Dang Gui
Botanical Name: Angelica sinensis (Oliv.) Diels.
Pharmacopoeial Name: Angelicae radix.
Synonym: Angelica polymorpha Maxim. var sinensis Oliv.
Common Names: Dang gui, dong quai, tang kuei, tang kwei, Chinese angelica.
Note: The phonetic “dong quai” Romanization is not the correct Pinyin transliteration, which is “dang gui.” “Tang kuei” is the earlier Wade Giles transliteration, less used today.
Family
Apiaceae.
Related Species
In East Asian commerce, several species may be traded as substitutes. Levisticum officinale Koch., or lovage, sometimes known as “European dang gui,” is a recorded adulterant, not a substitute.
Parts Used
Root; in East Asian traditional medicine, the head, body, and tail of the root are regarded as having different medicinal properties.
Common Forms
- Dried: Prepared root, smoke-dried; baked in wine.
- Fluid Extract: 1:1 70% ethanol, according to the Pharmacopoeia of the People's Republic of China (PPRC) .
- Standardized Extract: Liquid or dry extracts may be standardized to ligustilide content (0.8%-1.0%) and to ferulic acid (0.05%-0.01%).
Strategic Considerations
One of the better known herbs from the materia medica of classical Chinese medicine, dang gui (in traditional terms) supplements (nourishes) xue (blood), moves and dispels blood stasis, and regulates menses. It is also used for moistening dry conditions, dispersing swelling, and promoting the discharge of pus. The herb has been incorporated into Western herbal medicine, primarily as a women's tonic herb for menstrual disorders and infertility. Dang gui use for menopausal issues is not currently supported by clinical trial data. The herb is also used for its cardioprotective, hepatoprotective, and mild immunomodulatory effects. In the contemporary practice of Chinese medicine, it is widely used in many herbal formulae, as well as in combination with conventional treatments, such as myelosuppressive chemotherapy.
Much of the literature on dang gui is in Chinese-language journals, and many reports relate to formulae involving several ingredients, including dang gui. Few controlled trials are available, but there is a large body of traditional-use data, as well as a considerable number of uncontrolled trials in the East Asian medical literature. Many of the available studies, animal and human, involve parenteral administration, which cannot be readily extrapolated to oral administration used in the West. The herb is not referenced in official Western pharmacopoeias (although it was briefly in the USD in 1937) but has been official in the PPRC since 1977. The American Herbal Pharmacopoeia has produced a Western-oriented monograph, including a supplement on traditional Chinese usage, and McKenna et al. have reviewed much of the literature. Chen and Chen have reviewed both the pharmacology and the traditional uses of the herb.
Interactions concerns about dang gui are largely the result of extrapolations from experimental pharmacological data of isolated ingredients, such as ferulic acid, ligustilide, or polysaccharide fractions of the herb, and usually stress the risks of concomitant use with anticoagulants. The traditional precautions and contraindications for dang gui, which include bleeding disorders, hemorrhagic disease, excessive menses, and first-trimester pregnancy, may be seen as equally appropriate in Western contexts.
Effects on Drug Metabolism and Bioavailability
Minimal data are available on the effects of dang gui on the different aspects of drug detoxification. Two Japanese studies are available. One screened a number of umbelliferous crude drugs in vitro for general cytochrome P450 (CYP450) inhibitory effects and found weak but measurable inhibition by dang gui, as well as other Angelica spp. After high-performance liquid chromatography analysis, the authors attributed this to the activity of a coumarin-derivative constituent, imperatorin. A more specific in vitro study using rodent hepatic microsomes with various drug substrates found partial inhibition by dang gui extracts of CYP450 3A4, 2C9, and 2D6. A Chinese study examined the effects of dang gui polysaccharide administration in normal and liver-damaged (by prednisolone) rodents and found that the herb fraction increased hepatic microsomal CYP450, glutathione- S-transferase, and reduced-glutathione content. Pharmacokinetic interactions have not been reported, and in the case of warfarin have been ruled out as a mechanism of interaction (see following discussion). Nonetheless, such effects seem theoretically possible, and further research is required to clarify the extent and significance of any potential pharmacokinetic interactions.
Evidence: Warfarin (Coumadin, Marevan, Warfilone). Extrapolated, based on similar properties: Anisindione (Miradon), dicumarol, ethyl biscoumacetate (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar); other drugs affecting hemostasis.  | Minimal to Mild Adverse Interaction—Vigilance Necessary |
Probability:
4. PlausibleEvidence Base:
MixedEffect and Mechanism of Action
Addition of dang gui to previously stabilized warfarin anticoagulation regimens may require the dose of oral anticoagulant to be adjusted to prevent excessive anticoagulation. Only one report is available, suggesting the interaction is unlikely to be clinically significant. Dang gui has multiple effects on hemorheological parameters, the mechanisms of which are not fully elucidated, and whether this is a strict interaction or merely an additive common pharmacodynamic effect has not been established.
