허브-약물 상호작용 및 식물 및 허브 제품의 독성학적 위험의 임상적 중요성

2020

The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants and Herbal Products

https://www.intechopen.com/chapters/71771

The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants and Herbal Products

 

Table 1.

고혈압에 대한 허브/천연 제품의  장점과 단점.

Herbal/natural products for evidence of benefit    Herbs/herbal products for evidence of harm               Causes

Coenzyme Q10	Ephedra spec. (Ephedra)	Cardiac effects, hypertension, palpitations, tachycardia, stroke, seizures
Fish oil	Citrus × aurantium L. (Bitter orange)	Blood pressure increases occur in healthy people
Allium sativum L. (Garlic)	Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Siberian Ginseng)	Hypertension, tachycardia, palpitations
Vitamin C	Glycyhrriza glabra (Licorice)	Mineralocorticoid excess syndrome, subsequent hypertension

 

표 2. 신경학적 부작용을 일으키는 것과 관련된 약초 요법 .

*우리는 식물이나 그 제품의 대략적인 사용을 알고 있지만 표에 있는 일부 식물은 식물 요법에 사용하는 것이 바람직하지 않은 강력한 식물일지라도 일반적으로 중국 전통 의학에서 사용됩니다.

 

Herbs                                    Adverse effects                                                Potential drug interactions

Panax ginseng C.A.Mey.	Insomnia, vaginal bleeding, mastalgia, mania	Phenelzine, hypoglycemic drugs
Valeriana officinalis L. (Valerian)	Headache, GI symptoms, hangover	Other CNS depressants
Datura stramonium (Jimson weed)*	Ataxia, blurred vision, disorientation, other cholinergic signs	Other anti-cholinergic agents
Glycyrrhiza glabra (Licorice)	Mineral corticoid effects	Antihypertensives, corticosteroids, digoxin
Passiflora incarnata L. (Passionflower)	Nausea, drowsiness, ventricular tachycardia	Other CNS depressants
Mentha pulegium L. (Pennyroyale)	GI symptoms and cramps, confusion, hallucination, liver failure	Inhibitors of cytochrome P-450 system
Piper methysticum G.Forst. (Kava)*	GI symptoms, restlessness, allergies, hepatitis	Other CNS depressants
Ephedra sinica (Ma Huang)*	Anxiety, confusion, insomnia, psychosis	Other CNS-stimulants, beta-blockers, MAO-inhibitors, phenothiazines, theophylline
Ginkgo biloba L.	GI symptoms, allergies, headache, dizziness, bleeding	Anticoagulants
Tripterygium wilfordii (Thunder God Vine)*	Dryness of mouth, nausea, GI symptoms, leukopenia	Not known
Eucalyptus sp.	Cyanosis, delirium, GI symptoms	Not known
Hypericum perforatum (St. John’s wort)	GI symptoms, allergies, fatigue, anxiety	Serotonin reuptake inhibitors, hepatic enzyme inducer
Aconitum sp. (Aconite)*	Acidosis, bradycardia, diarrhea, hypokalemia	Antiarrhythmics, antihypertensives

Table 4.

심혈관계 치료에 일반적으로 사용되는 일부 허브

Herbs                                                Interacting drugs                       CYP, P-gp induction/inhibition

