be problematic with self- controlled plants. Botanic identitiy of the plant may even be problematic in the prepackaged commercially available materials or formulations 39 E. Yeşilada

40 “Gordolobo” (Verbascum thapsus) case: Latin Americans use the yellow flowers against cough in children as a safe remedy, In USA, a Mexican-originated American bought “Gordolobo” from a local Mexican market The material was obtained from a wrong plant “Senecio longilobus” which is known to possess toxic pyrazolidine alkaloids, Death was reported due to HVO in the baby. 40 E. Yeşilada

41 Real Ginseng: roots of [Panax ginseng & P. notoginseng]; Effect: increase stamina, physical performance, boost immune system, regulates CNS, regulates metabolism (diabetes, etc.), adaptogen 41 E. Yeşilada

42 Falcification; - Mandrake (Mandragora officinarum) or Rauwolfia roots, contain alkaloids: toxic - Siberian Ginseng (Eleuterococcus senticosus), roots; Possess a completely different chemical composition,; lignans Used as adaptogenic, weaker activity then Ginseng, In longer administration reported to induce hypertension, and not suggested for hypertensives, 42 E. Yeşilada

43 1993: Brussel Patients from a “Chinese Slimming Clinic” applied to “Immergency Centers” in hospitals after using a Chinese slimming formulation with the complaints of; Gradually increasing nonspecific fibrosis, tubular atrophy And related kidney disturbances 43 E. Yeşilada

44 Among 2000 woman were administered the formulation 100> nephropathy 80> connected to dializing unit /or subjected to kidney transplantation 44 E. Yeşilada

45 In TCM drug plants having the same Chinese name were used ; “Ma Tong”; Clematis sp., Stephania tetrandra, Cocculus sp. Akebia sp.’stems and Aristolochia manshuriensis “Fang-ji”; Stephania tetrandra, Cocculus sp. and Aristolochia fangchi roots 45 E. Yeşilada

46 In the formulation instead of Stephania tetrandra; Aristolochia fangchi or Aristolochia manschuinsis were used. Aristolochia sp.; contains aristolochic acid Nephrotoxic, carcinogenic and mutagenic E. Yeşilada 46

47 (2001) France: 7 nephropathy reports U.K.: 2 severe renal insufficiency China: 17 cases and 12 death Japan: 10 renal failure 47 E. Yeşilada

48 Adverse/toxic effect may be shown; Due to the wrong extraction procedures excessive amount of toxic principle might be extracted, Due to insufficient denaturation of toxic ingredients. E. Yeşilada 48

49 “Burçak”(Vicia sp.) (müdürmük) seed: hypoglycaemic remedy is used frequently by the diabetics, Contains vasoconstructor proteins, Excess amounts/longer applications may induce symptoms of having the feeling of pins and needles in limbs, even may lead to gangrene, Seeds should be roasted for a while before use for denaturation the toxic proteins in a pan on fire. 49 E. Yeşilada Lack of information regarding the preparation of remedy

50 Soy beans, reddish-colored bean etc. contain toxic lectins, phytohemaglutinins, and tripsine inhibitors. To remove these components is advised to be boiled at least 30 min in water before cooking and discard the boiled water. 50 E. Yeşilada Toxic components in foods

51 Potato tubers With the effect of direct sunlight may be turned to green in color indicating that poisonous alkaloids ( solanin etc.) are synthetised. These alkaloids have vasocontructor activity, excess amounts may lead to gangreneous symptoms. Green potatoes should not be used as food Shoots and surrounding parts should be scraped off/removed before using as food 51 E. Yeşilada Toxic components in foods

52 52 E. Yeşilada

53 In Hong Kong in a market survey on 14 OTC Ginkgo biloba preparations the level of potential allergenic principle ” ginkgolic acid” was investigated: In only 1 preparation was found within the limits suggested by WHO, In 13 prep. Limits were found times higher then suggested by WHO. E. Yeşilada 53

54 These types of contaminations are observed in drugs uncontrolled by official authorities: Unintentional: environmental contamination, During the processing; i.e., extraction incopper caldrons, etc. Intentional: In order to increase acute physiological response undeclared prescription drugs with potent activity may be added, In Eastern Traditional Medicines, i.e., Ayurveda, TCM, heavy metals or certain toxins may be intentionaly added as a part of the treatment 54 E. Yeşilada

