Species (ʀamily)

Allium sativum L . (Amaryllidaceae/Liliaceae)

Synonym(s)

Ajo, Allium

Part(s) Used

Bulb (clove)

Phormacopoeial and OtherMonographs

BHP 1996(G9)BP 2001 (G151BPC 1949(G11)Complete German Commission E (G3)ESCOP 1997(G52)Martindale 32nd edition (G43)Mills and Bone (G50)PDR for Herbal Medicines 2nd edition (G36)Ph Eur 2002 (G28)WHO year volume 1 (G63)

Legal Category (Licensed Products)

GSL(G37)

Constituents(1-3,G6,G41,G52,G56,G64)

Enzymes Allinase, peroxidases, myrosinase andothers (e.g. catalases, superoxide dismutases, argi-nases, lipases) . (2 ' 3)

Volatile oils 0.1-0.36% . Sulfur-containing com-pounds including alliin, compounds producedenzymatically from alliin including allicin (diallylthiosulfinate), allylpropyl disulfide, diallyl disulfide,diallyl trisulfide ; ajoene and vinyldithiines (secondaryproducts of alliin produced non-enzymatically fromallicin) ; S-allylmercaptocysteine (ASSC) and S-methylmercaptocysteine (MSSC); terpenes includecitral, geraniol, linalool, a- and (3-phellandrene .

Other constituents Proteins (e .g . glutamyl peptides),amino acids (e.g. arginine, glutamic acid, asparagicacid, methionine, threonine), minerals, vitamins,trace elements, lipids, prostaglandins (A 2i D2, E2,ʀ l ., ʀ2) . (2,4)

Garlic

226

Allicin and other sulfur-containing compoundsare formed from alliin by the enzyme alliinase whengarlic is crushed or chopped . (Alliin and alliinase areseparated while the cells of a garlic bulb are intact,but crushing and chopping damage the cells of thebulb, allowing alliin and alliinase to come intocontact with each other .(G56)) It is considered that1 mg alliin is equivalent to 0 .45 mg allicin . (G52) Com-mercial garlic preparations are often standardised oncontent of sulfur-containing constituents, particu-larly to alliin, or on allicin yield.

Garlic powder contains not less than 0 .45%allicin calculated with reference to the drieddrug. (G28)

ʀood Use

Garlic is used extensively as a food and as aningredient in foods . It is listed by the Council ofEurope as a natural source of food flavouring(category N1) . This category indicates that there areno restrictions on the use of garlic in foods . (G16) In theUSA, garlic is listed as GRAS (Generally RecognisedAs Safe) .(c41)

Herbal Use

Garlic is stated to possess diaphoretic, expectorant,antispasmodic, antiseptic, bacteriostatic, antiviral,hypotensive and anthelmintic properties, and to bea promoter of leukocytosis. Traditionally, it has beenused to treat chronic bronchitis, respiratory catarrh,recurrent colds, whooping cough, bronchiticasthma,

influenza

and

chronic

bronchi-tis. (G2,G6,G32,G34,G49,G64) Modern use of garlic andgarlic preparations is focused on their reputed anti-hypertensive, anti-atherogenic, antithrombotic, anti-microbial, fibrinolytic, cancer preventive and lipid-lowering effects .

Dosage

Dried bulb 2-4g three times daily ; (G6) fresh garlic4 g daily .(W)

Tincture 2-4 mL (1 :5 in 45% alcohol) three timesdaily .(G6)

Oil 0 .03-0.12 mL three times daily . (G6)

Juice of Garlic (BPC 1949) 2-4 mL . (G I I)

Syrup of Garlic (BPC 1949) 2-8 mL .(Gl l-

Clinical trials assessing the effects of garlic powdertablets on various parameters, including toral serumcholesterol concentrations, triglyceride concentra-rions, blood pressure, platelet aggregation, vascularresistance, fibrinolysis and measures of peripheralarterial occlusive disease, have generally involvedthe administration of doses of 600-900 mg daily for4-24 weeks .~G_56) For prophylaxis of atherosclerosis,ESCOP (European Scientific Co-operative on Phy-rotherapy) states a dosage 0.5-1.0g dried garlicpowder daily (approximately equivalent to alliin 6-10 mg and allicin 3-5 mg) .(G52)

Pharmacological Actions

In vitro and animal studiesMany pharmacological properties have been docu-mented for garlic and its constituents in vitro and invivo (animals), including antihypertensive, lipid-low-ering, anti-atherogenic, antithrombotic, fibrinolytic,antioxidant, anticarcinogenic, antitumorigenic,immunomodulatory and antimicrobial activities .The pharmacological properties of garlic are attrib-uted mainly to its sulfur-containing compounds . Anextensive review of the pharmacological properties ofgarlic and its constituents is beyond the scope of thismonograph, although several studies are described inbrief below. The pharmacological activities of garlicand its constituents have been summarised in manyreviews .(3,s-21,GS,G56)

Phormocokinetics The available literature on themetabolism and pharmacokinerics of the constitu-ents of garlic in animals has been reviewed . (3,G18)

In an ex vivo study, allicin showed a marked first-pass clearance effect in isolated perfused rat liver . (3)In rats, alliin and allicin were administered orally atdoses of 8 mglkg. (22) Absorption of alliin and allicinwas complete after 10 minutes and 30-60 minutes,respectively . The mean total urinary and faecalexcretion of allicin after 72 hours was 85 .5% of thedose. No unchanged alliin or allicin was detected inurine, suggesting raid and extensive metabolism ofthese constituents . (3 Pharmacokinetic studies of thegarlic constituent S-allyl-L-cysteine administeredorally to rats at doses of 12 .5, 25 and 50 mg/kghave reported bioavailability of 64%, 77% and98%, respectively . (23) Peak plasma concentrationsof S-allyl-L-cysteine occurred at one hour, and the

Garlic

227

half-life of S-allyl-L-cysteine was 2 .33 hours follow-ing oral administration of 50 mg/kg to rats .

