Herbal Medicine for the Treatment of Cardiovascular Disease Clinical Considerations Nick H. Mashour, MD; George L. 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 hu- man pharmacotherapy. For cardiovascular diseases, herbal treatments have been used. in patients with congestive heart failure, systolic hypertension, angina pectoris, ath- erosclerosis, cerebral insufficiency, venous insufficiency, and arrhythmia, However, many herbal remedies used today have not undergone careful scientific assessment, and some have the poten- tial 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 car- diac disease and be informed about the potential for benefit and harm. Continuing research is nec- essary to elucidate the pharmacological activities of the many herbal remedies now being used to treat cardiovascular diseases. Since the beginning of human civiliza tion, herbs have been an integral part of society, valued for both their culinary and ‘medicinal properties. Herbal medicine has made many contributions to commercial drug preparations manufactured today in- cluding ephedrine from Ephedra sinica (ma-huang), dightoxin from Digitalis pu purea (foxglove), salicin (the source of as- pirin) from Salix alba (willow bark), and reserpine from Rauwolfia serpentina (snakeroot), to name just a few. A natu- rally occurring B-adrenergic blocking agent with partial agonism has been identified in an herbal remedy.’ The recent discov- ery of the antineoplastic drug paclitaxel from Taxus brevifolia (pacific yew tree) stresses the role of plants as a continuing resource for modern medicine However, with the development of patent medicines in the early part of the 2oth century, herbal medicine has been losing ground to new synthetic medi- cines touted by seientists and physicians to be more effective and reliable. Neves theless, about 3% of English-speaking adults in the United States still report hhaving used herbal remedies in the pre- Arch Intern Med, 1998;158:2225-2234 ceding year? This figure is probably much higher for non-English-speaking Americans. Despite this heavy use of herbal medicines in the United States, health practitioners often fail to ask about their use when taking clinical his- tories. It is imperative that physicians become more aware of the wide array of herbal medicines available, as well as learning more about their beneficial and adverse ellects, Part ofthe problem forboth consum- cers and physicians has been the paucity of scientific data on herbal medicines used in the United States." As a result, those who wish to obtain factual information regard- {ng the therapeutic use or potential harm ‘of herbal remedies would have to obtain it from books and pamphlets, most of which base their information on traditional rept tation rather than relying on existing sei- entific research, One may wonder why the hherbal industry never chose to simply prove fits products safe and effective. The answer is primarily economical. With the slim chance of patent protection for the many hherbs that have been in use for centuries, pharmaceutical companies have not pro- vided financial support for research on the ‘merits of herbal medicine.” At the same From the Department of Medicine, The Albert Einstein Collegeof Medicine, Bronx, NY (r Mashout) the Department of Family Medicine, Columbia Presbyterian Medical (Center, New York NY (Dr Lin); and the Departments of Medicine and Pharmacology New York Medical CollegeWestchester Medical Cente, Valhalla, NY (Dr Fishman) ‘ume, the National Institutes of Health have only been able to offer limited funding for this purpose. (©1998 American Medical Association. Al rights reserved,This review examines herbal ‘medicines that affect the eardiovas- cular system both in terms of efli- ceacy and safety as gleaned from the scientific literature that is avai able. These herbs are categorized un- der the primary diseases they treat However, most herbal medicines have multiple cardiovascular ef- fects that frequently overlap. The purpose of this organization is 10 simplify, not to pigeonhole herbs un- der specific diseases. In general, the dilution of active components in herbal medicines results in fewer ad- verse and toxic effects in compari son with the concentration of ac- live components in the allopathic medicines. However, these adverse effects and drug interactions should. not be overlooked; cardiovascular disease isa serious health hazard and no herbal remedy regimen should be {initiated without eareful consider ation ofits potential impact (Table). CONGESTIVE HEART FAILURE A number of herbs contain potent cardioactive glycosides, which have positive inotropic actions on the heart. The drugs digitoxin, derived from either D purpurea (foxglove) or Digitalis lanata, and digoxin, d rived from D lanataalone, have been used in the treatment of congestive hheart failure for many decades, Car- diac glycosides have alow therapes- luc index, and the dose must be ad- justed to the needs of each patient The only way to control dosage isto use standardized powdered digi- talis, digitoxin, or digoxin. When 12 different strains of D lanata plants were cultured and exam- fined, their total cardenolide yield. ranged from 30 to almost 1000 nmol/l g." As is evident, treating congestive heart failure with non- standardized herbal drugs would be dangerous and foolhardy ‘Some common plant sources of cardiac glycosides include D pur- purea (Foxglove, already men- tioned), Adonis microcarpaand Ado- nis vernalis (adonis), Apocynum