55 Ginseng Improves the physical capacity and other physiological effects only after 15 to 20 days of administration; To provide rapid acute response Caffeine containing extracts [Cola extr., Guarana, Green Tea extr.] or pure caffeine etc. stimulant drugs may be added without any notification on label. Caffeine intoxication may be observed In longer applications or higher doses In hypertensive and related CV patients: Hypertension Gastritic & complaints Nervousness: Agitations, Sleep disturbances, insomnia 55 E. Yeşilada

56 TCM or Ayurvedic formulations may contain as a part of treatment ; o Arsenic disulfas (realgar), o mercury chloride (calomel), o mercury sulfas (cinnabaris), o red mercury oxide (hydrargyri oxydum rubrum) etc. 56 E. Yeşilada

57 In at least (32%) were found to possess undeclared Active constituents; i.e., ephedrine, chlorpheniramine, phenacetine, methyltestosterone, etc.) or Heavy metals;i.e., lead, arsenic, mercury etc. 57 E. Yeşilada

58 In Singapour [ ]; 42 TCM formulations contains high levels of heavy metals, 32 prep. 19 different synthetic active drug agents; berberine, antihistaminics (chlorpheniramine, promethacine, ciproheptadine), NSAIDs (diclofenac, indomethacin, ibuprofen), analgesics-antipyretics (paracetamol, dipyrone), corticosteroids (prednisolone, dexamethasone, fluocinonid), symphatomimetics (ephedrine), broncodilators (teophylline), diuretics (hydrochlorthiazides), antidiabetics (phenphormine) etc. 58 E. Yeşilada

59 In Turkey ( ) Slimming formulations Contains “sibutramin” 3x higher than suggested dose. Not notified on the label. 59 E. Yeşilada

60 Microbiologic, Microbiologic, Insect, Insect, Pesticide, Pesticide, Fumigant, Fumigant, Environmental waste, Environmental waste, Heavy metals, Heavy metals, Radiation etc. lar. Radiation etc. lar. 60 E. Yeşilada

61 In Pharmacopeias plant materials may contain < g/CFU aerobic bacteria/ fungi; Infection rate may increase depending upon the; Incorrect cultivation/growing conditions, Wrong harvesting, i.e., in rainy weathers Inconvenient processing Inconvenient storage conditions Composition of the material, i.e., starch, etc. CFU: colony forming unit 61 E. Yeşilada

62 62 Dangerous contaminants in HMPs: NOT ALLOWED Patogenic organisms; Enterobacter, Enterococcus, Clostridium, Pseudomonas, Shigella, Streptococcus vd.’ Endotoxins and mycotoxins: Aspergillus flavus ; aflatoxins No limit in European Pharmacopeia x 10 times difference in Europe and USA

63 Pesticides: To protect crop from pests; * Cultivars or * Materials collected nearby to cultivation area; - Chlorinated hydrocarbons; DDT etc., - Organophosphates, - Carbamates, - Polychlorinated biphenyls, etc. 63 E. Yeşilada LIMITS SHOULD BE TESTED

64 Fumigants: To protect the processed plant material phosphin, 1,3-dichloropropene, chloropicrin, methyl isocyanate, hydrogen cyanide, sulfuryl fluoride, formaldehyde, iodoform etc. - Due to the suspected carcinogenic effect of ethylene oxide is forbidden in Europe, Methyl bromide is restricted due to ozon depleting effect by Montreal Convention. - Should be controlled for imported products, 64 E. Yeşilada LIMITS SHOULD BE TESTED

65 Contamination with Environmental Pollutants/wastes : Heavy metals : - lead, cadmium, mercury, tallium and arsenic etc. Radioactive wastes; 65 E. Yeşilada LIMITS SHOULD BE TESTED

66 DRUG INTERACTIONS 66 E. Yeşilada

67 1. Inhibitory effects on drug metabolizing enzymes May influence on the enzyme profile of the liver/intestines  Potentiate the effects of drugs metabolized by those isoenzymes,  Creating the potential for an increased risk of side effects; silymarin, licorice, etc. 67 E. Yeşilada