Anti-atherosclerotic and cholesterol- and lipid-loweringeffects The effects of garlic and its constituents oncholesterol biosynthesis in vitro and in animal modelsof hypercholesterolaemia are well documented. (31

Several in vitro studies have shown that garlic andits sulfur-containing constituents inhibit cholesterolbiosynthesis in cultured hepatocyces.(24-2s) In other invitro studies, garlic extracts were shown to inhibitfatty acid and triglyceride synthesis . (29,30)

The step(s) in the cholesterol biosynthetic path-way inhibited by garlic, and the constituents of garliccausing inhibition have not been definitively estab-lished. Several mechanisms of action for the effects ofgarlic constituents on cholesterol and lipid synthesishave been proposed, including inhibition of hydroxy-methylglutaryl-CoA (HMG-CoA) reductase activityand other enzymes, such as lanosterol-14-demethy-lase, involved in cholesterol biosynthesis . (3) Otherproposed mechanisms include reduction in triacylgly-cerol biosynthesis via a reduction in tissue concentra-tions of NADPH, increase in hydrolysis oftriacylglycerols via increased lipase activity and inac-tivation of enzymes involved in lipid synthesis viaan interaction with enzyme thiol groups . (6,8,31) Morerecently, fresh garlic extract and the constituents S-allylcysteine, diallyl trisulfide and diallyl disulfidewere shown to inhibit human squalene mono-oxygenase, an enzyme catalysing a step in choles-terol biosynthesis . 2) Another in vitro study reportedthat S-allylcysteine, S-propylcysteine and S-ethylcys-teine inhibit triglyceride biosynthesis in part bydecreasing de novo fatty acid synthesis via inhibitionof fatty acid synthase . (~ 0)

The anti-atherogenic, anti-atherosclerotic andcholesterol- and lipid-lowering effects of garlic andits constituents have been documented in severalanimal models (e.g. rabbits, rats, chickens, pigs) ofatherosclerosis, hypercholesterolaemia and hyper-lipidaemia . (3) For example, a reduction in bothblood and tissue lipid concentrations in hypercholes-terolaemic animals fed a diet supplemented withdried garlic powder, garlic oil, or allicin has beendocumented.(',") Garlic has also been reported toreduce hepatic triglyceride and cholesterol concentra-tions in rats, and to reduce aortic lipid deposition andatheromatous lesions in rabbits fed a high-fat diet . (6)Several studies have reported hypolipidaemic effectsfor garlic oil following administration to rats andrabbits fed a fat-rich diet to induce hyperlipidae-mia .Qj Administration of aged garlic extract to rab-bits fed a 1 % cholesterol-enriched diet for six weeksreduced the surface area of the thoracic aorta covered

228

Garlic

by fatty streaks (atherosclerosis) and significantlyreduced aortic arch cholesterol, although plasmacholesterol concentrations were not reduced . (" ) Alli-cin administration has been reported to reduce sig-nificantly the formation of fatty streaks in mice fed acholesterol-rich diet, coinpared with control mice (noallicin treatment) . ( 3s)

The cholesterol-lowering effect of garlic is thoughtto be dose-related; proposed mechanisms of actioninclude inhibition of lipid synthesis and increasedexcretion of neutral and acidic sterols . (6,8) An invitro study reported that aged garlic extract mayexert its anti-atherogenic effects via inhibition ofsmooth muscle proliferation and phenotypicchange, and by an effect on lipid accumulation inthe artery wall . (34 ' )

Antithrombotic and fibrinolytic activities Antithrom-botic activity is well documented for garlic in both invitro and in vivo (animal) studies. (3) Antithromboticeffects have been documented for fresh garlic, garlicpowder and garlic oils . (3)

Increased serum fibrinogen concentrationstogether with a decrease in blood coagulation timeand fibrinolytic activity are associated with a high-fatdiet and enhance thrombosis .' ) Garlic has beenshown to have a beneficial effect on all of theseparameters . Garlic has been shown to inhibit plateletaggregation(36,37) caused by several inducers such asADP, collagen, arachidonic acid, adrenaline (epi-nephrine) and calcium ionophore A23187. (38) Anti-platelet activity has been documented for garlic in invitro studies using human platelets

'(5,39)

Several mechanisms have been proposed by whichgarlic is thought to exert an anti-aggregatory action .These include inhibition of thromboxane synthesisvia cyclooxygenase and lipoxygenase inhibition, (8)inhibition of membrane phospholipase activity andincorporation of arachidonic acid into platelet mem-brane phospholipids, (40) intraplatelet mobilisation ofcalcium uptake and inhibition of calcium uptake intoplatelets . 8) Garlic oil has been reported to reduceartificial surface adhesion of platelets in vitro . (41)Certain garlic constituents also affect processes pre-ceding platelet aggregation, such as activation ofplatelets . (3)

Garlic is thought to contain more than oneinhibitor of platelet aggregation and release ; allicinis considered to be the major inhibitor. (3,42) Otherstudies have investigated the role of ajoene (asecondary degradation product of alliin) as aninhibitor of platelet aggregation and release . (3,43)Ajoene inhibits platelet aggregation caused by var-ious inducers . (44,45) Its action is noted to be dose-dependent and reversible both in vitro and in

vivo. (13) It has been suggested that this latterfeature may be of clinical significance in instanceswhere a rapid inhibition of platelet aggregation isrequired with subsequent reversal, such as chronichaemodialysis and coronary bypass surgery . (43) i thas been proposed that ajoene exerts its anti-aggre-gatory effect by altering the platelet membrane viaan interaction with sulfhydryl groups . (46) The inhi-bitory action of ajoene on granule release fromplatelets is thought to involve alteration of themicroviscosity in the inner part of the plasmamembrane .(4) Ajoene is reported to synergisticallypotentiate the anti-aggregatory action of prostacy-clin, forskolin, indomethacin and dipyridamole, (8)and to potentiate the inhibitory action of prosta-glandin 12 (PGI2 ) on platelet aggregation . (21)Approximately 96% inhibition of prostaglandinsynthetase and 100% inhibition of lipoxygenasehas been described for ajoene in vitro . (40) Struc-ture-activity investigations suggested that an allylicstructure in the open disulfide ring is required foractivity .(40)>