Research
The literature on hemorheological activities of dang gui is dominated by an emphasis on isolated constituents (e.g., ferulate, butylidenephthalide) with parenteral administration at high dose levels in animal and human studies. The trend of the data supports a possible antiplatelet effect, probably operating through arachidonic acid metabolism. Other hemorheological effects were observed in a study using parenteral dang gui (200 mL aqueous solution, intravenous administration daily for 20 days), in a group of 50 patients after acute ischemic stroke, where administration resulted in significant reductions ( p<0.001) in platelet adhesion, red blood cell (RBC) and platelet electrophoresis times, erythrocyte sedimentation rate (ESR) and serum fibrinogen, and blood and plasma adhesion ratios. Oral administration of an aqueous decoction of dang gui and the related Angelica acutilobawere given to six healthy patients, and whole-blood viscosity was reduced ( p<0.05) after 180 minutes compared with controls.
A study of warfarin and dang gui coadministration in rabbits investigated the effect of adding single-dose warfarin to animals pretreated with dang gui, as well as addition of dang gui to warfarin-stabilized animals, as measured by coagulation parameters. In the first case, adding warfarin to a dang gui pretreated group led to a ( p<0.05) lowering of prothrombin time (PT) compared with warfarin alone. Pharmacokinetic parameters of warfarin were not changed in the presence of dang gui pretreatment. Addition of dang gui to stable, warfarinized animals led to no significant change in PT or warfarin levels. In this study, warfarin was given at high dose levels subcutaneously, and a 2:1 extract of dang gui was given at 2 g/kg orally. The implication of this study appears to be that adding dang gui to stabilized warfarin is less problematic than adding drug to stabilized dang gui (in rabbits), although pharmacokinetic interactions were not observed.
Reports
In a single but much-cited report, a 46-year-old female warfarinized patient experienced an unexplained rise in international normalized ratio (INR) to 4.05. Investigations revealed no identifiable cause, and she was advised to discontinue her 5-mg warfarin dose for 24 hours. The INR remained elevated on retesting 1 week later. The patient admitted taking a herbal preparation (Nature's Way brand of dang gui), 565 mg twice daily. She was advised to stop the herb, and the INR declined to 3.41, then to 2.48 after 1 week. Concomitant medications included digoxin and furosemide. Fugh-Berman and Ernst evaluated the interaction as “likely,” scoring 8 of 10 on their report reliability scale.
Clinical Implications and Adaptations
The lack of reports of spontaneous bleeding associated with dang gui consumption alone, with only one report of the warfarin–dang gui interaction to date, suggests that concerns about the incidence and severity of the interaction are exaggerated. As always, self-prescription is a separate issue, and many warfarinized patients are poorly compliant with their monitoring test schedules. As a guideline, prescribing dang gui to warfarinized patients should generally be avoided unless there are compelling reasons for coadministration. In such cases, close monitoring of INR is required.
However, as is often the case from an integrative perspective, the potential interaction may be beneficial under specific circumstances. Dang gui has cardioprotective and thrombolytic effects that may be beneficial depending on the situation. For example, patients receiving a typical 1 mg/day oral dose of Coumadin after temporary installation of vascular access ports/catheters for prevention of thrombosis at the catheter tip may benefit from the addition of dang gui, combined with natural antiplatelet and fibrinolytic agents, particularly if there are other indications for prescribing the herb. However, checking PT/INR weekly would be appropriate if coadministration is considered, because 1 mg Coumadin could affect PTs if circumstances altered (e.g., vitamin K deficiency).
Epoetin alpha (EPO, epoeitin alfa, recombinant erythropoietin; Epogen, Eprex, Procrit), epoetin beta (NeoRecormon), darbepoetin alpha (darbepoetin alfa; Aranesp).  | Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management |
Probability:
4. PlausibleEvidence Base:
InadequateEffect and Mechanism of Action
Recombinant analogs of endogenous erythropoietin are used parenterally to correct anemia in seriously ill patients (cancer and chronic renal failure). The interaction is a pharmacodynamic additive effect on hematopoiesis. Dang gui may also help facilitate responsiveness to the drug.