68 Grapefruit juice, furanocoumarins Inhibitory effect on Cytochrome p450 3A4 in the intestinal wall Leading to decreased first-pass metabolism and increased bioavailability. Metabolism of drugs metabolized through 3A4 enzyme is slowed down Due to the reduced metabolism rate, the rate of unmetabolised drug absorption increased May induce adverse effect/toxicity E.g. Statins 68 E. Yeşilada  Inhibitory effects on drug metabolizing enzymes may potentiate the effect of pharmacotherapy

69 2. Upregulation of drug metabolizing enzymes:  Accelerate the metabolism rate and speed of certain drugs,  Plasma level of drug has rapidly reduced and may lead to therapeutic failure;  MAY BE DANGEROUS IN PATIENTS NEED CONTINUOUS MEDICATION, i.e., St.John’s wort  Organ transplantation; In order to prevent organ rejection immunosupressants like cyclosporine must NOT be used in the rest of the patients’ life, Reduced level of immunosupressants agent in plasma may lead to organ rejection 69 E. Yeşilada

70 Potentiazation in serotonergic effects may be observed concurrent use of Serotonin reuptake-inhibitors (SRI), [centralin, paroxetine etc.] Concurrent use of MAOI (phenelsine) may induce headache, tremor and mania 70 E. Yeşilada

71 Digoxin should be continuously provided in certain level in the plasma of cardiac patients, Due to P-glycoprotein induction effect of St.John’s wort, plasma level of digoxin may not be ensured 71 E. Yeşilada

72 72 Drug name Effect Results of interaction Possible mechanism Cyclosporine Immuno- suppresant Decrease in plazma concentration of drug; organ rejection P-glycoprotein induction Ethynyl estradiol/ Desogestrel Oral contraseptive Bleeding Hepatic enzyme induction TeophyllineAntiasthmatic Decrease in plazma concentration of drug Hepatic enzyme induction Phenprocoumone Anticoagulant Decrease in plazma concentration of drug Decrease in anticoagulant activity Hepatic enzyme induction Warfarin AmitriptilineAntidepressant Decrease in plazma concentration of drug Hepatic enzyme induction Indinavir Antiviral (AIDS) Decrease in plazma concentration of drug Hepatic enzyme induction P-glycoprotein induction DigoxineCardiotonic Decrease in plazma concentration of drug P-glycoprotein induction NephazodonSertralineParoxetineAntidepressant Serotonin syndrome Synergistic SRI inhibition

73 Effect on GI absorption rate: Impairment of renal excretion, Displacement from plasma protein binding sites, Competition for receptor sites, resulting in interference with the pharmacological response. 73 E. Yeşilada

74 Synergistic effect: Prolonged blood coagulation time (Prothrombine time) In patients receiving oral anticoagulant therapy (OACT)/antiplatelet agents, due to the narrow therapeutic range interference may lead to a medical emercency 74 E. Yeşilada

75 Plants containing compounds with coumarin-like activity prolong the coagulation time in higher doses/long term administrations Concurrent use of agents of Anticoagulants; Warfarin/ NSAIDs/ with plants with antiplatelet activity, i.e., Ginseng, Ginkgo, Garlic, horse chestnut, etc. should be avoided 75 E. Yeşilada Synergistic effect

76 Hypoglycaemic shock Plants with Hypoglycaemic activity may potentiate the effect of hypoglycaemic agents; i.e., Ginseng or Garlic, with glibenclamide or insulin 76 E. Yeşilada Synergistic effect

77 Concurrent use of plants with known Hypertansive effect, i.e., Siberian Ginseng, or licorice would have a negative effect on the antihypertansive pharmacotherapy 77 E. Yeşilada

78 Long term or high dose administration of herbal diuretics ; May increase the diuretic pharmacotherapy and affect hypotansive/hypertansive treatment Due to loss of potassium, effect of cardioactive drugs (digoxin etc.) may be potentiated 78 E. Yeşilada Hypokalemia may potentiate the effect of Cardioactive drugs