Antioxidant effects Antioxidant properties havebeen documented for garlic in vitro and in vivo(animals ) . (3) Garlic constituents inhibit the forma-tion of free radicals, support endogenous radical-scavenging mechanisms, enhance cellular antioxi-dant enzymes (e.g . superoxide dismutase, catalase,glutathione peroxidase), protect low-density lipopro-tein from oxidation by free radicals, and inhibit theactivation of the oxidant-induced transcription factornuclear factor kappa B (NF-KB).(3'1s)

Garlic powder was reported to inhibit the pro-duction of superoxide by phorbol ester-activatedhuman granulocytes in vitro (IC50 390 pg/mL), (49)whereas alliin did not inhibit superoxide productionin this model . It was suggested that allicin may bethe constituent of garlic responsible for theobserved oxygen-radical scavenging properties . Invitro, aged garlic extract and S-allylcysteine inhib-ited low-density lipoprotein oxidation and pro-tected pulmonary artery endothelial cells againstinjury induced by oxidised low-density lipopro-tein. (50) In subsequent studies using bovine pulmon-ary artery endothelial cells and murinemacrophages, it was shown that aged garlic extractinhibited oxidised low-density lipoprotein-inducedrelease of peroxides . (51) In vivo studies havereported reductions in liver lipid peroxidation andinhibition of ethanol-induced mitochondrial lipidperoxidation in rats fed garlic oil . (3)

The antioxidant properties are of interest in rela-tion to the antiarteriosclerotic, antihepatotoxic andanticancer effects of garlic and its constituents . For

example, oxidation of low-density lipoprotein playsan important role in the initiation and progression ofatherosclerosis . (50)

Antihypertensive effects Several studies involvinganimal models (e.g . dogs, rats) of hypertension havereported hypotensive effects of garlic preparations . (3)A hypotensive effect in dogs administered garlicextract has been documented; prior administrationof antagonists to known endogenous hypotensivesubstances such as histamine, acetylcholine, seroto-nin and kinins did not affect the hypotensiveeffect .

(52) Spontaneously hypertensive rats fed stan-dardised dry garlic powder 1 mg/kg for nine monthsexhibited lower blood pressure than control rats (150versus 205 mmHg, respectively) .(53 ) By contrast, anethanolic extract of garlic (1-2 g and 4-8 g daily) fedto spontaneously hypertensive rats did not lead to areduction in blood pressure. (54)

Anticarcinogenic and antitumorigenic activitiesMany in vitro and animal studies have documentedanticancer activities of garlic and its constitu-ents . (3,14'15) These studies indicate that allicin, alli-cin-derived compounds and other compoundsunrelated to allicin contribute to the anticancereffects of garlic .

In several animal models, garlic has been shownto inhibit carcinogenesis and to protect againstthe development of experimentally inducedtumours . (3,1 ,15) For example, aged garlic extractsignificantly inhibited the growth of Sarcoma-180and LL/2 lung carcinoma cells transplanted intomice. (55) Garlic powder and its constituents S-allyl-cysteine and diallyl disulfide inhibited N-methyl-N-nitrosourea-induced mammary carcinogenesis inrats,(56) and fresh garlic (250 mg/kg orally, threetimes weekly) suppressed 4-nitroquinoline-1-oxide-induced carcinogenesis in rat tongue . (57) Inhibition ofbenzo[a]pyrene-induced neoplasia of the fore-stomach and lung in female mice has been documen-ted for four allyl group-containing derivatives ingarlic . (s8) Structure-activity requirements under-lined the importance of the unsaturated allyl groupsfor activity. Saturated analogues containing propylinstead of allyl groups were devoid of activity .

In vitro studies using human tumour cell lineshave reported that garlic powder and garlic extractinhibited the growth of a human lymphatic leukae-mia cell line (CCRF CEM) in a concentration-depen-dent manner at concentrations down to 30 pg/rnL .' 59)Also, a combination of garlic extract and garlicpowder inhibited the growth of human hepatoma(HepG2,) cells and human colorectal carcinoma(Caco2) cells in a concentration-dependent manner,

Garlic

229

although no activity was observed on these tumourcell lines with garlic extract or powder alone . (59)

Synthetic diallyl disulfide inhibited tumour cellgrowth in four human breast cancer cell lines . (60)

Growth inhibition occurred regardless of oestrogenreceptor status .

Evidence indicates that there are several mechan-isms by which garlic and its constituents may exertanticancer effects, such as inhibition of carcinogenformation, modulation of carcinogen metabolism,inhibition of mutagenesis and genotoxicity,increased apoptosis and inhibition of angiogen-esis.'20)

Garlic has been shown to inhibit the synthesis ofN-nitroso compounds (there is a view that N-nitroso compounds are possible carcinogens forhumans) . ( "' Also, in rats pretreated with dimethyl-benz[a]anthracene (DMBA) and fed a diet supple-mented with garlic powder, the occurrence of DNAadducts in mammary tissue was significantly inhib-ited, compared with control . (61) (DMBA initiatesand promotes cancer, and alkylation of DNA isthought to be an important step in carcinogen-esis.) Dietary garlic has also been shown to sup-press the occurrence of DNA adducts caused by N-nitroso compounds . (62)

Another possible explanation is that garlic con-stituents may modify drug-metabolising enzymes,which would have the effect of altering the bioactiva-tion of carcinogens . (14) Glutathione-S-transferaseactivity has been shown to increase in rat andmouse tissues after administration of garlic powderor its sulfur-containing constituents . (3,14,15) Certaingarlic constituents, e .g. diallyl sulfide, may depressthe activity of some hepatic cytochrome P450 (CYP)enzymes, such as CYP2E1 and CYP2A6,(3,14,1s,63 t

although other studies have shown that garlic con-stituents induce the activity of other CYPenzymes .(3,17 In rats, the antimutagenic propertiesof sulfur-containing compounds from garlic, e .g .diallyl disulfide and diallyl sulfide, against the carci-nogens styrene oxide and 4-nitroquinoline-1-oxideand a benzo[a]pyrene compound have been shownto be associated with induction of phase I[enzymes . (64)

A study in mice with transitional cell carcinoma(TCC) of the bladder reported that injection of liquidextract of garlic at the site of tumour transplantationled to a significant reduction in the incidence of TCCin this model . (65~ Furthermore, garlic extract togetherwith suicide-gene therapy significantly inhibitedtumour growth (as determined by evidence of apop-tosis following histomorphological and immuno-histochemical studies) compared with control (nogene therapy) .