cannabinum (black Indian hemp), Asclepiascurassavica (redheaded cot- ton bush), Asclepias riticosa (bal- loon cotton), Calotropis precera (King’s crown), Carissa spectabilis (ovintersweet), Cerebra manghas (sea Herbs for Cardiovascular Conditions With Severe Adverse Reactions Notable Drug Interactions Herel meaene| ‘Adverse Reaton Drug neracion Treatment Turd cardiac gheosdes Venter chyarthmabradjearda,_Digo-specie (0 plant soutes) and heat bck Fab attody Veratum Braiyeada, A dissociation, hypotension, ECG changes espnsive thalebore) nd (ray sires ‘watopine Crataegus Poantates digits act ma (pavthar) ‘ata mitra Poantates stanin etty a (car-shor) ‘Aesculus ippoastanum — Renal and hepatic oxi cs Dass to reduce (horsechestnut tax leas ‘AV indeatesatervenous anastomoss; E08, eecrocardagraphi, and MA data rot appleate. mango), Cheiranthus cheiri (walle ander intoxication, as well as other flower), Convallaria majalis (ly of natural glycosides is virtually iden the valley, convallari), Cryptoste- tical to digoxin overdose. Morbid- gia grandiflora rubber vine), Hel- ity and mortality re mainly related ichorus niger (black hellebore),Hel- to cardiotoxie adverse effeets that leborus viridus, Nertwm oleander usually include life-threatening ven- (oleander), Plumeria rubra (frangi-_icular tachyarthythmias, brady- pant), Selenicerus grandiflorus(eac- cardia, and heart block. The diag- tus grandilorus), Strophanthus his- nosis should rely on the clinical pidus and Strophanthus kombe presentation of unexplained hype (strophanus), Thevetia peruviana _kalemia, and eardiae, neurologic, (ellow oleander),and Urginea mar- and gastrointestinal symptoms." itima (squill)* Even the venom The diagnosis can be further glands of the animal Bufo marinus supported by the detection of the (cane toad) contain cardise glyeo- substance digoxin ina radioimmu- sides"Recently the digitalisikeste-_noassay for digoxin. However, the roid inthe venom of the B marinus extent of cross-reactivity between the toad was identified as a previously cardiac glycosides from herbal described steroid, marinobufa- Sources and antibodies used in the enin, Marinobulagenin demon radioimmunoassay’ has not been strated high digoxinlike immuno- clearly defined. For this reason, di reactivity andwasantagonized with _goxin assays may serve to confirm anantidigoxin antibody." the suspected diagnosis but not 0 ‘Accidental poisoningsandeven quantify the severity. Once the di- suicide attempts with ingestion of agnosis hasbeen established, the use cardiac glycosides are abundant im of digoxin-specific Fab antibody the medical literature.'"" Some fragments may be helpful in the herbal remedies (eg, Siberian gin- treatment of severe intoxication. seng) can elevate synthetic digoxin Other modalities, such as dialysis drug levels and cause toxte ef cannot be easily facilitated be- fects Inthe United States, thereare cause, like digoxin, natural glyeo- about 15000 intoxicationsductoac- sides are distributed extensively into ‘dental or intentional ingestion of peripheral issues. poisonous plants annul.” In 1993, 2388 toxic exposures in the United HYPERTENSION States were reported to be due to plant glycosides. Of these, thelarg- The root of R serpentina (snake fstpercentage wereatibutedto le- root) the natural source of the alka- ander (ie, 25%)-"Inthe case ofole- oid reserpine, has been a Hindu anderll plant ussues,including the Ayurvedic remedy since ancient seeds, roots, stems, leaves, berries, times, In 1931, Indian iterate fist and blossoms, are considered ex- described the use of &serpentna root tremely toxic: Infact death in hu- for the treatment of hypertension manshasbeenreportedfollowingine and psychoses: however, the use of gestion ofasliteas loleanderleaL —Rauwolfia alkaloids in Western The clinical manifestations of ole- medicine did not begin until the (©1998 American Medical Association. Al rights reserved, jamanetwork.comy on 05/28/2021‘mid19406.” Both standardized whole rool preparations of Rserpentina and its reserpine alkaloid are officially monographed in the United States Pharmacopeia.* A powdered whole root of 200 10 300 mg orally isequiva lent to 0.5 mg of reserpine” Reserpine was one of the first, drugsused onalargescaletotreatsys- temic hypertension. Iactsby rrevers- ibly blocking the uptake of biogenic amines (norepinephrine, dopamine, and serotonin) in thestorage vesicles of central and peripheral adrenergic neurons, thus leaving the catechol- amines to be destroyed by the intra- ‘neuronal monoamine oxidase in the cytoplasm. Thedepletion ofeatechol- aminesaccounis for reserpine’ssym- patholytic and antihypertensive ac- tions, Reserpine’selfectsarelonglast- Ang, since recovery of sympathetic function requires synthesis of new storage vesicles, which takes days 10 weeks. Reserpine lowers blood pres sureby decreasing eardiac output, pe ripheral vascular resistance, heart rate, and renin secretion. With the intro duction of other anuihypertensive drugs with fewer central nervoussys- temadverse effects the use of rese pine has diminished, The daily oral dose of reserpine should be 0.25 mg. orless,andas litle as0.05 mgifgiven witha diuretic. Using the whole root, theustal adult doses 50.0 200me/e administered once daily oF in 2 die vided doses?” Rauwolfia alkaloids are contra indicated for use in patients with previously demonstrated hypersen- sitivity to these substances, in pa- tents with « history of mental de- pression (especially with suicidal tendencies), in patients with active peptic ulcer disease or ulcerative co- lits, and in patients receiving elec troconvulsive therapy. The most common adverse effects are seda- don and inability to concentrate and perform complex tasks. Reserpine ‘may cause mental depression, some- limes resulting in suicide, and itsuse ‘must be discontinued a the Hirst sign of depression. Reserpine’s sympa- tholytic effect and its enhancement of parasympathetic ations account forts well-described adverse ellects: nasal congestion, increased gastric secretion, and mild diarthea.”””