Herbal Medicine for the Treatment of Cardiovascular Disease Clinical Considerations

REVIEW ARTICLE Herbal Medicine for the Treatment of Cardiovascular Disease Clinical Considerations

Nick H. Mashour, MD; George I. Lin, MD; William H. Frishman, MD

erbs have been used as medical treatments since the beginning of civilization and some derivatives (eg, aspirin, reserpine, and digitalis) have become mainstays of human pharmacotherapy. For cardiovascular diseases, herbal treatments have been used in patients with congestive heart failure, systolic hypertension, angina pectoris, ath- Herosclerosis, cerebral insufficiency, venous insufficiency, and arrhythmia. However, many herbal remedies used today have not undergone careful scientific assessment, and some have the potential to cause serious toxic effects and major drug-to-drug interactions. With the high prevalence of herbal use in the United States today, clinicians must inquire about such health practices for cardiac disease and be informed about the potential for benefit and harm. Continuing research is necessary to elucidate the pharmacological activities of the many herbal remedies now being used to treat cardiovascular diseases. Arch Intern Med. 1998;158:2225-2234 Since the beginning of human civiliza- ceding year.2 This figure is probably tion, herbs have been an integral part of much higher for non–English-speaking society, valued for both their culinary and Americans. Despite this heavy use of medicinal properties. Herbal medicine has herbal medicines in the United States, made many contributions to commercial health practitioners often fail to ask drug preparations manufactured today in- about their use when taking clinical his- cluding ephedrine from Ephedra sinica tories. It is imperative that physicians (ma-huang), digitoxin from Digitalis pur- become more aware of the wide array of purea (foxglove), salicin (the source of as- herbal medicines available, as well as pirin) from Salix alba (willow bark), and learning more about their beneficial and reserpine from Rauwolfia serpentina adverse effects.3 (snakeroot), to name just a few. A natu- Part of the problem for both consum- rally occurring ␤-adrenergic blocking agent ers and physicians has been the paucity of with partial agonism has been identified scientific data on herbal medicines used in in an herbal remedy.1 The recent discov- the United States.4 As a result, those who ery of the antineoplastic drug paclitaxel wish to obtain factual information regard- from Taxus brevifolia (pacific yew tree) ing the therapeutic use or potential harm stresses the role of plants as a continuing of herbal remedies would have to obtain it resource for modern medicine. from books and pamphlets, most of which However, with the development of base their information on traditional repu- patent medicines in the early part of the tation rather than relying on existing sci- 20th century, herbal medicine has been entific research. One may wonder why the losing ground to new synthetic medi- herbal industry never chose to simply prove cines touted by scientists and physicians its products safe and effective. The answer to be more effective and reliable. Never- is primarily economical. With the slim theless, about 3% of English-speaking chance of patent protection for the many adults in the United States still report herbs that have been in use for centuries, having used herbal remedies in the pre- pharmaceutical companies have not pro- vided financial support for research on the 5 From the Department of Medicine, The Albert Einstein College of Medicine, Bronx, NY merits of herbal medicine. At the same (Dr Mashour); the Department of Family Medicine, Columbia Presbyterian Medical time, the National Institutes of Health have Center, New York, NY (Dr Lin); and the Departments of Medicine and Pharmacology, only been able to offer limited funding for New York Medical College/Westchester Medical Center, Valhalla, NY (Dr Frishman). this purpose.

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 This review examines herbal medicines that affect the cardiovas- Herbs for Cardiovascular Conditions With Severe Adverse Reactions cular system both in terms of effi- or Notable Drug Interactions* cacy and safety as gleaned from the scientific literature that is avail- Herbal Medicine Adverse Reaction/Drug Interaction Treatment able. These herbs are categorized un- Natural cardiac glycosides Ventricular tachyarrhythmia, bradycardia, Digoxin-specific (Ͼ20 plant sources) and heart block Fab antibody der the primary diseases they treat. Veratrum Bradycardia, A-V dissociation, hypotension, ECG changes responsive However, most herbal medicines (hellebore) and (rarely) seizures to atropine have multiple cardiovascular ef- Crataegus Potentiates digitalis activity NA fects that frequently overlap. The (hawthorn) purpose of this organization is to Salvia miltiorrhiza Potentiates warfarin activity NA simplify, not to pigeonhole herbs un- (dan-shen) Aesculus hippocastanum Renal and hepatic toxic effects Dialysis to reduce der specific diseases. In general, the (horse chestnut) toxic levels dilution of active components in herbal medicines results in fewer ad- *A-V indicates arteriovenous anastomosis; ECG, electrocardiographic; and NA, data not applicable. verse and toxic effects in comparison with the concentration of ac- mango), Cheiranthus cheiri (wall- ander intoxication, as well as other tive components in the allopathic flower), Convallaria majalis (lily of natural glycosides, is virtually iden- medicines. However, these adverse the valley, convallaria), Cryptoste- tical to digoxin overdose. Morbid- effects and drug interactions should gia grandiflora (rubber vine), Hel- ity and mortality are mainly related not be overlooked; cardiovascular leborus niger (black hellebore), Hel- to cardiotoxic adverse effects that disease is a serious health hazard and leborus viridus, Nerium oleander usually include life-threatening ven- no herbal remedy regimen should be (oleander), Plumeria