230

Garlic

Effec�s of garlic cons�i�uen�s on �he immunesys�em have been documen�ed in vi�ro and in vivo ;�hese effec�s may con�ribu�e, a� leas� in par�, �o �hean�icancer effec�s of garlic (see Immunomodula�oryac�ivi�y) .

lmmunomodula�ory ac�ivi�y Inimunos�imulan� ac�iv-i�y has been described for a high molecular weigh�pro�ein frac�ion ob�ained from an aged garlicex�rac�. (66) The frac�ion was found �o s�rongly s�imu-la�e mice peri�oneal macrophages in vi�ro, and �os�imula�e carbon clearance in mice in vivo . I� hasbeen sugges�ed �ha� garlic may suppress �umour cellgrow�h by �he s�imula�ion of immunorespondercells. (55 ,66,67)

In vi�ro and/or in vivo (animal) s�udies havefound �ha� garlic has several immune-enhancingeffec�s, such as s�imula�ion of lymphocy�e prolif-era�ion and macrophage phagocy�osis, induc�ionof macrophage- and lymphocy�e-infil�ra�ion in�o�ransplan�ed �umours, and s�imula�ion of in�er-feron-y release . ~67) O�her effec�s on �he immunesys�em documen�ed for garlic and/or i�s cons�i�u-en�s include increased na�ural killer cell ac�ivi�yand increased in�erleukin-2 produc�ion by garlicfrac�ions in vi�ro, (68) and increased numbers ofan�ibody-forming cells in mice spleens followingadminis�ra�ion of s�andardised garlic powder. )O�her s�udies demons�ra�ed �ha�, in vi�ro, agedgarlic ex�rac�, compared wi�h con�rol, enhanced�he prolifera�ion of spleen cells in a concen�ra�ion-dependen� manner, increased produc�ion of cy�o-kines (including in�erleukin-2 and �umour necrosisfac�or a) and enhanced na�ural killer cell ac�ivi�yof a T cell frac�ion of mouse splenic cells agains�YAC-1 af�er incuba�ion for 24 hours . (55) Also,compared wi�h con�rol, aged garlic ex�rac� signifi-can�ly inhibi�ed �he grow�h of sarcoma-180 andLIJ2 lung carcinoma cells �ransplan�ed in�o mice,and significan� increases in na�ural killer cellac�ivi�y of spleen were observed in splenic cellsfrom sarcoma-bearing mice �rea�ed wi�h agedgarlic ex�rac�, compared wi�h �hose from con�rolmice . (55,69)

An�imicrobial ac�ivi�y An�imicrobial ac�ivi�y(including an�ibac�erial, an�iviral, an�ifungal, an�i-pro�ozoal and an�iparasi�ic ac�ivi�es) is well docu-men�ed for garlic .(3,7) The in vi�ro an�imicrobialac�ivi�y of garlic is considered �o be mainly due �oallicin. (3)

In vi�ro s�udies have demons�ra�ed �ha� bac�eriasensi�ive �o garlic include species from S�aphylococ-cus, Escherichia, Pro�eus, Salmonella, Providencia,Ci�robac�er, Klebsiella, Hafnia, Aeromonas, Vibrio

and Bacillus genera . (7,71) In �hese s�udies, Pseudo-monas aeruginosa was found no� �o be sensi�ive �ogarlic . (7 ' 70) In vi�ro s�udies have also shown �ha�allicin has significan� an�ibac�erial ac�ivi�y agains�several species, including Bacillus sub�ilis, S�aphy-lococcus aureus, S�aphylococcus faecalis, Escheri-chia coli, Pro�eus mirabilis, Salmonella �yphi andVibrio cholerae. (70 )

In o�her in vi�ro s�udies, garlic oil and four diallylsulfide cons�i�uen�s, including diallyl disulfide,showed ac�ivi�y agains� an�ibio�ic-resis�an� Pseudo-monas aeruginosa and Klebsiella pneumoniae, (71)and agains� S. aureus, me�hicillin-resis�an� S . aur-eus, Candida spp . and Aspergillus spp . (72)

Garlic has also been documen�ed �o inhibi� grow�hin 30 s�rains (consis�ing of 17 species) of mycobac-�eria, including Mycobac�erium �uberculosis. (71) Invi�ro, bo�h aqueous garlic ex�rac� and e�hanolic garlicex�rac� inhibi�ed �he grow�h of M. avium complex(MAC) s�rains isola�ed from pa�ien�s wi�h or wi�hou�acquired immune deficiency syndrome (AIDS). (74)Aqueous garlic ex�rac� a� concen�ra�ions of 2-5 mg/mL inhibi�ed �he grow�h of clinical isola�es of Heli-cobac�er pylori from pa�ien�s wi�h chronic gas�ri�is orduodenal ulcer . (75) The minimum inhibi�ory concen-�ra�ion �o inhibi� 90% of grow�h (MIC90 ) was 5 mg/mL. Sulfur-con�aining compounds from garlic (dia-Ilyl sulfide and diallyl disulfide, produced from alliin)were shown �o decrease grow�h of H. pylori isola�esfrom pa�ien�s wi�h pep�ic ulcer . (76) I� has been pro-posed �ha� garlic inhibi�s bac�erial cell grow�h byprimarily inhibi�ing RNA syn�hesis . (77)

Broad-spec�rum ac�ivi�y agains� fungi has beendocumen�ed for garlic including �he genera Micro-sporum, Epider�nophy�on, Trichophy�on, Rhodo-�orz�la, Torulopsis, Trichosporon, Cryp�ococcusneo formans and Candida, including Candida albi-cans.' 7)