Research
Several Chinese experimental studies have examined the effects of dang gui, particularly the polysaccharide fraction, in stimulating hematopoiesis and erythropoiesis. Hemoglobin, RBC count, and progenitor cells were all increased by the administration of the herb in normal and anemic mice as well as in cell culture systems. Murine studies have demonstrated myeloprotective effects of dang gui and its polysaccharide fractions against cyclophosphamide-induced and radiation-induced leukopenia.
Reports
Bradley et al. reported a single case of an anemic hemodialysis patient who was apparently resistant to the recombinant drug. The patient started self-prescription of a decoction of dang gui and Paeonia lactiflora,and after 1 month the hematocrit increased from 29.7% to 34.4%, and the amount of the drug was reduced by more than 90%. The effect of the other component of the formula cannot be ascertained.
Integrative Therapeutics, Clinical Concerns, and Adaptations
Published data substantiating this interaction are currently inadequate. However, the Chinese materia medica for Supplementing the Xue/Bloodis an established part of protocols for supporting patients undergoing myelosuppressive chemotherapies in Chinese medicine. Dang gui is incorporated into many of these formulae, which are based on different patterns of bone marrow suppression according to traditional diagnostic criteria. Specialist review of these formulae is available from clinical texts, including Peiwen. The risk/benefit ratios of this approach are favorable, and the combination requires further investigation by preclinical and controlled clinical studies.
APAP, paracetamol (Tylenol); combination drugs: acetaminophen and codeine (Capital with Codeine, Phenaphen with Codeine, Tylenol with Codeine); acetaminophen and hydrocodone (Anexsia, Anodynos-DHC, Co-Gesic, Dolacet, DuoCet, Hydrocet, Hydrogesic, Hy-Phen, Lorcet 10/650, Lorcet-HD, Lorcet Plus, Lortab, Margesic H, Medipain 5, Norco, Stagesic, T-Gesic, Vicodin, Vicodin ES, Vicodin HP, Zydone); acetaminophen and oxycodone (Endocet, Percocet 2.5/325, Percocet 5/325, Percocet 7.5/500, Percocet 10/650, Roxicet 5/500, Roxilox, Tylox); acetaminophen and pentazocine (Talacen); acetaminophen and propoxyphene (Darvocet-N, Darvocet-N 100, Pronap-100, Propacet 100, Propoxacet-N, Wygesic).
Dang gui extracts and polysaccharide fractions have been shown to have some moderate hepatoprotective activity. One study examined CCl4 and acetaminophen-induced hepatotoxicity and found that hepatoprotective effects for dang gui extracts were more pronounced in the case of acetaminophen, suggesting a glutathione-dependent mechanism for the protective effects. The “interaction” of acetaminophen with dang gui described by Chen and Chen is thus more likely an effect of general antioxidant hepatoprotective activity mediated by glutathione.
Cycloheximide (Acti-aid, ActiDione, Actispray, actidone, hizaricin, kaken, naramycin, naramycin A, neocycloheximide), scopolamine (Scopace Tablet, Transderm Scop Patch).
A study with a rodent behavioral model examined the effects both hexane and methanol extracts of dang gui on amnesia induced by scopolamine and cycloheximide and p-chloroamphetamine. High doses of the hexane extract (1 g/kg) appeared to attenuate the amnesia induced by scopolamine and cycloheximide but not by chloramphetamine in this model. The authors suggest this implies an effect on memory function, but the significance of this for therapeutic doses of conventional extracts of dang gui in humans remains unclear.
Nifedipine (Adalat, Adalat CC, Nifedical XL, Procardia, Procardia XL); combination drug: nifedipine and atenolol (Beta-Adalat, Tenif).
Coadministration of nifedipine and dang gui in 40 patients with chronic obstructive pulmonary disease (COPD) led to a greater degree of reduction of pulmonary arterial pressure than in untreated controls or those treated with nifedipine alone. Dose of dang gui was high (250 mL 25% solution/day) and was administered parenterally, which makes extrapolation from this study problematic, although some clinical evidence suggests that dang gui alone may have a vasodilator effect on the pulmonary circulation. More investigation is needed before this is confirmed as a clinically consequential interaction, particularly in light of the in vitro evidence suggesting a pharmacokinetic reduction of nifedipine level by inhibition of CYP450 3A4 and 2D6 by dang gui.
Oral contraceptives:monophasic, biphasic, and triphasic estrogen preparations:
Ethinyl estradiol and desogestrel (Desogen, Ortho-TriCyclen).
Ethinyl estradiol and ethynodiol (Demulen 1/35, Demulen 1/50, Nelulen 1/25, Nelulen 1/50, Zovia).
Ethinyl estradiol and levonorgestrel (Alesse, Levlen, Levlite, Levora 0.15/30, Nordette, Tri-Levlen, Triphasil, Trivora).