rubra (frangi- tricular tachyarrhythmias, brady- initiated without careful consider- pani), Selenicerus grandiflorus (cac- cardia, and heart block. The diag- ation of its potential impact (Table). tus grandiflorus), Strophanthus his- nosis should rely on the clinical pidus and Strophanthus kombe presentation of unexplained hyper- CONGESTIVE HEART FAILURE (strophanus), Thevetia peruviana kalemia, and cardiac, neurologic, (yellow oleander), and Urginea mar- and gastrointestinal symptoms.19 A number of herbs contain potent itima (squill).5,7-15 Even the venom The diagnosis can be further cardioactive glycosides, which have glands of the animal Bufo marinus supported by the detection of the positive inotropic actions on the (cane toad) contain cardiac glyco- substance digoxin in a radioimmu- heart. The drugs digitoxin, derived sides.8 Recently, the digitalislike ste- noassay for digoxin. However, the from either D purpurea (foxglove) or roid in the venom of the B marinus extent of cross-reactivity between the Digitalis lanata, and digoxin, de- toad was identified as a previously cardiac glycosides from herbal rived from D lanata alone, have been described steroid, marinobufa- sources and antibodies used in the used in the treatment of congestive genin. Marinobufagenin demon- radioimmunoassays has not been heart failure for many decades. Car- strated high digoxinlike immuno- clearly defined.26 For this reason, di- diac glycosides have a low therapeu- reactivity and was antagonized with goxin assays may serve to confirm tic index, and the dose must be ad- an antidigoxin antibody.16 the suspected diagnosis but not to justed to the needs of each patient. Accidental poisonings and even quantify the severity. Once the di- The only way to control dosage is to suicide attempts with ingestion of agnosis has been established, the use use standardized powdered digi- cardiac glycosides are abundant in of digoxin-specific Fab antibody talis, digitoxin, or digoxin. When the medical literature.17-21 Some fragments may be helpful in the 12 different strains of D lanata herbal remedies (eg, Siberian gin- treatment of severe intoxication. plants were cultured and exam- seng) can elevate synthetic digoxin Other modalities, such as dialysis, ined, their total cardenolide yield drug levels and cause toxic ef- cannot be easily facilitated be- ranged from 30 to almost 1000 fects.22 In the United States, there are cause, like digoxin, natural glyco- nmol/1 g.6 As is evident, treating about 15 000 intoxications due to ac- sides are distributed extensively into congestive heart failure with non- cidental or intentional ingestion of peripheral tissues. standardized herbal drugs would be poisonous plants annually.23 In 1993, dangerous and foolhardy. 2388 toxic exposures in the United HYPERTENSION Some common plant sources of States were reported to be due to cardiac glycosides include D pur- plant glycosides. Of these, the larg- The root of R serpentina (snake- purea (foxglove, already men- est percentage were attributed to ole- root), the natural source of the alka- tioned), Adonis microcarpa and Ado- ander (ie, 25%).24 In the case of ole- loid reserpine, has been a Hindu nis vernalis (adonis), Apocynum ander, all plant tissues, including the Ayurvedic remedy since ancient cannabinum (black Indian hemp), seeds, roots, stems, leaves, berries, times. In 1931, Indian literature first Asclepiascurassavica (redheaded cot- and blossoms, are considered ex- described the use of R serpentina root ton bush), Asclepias friticosa (bal- tremely toxic.19 In fact, death in hu- for the treatment of hypertension loon cotton), Calotropis precera mans has been reported following in- and psychoses; however, the use of (king’s crown), Carissa spectabilis gestion of as little as 1 oleander leaf.25 Rauwolfia alkaloids in Western (wintersweet), Cerebra manghas (sea The clinical manifestations of ole- medicine did not begin until the

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 mid1940s.27 Both standardized whole nese medicine to treat hyperten- ent extracted from L wallichii, inhibits root preparations of R serpentina and sion. Tetrandrine, an alkaloid ex- platelet aggregation in vitro and low- its reserpine alkaloid are officially tract of S tetrandra, has been shown ers blood pressure by vasodilation in monographed in the United States to be a calcium ion channel antago- dogs. With its actions independent Pharmacopeia.28 A powdered whole nist, paralleling the effects of verap- of the endothelium, tetramethylpyr- root of 200 to 300 mg orally is equiva- amil. Tetrandrine blocks T and L cal- azine’s vasodilatory effect is mediated lent to 0.5 mg of reserpine.29 cium channels, interferes with the by calcium channel antagonism and Reserpine was one of the first binding of diltiazem and methoxyver- nonselective antagonism of ␣- drugs used on a large scale to treat sys- apamil at calcium-channel binding adrenergic receptors. Some evidence temichypertension.Itactsbyirrevers- sites, and suppresses aldosterone pro- suggeststhattetramethylpyrazineacts ibly blocking the uptake of biogenic duction.31,32 A parenteral dose (15 mg/ on the pulmonary vasculature.31 Cur- amines (norepinephrine, dopamine, kg) of tetrandrine in conscious rats rently, there is insufficient informa- and serotonin) in the storage vesicles decreases mean, systolic, and dias- tion to evaluate the safety and efficacy of central and peripheral adrenergic tolic blood pressures for more than of this herbal medicinal. neurons, thus leaving the catechol- 30 minutes; however, an intrave- Uncaria rhynchophylla is some- amines to be destroyed by the intra- nous 40-mg/kg dose killed the rats by times used in traditional Chinese neuronal monoamine oxidase in the myocardial depression. In stroke- medicine to treat hypertension. Its cytoplasm. The depletion of catechol- prone hypertensive rats, an oral dose indole alkaloids, rhynchophylline amines accounts for reserpine’s sym- of 25 or 50 mg/kg produced a gradual and hirsutine, are