Piper longum L.	Verapamil, digoxin, propranolol	CYP3A4, CYP2D6 and CYP1A2 (inhibition)
Curcuma longa L.	Losartan, rosuvastatin, warfarin, clopidogrel	CYP3A4, CYP1A2, CYP2B6, CYP2C19, CYP2C9 (inhibition)
	Talinolol	P-gp induction, intestinal P-gp in subjects with ABCB1 C3435T genotype inhibition
Fucus vesiculosus L.	Amiodarone, valsartan	CYP1A (induction), CYP2C9 (inhibition)
Zingiber officinale Roscoe	Nifedipine, phenprocoumon	CYP2C9 (potent inhibition) CYP2C19, CYP3A4 (moderate inhibition)
Terminalia bellirica (Gaertn.) Roxb.	Diltiazem	CYP3A4 CYP2D6
Salvia miltiorrhiza Bunge	Warfarin	CYP3A4 (induction) CYP1A2, CYP2C9, CYP1E1, CYP2C6, CYP2C11 (inhibition)
Allium sativum	Atorvastatin, cilostazol	CYP2C9, CYP3A4 and CYP2D6 (inhibition) P-gp induction
Ginkgo biloba	Diltiazem, cilostazol	CYP1A2, CYP3A, and CYP2C9 (P-gp inhibition inhibition) CYP2C19 (induction)
	Nifedipine	Unknown
	Talinolol	Intestinal P-gp inhibition
Glycrrhiza glabra	Atorvastatin, simvastatin, lovastatin	CYP2B6, CYP2C9, CYP2C19 (inhibition) CYP3A4 (induction)
Panax ginseng	Warfarin	CYP3A4 (induction), CYP2C11 (inhibition)
	Nifedipine	CYP3A4 (inhibition)
Pueraria montana (Lour.) Merr. var. lobata (Willd.) Sanjappa & Pradeep	Warfarin	CYP 1A2 (induction) CYP2D6, CYP3A4, and OATs (inhibition)
Citrus paradisi Macfad.	Felodipine	CYP3A4 (inhibition)
	Talinolol	OATP inhibition
	Aliskiren	OATP2B1 inhibition
	Atorvastatin	Intestinal CYP3A4 inhibition
	Lovastatin	Intestinal CYP3A4 inhibition
	Simvastatin	Intestinal CYP3A4 inhibition
Mentha × piperita L.	Felodipine	CYP3A4 (inhibition)
Hypericum perforatum	Nifedipine	CYP3A4 (induction)
	Verapamil
	Digoxin	P-gp induction
	Talinolol	P-gp induction
	Phenprocoumon	CYP2C9 induction, CYY3A4 induction
	Atorvastatin	CYP3A4 induction, P-gp induction
	Pravastatin	Intestinal CYP3A4 inhibition
	Simvastatin	CYP3A4 induction, P-gp induction
	Rosuvastatin	P-gp induction
Camellia sinensis (L.) Kuntze.	Digoxin	P-gp induction, digoxin uptake inhibition
	Nadolol	Intestinal OATP1A2 inhibition
	Rosuvastatin	Intestinal OATP1A2/OATB2P inhibition
Malus pumila Mill.	Atenolol	Unknown (possible mediated by OATP function and modulation of intestinal drug uptake)
	Aliskiren	OATP2B1 inhibition
Schisandra chinensis (Turcz.) Baill.	Talinolol	P-gp inhibition
Citrus × sinensis (L.) Osbeck	Aliskiren	OATP2B1 inhibition
Silybum marianum (L.) Gaertn.	Losartan	CYP2C9 inhibition

표 5.

인간 대상에서 수행된 화학요법제와의 한약 상호작용 연구

Herbs     Cancer drugs     Study type                                    Results

      

Echinacea	Etoposide	Case report	It was found that taking echinacea with etoposide rarely reduced platelet (16 × 103/L) compared to etoposide alone (44 × 103/L)
	Docetaxel	Prospective study in 10 cancer patients	Echinacea did not cause a significant change in the pharmacokinetics of docetaxel
Garlic	Docetaxel	Prospective, patient controlled, pharmacokinetic	Garlic was found to reduce docetaxel clearance. Although this reduction is not statistically significant, it can potentially increase side effects due to docetaxel accumulation
Ginseng	Imatinib	Case report	After receiving ginseng in patients receiving imatinib for 7 years, hepatotoxicity symptoms began to appear. Hepatotoxicity improved upon discontinuation of ginseng
Grapefruit juice	Docetaxel	Case report	Grapefruit juice has been found to reduce the clearance of docetaxel, while increasing the AUC and terminal half-life of docetaxel
	Nilotinib	Open label, randomized, 2 period crossover	It was found that grapefruit juice increased the AUC and the peak concentration of nilotinib, but did not affect the elimination half-life
Milk thistle	Irinotecan	Pharmacokinetic study	It has been found that milk thistle causes a statistically insignificant decrease in irinotecan clearance, which is unlikely to cause a clinical effect
St John’s wort	Docetaxel	Pharmacokinetic study	St John’s wort was found to cause a significant decrease in plasma docetaxel concentration
	Irinotecan	Unblinded, randomized crossover study	St John’s wort caused a 42% reduction in plasma concentrations of the active metabolite (SN-38)
	Imatinib	Open-label, crossover pharmacokinetic study	St John’s wort reduced the plasma concentration of imatinib by 32% and reduced the half-life of imatinib by 21%
		2-period, open-label, fixed sequence study	St John’s wort increased the imatinib clearance by 43% and decreased the plasma concentration by 30%

 

표 7.