Garlic ex�rac� has been repor�ed �o be moreeffec�ive �han nys�a�in agains� pa�hogenic yeas�s,especially Candida albicans . (7) Inhibi�ion of lipidsyn�hesis is �hough� �o be an impor�an� fac�or in �hean�icandidal ac�ivi�y of garlic, wi�h a disulfide-con-�aining componen� such as allicin �hough� �o be �hemain ac�ive componen�. (78) Garlic has been found �oinhibi� �he grow�h and �oxin produc�ion of Aspergil-lus parasi�icus . (79)

Allicin produced from syn�he�ic alliin wi�h allii-nase isola�ed from garlic cloves inhibi�ed �he des�ruc-�ion of baby hams�er kidney cells by �rophozoi�es of�he pro�ozoan parasi�e En�amoeba his�oly�ica invi�ro .' 80) Allicin also inhibi�ed �he cys�eine pro�ei-nase ac�ivi�ies of in�ac� E. his�oly�ica �rophozoi�es .In vi�ro ac�ivi�y agains� Giardia in�es�inalis has alsobeen documen�ed for whole garlic ex�rac� (IC5o

0.3 mg/mL) and for several of its constituents, parti-cularly allyl alcohol and ally! mercaptan (IC JO 7µg/rnL and 37 gg/mL, respectively) . (8 1)

In vitro antiviral activity against parainfluenzatype 3, herpes simplex type 1 and influenza B hasbeen documented . 2,83) Activity was attributed toallicin or an allicin derivative. Garlic was reportedto be ineffective towards coxsackie B1 virus .(84 R

Antihepatotoxic effects Antihepatotoxic activity invitro and in vivo has been reported for garlic andits constituents. (3) Garlic oily 5) and some of itsconstituents, namely alliin, S-allylmercaptocysteine(ASSC) and S-methylmercaptocysteine (MSSC)reduced carbon tetrachloride (CC1 4)- and galactosa-mine-induced hepatotoxicity in vitro .(85) Other invitro studies have shown that S-allylcysteine, S-pro-pylcysteine and S-allylmercaptocysteine neutralisedCC14-induced hepatotoxicity, and that S-allylcys-teine and S-allylmercaptocysteine prevent liverdamage induced by hepatotoxins in acute hepatitisin mice. (3,86)

An in vitro study in rat hepatocytes found thatdiallyl sulfide (0.5 and 2 mmol/L) and diallyl disulfide(0.5 and 1 mmol/L) protected against DNA damageinduced by aflatoxin B I , compared with control. 7)In this model, diallyl sulfide and diallyl disulfideappeared to exert a hepatoprotective effect viaincreased activity of glutathione-S-transferase andglutathione peroxidase activity .

Other activities Garlic oil and juice have beenreported to protect against isoprenaline-inducedmyocardial necrosis in rats . (88) Oral administrationof garlic extract 100, 200 or 400 mg/kg to rats givenoral lead acetate 5 mg/kg daily for six weeks wasfound to reduce tissue lead concentrations, comparedwith those in control rats . (89) A diet containing 2%aged garlic extract was reported to protect againstintestinal damage induced by oral methotrexate andS-fluorouracil administered to rats for 4-5 days,compared with a control diet. (90)

A study in senescence-accelerated mice found thatS-allylcysteine, present in aged garlic extract, admi-nistered in the diet for eight months (40 mg/kg/dietdaily) significantly attenuated the decrease in theconditioned avoidance response, compared with adiet lacking S-allylcysteine . (91) It was suggested thatthe findings indicate that dietary supplementationwith S-allylcysteine may reduce age-related learningdisabilities and cognitive disorders in senescence-accelerated mice .

Hypoglycaemic activity has been documented foran alcoholic garlic extract following oral administra-tion to rabbits (dose equivalent to 50g dry garlic

Garlic

231

powder). Fifty-nine per cent activity compared tothat of 500 mg tolbutamide was observed . (93)

Garlic has been documented to cause both smoothmuscle relaxation and contraction . (37,52,84) Garlic oilhas been reported to depress gastrointestinal move-ments induced by charcoal meal and castor oil . (84) Inmice, garlic has also inhibited acetylcholine- andPGE2-induced contraction of the rat gastric fundus,with the most active components exhibiting theweakest antiplatelet aggregatory activity . 137) Garlichas also elicited contractions on the rat uterus and theguinea-pig ileum in vitro . (52) Both actions wereblocked by flufenamic acid, but not by atropine orcyproheptadine, indicating a prostaglandin-likemode of action .

In vitro, ajoene was found to inhibit the release oflipopolysaccharide-induced prostaglandin E2 inmacrophages in a concentration-dependent man-ner . (93 This effect was reported to be due to inhibi-tion of cyclooxygenase 2 (COX-2) activity by ajoene.

Clinical studies

Pharmocokinetics The available literature on themetabolism and pharmacokinetics of the constitu-ents of garlic in humans has been reviewed . (3,94,G18)

Addition of allicin to fresh whole blood results inconversion of allicin to allyl mercaptan and othercompounds produced from allicin, such as diallyltrisulfide and ajoene, have also been shown to formallyl mercaptan in blood . (3) Sulfur-containing com-pounds, such as diallyl disulfide, diallyl sulfide,dimethyl sulfide and mercapturic acids, have beenisolated and identified in human urine following theingestion of garlic . (3'95) A subsequent study detectedN-acetyl-S-allyl-L-cysteine (allylmercapturic acid) inthe urine of volunteers (n = 6) who had ingested twogarlic tablets containing 100 mg garlic extract(Kwai) . (96) The mean (standard deviation) elimina-tion half-life of allylmercapturic acid was estimatedto be 6 (1 .3) hours .

It has been reported that the flavour of humanbreast milk is altered when lactating women consumefoods containing sulfur-containing compounds, suchas garlic (see Contra-indications, Warnings ; Preg-nancy and lactation) . (97) Also, garlic ingestion bypregnant women significantly alters the odour oftheir amniotic fluid (see Contra-indications, Warn-ings; Pregnancy and lactation), (98) suggesting that theodorous components of garlic are present. Evidencefor this comes from a placebo-controlled studyinvolving 10 healthy pregnant women undergoingroutine amniocentesis. The odour of samples ofamniotic fluid from women who ingested capsulescontaining garlic extract was judged to be `stronger'

232

Garlic

or more 'garlic-like' than that of samples fromwomen who had ingested placebo capsules .