thought to be the patholytic and antihypertensive ac- and sustained hypotensive effect af- active principles of U rhynchophyl- tions. Reserpine’s effects are long last- ter 48 hours without affecting plasma la’s vasodilatory effect. The mecha- ing, since recovery of sympathetic renin activity.33 In addition to its nism of U rhynchophylla’s actions is function requires synthesis of new cardiovascular actions, tetrandrine unclear. Some studies point to an al- storage vesicles, which takes days to has reported antineoplastic, immu- teration in calcium ion flux in re- weeks. Reserpine lowers blood pres- nosuppressive, and mutagenic sponse to activation, whereas oth- sure by decreasing cardiac output, pe- effects.31 ers point to hirsutine’s inhibition of ripheralvascularresistance,heartrate, Tetrandrine is 90% protein- nicotine-induced dopamine re- and renin secretion. With the intro- bound with an elimination half-life lease.31 One in vitro study has shown duction of other antihypertensive of 88 minutes, according to dog U rhynchophylla extract relaxes nor- drugs with fewer central nervous sys- studies; however, rat studies have epinephrine-precontracted rat aorta tem adverse effects, the use of reser- shown a sustained hypotensive ef- through endothelium-dependent pine has diminished. The daily oral fect for more than 48 hours after a and -independent mechanisms. For dose of reserpine should be 0.25 mg 25- or 50-mg oral dose. Tetran- the endothelium-dependent com- or less, and as little as 0.05 mg if given drine causes liver necrosis in dogs ponent, U rhynchophylla extract ap- with a diuretic. Using the whole root, orally administered 40 mg/kg of tet- pears to stimulate endothelium- the usual adult dose is 50 to 200 mg/d randrine 3 times weekly for 2 derived relaxing factor and/or nitric administered once daily or in 2 di- months, reversible swelling of liver oxide release without involving mus- vided doses.27-29 cells with a 20-mg/kg dose, and no carinic receptors.39 Also, in vitro and Rauwolfia alkaloids are contra- observable changes with a 10- in vivo studies have shown that indicated for use in patients with mg/kg dose.31 Given the evidence of rhynchophylline can inhibit plate- previously demonstrated hypersen- hepatotoxicity, many more studies let aggregation and reduce platelet sitivity to these substances, in pa- are necessary to establish a safe dos- thromboses induced with collagen tients with a history of mental de- age of tetrandrine in humans. or adenosine diphosphate plus epi- pression (especially with suicidal More recently, tetrandrine has nephrine.31 Safety and efficacy can- tendencies), in patients with active been implicated in an outbreak of not be evaluated at this time be- peptic ulcer disease or ulcerative co- rapidly progressive renal failure, cause of a lack of clinical data. litis, and in patients receiving elec- termed Chinese herb nephropathy. Veratrum (hellebore) is a pe- troconvulsive therapy. The most Numerous individuals developed the rennial herb grown in many parts of common adverse effects are seda- condition after using a combina- the world. Varieties include Vera- tion and inability to concentrate and tion of several Chinese herbs as part trum viride from Canada and the perform complex tasks. Reserpine of a dieting regimen. It has been hy- eastern United States, Veratrum cali- may cause mental depression, some- pothesized that the cause may be at- fornicum from the western United times resulting in suicide, and its use tributed to misidentification of S tet- States, Veratrum album from Alaska must be discontinued at the first sign randra; nonetheless, questions still and Europe, and Veratrum japoni- of depression. Reserpine’s sympa- remain as to the role of tetrandra in cum from Asia. All Veratrum plants tholytic effect and its enhancement the development of this serious toxic contain poisonous alkaloids known of parasympathetic actions account effect.34-37 to cause vomiting, bradycardia, and for its well-described adverse effects: The root of Lingusticum wallichii hypotension. Most cases of Vera- nasal congestion, increased gastric is used in traditional Chinese medi- trum poisonings are due to mis- secretion, and mild diarrhea.27-30 cine as a circulatory stimulant, hypo- identification with other plants. Stephania tetrandra is an herb tensive drug, and sedative.38 Tetra- Although once a treatment for hy- sometimes used in traditional Chi- methylpyrazine, the active constitu- pertension, the use of Veratrum al-

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 kaloids has lost favor owing to a low cally active substances, such as oligo- a potentially reduced arrhythmo- therapeutic index and unaccept- meric procyanins, flavonoids, and genic risk because of its ability to able toxicity, as well as the intro- catechins. From current studies, prolong the effective refractory pe- duction of safer antihypertensive Crataegus extract appears to have an- riod, while the other drugs men- drug alternatives.40 tioxidant properties and can in- tioned previously all shorten this pa- Veratrum alkaloids enhance hibit the formation of throm- rameter.55,56 Also, it should be noted nerve and muscle excitability by in- boxane as well.44,45 that concomitant use of hawthorn creasing sodium ion conductivity. Also, Crataegus extract antago- with digitalis can markedly en- They act on the posterior wall of the nizes the increases in cholesterol, tri- hance the activity of digitalis.5,57 Un- left ventricle and the coronary si- glyceride, and phospholipid levels in doubtedly, more studies are needed nus baroreceptors, causing reflex hy- low-density lipoprotein (LDL) and to show that hawthorn can be used potension and bradycardia via the very low-density lipoprotein in rats safely and effectively. vagus nerve (Bezold-Jarisch re- fed a hyperlipidemic diet; thus, it Because of its resemblance to flex). Nausea and vomiting are sec- may inhibit the progression of ath- Panax ginseng (Asian ginseng), Panax ondary to the alkaloids’ actions on erosclerosis.46 This hypocholester- notoginseng has acquired the com- the nodose ganglion.40 olemic action may be due to an up- mon name of pseudoginseng, espe- The diagnosis of Veratrum tox- regulation of hepatic LDL receptors cially since it is often an adulterant of icity is established by history, iden- resulting in greater influx of plasma P ginseng preparations. In tradi- tificationoftheplant,andstrongclini- cholesterol into the liver. Cratae- tional Chinese medicine, the root of cal suspicion. Clinical symptoms usu- gus also prevents cholesterol accu- P notoginseng is used for analgesia and ally occur quickly, often within 30 mulation in the liver by enhancing hemostasis. It is also often used in the minutes.41 Treatment is mainly sup- cholesterol degradation to bile ac- treatment of patients with angina and portive and directed at controlling ids, as well as suppressing choles- coronary artery disease.38 Panax no- bradycardia and hypotension. terol biosynthesis.47 toginseng has been described as a cal- Veratrum-induced bradycardia usu- According to another study, Cra- cium ion channel antagonist in vas- ally responds to treatment with atro- taegus extract, in high concentra- cular tissue. More specifically, its pine; however, the blood pressure re- tions, has a cardioprotective effect on pharmacological action may be as a sponse to atropine is more variable ischemic-reperfused hearts without novel and selective calcium ion an- and requires the addition of pressors. causing an increase in coronary blood tagonist that does not interact with the Other electrocardiographic changes, flow.48 On the other hand, oral and L-type calcium ion channel but rather such as atrioventricular dissociation, parenteral administration of oligo- may interact with the receptor- may also be reversible with atropine.42 meric procyanins of Crataegus has operated calcium ion channel.58 Seizures are a rare complication and been shown to lead to an increase in Although clinical trials are lack- may be treated with conventional an- coronary blood flow in both cats and ing, in vitro studies using P notogin- ticonvulsants. For patients with pre- dogs.49,50 Double-blind clinical trials seng suggest possible cardiovascular existing cardiac disease, the use of ␤- have demonstrated simultaneous car- effects. One study that used purified agonists or pacing may be necessary. diotropic and vasodilatory actions of notoginsenoside R1, extracted from Nausea may be controlled with phe- Crataegus.51 In essence, Crataegus in- P notoginseng, on human left umbili- nothiazineantiemetics.Recoveryusu- creases coronary perfusion, has a mild cal vein endothelial cells showed a ally occurs within 24 to 48 hours.40 hypotensive effect, antagonizes ath- dose- and time-dependent synthesis Evodia rutaecarpa (wu-chu- erogenesis, and has positive inotro- of tissue-type plasminogen activat- yu) is a Chinese herbal drug that has pic and negative chronotropic ac- ing factor without affecting the syn- been used as a treatment for hy- tions.46,52 In a recent multicenter, thesis of plasminogen activating in- pertension. It contains an active placebo-controlled, double-blind hibitor. Thus, fibrinolytic parameters vasorelaxant component called ru- study, an extract of Crataegus was were enhanced.59 Another study sug- taecarpine that can cause endothe- shown to clearly improve the car- gests that P notoginseng saponins may lium-dependent vasodilation in diac performance of patients with inhibit atherogenesis by interfering experimental models.43 New York Heart Association class II with the proliferation of smooth heart failure. In this study, the pri- muscle cells.60 In vitro and in vivo ANGINA PECTORIS mary parameter analyzed was the studies using rats and rabbits dem- heart rate product (systolic blood onstrate that P notoginseng may be Crataegus hawthorn, a name encom- pressure ϫ heart rate).53 Recent stud- useful as an antianginal drug, since passing many Crataegus species ies have suggested that the mecha- it dilates coronary arteries in all con- (such as Crataegus oxyacantha and nism of cardiac action for Crataegus centrations. The role of P notogin- Crataegus monogyna in the West and species may be due to the inhibition seng in the treatment of hyperten- Crataegus pinnatifida in China) has of the 3Ј,5Ј-cyclic adenosine mono- sion is less certain, since P notoginseng acquired the reputation in modern phosphate phosphodiesterase.54 causes vasodilation or vasoconstric- herbal literature as an important Hawthorn is relatively devoid tion depending on the concentra- tonic for the cardiovascular system of adverse effects. In fact, in com- tion and target vessel.61 The results that is particularly useful for an- parison with other inotropic drugs of these in vitro and in vivo studies gina. Crataegus leaves, flowers, and such as epinephrine, amrinone, mil- are encouraging; however, clinical tri- fruits contain a number of biologi- rinone, and digoxin, Crataegus has als will be necessary to make a more

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 informed decision regarding the use cades, research has focused on larger, more rigorously designed tri- of P notoginseng. garlic’s use in preventing atheroscle- als may be necessary to better de- Salvia miltiorrhiza (dan- rosis. Garlic, like many of the other termine its utility in preventing car- shen), a relative of the Western sage herbal medicines discussed previ- diovascular disease. Salvia officinalis, is native to China. ously, has demonstrated multiple Garlic has also been studied in In traditional Chinese medicine, the beneficial cardiovascular effects. A hypertensive patients as a blood root of S miltiorrhiza is used as a cir- number of studies have demon- pressure–lowering agent. Similar to culatory stimulant, sedative, and strated these effects that include low- its lipid effects, no conclusive stud- cooling drug.38 Salvia miltiorrhiza ering blood pressure, inhibiting ies have been conducted and many may be useful as an