신부전 환자가 사용하는 약초 및 안전 문제

 

Herbs                     Dosage form/                            doses associated with safety concernsSafety concerns

Panax ginseng	Crude and standardized Ginseng root extract, high doses, combined preparation	It may hypoglycemic effect and can cause hypertension, as well as may interact with anticoagulants
Ginkgo biloba	Standardized Ginkgo extract (EGb 761, 80 mg/day), crude Ginkgo plant parts (5 ppm of toxic ginkgolic acid)	It may interact with anticoagulants and can cause a severe allergic reaction
Cinnamomum cassia (L.) J.Presl	Cinnamon extract	It may have hypoglycemic effect and may cause worsen liver conditions
Zingiber officinale	Dried root, liquid extract, doses >10 g/day	It may interact with anticoagulants
Allium sativum	Fresh garlic, dried powder (>7 g/day), higher doses than usual dietary intake	It may interact with anticoagulants, antihypertensive, anti-hyperlipidemic, and hydrochlorothiazide
Andrographis paniculata (Burm.f.) Nees	Andrographis paniculata extract (50 and 100 mg/kg/day) for 14 days, standardized Andrographis extract	It may interact with hepatic metabolizing enzymes, anticoagulant, antiplatelet, anti-hyperglycemic, barbiturates
Momordica charantia L.	Bitter melon tea, bitter melon extract administered intravenously and intraperitoneally, high-dose bitter melon seed	It may hypoglycemic effect and may interact with hypoglycemic agents, death in children
Punica granatum L.	Pomegranate juice, pomegranate extract	It may possibly interact with anticoagulants
Angelica sinensis (Oliv.) Diels	Dong Quai extract (tablet), dose: 565 mg (1–2 tab/day) for 4 weeks	It may increase the risk of bleeding, increase cancer risk, as well as may interact with anticoagulants, antiplatelet, estrogen (augments the effect of estrogen)
Medicago sativa L.	Alfalfa seed products	It may cause autoimmune diseases (SLE, multiple sclerosis, rheumatoid arthritis), photosensitivity, estrogen-like and hypoglycemic effects, and may interact with immunosuppressants, warfarin, oral contraceptives, estrogen conjugates, oral hypoglycemic agents, iron, vitamin
Trigonella foenum-graecum L.	Fenugreek seeds, fenugreek seed powder (>5 g)	It may have a hypoglycemic and estrogen-like effects
Camellia sinensis	Tea (high dose >600 mg/day or 2.25–4.5 L/day)	It may cause liver problems, and may interact with nadolol (beta-blocker), diuretics
Morinda citrifolia L.	Noni juice, dose >400 mL	It may cause liver toxicity, and contains high potassium
Spirulina	A product containing blue-green algae	It may increase the risk of bleeding, may interact with immunosuppressant, antiplatelet, anticoagulants, NSAIDs, other herbs that reduce blood clotting (e.g., ginseng, garlic, ginkgo)

 

표 8.

폐경기에 대한 허브와 허브 약물 상호 작용.

 

Herbs                               HID             

Cimicifuga racemosa	Increase the activity of antihypertensive agents
Angelica sinensis	Inhibit platelet aggregation and increase risk of bleeding if co-medicated with anticoagulants
Oenothera biennis L.	Potentially interacts with anti-inflammatory drugs, corticosteroids, beta-blockers, antipsychotics and anticoagulants
Trifolium pratense L.	Increase the activity of CYP3A4 and alters the metabolism of drugs
Humulus lupulus L.	Interact with CNS depressants, antipsychotics, hormones and CYP-metabolized drugs

 

 

표 9.

허브-미량 영양소 상호 작용 및 그 메커니즘.

 

Phytochemicals                                      Micronutrient           affectedEffect and interaction mechanisms  

Plant polyphenols (PPs) (tea catechins, phloretin, quercetin)	Iron	PPs reduce absorption through complexation
	Folate, ascorbate	PPs reduce absorption through uptake transporter inhibition
Silymarins	Iron	They reduce absorption through complexation
Phytic acid	Calcium, iron, zinc	It reduces absorption through complexation
Hyperforin (St. John’s wort)	Vitamin D3	It enhances plasma clearance through induction of CYP3A4 metabolism

 

표.10

2018년 '약초에 대해' 데이터베이스에서 액세스한 상위 10개 

 

Common nameScientific name of the plants/dietary supplementsKey interaction and concernsAvoid in