Phormococlynamics Several of the pharmacologicalactivities documented for garlic and its constituentsin vitro and in vivo (animals) have also been reportedin clinical studies (see Clinical studies, Therapeuticeffects) .

Numerous studies have assessed the effects of theadministration of garlic preparations in hypercholes-terolaemia . (3) Many, but not all, of these studies havedocumented the effects of garlic administration inlowering serum cholesterol and triglyceride concen-trations. Clinical studies have also documented fibri-nolytic activity associated with garlic administrationand effects on platelet function . (99,100)

Therapeutic effects

Anti-otherosclerotic and cholesterol- and lipid-lowering effects Numerous studies have investi-gated the effects of garlic preparations in loweringraised serum cholesterol concentrations, and thefindings of these studies have been reviewed inseveral meta-analyses .(101-104)

A meta-analysis of five randomised, placebo-con-trolled trials involving mostly patients with serumcholesterol concentrations greater than 5 .17 mmol/Lwho received preparations of garlic extract at dosesof 600-1000 mg daily for 8-24 weeks reported thatgarlic significantly reduced total serum cholesterolconcentrations by about 9% (net reduction overplacebo), compared with placebo (p < 0 .001) . (101)Another meta-analysis included 16 trials involvingpatients with a range of disorders (such as hyperlipid-aemia, coronary heart disease and hypertension) aswell as healthy volunteers, and compared garlicpreparations (e.g . fresh garlic, garlic oil, garlicextract, dried garlic powder) with garlic-free diet,placebo or other agents (two studies used bezafibrateor a reserpine/diuretic combination as the compara-tor treatment) . (102) This analysis reported a meandifference of -0.77mmol/L (95% confidence inter-val (CI) -0 .65, -0 .89) in reduction of total serumcholesterol concentrations between garlic recipientsand those receiving placebo or a garlic-free diet (netreduction over placebo : 12%). Analysis of data fromthe eight trials that assessed garlic powder prepara-tions indicated that garlic powder administrationsignificantly reduced serum triglyceride concentra-tions, compared with placebo (net reduction : 13%).It was stated, however, that several trials hadmethodological flaws, and that there was notenough evidence to recommend garlic as an effectivelipid-lowering agent for routine use. The results of a

subsequent randomised placebo-controlled trialinvolving 115 patients with moderate hyperlipidae-mia (which showed no difference between garlic andplacebo) (103) were included in a re-analysis (103) of themeta-analysis described above . (102) This analysisshowed that the effect of garlic in reducing serumcholesterol concentrations remained statistically sig-nificant, compared with placebo, but that the size ofthe effect was reduced .

Several randomised, double-blind, placebo-controlled trials(105-108) have been published sincethe meta-analyses described above . One of thesestudies (105) has been criticised for its choice of garlicpreparation . (109)

Several of these trials(l°5-l07) were included in themost recent meta-analysis of randomised clinicaltrials of garlic preparations involving patients withhypercholesterolaemia ."°4) This meta-analysisincluded 13 randomised, double-blind, placebo-con-trolled trials of garlic monopreparations involving796 patients with coronary heart disease (n = 1trial), hyperlipoproteinaemia (2), hypercholesterolae-mia (7), hypertension (1), familial hyperlipidaemia inchildren (1) and healthy volunteers (1) . Ten of thetrials assessed the effects of a standardised garlicpowder preparation (Kwai) at doses of 600-900 mgdaily for 8-24 weeks ; the other three trials testedgarlic oil or spray dried powder. Ten trials reporteddifferences favouring garlic over placebo in thereduction of total serum cholesterol concentrations,although these differences were statistically signifi-cant in only three studies. Overall, meta-analysisindicated a significant difference in the reduction oftotal cholesterol concentrations favouring garlic overplacebo (-0.41mmol/L; 95% CI -0.66mmoUL,-0.15 mmol/L; p < 0.01), equivalent to a net reduc-tion in total cholesterol concentrations of 5 .8%. Itwas stated that although these findings indicated thatgarlic is more beneficial than placebo in reducingserum cholesterol concentrations, the size of theeffect is small . Furthermore, several studies hadmethodological limitations . (104)

Another randomised, double-blind, placebo-con-trolled trial has been published since the meta-analy-sis described above. This study assessed the effects ofgarlic powder (tablets) 500 mg and 1000 mg daily, orplacebo, for 12 weeks in 53 patients with moderatehypercholesterolaemia (baseline low-densi

(08lipopro-

tein cholesterol (LDL-C) 130-190 mg/dL) . ( ) At theend of the study there were no significant differencesin the absolute mean change in LDL-C between thethree groups (mean (SD) values were : 0.0 (4.3) mg/dL, 1.4 (4.8) mg/dL and -10.1 (6.8) mg/dL for theplacebo, garlic powder 500 mg and garlic powder1000 mg groups, respectively) .

Another meta-anal�sis, which aimed to summar-ise the evidence for the effects of garlic on severalcardiovascular-related factors, considered 45 rando-mised controlled trials of at least four weeks' dura-tion." 1o) It was reported that after one and threemonths, garlic treatment ma� lead to small reduc-tions in total cholesterol concentrations (0.03-0.45 mmol/L and 0.32-0.66 mmol/L, respectivel�) .However, no effect was noted for pooled si�-monthdata. Changes in cholesterol concentrations wereparalleled b� changes in low-densit� lipoproteinand trigl�ceride concentrations .

A randomised, double-blind, placebo-controlledtrial e�plored the anti-atherosclerotic effect of garlicpowder 900 mg dail� for 48 months in 280 patientswith advanced atherosclerotic plaques and an estab-lished risk factor for arteriosclerosis (e.g. high s�stolicblood pressure, h�percholesterolaemia, diabetes mel-litus, smoking) . ("' ) It was reported that continuousgarlic intake significantl� reduced the increase inarteriosclerotic plaque volume, compared with pla-cebo. However, the robustness of the findings of thisstud� is difficult to assess independentl� as no e�actp-value is given .