79 Antracen derivatives of laxatives, in long term administration; May induce reduction in serum potassium level, Potentiate the effect of cardiotonic glycosides (Digoxine, Lanatoside etc.) and antiarythmic agents. 79 E. Yeşilada Hypokalemia may potentiate the effect of Cardioactive drugs

80 Pre-, Peri- and Post-operative interactions: May induce severe complications Even death 80 E. Yeşilada

81 Myocardial infarction, Stroke, Paralysis Increase bleeding risk, Insufficient coagulation, Increase in Anesthesia period, Insufficient anesthesia, Interactions with drugs administered during operation, Tissue rejection in Organ transportions, 81 E. Yeşilada

82 Due to interaction with cyclosporine and St.John’s wort (kantaron); acute tissue rejection in 2 heart transplantation cases Concurrent administration of Valerian and kava-kava (CNS sedative), with drugs effective on CNS may increase the anesthesia period in surgical operations; SHOULD BE STOPPED AT LEAST ONE WEEK PRİOR TO SURGICAL OPERATIONS 82 E. Yeşilada

83 Physiologic discomfort/disease, Genetics, Metabolism rate, Sensitivity, Age, Nutrition, Durability. 83 E. Yeşilada

84 Immune insufficiency patients; AIDS, tuberculosis, lupus, MS, ALD, leucosis, collagen disease, etc.; Immune-stimulating HMP may induce deterioration in arhtritis etc. complications due to excessive stimulation of autoimmune system 84 E. Yeşilada

85 Since elimination rates of certain compounds may be affected may lead to severity in symptoms. 85 E. Yeşilada

86  Oral applications: Sudden Type I hypersensibility reactions; rhinitis, headache, dermatitis, anaphylactic shock,  Topic applications; Type IV contact dermatitis, 86 E. Yeşilada

87  Asteraceae (Daisy family) plants frequent cause of allergic reactions due to sesquiterpene lactones in sensitive people; - Echinacea prep.: Popular and safe immunostimulants against COLD (Chronic Obtructive Lung Diseases) 2 anaphylaxis were reported in Australia, - Feverfew : Effective in migrain pain May stimulate pain in allergic individuals E. Yeşilada 87

88 Not allowed to use any Herbal remedy during pregnancy and/or nursing, due to low number of randomized studies and lack of scientific data E. Yeşilada 88

89 Possible interactions Teratogenic, Embryocidal, Carcinogenic, Abortifacient, and other possible adverse effects etc. 89 E. Yeşilada

90 90 Abortive etffect: Feverfew (Tanacetum parthenium) stimulate menstration, during pregnancy may induce abortion depending on dose

91 1. Since it is rare to have any information on the effects of an herbal agent on the fetus, their use during pregnancy should be avoided. 2. Little is known about the transfer of active principles in mother’s milk for most herbs, so their use in nursing mothers should be avoided. 3. In the absence of specific knowledge of herbals interactions with prescription medications, concomitant use should be discouraged or monitored closely. 4. Except for agents with known estrogenic or androgenic properties, little is known about the effects of most herbs on fertility. 91 E. Yeşilada

92 5. Oral anticoagulant therapy has always been a corcern regarding drug- drug interactions and this is also true regarding herb-drug interactions. Concomitant use of most herbs should be avoided. 6. Generally there is little known about the effects of continued use over long periods of time. A periodic “resting period” is probably a good idea, but how frequently this should occur, and how long it should be, are a matter of pure speculation given the lack of pharmacokinetic data most cases. 7. There is some corcern about the possibility that herbal medicines may create undue risk in the peri-operative period. Withdrawal 7-10 days prior to surgery may be advisable for most herbs, but in some cases, for example Valerian, a gradual reduction in dosage may be necessary. 8. Children generally are not good candidates for herbal therapy. They may have greaer relative exposure, less well-developed biotransforming enzymes, a higher rate of cell division, making them more vulnerable to mutagenesis. 92 E. Yeşilada

93 Many of the adverse effect and toxicity reports are due to Insufficient standardization Scanty control Falcification High-dose applications Long term administration Individual factors; sensitivity, function disorders 93 E. Yeşilada


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