Chaga	Inonotus obliquus (Ach. ex Pers.) Pilát	High in oxalates Anticoagulants Anti-platelets Antihyperglycemic agents	Renal disease Diabetic patients on treatment (acarbose)
Turmeric	Curcuma longa	High in oxalates CYP2C9 enzyme	Renal disease
Ashwagandha	Withania somnifera (L.) Dunal	Increase testosterone levels in men	Prostate cancer
Reishi mushroom	Ganoderma lucidum (Curtis) P.Karst.	Anticoagulants Anti-platelets	Radiation therapy
Graviola	Annona muricate L.	Antihyperglycemic agents	Diabetic patients on treatment
AHCC	Active Hexose-Correlated Compound	CYP2D6 enzyme inducer	Breast cancer patients on doxorubicin, zofran, and aromatase inhibitor (letrozole)
Boswellia	Boswellia serrata Roxb. ex Colebr.	Unknown	Contact dermatitis
Dandelion	Taraxacum mongolicum Hand.-Mazz., T. officinale (L.) Weber ex F.H.Wigg	CYP1A2 enzyme Diuretic Antihyperglycemic agents Estrogenic activity	Hormone-sensitive breast cancer
Green tea	Camellia sinensis	High doses or taken on an empty stomach can cause liver toxicity Bortezomib	Elevated liver function tests
Turkey tail mushroom	Trametes versicolor (L.) Lloyd	Unknown	Patients on immunosuppressants (in theory)

 

표 11.

일부 약초 상호 작용

 