* ‘Stephania tetrandra is an herb sometimes used in traditional Chi nese medicine to treat hyperten- sion. Tetrandrine, an alkaloid ex- tract of $tetrandra, has been shown to bea caleitin ton channel antago- nist, paralleling the effects of verap- mil. Tetrandrine blocks Tand Lcal- ‘ciutn channels, interferes with the binding of diltiazem and methoxyver- apamil at caleium-channel binding sites, and suppresses aldosterone pro- dduction.***A parenteral dose (15 mg/ kg) of tetrandrine in conscious rats decreases mean, systolic, and dias- tolic blood pressures for more than 30 minutes; however, an intrave- nous 40-mg/kg dose killed the rats by myocardial depression. In stroke- prone hypertensive rats, an oral dose (of 25 oF 50 mg/kg produced a gradual ‘and sustained hypotensive elfeet a terd8 hours without affecting plasma renin activity.” In addition to its cardiovascular actions, tetrandrine has reported antineoplastic, immu- nosuppressive, and mutagenic effects." trandrine is 90% protein- bound with an elimination hal-life of 8S minutes, according to dog studies; however, rat studies have shown a sustained hypotensive ef- fect for more than 48 hours alter a 25- of 50-mg oral dose. Tetran- rine causes liver necrosis in dogs orally administered 40 mg/kg of tet- randrine 3 times weekly for 2 months, reversible swelling of liver cells with a 20-mg/kg dose, and no observable changes with « 10- mg/kg dose.” Given the evidence of hepatotoxicity, many more studies are necessary to establish a safe dos- age of tetrandrine in humans. More recently, tetrandrine has been implicated in an outbreak of rapidly progressive renal failure termed Chinese herb nephropathy Numerous individuals developed the condition after using a combina tion of several Chinese herbs as part ‘ofadieting regimen. Ithas been hy- pothesized that the cause may beat- luibuted to misidentiication of Stet randra; nonetheless, questions still remain as to the role of tetrandra in the development of this serious oxic effect." Theroot of ingusticum wallichit is used in traditional Chinese medi- ‘ineasa circulatory stimulant, hypo- tensive drug, and sedative. Tetra- methylpyrazine, the active constitu- centextracted from wallichi, inhibits plateletaggregation invitroandlow= ersblood pressure by vasodilation in dogs. With ils actions independent ofthe endothelium, tetramethylpyr- azine's vasodilatory elfectis mediated. bycaleium channel antagonismand nonselective antagonism of a= adrenergic receptors. Some evidence suggests that tetramethylpyrazineacts onthe pulmonary vasculature." Cur rently, thereis insufficient informa- tion toevaluate the safety and efficacy of this herbal medicinal Uncaria rhynchophylla is some- limes used in traditional Chinese ‘medicine to treat hypertension. ts indole alkaloids, rhynchophylline and hirsutine, are thought to be the active principles of U rhynchophyl- la’s vasodilatory effect. The mecha- ‘nism of U rhynchophylla’s actions is unclear. Some studies point oan al- {eration in calcium ton flux in re sponse to activation, whereas oth- cers point to hirsutine’s inhibition of nicotine-induced dopamine re- lease." One in vitro study has shown, Urhynchophylla extract relaxes nor- epinephrine-precontracted rat aorta through endothelium-dependent fand-independent mechanisms. For the endotheliaim-dependent com- ponent, U rhynchophylla extract ap- pears Co stimulate endothelium- derived relaxing factor and/or nitric oxide release without involving mus- carinie receptors.” Also, in vitroand. in vivo studies have shown that thynchophylline ean inhibit plate- let aggregation and reduce platelet thromboses induced with collagen, or adenosine diphosphate plus epi- nephrine.” Safety and efficacy ean not be evaluated at this time be- cause of a lack of clinical data, Veratrum (hellebore) is a pe- rennial herb grown in many parts of the world, Varieties include Vera- trum viride from Canada and the eastern United States, Veratrum cali- Jornicum from the western United States, Veratrum album from Alaska and Europe, and Veratrum japoni- ‘cum from Asia, All Veratrum plants contain poisonous alkaloids known to cause vomiting, bradycardia, and hypotension. Most cases of Vera trum poisonings are due to mis- identification with other plants. Although once a treatment for hy- pertension, the use of Veratrum al- (©1998 American Medical Association. Al rights reserved, jamanetwork.comy on 05/28/2021kkaloids has lost favor owing toalow therapeutic index and unaccept- able toxicity, as well as the intro- duction of safer antihypertensive drug alternatives.” Veratrum alkaloids enhance nerve and muscle excitability by in- creasing sodium jon conductivity. They act on the posterior wall of the left ventricle and the coronary si ‘nus baroreceptors, causing reflex hy= potension and bradycardia via the vagus nerve (Bezold-Jarisch re flex). Nausea and vorniting are sec- ondary to the alkaloids’ actions on the nodose ganglion." The diagnosis of Veratrum tox- {city is established by history, iden- Lifcation ofthe plant, and strongelini- calsuspicion, Clinicalsymploms st ally oecur quickly, often within 30 minutes." Treatment is mainly sup- portive and directed at controlling bradycardia and hypotension. Veratrum-induced bradycardia ust- ally respondsto treatment with atro- pine; however, the blood pressure re- sponse lo atropine is more variable and requiresthe addition of pressors. Other electrocardiographie change suchasatrioventricular dissociation, may also be reversible withatropine."