antianginal drug platelet aggregation, enhancing fi- methodological shortcomings exist because it has been shown to dilate brinolytic activity, reducing serum in study designs. The results of one coronary arteries in all concentra- cholesterol and triglyceride levels, meta-analysis that considered 8 dif- tions, similar to P notoginseng. Also, and protecting the elastic proper- ferent trials suggest some clinical use S miltiorrhiza has variable action on ties of the aorta. for patients with mild hyperten- other vessels depending on its con- Consumption of large quanti- sion, but there is insufficient evi- centration, so it may not be as help- ties of fresh garlic (0.25 to 1.0 g/kg dence to recommend its use as rou- ful in treating hypertension.61 In or about 5-20 average sized 4-g tine clinical therapy.68 Garlic has also vitro, S miltiorrhiza, in a dose- cloves in a person weighing 78.7 kg) been shown to possess antiplatelet dependent fashion, inhibits plate- has been shown to produce the ben- activity. In the past, this action was let aggregation and serotonin re- eficial effects mentioned earlier.66 In mostly documented in vitro.75 A new lease induced by either adenosine support of this, a recent double- study examined the effect of the con- diphosphate or epinephrine, which blind cross-over study was consumption of a fresh clove of garlic is thought to be mediated by an in- ducted on moderately hypercholes- on platelet thromboxane produc- crease in platelet cyclic adenosine terolemic men that compared the tion and showed that after 26 weeks, monophosphate caused by S milti- effects of 7.2 g of aged garlic ex- serum thromboxane levels were re- orrhiza’s inhibition of cyclic aden- tract with placebo on blood lipid lev- duced about 80%.76 This may prove osine monophosphate phosphodi- els. This study found that there was to be beneficial in the prevention of esterase.62 Salvia miltiorrhiza appears a maximal reduction of 6.1% in to- thrombosis in the future. Recently, to have a protective action on ische- tal serum cholesterol levels and 4.6% the effect of long-term garlic intake mic myocardium, enhancing the in LDL cholesterol levels with gar- on the elastic properties of the aorta recovery of contractile force on lic compared with placebo.67 was also studied. Participants in the reoxygenation.63 More recently, S However, despite positive evi- trial (limited to those aged 50-80 miltiorrhiza has been shown to pro- dence from numerous trials, some years) consumed 300 mg/d of stan- tect myocardial mitochondrial mem- investigators have been hesitant to dardized garlic powder for more than branes from ischemia-reperfusion in- outright endorse the routine use of 2 years. The results showed that the jury and lipid peroxidation because garlic for cardiovascular disease be- pulse-wave velocity and standard- of its free radical–scavenging ef- cause many of the published stud- ized elastic vascular resistance of the fects.64 Qualitatively and quantita- ies had methodological shortcom- aorta were lower in the garlic group tively, a decoction of S miltiorrhiza ings,66,68-72 perhaps because than in the control group. Conse- was as efficacious as the more ex- constituent trials were small, lack- quently, long-term garlic powder in- pensive isolated tanshinones.59 ing statistical power. Also, inappro- take may have a protective effect on Clinical trials will be neces- priate methods of randomization, the elastic properties of the aorta re- sary to evaluate the safety and effi- lack of dietary run-in period, short lated to aging.77 In these ways, gar- cacy of S miltiorrhiza. Of note, it has duration, or failure to undertake in- lic has shown numerous beneficial been observed clinically that when tention-to-treat analysis may ex- cardiovascular effects that need to be S miltiorrhiza and warfarin sodium plain the cautious acceptance of pre- investigated further to determine its are coadministered, there is an in- vious meta-analyses.73 In fact, one therapeutic utility. creased incidence in warfarin- recent study found no demon- Intact cells of garlic bulbs in- related adverse effects; in rats S milti- strable effect of garlic ingestion on clude an odorless, sulfur-contain- orrhiza was shown to increase the lipid and lipoprotein levels. This ing amino acid known as allinin. plasma concentrations of warfarin as study used a cross-over design pro- When garlic is crushed, allinin well as the prothrombin time.65 tected by a washout period to re- comes into contact with allinase, duce between-subject variability as which converts allinin to allicin. Al- ATHEROSCLEROSIS well as close assessment and report- licin has potent antibacterial prop- ing of dietary behavior, which had erties, but it is also highly odorifer- In addition to its use in the culi- been lacking in previous trials.74 An- ous and unstable. Ajoenes, self- nary arts, garlic (Allium sativum) has other study found no effect of gar- condensation products of allicin, been valued for centuries for its me- lic on cholesterol absorption, cho- appear to be responsible for garlic’s dicinal properties. Garlic is one of lesterol synthesis, or cholesterol antithrombotic activity. Most au- the herbal medicines that has been metabolism.71 As is evident, the pre- thorities now agree that allicin and examined more closely by the sci- cise extent of garlic’s impact on ath- its derivatives are the active con- entific community. In recent de- erosclerosis remains controversial; stituents of garlic’s physiological ac-