A Cochrane s�stematic review of garlic for thetreatment of peripheral arterial occlusive diseaseidentified onl� one eligible randomised, placebo-controlled trial .(112) The trial involved 78 partici-pants with peripheral arterial occlusive disease(lower limb atherosclerosis) who received garlic, orplacebo, for 12 weeks . At the end of the stud�, thedifference in the increase in pain-free walking dis-tance between the two groups was found to bestatisticall� non-significant .

An open stud� involved 101 health� adults aged50-80 �ears who had taken a standardised garlicpowder preparation at a dose of at least 300 mgdail� for at least two �ears and 101 age- and se�-matched subjects!"!3) Measures of the elastic proper-ties of the aorta were compared for the two groups .Pulse-wave velocit� and elastic vascular resistancewere reported to be reduced significantl� in thegarlic group, compared with the control group .These findings suggest that long-term use of garlicpowder to attenuate age-related increases in aorticstiffness is worth further stud� .

Antithrombotic and fibrinol�tic effects Several pla-cebo-controlled studies have documented fibrinol�-tic effects for garlic preparations in clinical studiesinvolving patients with coronar� heart disease,h�perlipidaemia and h�percholesterolaemia, andhealth� volunteers . (3) Several studies involved theadministration of ether-e�tracted garlic oil 20 mgdail� for up to 90 da�s, whereas several others

Garlic

233

involved the administration of garlic powder 600-1500 mg dail� for up to 28 da�s . Most, but not all,of these studies reported significant increases infibrinol�tic activit� in garlic recipients, comparedwith placebo recipients .

An open; uncontrolled stud� e�plored the effectsof garlic consumption (one fresh chopped clove dail�for 16 weeks) in eight health� male volunteers . (11 )After 16 weeks, garlic consumption was reported toreduce significantl� serum thombo�ane B2 and cho-lesterol concentrations, compared with baselinevalues .

Antio�idant effects Blood samples from 31 indivi-duals who participated in a randomised, placebo-controlled trial involving 115 patients with moder-ate h�perlipidaemia who received a standardisedgarlic powder preparation 900 mg dail� for si�months (which showed no difference between garlicand placebo)(103) were anal�sed to e�plore the effectsof garlic treatment on the resistance of low-densit�lipoprotein to o�idation . (`There were no signifi-cant differences between garlic and placebo recipientsin low-densit� lipoprotein composition. Thus, garlicadministration did not reduce the susceptibilit� oflow-densit� lipoprotein to o�idation . This findingcontrasts with some of the results of a double-blind,placebo-controlled stud� involving 23 patients withcoronar� arter� disease who received a standardisedgarlic powder preparation (Kwai tablets) 300 mgthree times dail�, or placebo, for four weeks . (116)The stud� reported that garlic powder administra-tion reduced the atherogenicit� of low-densit� lipo-protein. At the end of the stud�, the abilit� of low-densit� lipoprotein to induce intracellular cholesterolaccumulation was decreased b� 38%, compared withbaseline values . Decreases in the susceptibilit� of low-densit� lipoprotein to o�idation and in low-densit�lipoprotein-stimulated cell proliferation (an indicatorof low-densit� lipoprotein atherogenicit�) were alsodocumented .

The effects of standardised garlic powder tablets(Sapec; alliin 1 .3%, allicin 0.6%) 900 mg dail� fortwo months on o�idative stress status were e�ploredin an open, uncontrolled stud� involving 25 health�volunteers."" ) At the end of the stud�, a reductionin serum malondialdeh�de concentrations wasobserved, compared with baseline values . It wasstated that this finding indicates that standardisedgarlic powder ma� have antio�idant activit� inhumans.

Antih�pertensive effects A meta-anal�sis of rando-mised controlled trials of garlic preparations assessedthe evidence for the effects of garlic on blood pres-

234

Garlic

sure." 18) Eight trials involving 415 participants wereincluded in the review, all of which had tested theeffects of an allicin-standardised garlic powder pre-paration (Kwai tablets) at doses of 600-900 mg dailyfor 4-52 weeks . Overall, the absolute change in meansystolic blood pressure was 7 .7 mmHg greater for thegarlic group, compared with the placebo group (95%Cl 4 .3-11 .0). However, only three trials specificallyinvolved subjects with hypertension and, as reportedby other meta-analyses of trials of garlic prepara-tions, several trials had methodological limitations .Thus, it was stated that there was insufficient evi-dence to recommend garlic treatment for routinemanagement of hypertension .

Another overview of trials reported that the effectsof garlic treatment on blood pressure are 'insignif-icant' . (110)

Anticancer effects The protective effects of garlicconsumption against various different cancers(including colon, stomach, larynx, breast and endo-metrial) have been explored in several epidemiolo-gical studies, and their findings have beensummarised. (3 °119) Most, but not all, of these studiessuggest that garlic consumption may have a protec-tive effect, particularly against cancers of the gastro-intestinal tract . (3,119) However, the findings shouldbe interpreted cautiously, as bias and/or confound-ing cannot be excluded, and there are other metho-dological issues, for example, most studies did notdistinguish between consumption of raw or cookedgarlic .

Antimicrobial effects An epidemiological study com-prising a dietary interview and measurement of serumH. pylori antibodies was conducted among 214adults in a low-risk area of Shandong Province inChina . (120) The findings suggested a protective effectof garlic consumption against H . pylori infection .

An open, uncontrolled study involving 34 patientswith tinea pedis explored the effectiveness of ajoenecream (0 .4% w/w) .(121) After seven days' treatment,complete cure of the infection was recorded for 27(79%) participants . The remaining seven patientsexperienced complete cure after a further sevendays' treatment . All patients were evaluated forrecurrence of infection 90 days after the end oftreatment ; all found to be infection free as deter-mined by negative cultures for the fungus .