= Seizuresarea rare complication and ‘ay be trated with conventional an- Liconvalsants. For patients with pre- existing cardiacdisease, the use of - agonists or pacing may be necessary. Nauisea may be controlled with phe- rnothiazine antiemetics, Recovery Wsit- ally occurs within 24 to 48 hours." Eyodia rutaecarpa (wu-chu- yu) isa Chinese herbal drug that has, been used as a treatment for hy- perlension, It contains an active vasorelaxant component called ri taecarpine that ean cause endothe- lium-dependent vasodilation in experimental models.” ANGINA PECTORIS (Crataegus hawthorn, a name encom- passing many Crataegus species (such as Crataegus axyacantha and, Crataegus monogyna in the West ad Crataegus pinnatifida in China) has acquired the reputation in modern, herbal literature as an important tonic for the cardiovascular system. that is particularly useful for an- gina. Crataegus leaves, flowers, and {ruits contain a number of biologi cally ative substances, such as oligo meric procyanins, flavonoids, and catechins. From current studies, Crataegus extract appeats to have a oxidant proper! hibit the formation of throm- es and ean ine boxane as well Also, Crataegus extract antago nizes the inereasesin cholesterol, i= alyeeride, and phospholipid levelsin low-density lipoprotein (LDL) and very low-density lipoprotein in rats fed a hyperlipidemic diet; thus, it may inhibit the progression of ath- cerosclerosis.* This hypocholester- ‘olemie action may be due to an up- regulation of hepatic LDL receptors resulting in greater influx of plasma cholesterol into the liver. Cratae- {gus also prevents cholesterol accu- mulation in the liver by enhancing cholesterol degradation to bile ac- ids, as well as suppressing choles terol biosynthesis.” According_o anotherstudy, Cra- tacgus extract, in high concentra tions, has a cardioprotective eect on ischemic-reperfused hearts without ‘eausing an increase in coronary blood flow.** On the other hand, oral and parenteral administration of oligo meric procyanins of Crataegus has ‘been shown to lead to an increase in coronary blood flow in both eats and dogs." Double-blind clinical tials havedemonstrated simultaneous car- diotropic and vasodilatory actions of Crataegus.” nessenee, Crataegus i ‘ereases coronary perfusion, has mild hypotensive effect, antagonizes ath- ‘erogenesis, and has positive inotro- pic and negative chronotropie ae~ tions.*** In a recent multicente placebo-controlled, double-blind study, an extract of Crataegus was shown to clearly improve the ear- dae performance of patients with New York Heart Association class IL heart failure. tn this study, the pri- mary parameter analyzed was the heart rate product (systolic blood pressure X hear rate)” Recent stud ies have suggested that the mecha- nism of cardiae action for Crataegus species may be due tothe inhibition of the 3, 5'-cyelic adenosine mono- phosphate phosphodiesterase.* Hawthorn is relatively devoid of adverse effects. In fact, in com parison with other inotropie drugs suchas epinephrine, amrinone, mile rinone, and digoxin, Crataegus has 1 potentially reduced arrhythmo- genic risk because of its ability to prolong the ellective refractory pe- Hod, while the other drugs men- ‘doned previously all shorten this pa- rameter. Also, itshould be noted. that concomitant use of hawthorn with digitalis can markedly en- hhance the activity of digitalis." Un- doubtedly, more studies are needed to show that hawthorn ean be used. safely and effectively Because of its resemblance to Pana ginseng (Asian ginseng), Pana notoginseng has acquired the com- ‘mon name of pseudoginseng, espe- cially since itis often an adulterant of P ginseng preparations, In tradi- tional Chinese medicine, the root of P notaginsengis used for analgesiaand hemostasis. tis also often used in the ‘rcatment of patients with anginaand, coronary artery disease." Panas no- Loginseng has been described asacal- cum ion channel antagonist in vas- cular tissue, More specifically, its pharmacological action may be as a novel and selective calcium fon at tagonist that does not interact with the Lype caleium ion channel but rather may interact with the receptor ‘operated calcium ion channel.” Although clinial trials are lack- ng, in vitro studies using P notogin- seng suggest possible cardiovascular effects. One study that used purified notoginsenoside RL, extracted from Prnotoginseng, on human left umbili- cal vein endothelial cells showed a dose- and time-dependent synthesis, of tissue-type plasminogen activa {ng factor without affecting the syn thests of plasminogen activating in- hubitor. Thus, fibrinolytic parameters were enhanced.” Another study sug- gests that Pnotoginseng saponins may inhibit atherogenesis by interfering, with the proliferation of smooth, muscle cells." In vitro and in vivo studies using rats and rabbits dem- onstrate that P notoginseng may be useful as an antianginal drug, since Adilates coronary arteries in al con- centrations. The