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 tivity. Fresh garlic releases allicin in decreased LDL cholesterol levels by groups of substances within G bi- the mouth during the chewing pro- 12.5% and the total cholesterol–high- loba extract (GBE) demonstrate ben- cess. Dried garlic preparations lack density lipoprotein cholesterol ratio eficial pharmacological actions. The allicin but contain allinin and allin- by 11.1%, whereas the levels were un- flavonoids reduce capillary perme- ase. Since allinase is inactivated in changed in the placebo group.83 ability as well as fragility and serve the stomach, dried garlic prepara- Besidesbeingpotentiallyaseffec- as free radical scavengers. The ter- tions should be coated with enteric tive in lowering blood lipid levels as penes (ie, ginkgolides) inhibit plate- so that they pass through the stom- modern hyperlipidemic drugs, gugu- let-activating factor, decrease vas- ach into the small intestine where al- lipid may even be safer. In the trial cular resistance, and improve linin can be enzymatically con- mentionedpreviously,compliancewas circulatory flow without apprecia- verted to allicin. Few commercial greater than 96%, with only the ad- bly affecting blood pressure.57,87 Con- garlic preparations are standard- verse effects of headache, mild nau- tinuing research appears to sup- ized for their allicin yield based on sea, and hiccups noted.83 However, it port the primary use of GBE for allinin content, hence making their has been shown that gugulipid may treating cerebral insufficiency and its effectiveness less certain.5 How- affect the bioavailability of other car- secondary effects on vertigo, tinni- ever, one double-blind, placebo- diovascular drugs, namely, proprano- tus, memory, and mood; also, GBE controlled study involving 261 pa- lol hydrochloride and diltiazem hy- appears to be useful for treating pe- tients for 4 months using one drochloride. Gugulipid significantly ripheral vascular disease, includ- 800-mg tablet of garlic powder daily, reduced the peak plasma concentra- ing diabetic retinopathy and inter- standardized to 1.3% allinin con- tion and area under the curve of both mittent claudication.5,57,87-91 tent, demonstrated significant re- these drugs, which may lead to dimin- In a randomized, placebo- ductions in total cholesterol (12%) ished efficacy or nonresponsiveness.84 controlled, double-blind study, EGb and triglyceride levels (17%).78 Undoubtedly, gugulipid is a natural 761, which is a standardized ex- Aside from a garlic odor on the lipid-lowering drug with potential for tract of G biloba with respect to its breath and body, moderate garlic con- therapeutic use, but rigorous, larger flavonol glycoside and terpene lac- sumption causes few adverse ef- clinical trials will be necessary to fur- tone content, was shown to signifi- fects. However, consumption in ex- ther evaluate its safety and efficacy be- cantly decrease the areas of ische- cess of 5 cloves daily may result in fore it can be endorsed as an alterna- mia as measured by transcutaneous heartburn, flatulence, and other gas- tive therapy for hyperlipidemia and partial pressure of oxygen during ex- trointestinal disturbances. Some prevention of atherosclerosis. ercise. Because of its rapid anti- people have reported allergic reac- Maharishi amrit kalash-4 and ischemic action, EGb 761 may be tions to garlic, most commonly al- Maharishi amrit kalash-5 are 2 com- valuable in the treatment of inter- lergic contact dermatitis. Patch test- plex herbal mixtures with signifi- mittent claudication and periph- ing with 1% diallyl disulfide is cant antioxidant properties that have eral artery disease in general.92 recommended when garlic allergy is been shown to inhibit LDL oxida- Also, studies have been exam- suspected.79 Because of its antithrom- tion in patients with hyperlipid- ining the cardioprotective efficacy of botic activity, garlic should be used emia. In experimental studies, the EGb 761 in regard to its anti–free with caution in people taking oral an- herbal mixtures have also been shown radical action in myocardial isch- ticoagulants concomitantly.5,80 to inhibit enzymatic- and nonenzy- emia–reperfusion injury. In vitro The resin of Commiphora mukul matic-induced microsomal lipid per- studies with animal models have (gugulipid), a small, thorny tree na- oxidation and platelet aggregation.85 shown that this compound may ex- tive to India, has long been used in ert such an effect.93,94 A clinical study Ayurvedic medicine to treat lipid dis- CEREBRAL AND PERIPHERAL of 15 patients undergoing coronary orders. The primary mechanism of VASCULAR DISEASE bypass surgery demonstrated that action of gugulipid is through an in- oral EGb 761 therapy may limit free crease in the uptake and metabo- Having existed for more than 200 radical–induced oxidative stress oc- lism of LDL cholesterol by the liver.81 million years, Ginkgo biloba (maid- curring in the systemic circulation In a double-blind, cross-over study enhair tree) was apparently saved and at the level of the myocardium completed in 125 patients taking gu- from extinction by human interven- during these operations.95 It re- gulipid compared with 108 patients tion, surviving in Far Eastern temple mains to be studied whether ex- taking clofibrate, the average de- gardens while disappearing for cen- tracts of G biloba may be used as crease in serum cholesterol and tri- turies in the West. It was reintro- pharmacological adjuvants to limit glyceride levels was 11% and 16.8%, duced to Europe in 1730 and be- tissue damage and metabolic alter- respectively, with gugulipid com- came a favorite ornamental tree.38,86 ations following coronary bypass pared with 10% and 21.6%, respec- Although the root and kernels of G surgery, coronary angioplasty for tively, with clofibrate. In general, hy- biloba have long been used in tradi- acute myocardial infarctions, or even percholesterolemic patients tional Chinese medicine, the tree in managing coronary thrombosis. responded more favorably to gugu- gained attention in the West dur- Although approved as a drug lipid therapy than hypertriglyceride- ing the 20th century for its medici- in Europe, Ginkgo is not approved mic patients.82 Moreover, it was nal value after a concentrated ex- in the United States and is instead shown in another randomized, tract of G biloba leaves was marketed as a food supplement, double-blind trial that C mukul also developed in the 1960s. At least 2 usually supplied as 40-mg tablets