Ethinyl estradiol and norethindrone/norethisterone (Brevicon, Estrostep, Genora 1/35, GenCep. 1/35, Jenest-28, Loestrin 1.5/30, Loestrin1/20, Modicon, Necon 1/25, Necon 10/11, Necon 0.5/30, Necon 1/50, Nelova 1/35, Nelova 10/11, Norinyl 1/35, Norlestin 1/50, Ortho Novum 1/35, Ortho Novum 10/11, Ortho Novum 7/7/7, Ovcon-35, Ovcon-50, Tri-Norinyl, Trinovum).
Ethinyl estradiol and norgestrel (Lo/Ovral, Ovral).
Mestranol and norethindrone (Genora 1/50, Nelova 1/50, Norethin 1/50, Ortho-Novum 1/50).
Related, internal application: Etonogestrel/ethinyl estradiol vaginal ring (Nuvaring).
Hormone replacement therapy, estrogens:Chlorotrianisene (Tace); conjugated equine estrogens (Premarin); conjugated synthetic estrogens (Cenestin); dienestrol (Ortho Dienestrol); esterified estrogens (Estratab, Menest, Neo-Estrone); estradiol, topical/transdermal/ring (Alora Transdermal, Climara Transdermal, Estrace, Estradot, Estring FemPatch, Vivelle-Dot, Vivelle Transdermal); estradiol cypionate (Dep-Gynogen, Depo-Estradiol, Depogen, Dura-Estrin, Estra-D, Estro-Cyp, Estroject-LA, Estronol-LA); estradiol hemihydrate (Estreva, Vagifem); estradiol valerate (Delestrogen, Estra-L 40, Gynogen L.A. 20, Progynova, Valergen 20); estrone (Aquest, Estragyn 5, Estro-A, Estrone ‘5’, Kestrone-5); estropipate (Ogen, Ortho-Est); ethinyl estradiol (Estinyl, Gynodiol, Lynoral).
Hormone replacement therapy, estrogen/progestin combinations:Conjugated equine estrogens and medroxyprogesterone (Premelle cycle 5, Prempro); conjugated equine estrogens and norgestrel (Prempak-C); estradiol and dydrogesterone (Femoston); estradiol and norethindrone, patch (CombiPatch); estradiol and norethindrone/norethisterone, oral (Activella, Climagest, Climesse, FemHRT, Trisequens); estradiol valerate and cyproterone acetate (Climens); estradiol valerate and norgestrel (Progyluton); estradiol and norgestimate (Ortho-Prefest).
Hormone replacement therapy, estrogen/testosterone combinations: Esterified estrogens and methyltestosterone (Estratest, Estratest HS).
Selective estrogen response modulators (SERMs):Raloxifene (Evista), tamoxifen (Nolvadex), toremifene (Fureston).
Partly because of its reputation as a “female tonic” herb, some sources suggest interaction of dang gui with female sex hormones (ERT, HRT) or hormone-modulating drugs (e.g., SERMs, aromatase inhibitors). Known phytoestrogenic compounds have not been recorded in the root, and a controlled clinical trial of postmenopausal women found no changes in endometrial thickness or vaginal cell proliferation after 24 weeks’ administration of a standardized extract of dang gui. However, a cell line model found some evidence for both estrogen-dependent and estrogen-independent proliferative activity by a water extract of dang gui. Recent reviews of botanicals for menopause have found no positive evidence of effects of dang gui alone on menopausal symptoms. In the absence of estrogenic clinical effects or pharmacological estrogen receptor binding, suggestions of female hormone interactions with dang gui by some authors are unsupported at this time.
Evidence: Ouabain (g-strophanthin).
Extrapolated, based on similar properties: Amiodarone (Cordarone, Pacerone), deslanoside (cedilanin-D), digitoxin (Cystodigin), digoxin (Digitek, Lanoxin, Lanoxicaps, purgoxin), disopyramide (Norpace), dofetilide (Tikosyn), flecainide (Tambocor), ibutilide (Corvert), procainamide (Pronestyl, Procan-SR), quinidine (Quinaglute, Quinidex, Quinora), sotalol (Betapace, Betapace AF, Sorine).
Some experimental evidence exists for an antiarrhythmic effect of parenteral dang gui extracts, in animal models, including ouabain-induced ventricular fibrillation, as well as in digitalis- and epinephrine-induced arrhythmias. Some secondary sources suggest that the herb must interact adversely with antiarrhythmic drugs, but logically a beneficial interaction would be suggested, and clinical reports of the adverse interaction are lacking.
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