role of P notogin- seng in the treatment of hyperten- sion less certain, since Pnologinseng causes vasodilation oF vasoconstric= ion depending on the concentra- don and target vessel The results of these in vitro and in vivo studies are encouraging:however, clinical t- als will be necessary to make a more (©1998 American Medical Association. Al rights reserved, jamanetwork.comy on 05/28/2021{informed decision regarding the use of Pnotoginseng Salvia miltiorrhiza (dan- shen), relative of the Western sage Salvia officinalis is native to China Intraditional Chinese medicine, the root of S miltiorhiza is used asa cir- culatory stimulant, sedative, and cooling drug.” Salvia miltiorrhiza ray be useful asan antianginal drug because it has been shown to dilate coronary arteries in all concentra- tions, similar to Pnotoginseng. Also, S milliorrhiza has variable action on other vessels depending on its con- centration, so it may not be as help- ful in treating hypertension.” In vitro, § miltiorrhiza, in a dos dependent fashion, inhibits plat let aggregation and serotonin re- lease induced by either adenosine diphosphate or epinephrine, which fs thought to be mediated by an in- crease in platelet cyclic adenosine monophosphate caused by 5 milti- orrhiza’s inhibition of eyelie aden- cosine monophosphate phosphodi- esterase Salvia miliorrhiza appears tw have a protective action on ische- mic myocardium, enhaneing the recovery of contractile force on reoxygenation.” More recently, 5 niltiorshiza has been shown to pro- tect myocardial mitochondrial mem- bbranes from ischemiacreperfusion in jury and lipid peroxidation beeause of its free radical-seavenging ¢ fects. Qualitatively and quantita- tively, a decoction of S milliorrhiza was as efficacious as the more ex- pensive isolated tanshinones.” Clinical trials will be neces sary to evaluate the safety and efli- cacy of S iltiorrhiza. Of note, it has bbeen observed clinically that when S miltiorrhiza and warfarin sodium are coadministered, there is an in creased incidence in warfarin- related adverse elects; i rts S mil srrhiza was shown to inerease the plasma concentrations of warfarin as Well as the prothrombin time." ATHEROSCLEROSIS In addition to its use in the culi- nary ats, garlic (Allium sativum) has been valited for centuries for its me- dicinal properties. Garlic is one of the herbal medicines that has been examined more closely by the se entific community. In recent cades, research has focused on garlic use in preventing atherosele- rosis. Garlic, like many ofthe other herbal medicines discussed previ- ously, has demonstrated multiple beneficial cardiovascular effects. A number of studies have demon- strated these ellects that include low- tering blood pressure, inhibiting platelet aggregation, enhancing fi- brinolytic activity, reducing serum cholesterol and triglyceride levels, and protecting the elastic prope lies of the aorta. Consumption of large quanti- ties of fresh garlic (0.25 to 1.0 g/kg oF about 5-20 average sized 4-g cloves ina person weighing 78.7 kg) has been shown to produce the ben- ficial effects mentioned earlier." In support of this, a recent double- blind cross-over study was con- ducted on moderately hy} terolemic men that compared the clfects of 7.2 g of aged garlic ex- tract with placebo on blood lipid lev- cls, This study found that there was ercholes ‘a maximal redsiction of 6.19% in to- tal serum cholesterol evelsand 4.6% in LDL cholesterol levels with gar- lic compared with placebo.” However, despite positive evi- dence from numerous trials, some investigators have been hesitant to ‘outright endorse the routine use of garlic Tor cardiovascular disease be- ‘cause many of the published stud- ies had methodological shortcom- ings," perhaps because ‘constituent trials were stall, lack ing statistical power. Also, inappro- priate methods of randomization, Incl of dictary run-in period, short duration, oF fare to undertake in- Lention-to-treat analysis may ex: plain the cautious acceplance of pr vious meta-analyses.” tn fact, one recent study found no demon- strable elfect of garlic ingestion on lipid and lipoprotein levels. This siudy used a cross-over design pro- tected by a washout period to re- duce between-subject variability as ‘well as close assessment and report- ing of ditary behavior, which had ‘heer lacking in previous trials.” An- cther study found no elfect of gar~ lic on cholesterol absorption, cho- lesterol synthesis, oF cholesterol rctabolisin.” As evident, the pre- ‘ise extent of galic's impact on ath- ‘rosclerosis remains controversial: larger, more rigorously designed tri- als may be necessary to better de- {ermine its utility in preventing car diovascular disease. Garlic has also been studied in hypertensive patients as a blood pressure-lowering agent. Similar to its lipid effects, no conclusive stud- {es have been conducted and many methodological shortcomings exist {in study designs, The results of one ‘meta-analysis that considered 8 dif {erent trials suggest some clinical use for patients with mild hyperten- sion, but there is insufficient evi- dence to recommend its use as rou tine clinieal therapy" Garli has also been shown to possess antiplatelet activity. Inthe past, this ation was ‘mostly documented in vitro.” A new study examined the effect ofthe con- sumption of a fresh clove of garlic on platelet thromboxane produc- tion and showed that after 26 weeks, serum thromboxane levels were re- duced about 80%.” This may prove to be beneficial