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 of extract. Since most of the inves- cause gastrointestinal and kidney tive treatment of patients with tigations examining the efficacy of disturbances in large doses.5,101 Un- chronic venous insufficiency.107 Also, GBEs used preparations such as til more studies are done, rosemary HCE has been shown to markedly EGb 761 or LI 1370, the bio- should probably be limited to its use improve other symptoms associ- equivalence of other GBE prod- as a culinary spice and flavoring ated with chronic venous insuffi- ucts has not been established. The agent rather than as a medicine. ciency, such as pain, tiredness, itch- recommended dosage in Europe is ing, and tension in the swollen leg, one 40-mg tablet taken 3 times VENOUS INSUFFICIENCY in a case-observation study.108 Aside daily with meals (120 mg/d).5,87 from effects on venous insuffi- Adverse effects due to GBE are The seeds of horse chestnut, Aescu- ciency, prophylactic use of HCE has rare but can include gastrointesti- lus hippocastanum, have long been been thought to decrease the inci- nal disturbances, headache, and used in Europe to treat venous dis- dence of thromboembolic compli- allergic skin rash.5,87 orders such as varicose veins. The sa- cations of gynecological surgery. Known mostly as a culinary ponin glycoside aescin from horse However, since this issue is still con- spice and flavoring agent, Rosmari- chestnut extract (HCE) inhibits the troversial,109 this does not appear to nus officinalis (rosemary) is listed in activity of lysosomal enzymes thought be the case.109 many herbal sources as a tonic and to contribute to varicose veins by Standardized HCE is prepared as all-around stimulant. Tradition- weakening vessel walls and increas- an aqueous alcohol extract of 16% to ally, rosemary leaves are said to en- ing permeability, which result in di- 21% of triterpene glycosides, calcu- hance circulation, aid digestion, el- lated veins and edema.5 In fact, related as aescin. The usual initial dos- evate mood, and boost energy. When cent research has shown that A age is 90 to 150 mg/d of aescin, which applied externally, the volatile oils hippocastanum inhibits only against may be reduced to 35 to 70 mg/d if are supposedly useful for arthritic hyaluronidase but not elastase, and clinical benefit is seen.5 Standardized conditions and baldness.5 this activity is linked mainly to the sa- HCE preparations are not available in Although research on rose- ponin escin.102 In animal studies, the United States, but nonstandard- mary is scant, some studies have fo- HCE, in a dose-dependent fashion, in- ized products may be available. cused on antioxidant effects of di- creases venous tone, venous flow, and Some manufacturers promote terpenoids, especially carnosic acid lymphatic flow. It also antagonizes the use of topical preparations of HCE and carnosol, isolated from rose- capillary hyperpermeability in- for treatment of varicose veins as well mary leaves. In addition to having duced by histamine, serotonin, or as hemorrhoids; however, at least one antineoplastic effects, antioxidants chloroform. This extract has been study has demonstrated poor aescin in rosemary have been credited with shown to decrease edema forma- distribution at sites other than the skin stabilizing erythrocyte membranes tion of lymphatic and inflamma- and muscle tissues underlying the ap- and inhibiting superoxide gener- tory origin. Horse chestnut extract plication site.110 Moreover, the in- ation and lipid peroxidation.96,97 has antiexudative properties, sup- volvement of arterioles and veins in Essential oils of rosemary have dem- pressing experimentally induced the pathophysiology of hemor- onstrated antimicrobial, hypergly- pleurisy and peritonitis by inhibiting rhoids makes the effectiveness of HCE cemic, and insulin-inhibiting prop- plasma extravasation and leukocyte doubtful, since HCE has no known erties.98,99 Rosemary leaves contain emigration, and its dose-dependent effects on the arterial circulation. For high amounts of salicylates, and its antioxidant properties can inhibit in now, research studies have yet to con- flavonoid pigment diosmin is re- vitro lipid peroxidation.103,104 Ran- firm any clinical effectiveness of topi- ported to decrease capillary perme- domized, double-blind, placebo- cal HCE preparations. ability and fragility.57,100,101 controlled trials with HCE show are Although adverse effects are un- Despite the conclusions de- eduction in edema, measured using common, HCE may cause gastroin- rived from in vitro and animal stud- plethysmography.105,106 testinal irritation. Parenteral aescin ies, the therapeutic use of rosemary In another recent random- has produced isolated cases of ana- for cardiovascular disorders re- ized, placebo-controlled study, the phylactic reactions, as well as he- mains questionable, because few, if efficacy and safety of class 2 com- patic and renal toxic effects.5,111-113 In any, clinical trials have been con- pression stockings and dried HCE the event of toxicity, aescin can be ducted using rosemary. Because of were compared. Both HCE and the eliminated via dialysis, with elimina- the lack of studies, no conclusions compression stockings decreased tion dependent on protein-bind- can be reached regarding the use of lower leg edema after 12 weeks of ing.114 Horse chestnut extract is also the antioxidants of rosemary in in- therapy; the results showed an av- one of the components of veno- hibiting atherosclerosis. Although erage 43.8-mL reduction with HCE curan, a drug marketed as a treat- external application may cause cu- and 46.7-mL with compression ment for venous disorders. In 1975, taneous vasodilation from the coun- stockings, while the placebo group venocuran was determined to cause terirritant properties of rosemary’s showed an increase of 9.8 mL. Both a pseudolupus syndrome character- essential oils, there is no evidence to HCE and compression therapy were ized by recurrent fever, myalgia, ar- support any prolonged improve- well tolerated, with no serious ad- thralgia, pleuritis, pulmonary infil- ment in peripheral circulation.5 verse effects. This study may indi- trates, pericarditis, myocarditis, and While rosemary does have some car- cate that both of these modalities are mitochondrial antibodies in the ab- minative properties, it may also reasonable alternatives for the effec- sence of nuclear antibodies after pro-