PlantsEffect and usageDrugsInteractions

Allium sativum	Antihypertensive, antithrombotic, fibrinolytic, antimicrobial, antidiabetic and lipid-lowering properties [20]	Anticoagulant	May lead to increased anticoagulation effect of warfarin and may increase the risk of bleeding [21, 22, 23]
		Antiretroviral (saquinavir)	May decrease the plasma level of protease inhibitor saquinavir [24, 25]
		Antidiabetic (metformin, chlorpropamide)	May occur greater reduction in blood glucose level [26, 27]
		Paracetamol (acetaminophen)	May change some pharmacokinetic variables of paracetamol [28]
Aloe vera L.	Laxative antidiabetic [20]	Corticosteroids and potassium-depleting diuretics	Laxative and potassium lowering effect may result in hypokalemia [29, 30]
		Cardiac glycosides and antiarrhythmic drugs	May enhance the hypokalemia-related arrhythmia [29, 30]
		Antidiabetics	Because of the glucose-lowering effects, diabetic patients should be careful when combining with an antidiabetic agent [31]
Cassia senna L.	Laxative [20]	Corticosteroids and potassium-depleting diuretics	May lead to hypokalemia, since senna can cause excessive water and potassium loss, theoretically [20]
		Digitalis glycosides	Risk of digitalis toxicity due to hypokalemic effect of senna, theoretically [20]
Echinacea purpurea (L.) Moench.	As immunostimulant and in treatment of upper respiratory tract infections [20]	Anabolic steroids, amiodarone (antiaritmic), methotrexate (chemotherapy agent-immunosuppressant), ketoconazole (antifungal), and acetaminophen	The risk of hepatoxicity by concomitant usage of potentially hepatoxic Echinacea [32, 33]
		Immunosuppressants	Might decrease the effects of immunosuppressants, theoretically [34]
		Midazolam (benzodiazepine)	May increase oral bioavailability of midazolam or [20]
Ginkgo biloba	To improve cognitive functions, cerebrovascular disorders and vertigo [20]	Phenobarbital	Reduces the therapeutic potency of phenobarbital [35]
		Ibuprofen (NSAID)	May cause fatal intracerebral bleeding [36]
		Anticoagulant (warfarin) and antiplatelet (aspirin) drugs	Possible additive inhibition on platelet aggregation [37, 38]
		Antidepressant (trazodone)	Ginkgo flavonoids increase the production of 1-(m-chlorophenyl) piperazine (mCPP), an active metabolite of trazodone. Flavonoids and mCPP may induce the enhancement of GABAergic activity [34]
		Thiazide diuretic (not specified in the original paper)	Further increase in blood pressure [39]
		Nicardipine (a calcium channel blocker)	Decreasing the hypotensive activity of drugs [40]
		Nifedipine, diltiazem (calcium channel blockers) and talinolol (β-blocker)	Possible increased antihypertensive activity resulting from high bioavailability [41, 42, 43, 44]
		Cyclosporine	Decreased bioavailability of drug [45]
		Midazolam (benzodiazepine)	Decreased bioavailability of drug [46]
		Propranolol (β-blocker)	Decreased the plasma concentrations of propranolol [47]
		Theophylline	Less efficacy with Ginkgo [48]
		Omeprazole (proton pump inhibitor)	May induce the metabolism, and reduce the effect of omeprazole [49]
		Tolbutamide (an antidiabetic drug)	May increase or decrease the hypoglycemic effect of tolbutamide [50]
		Amikacin (aminoglycoside)	Amikacin ototoxicity may enhance [51]
Glycyrrhiza glabra	Expectorant, antispasmodic and anti-inflammatory properties and in treatment of peptic and duodenal ulcers [20]	Prednisolone (corticosteroid)	Glycyrrhizin increases the plasma concentrations and potentiates pharmacological effects of prednisolone [52, 53]
		Hydrocortisone (corticosteroid)	Glycyrrhetinic acid potentiates the activity the topical cutaneous vasoconstrictor effect [54]
		Dexamethasone (corticosteroid)	Dexamethasone induces the mineralocorticoid effects of glycyrrhizin [55]
		Antihypertensives	Mineralocorticoid effects (sodium and water retention and hypokalemia) of plant reduce the efficacy of the drugs that use to lower blood pressure. Hypokalemic effect of the plant may increase the effect of the loop and thiazide diuretics [20]
Hypericum perforatum	To treat depression, seasonal affective disorder, anxiety and insomnia, especially related to menopause [20]	Gliclazide (an antidiabetic drug)	Increases the apparent clearance of gliclazide [56]
		Carbamazepine, phenytoin and phenobarbital (antiepileptics)	Clinically significant interaction is unlikely, but Hypericum should be used carefully with these antiepileptic drugs [20]
		Alprazolam, midazolam, triazolam and quazepam (benzodiazepines)	Since the main compound hyperforin induces the enzyme CYP3A4, bioavailability may decrease [20, 57]
		Indinavir (protease inhibitor) Nevirapine (nonnucleoside reverse transcriptase)	May decrease the antiretroviral drugs and may lead to development of drug resistance [58, 59]
		Cyclosporine, tacrolimus, (Immunosuppressants)	May decrease the blood levels and may lead the acute organ rejection in transplant patients [60, 61, 62]
		Warfarin and phenprocoumon (anticoagulants)	May cause a moderate reduction in the anticoagulant effects of the drugs [20]
		Simvastatin and atorvastatin (antihyperlipidemic agents)	May observe the increasing serum level of total cholesterol [63, 64]
		Nifedipine, verapamil (calcium channel blockers) and talinolol (a β-adrenoceptor blocker)	May decrease the bioavailability of drugs [65]
		Oral contraceptives	Associated with increased metabolism of ethinyl estradiol, norethindrone, and ketodesogestrel, and may cause bleeding and unwanted pregnancy [66, 67, 68, 69]
		Carbamazepine (antiepileptic)	Should be considered a mild interaction between carbamazepine and Hypericum
		Sertraline, nefazodone (selective serotonin reuptake inhibitors)	May be occurred the symptoms of central serotonergic syndrome [70]
Linum usitatissimum L.	Demulcent for bronchitis and coughs, and topically used for burns [20]	Anticoagulant or antiplatelet drugs	In the view of the thought that omega-3 fatty acids such as linolenic acid have antiplatelet effects, should be concerned about the possibility of prolonged bleeding [20]
Panax ginseng	Adaptogenic [20]	Phenelzine (MAO inhibitor)	Additive nervous system effect of drug such as headache, tremor, sleeplessness and mania [34]
		Warfarin (anticoagulant)	INR may decrease by concomitant usage [71]
		Warfarin, heparin, aspirin, and NSAIDs	There is no clear data, but due to the antiplatelet components in P. ginseng, it should be avoided concomitant using [32]
		Caffeine	Possible additive stimulant effects [20]
Piper methysticum	Anxiolytic, sedative, aphrodisiac	Barbiturates and benzodiazepines	Might potentiate the effects of central nervous system depressants [72]
		Alprazolam (benzodiazepine)	Risk of coma due to possible additive effect on GABA receptor [72]
		Levodopa	May reduce the efficacy due to possible dopaminergic antagonism [73]
		Acetaminophen	May enhance the risk of hepatotoxicity [33]
Valeriana officinalis	Used for stress and insomnia as sedative and anxiolytic [20]	Barbiturates	Excessive sedation. The active component valerenic acid seems to likely to have the additive effect to phenobarbital [74]
		Other central nervous system depressants such as benzodiazepines and opioids	Possible additive sedative effects [20]
		Caffeine	Possible reverse effect to the sedative effect of Valerian [20]
Zingiber officinale	To reduce nausea and emesis induced by pregnancy, chemotherapy, and postoperative ileus [75]	NSAIDs	May reduce the platelet aggregation and enhance the bleeding tendency [33]
		Nifedipine	May potentiate the antiplatelet effects [76]
		Metronidazole	May increase the bioavailability [77]
		Glibenclamide (antidiabetic)	May reduce the blood glucose level [26]

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