in the prevention of thrombosis in the furure. Recently, the effect of long-term garlic intake on the elastic properties of the aorta was also studied, Participants in the trial (limited to those aged 50-80 years) consumed 300 mg/d of stan- dardized garlic powder for more than. 2years. The results showed that the pullse-wave velocity and standard- {zed elastic vascular resistance of the aorta were lower in the garlic group, than in the control group. Conse- quently, long-term garlic powder in- take may havea protective effect on the elastic properties of the aorta re- lated to aging,” In these ways, gar lic has shown numerous beneficial cardiovascular fects that need to be investigated farther to determine its therapeutic wulity Intact cells of garlic bulbs in- clude an odorless, sulfur-contain- ing amino acid known as allinin. When garlic is crushed, allinin comes into contact with allinase, which converts allinin toallicin, AL- licin has potent antibacterial prop- erties, but itis also highly odorife ous and unstable. Ajoenes, sell- condensation products of allicin, appear to be responsible for garlics antithrombotic activity. Most au thorities now agree that allicin and lus derivatives are the active con- stituents of garic's physiological ac- (©1998 American Medical Association. Al rights reserved, jamanetwork.comy on 05/28/2021Livity, Presh garlic releases allicin in the mouth during the chewing pro- cess. Dried garlic preparations lack allicin but contain allinin and allin- ase. Since allinase is inactivated in the stomach, dried garlic prepara- tions should be coated with enteric so that they pass through the stom- ach into the small intestine where al- linin can be enzymatically con- verted to allicin, Few commercial garlic preparations are standard- ized for their allicin yield based on allinin content, hence making their effectiveness less certain.” How- ever, one double-blind, placebo- controlled study involving 261 pa tients for 4 months using one '800-mg tablet of garlic powder dai standardized to 1.3% allinin con- tent, demonstrated significant re- ductions in total cholesterol (129%) and triglyceride levels (179%).”* Aside froma garlic odor on the breath and body, moderate garlic con- sumption causes few adverse fects. However, consumption in ex- cess of 5 cloves daily may result in heartburn, flatulence, and other gas- twointestinal disturbances. Some people have reported allergic reac- Hons to garlic, most commonly al- lergic contact dermatitis. Patch test ing with 1% diallyl disulfide is recommended when garlic allergy is suspected.”” Because of itsanithrom- botie activity, garlic should be used with caution in people taking oral an- Lucoagulants concomitantly.” The resin of Commiphora mukul (gugulipid),asmall, thorny tree na- tive to India, has long been used in Ayurvedic medicine to treat lipid dis orders. The primary mechanism of action of gugulipid is through an in- crease in the uptake and metabo- lism of LDL cholesterol by the liver.” Ina double-blind, cross-over study completed in 125 patients taking gu gulipid compared with 108 patients taking clofibrate, the average d crease in serum cholesterol and tri alyceride levels was 119% and 16.8%, respectively, with gugulipid com- pared with 10% and 21.6%, respee- tively, with clofibrate. In general, hy~ percholesterolemic patients responded more favorably to gugu- lipid therapy than hypertriglyceride- mic patients."® Moreover, it was shown in another randomized, double-blind trial that C mutkul also decreased LDL cholesterol levels by 12.5%and the total cholesterol-high- density hpoprotein cholesterol ratio by 11.1%, whereas thelevelswereun- ‘changed in the placebo group. Besides being potentially aslee- Live in lowering blood lipid levels as modern byperlipidemicdrugs,gugu- lipid may’ even be safer. In the tral mentioned previously, compliance was greater than 96%, with only the ade vers effects of headache, mild nau sea,and hiccupsnoted.”* However i has been shown that gugulspid may alfect the bioavailability of other car- diovascular drugs, namely, proprano- lol hydrochloride and diltiazem hy- drochloride. Gugulipid significantly reduced the peak plasma concentra- Uonandares under the curve of both thesedrugs, which may eadto dine ished ellicacyornonresponsiveness." Undoubtedly, gugulipid isa natural lipid-lowering drug with potential for therapeutic use, but rigorous, lager clinical rials will be necessary to ar therevaluatetts safety andefficaey be- fore it can be endorsed as an alterna. tive therapy for hyperlipidemia and prevention of atherosclerosis ‘Maharishi amit kalash-# and Maharishi anit kalash-5 are 2 com- plex herbal mixtures with signifi ‘cant antioxidant properties that have bhcen shown to inhibit LDL oxida- tion in patients with hyperlipid- ‘emia, In experimental studies, the herbal mixtures have also been shown 1 inhibit enzymatie- and nonenzy- smatic-induced microsomal lipid pe ‘oxidation and platelet aggregation." (CEREBRAL AND PERIPHERAL VASCULAR DISEASE Having existed for more than 200 million years, Ginkgo biloba (maid- cenhair tree) was apparently saved from extinetion by human interven- tion, surviving in Par Eastern temple gardens while disappearing for cen- luries in the West. It was reintro- duced to Europe in 1730 and be- ‘came a favorite ornamental tree." Although the root and kernels of G biloba have long been used in tradi ional Chinese medicine, the tree gained attention in the West dur- ing the 20th century for its medici- nal