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 longed treatment.115,116 Venocuran has ography. The decrease was mea- ment of sick sinus syndrome. How- since been withdrawn from the mar- sured 2.5 hours after applying 4 to ever, more scientific research on xin ket; however, the nature of its patho- 6 g of a cream containing 64 to 96 bao and other antiarrhythmic Chi- physiologic action is still unknown. mg of Ruscus extract.120 In another nese herbs mentioned previously are Like A hippocastanum, Ruscus small trial (N = 18) it was shown that necessary before any recommenda- aculeatus (butcher’s broom) is also topical Ruscus extract may be help- tions can be made for their routine known for its use in treating ve- ful in reducing venous dilation dur- use in patients with sick sinus syn- nous insufficiency. Ruscus aculea- ing pregnancy.121 Oral agents may be drome or other arrhythmias. tus is a short evergreen shrub found useful as topical drugs for venous in- commonly in the Mediterranean re- sufficiency, although the evidence is COMMENT gion. Two steroidal saponins, rus- less convincing.122 cogenin and neurogenin, extracted Although capsule, tablet, oint- With the high prevalence of herbal from the rhizomes of R aculeatus are ment, and suppository (for hemor- medicine use in the United States, thought to be its active compo- rhoids) preparations of Ruscus extract health practitioners should remem- nents.101 In vivo studies on hamster are available in Europe, only capsules ber to inquire about such health prac- cheek pouch reveal that topical Rus- are available in the United States. tices when taking clinical histories and cus extract dose dependently antago- These capsules contain 75 mg of Rus- remain informed of the beneficial or nizes histamine-induced increases in cusextractand2mgofrosemaryoil.101 harmful effects of these treatments. vascular permeability.117 More- Asidefromoccasionalnauseaandgas- Continuing research is necessary to over, topical Ruscus extract causes tritis,adverseeffectsfromusing Racu- elucidate the pharmacological activi- dose-dependent constriction of ven- leatus have rarely been reported, even ties of the many cardiopotent herbal ules without appreciably affecting ar- in high doses.57 Nevertheless, one medicines and to stimulate future terioles.118 Topical Ruscus extract’s should be wary of any drug that has pharmaceutical development of thera- vascular effects are also tempera- not been thoroughly tested. Although peutically beneficial herbal drugs. ture dependent and appear to there is ample evidence to support the However, such research is currently counter the sympathetic nervous pharmacological activity of R aculea- lacking in the United States and re- system’s temperature-sensitive vas- tus, there is still a relative deficiency quires more support from govern- cular regulation: venules dilate at a of clinical data to establish its actual ment agencies before the full poten- lower temperature (25°C), con- safety and efficacy. Until more stud- tial of these types of treatments can strict at near physiologic tempera- ies are completed, no recommenda- be determined. At the same time, le- tures (36.5°C), and further con- tions regarding dosage can be offered. gal surveillance of herbal medicine use strict at higher temperatures (40°C); with low safety margins should be in- arterioles dilate at 25°C, are unaf- ARRHYTHMIA stituted for the sake of public health; fected at 36.5°C, and remain unaf- this is especially imperative for those fected or constrict at 40°C, depend- In traditional Chinese medicine, ar- herbs with adverse cardiovascular re- ing on Ruscus concentration.119 Based rhythmias are categorized by the actions125 and drug interactions. As on the influence of prazosin, diltia- characteristic symptoms of palpita- more information becomes available zem, and rauwolscine, the periph- tions and abnormal pulse. Numer- regarding the safety and efficacy of eral vascular effects of Ruscus ex- ous Chinese herbal medicines are herbal medicines through new clini- tract appear to be selectively identified to have antiarrhythmic ef- cal trials, research-supported claims mediated by effects on calcium chan- fects, such as xin bao, ci zhu wan, may one day become available to con- 123 nels and ␣1-adrenergic receptors bu xin dan, and several others. sumers and physicians in a manner with less activity at ␣2-adrenergic re- However, few clinical trials have similar to the allopathic medicines. ceptors.117,118 Also, R aculeatus ex- been conducted to study their ef- hibits strong antielastase activity and fects and safety. Xin bao is one agent Accepted for publication July 23, 1998. has little effect on hyaluronidase in that has begun to be examined. The Reprints: William H. Frishman, direct contrast to A hippocastanum. mechanism of action of xin bao is MD, New York Medical College, This activity may contribute to their thought to be through its stimula- Munger Pavilion, Valhalla, NY 10595. efficacy in the treatment of venous tion and increased excitability of the insufficiency since these enzyme sys- sinuatrial node.124 In one observa- tems are involved in the turnover of tional study, the effects of xin bao REFERENCES the main components of the peri- were documented in 87 patients with vascular amorphous substance.102 sick sinus syndrome. Xin bao was 1. Wu B-N, Huang Y-C, Wu H-M, Hong S-J, Chiang Several small clinical trials us- administered orally 2 to 3 times per L-C, Chen I-J. A highly selective (␣1-adrenergic ing topical Ruscus extract support its day for 2 months. 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