value afler a concentrated ex- tract of G biloba leaves was developed in the 1960s, At least 2 groups of substances within G bi- Toba extract (GBE) demonstrate ben- cficial pharmacological actions. The flavonoids reduce capillary perme- ability as well as fragility and serve as free radical seavengers. The te penes (ie, ginkgolides) inhibit pla Tetactivating factor, decrease vas- cular resistance, and improve circulatory flow without apprecia- blyatfeeting blood pressure." Con- tinuing research appears to sup- port the primary use of GBE for treating cerebral insulficieney and its secondary effects on vertigo, tinni- tus, memory, and mood; also, GBE appears to be useful for treating pe- ripheral vascular disease, includ= {ng diabetic retinopathy and inte rmittent claudication.2°”*"" In a randomized, placebo- controlled, double-blind study, EGb 7o1, which is a standardized ex- tract of G biloba with respect to its flavonol glycoside and terpene lac- tone content, was shown to signifi- cantly decrease the areas of ische- ‘mia as measured by transcutaneous partial pressure of oxygen during ex- ercise. Because of its rapid anti- {ischemic action, EGb 761 may be valuable in the treatment of inter- rmittent claudication and periph- eral artery disease in general.” Also, studies have been exam- {ning the cardioprotective efficacy of EGb 761 in regard to its anti-free radical aetion in myocardial isch- emia-reperfusion injury. In vitro studies with animal models have shown that this compound may ex- ert suchan effect?” clinical study of 15 patients undergoing coronary bypass surgery demonstrated that oral EGb 761 therapy may limit free radical-induced oxidative stress oc- curring in the systemic circulation and at the level of the myocardium during these operations.” It r rains to be studied whether ex- tracts of G biloba may be used as pharmacological adjuvants to limit tissue damage and metabolic ale ations following coronary bypass surgery, coronary angioplasty for acute myocardial infarctions, oreven in managing coronary thrombosis. Although approved as a drug {in Europe, Ginkgo is not approved {in the United States and is instead marketed as a food supplement, usually supplied as 40-mg tablets (©1998 American Medical Association. Al rights reserved, jamanetwork.comy on 05/28/2021of extract, Since most of the inves- tigations examining the efficacy of GBEs used preparations such as EGb 761 oF LI 1370, the bio- equivalence of other GBE prod- ucts has not been established. The recommended dosage in Europe is fone 40-mg tablet taken 3 times daily with meals (120 mg/d)."” Adverse effects due to GBE are rare but can include gastrointesti- nal disturbances, headache, and allergic skin rash.**” Known mostly as a culinary spice and flavoring agent, Rosmari- nus officinalis (rosemary) i listed in ‘many herbal sources as a tonic and all-around stimulant. Tradition- ally, rosemary leaves are said to en hance circulation, aid digestion, l vate mood, and boost energy. When applied externally, the volatile oils are supposedly useful for arthritic conditions and baldness.” Although research on ros rary isseant, some studies have fo- cused on antioxidant effects of di- terpenoids, especially carnosie acid and camosol, isolated from rose- rary leaves. In addition to having antineoplastic effects, antioxidants inrosemary have been credited with stabilizing erythrocyte membranes and inhibiting superoxide gener- ation and lipid peroxidation.”"”” Essential ols of rosemary have dem- onstrated antimicrobial, hypergly- cemic, and insulin-inhibiting prop- erties." Rosemary leaves contain high amounts of salieylates, and its flavonoid pigment diosmin is re ported to decrease capillary perme- bility and fragliy.*""™ Despite the conclusions de- rived from in vitro and animal stud~ fes, the therapeutic use of rosemary for cardiovascular disorders re~ rains questionable, because few, if any, clinical trials have been con- ducied using rosemary. Beeause of the lack of studies, no conclusions can be reached regarding the use of the antioxidants of rosemary in in- Iibiting atherosclerosis. Although external application may cause eu taneous vasodilation from the eoun- lerirritant properties of rosemary’s essential ols, theres no evidence to support any prolonged improve- ment in peripheral circulation? While rosemary does have some car- rminative properties, it may also ‘cause gastrointestinal and kidney disturbances in large doses."""* Un- til more studies are done, rosemary should probably be limited to ts use fs a culinary spice and flavoring ‘agent rather than as a medicine. VENOUS INSUFFICIENCY The seeds of horse chestnut, Aescue lus hippocastanum, have long been used in Europe to teat venous dis ‘orders sch as varicose veins, The st ponin glycoside aescin from horse ‘chestnut extract (HCE) inbibits the ctityoflysosomal enzymes thought to contribute to varicose veins by ‘weakening vessel walls and increas- ing permeability, which result in di- lated veins and edema. In fact, re- ccent research has shown that A hippocastanum inhibits only against hyaluronidase but not elastase, and thisactvitys linked mainly to these ponin escin.® In animal studies, HCE, inadose eit, 185-126-125. ppg’ set lou, Facer, ame rr facto aheotanenteton cons. onanderergy uno efisaned aterm. ‘jas Armartetctung 185 451157181 ‘Mora He Tne Taps Me ana, Can: eas Pubiting in: 108, oan CY. Vase tc of sect any peers gs derived from rational {lena eth. in Ep Parca Py 185, nara, “hang, Wor, ier BR. ect of tap serasde ent syas ofisuespe pus "iogen arti andpasrinoen ahr ior in catured human uma! vin nda. rie Tomb Vas ‘ge T0u0- 1085, Lin $6 eng XL, Gen OY, Sun a ot Panarnotegisang sponsors po ersten tetrad er smach sles sinuancbyrypectlsereme seam. Ong Kuo Yoo Hsueh Poa 103 S16, Livi, Chou G0, Carsoiseeuarphrmsctogy 1 Panag uh FH Chen Sa tort. Am Ji 1985 1445-152 Wang ober Grant P, ea Theat ‘fa aia Chinas heb on plete ten, Tham ieee 19828:301-206 ‘ag Fumo Tanoal etal Possible te components of ashen (Saar or ha orptacon te myocardium agaist [setemaendiced angen. Plan Me, ‘esss154 ‘hoo JargW,2o0¥ Hou. Xn Se ‘gig eso Satz mito on ea Caladits proten or myer tector ‘hal mabne tom canteen, ‘Bota Me al 108638 1171-182 (Chan Lo AC Yeung, Woo KS. The tes ashen Su mtr on wart par racadyaris and pharmacokinetics of ar fin enntomee nated Par Parc ios je Kips Ter Rita, ‘na andcirinsclar kata7 1 2 m 4 % % 0 cy a @ 8 ‘Downloaded From: https:/jamanetwork.com/ on 05/28/2021 ‘ton gina ihm onconmaily zal preparations ‘ruoinPharmaco e8020599-5, ‘Stn Xn Halt Lin. Ade bing eros-oe sud inbyperctlestutomie ‘neta compare the efecto! ge gui ‘ean placebo admiration an oa p= ‘de Am ln ar OS 70. ‘Sing CA, Nel HA A etna he {ect gation toed pressure. Hypertens. 25-68 ‘Slag Nel Gare pid vering agent tans J Col Pysins Land 184 oes, andar. Garin aia) andoin (A Amcapeiawot ta lnsip caso ‘aac eee, Pred 087 167-5, Isuesotn JL. Mose M, Sein EX at a. 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Paiet F, Len . ‘Spentncousspalopdralanatoma thas iar stncanton easier ‘oracaserepr Nesogey 10002530032 Sigh Val, Cand. apaor WK Sima lation ow ety ipopote ceptr yin er mara of ggpulserane ease tts, Pharmacol es 100 2237-44 Niyanand’5, Sivas, Aste OP. cle trl wth gol: nex hyp ent. Asoc Pysens Ids 18537 28528. Sg, HazM, Gosh. Hpac ane motets af Cormier las an ‘ajc to tay thay in pate wth hy brcholestralmia Caves Drage Ther fnaqaesecse Dal S, Nayak VK, Pon MDs HK ‘chiesagarWA Gupta KC ett gputpidan ‘analy of anand propane Soc Physicians indi T0042 1505 Sanaa V Hnna AN Lub GP, Kone, Falko iM, Sharma Hi Inhibition of ow 6. a. a8 ». . o w. 3 6. 6. wr. 8 . 100 oo 102 102, 104 10s, ens paprsincsiatonby oat mi ture Mari Art les nd sib ‘rts’ perigee pt.) ‘ded se. oorave3n2 310 usable Ru The pharmaclgy of extncn, J Etmophanmcol 1923-111 Arun A Ghigo: th and ey in Gera) ‘SchweRandch Md Poe 0534-8 jn Jie P Gg Biba ore rer insticiecy. 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Caras Os Ta s.r, ford A Mace, Rulfeu. tab Rosemary emponsnts inhi enollpree induced eatin una bronchial aa fees 1005182057202 aap, Sai T, kama Ya ‘onli prodson and superoxde ge. tan by cranes om Rasmarius 0 ‘ote, Pa 1958139 295, Lov, Aut C0-Toras MA An foi acy of esenca an abies. roi. 100582 71-172 Asudr A Hasn 2 AlN. pec andi kas by efits of osm isoform 13618217 21, Swan A, Duton SP Truswel AS, Saye intods J Am Der soe 108585 350360, Tiler VE Te Hoes rat A Sen Guo eotrteand Rad Se Ne York WY: Phase Prod Pres 188, Fano AM, Car My Stet A, ene Anlesas andar surance sf apni an sapogein tom He raha Asc ppocstanum ard Rusus euler ators conibng tat aie inthe exert of enous insticncy. Arch Pharm (Wann! 10928 720-728. Glue Pata nance. vs tarot, itty ea talsavengg ropes thse astute act Aznitterschung 109462535, atop! Vogel 6. Ne figs a the ej an made of acon af he rsa chest Spon asi i German], Azaiittosch ng. 197626225-235, De, Valbrect, Amano , Combe HU adil edema rotor lncalbenet ina ent with hr dep win compan a 107 10, 1 1 1 1 m6 16 1, m8 0, m1 2 (©1998 American Medical Association. Al rights reserved, placebo contol double-blind ty Vas, fare Br Pear Kuan, Puscinge? ‘acts of hare hasnt sad eat ra scaly tation in evan venous su ‘Segy i Garman. Sch ed Wochenschr ae 121-1220. Diem ,Tampisc Lange 8, Semi Cnparson te compessin soaking oa hors cst seed net trap pts theron. ane 186 ‘uran-208 Chest Penson BK Hoechst Inetantcintray proline tce-dugteapyinetoncvewusraticiney [esGoman Forse 106 11410620 Sehr, Gabe UF Props of tro. oobi comlcans neyo su ge) in Geman), Gebuestite Faueoika srr 26. Lang W. Sues onthe preuaneus abo tan of Seance. Res Ep Med Be) 1arrseeas- 17 “aagest KTotyana Okuda tat Acs enol ptr. Garou faospm 145215258 owt Janger cut postal te flour heap wih athoss and be ‘sscn|Geman Arssthas 1978278, Haber XRusthesh W, De Vie Ou in ‘hd ast eal restr uy ne "at. Thocoeh Vas ht 175 2530600 Lang W. Dasa of ase i German. ‘ansimitelorschng 184 34721-23. Grob Pa Mul Sao, oc A Jol ea HL. Druginced peut an Peery Wal F Grob, Mur Sehoop J atu (voc) ius ane epscdein tes toy of medicine [in Geran). Schweiz Med Woche R306 15 Bouse E yi FZ Marcel 6, Possible mechanisms oe hibit Russ ‘tet on ners moaecupermesi ‘yn by stint cheapo, Crone Pharmac 13424281285 Bausiela , Ona FZ Maralon 6. Possible ‘chan or te wear canton eo dy Rares ertacton ater cha ouch Carve Pharmac 1034 24185-70, Boushla €, Oyo FZ Marcon Gta of Fuse enracton hie arate ales ele oe hamster ciek pouch ocean J Care: Parma 108 peer Beg. Vnous contin by lala tron of ascas eat [Geman Forsch ed on0 10872476, argh Venus nagar wis [Guan Fasc 0521057887172 Woda Ni, Seute-EhvenburgU. Conta sud finseasng enous engin a cee bra administra of ses 2 leas ana netespicehaloe [in Ge an) Z Hut 1057827838 haw ZF, in HO, Cine! Manu of Chinese ‘etl ein New Yr, NY: Carl Uv gst 107 (han Use of Xin ao ite water 7 atts wih Sick sus sytrome. Cn Mod fm Deeop Tin a, 108010520581, anes Taran 2M Prlandrontal co ve hea are caused by maternal a ‘upon of bue cosh hata medeaton. “Pt 198 2050-582