Other effects A reduction in blood sugar concentra-tions and an increase in insulin have been observedfollowing allylpropyl disulfide administration to nor-mal volunteers, whereas another study reported thatgarlic exhibits hypoglycaemic actions in diabetic

patients but not in controls . ( ' ) It has also beenreported that garlic can prevent tolbutamide- andadrenaline-induced hyperglycaemia . (-S)

A randomised, placebo-controlled, crossover trialinvolving 100 Swedish participants working in a tick-endemic area found that administration of garlicpowder 1200 mg daily for eight weeks resulted infewer tick bites than did placebo administration . (122)

An open, uncontrolled study involving 15 patientswith hepatopulmonary syndrome explored the effectsof treatment with capsules containing a standardisedgarlic powder preparation for at least six months .(123)Improvements in arterial oxygenation and symptomswere documented for several participants . The effectsof garlic powder treatment in patients with hepato-pulmonary syndrome require further study .

Side-effects, Toxicity(" 9,G58)

Side-effects Garlic is generally considered to be non-toxic . (8,124) Adverse effects that have been documen-ted in humans include a burning sensation in themouth and gastrointestinal tract, nausea, diarrhoeaand vomiting . (8)

A meta-analysis of 13 randomised, double-blind,placebo-controlled trials of garlic monopreparations,10 of which assessed the effects of a standardisedgarlic powder preparation (Kwai) at doses of 600-900 mg daily for 8-24 weeks (see Clinical studies,Therapeutic effects, Anti-atherosclerotic and choles-terol- and lipid-lowering effects) reported that fewadverse events were documented in the includedtrials . (104) The frequency and nature of adverseevents reported for garlic were similar to those forplacebo. The most common adverse events reportedwere `garlic breath', body odour and gastrointestinalsymptoms .

The allergenic potential of garlic is well recog-nised, and allergens have been identified as diallyldisulfide, allylpropyl sulfide and allicin (the lattermay be an irritant) .(125 ) A garlic antigen in theserum of affected patients has also been identi-fied . (43) Cases of contact dermatitis resulting fromoccupational exposure to garlic have beenreported .(43,126,11 ) A case of garlic allergy asso-ciated with ingestion of raw or cooked garlic hasbeen documented . (127) There is an isolated report ofmultifaceted dermatitis artefacta associated withlocal alication of garlic by a 19-year-old indivi-dual .( 128) Garlic burns following local application ofgarlic have also been documented . (129,1-101

Garlic may enhance existing anticoagulant ther-apy; a potential interaction between garlic and war-farin has been documented . (131,132) Case reports havesuggested that garlic supplementation may increase

the risk of bleeding in patients undergoinggery(G21)sur-

Toxicity Erratic pulse rates, abnormal ECGs, weightloss, lethargy and weakness, soft faeces, dehydrationand tender skin on fore and hindlimbs have beenobserved in spontaneously hypertensive rats adminis-tered garlic extract at 0.25 and 0.5 mUkg every 6hours for 28 days."") The effects were most pro-nounced in animals receiving doses two or three timesa day. Conversely, acute toxicity studies for garlicextract in mice and rats have reported LD 50 valuesfor various routes of administration (by mouth,intraperitoneal injection, intravenous injection) asall greater than 30 mUkg . (124) Early studies, in1944, reported LD50 values for allicin in mice as120 mg/kg (subcutaneous injection) and 60 mg/kg(intravenous injection) . (43) Results of chronic toxi-city studies are stated to be conflicting . (13) High dosesare reported to cause anaemia due to both decreasedhaemoglobin synthesis and haemolysis. (43) A chronictoxicity study in rats given a garlic extract (2 g/kg)five times a week for six months, reported no toxicsymptoms . (134) High doses were found to decreasefood consumption slightly, but did not inhibit weightgain. There were no significant differences in urinary,haematological or serological examinations, and notoxic symptoms in histopathological examinations .Genotoxicity studies using the micronucleus test havereported both positive (135) and negative (1361 findings .No evidence of mutagenicity has been reported whenassessed using the Ames and Ree assay. (135)

Slight cytotoxic signs have been observed at highdoses in Hep2 and Chinese hamster embryo primarycultured cells . (135)

The literature relatin to the toxicity of garlic hasbeen reviewed .{3,G19,c2o~

Contra-indications, WarningsIn view of the pharmacological actions documentedfor garlic, therapeutic doses of garlic may interferewith existing hypoglycaemic and anticoagulanttherapies. There may be an increased risk of bleedingwith use of arlic supplements in patients undergoingsurgery . (G2111 Garlic may potentiate the antithrombo-tic effects of anti-inflammatory drugs such as aspirin,and may be synergistic with eicosapentaenoic acid(EPA) in fish oils . ~ Gastrointestinal irritation mayoccur particularly if the clove is eaten raw by indivi-duals not accustomed to ingesting garlic .

A study involving healthy volunteers detected N-acetyl-S-allyl-L-cysteine (allylmercapturic acid) intheir urine following ingestion of garlic tablets (see

Garlic

235

Clinical studies, Pharmacokinetics) .j 96) As allylmer-capturic acid is used as a biomarker for monitoringhuman exposure to allylhalides and other chemicalsleading to allylmercapturic acid excretion, it wassuggested that garlic consumption may interferewith and confound this monitoring process .

Pregnancy and lactation Garlic is reputed to act asan abortifacient and to affect the menstrual cycle, andis also reported to be utero-active . ~G30~ In vitrouterine contraction has been documented ."' )

Studies have shown that consumption of garlic bylactating women alters the odour of their breast milkand the suckling behaviour of their infants . (97)Further evidence for this comes from a blinded,placebo-controlled study involving 30 nursingwomen.(137) The results indicated that infants whohad no prior exposure to garlic odour in theirmothers' milk spent more time breast feeding aftertheir mothers ingested garlic capsules than did infantswhose mothers had repeatedly consumed garlic .Findings from a placebo-controlled study involving10 healthy pregnant women undergoing routineamniocentesis indicate that the odorous componentsof garlic can be found in amniotic fluid followinggarlic consumption . (98) The odour of samples ofamniotic fluid from women who ingested capsulescontaining garlic extract was judged to be `stronger'or more 'garlic-like' than that of samples fromwomen who had ingested placebo capsules . Theeffects of in utero exposure to garlic odour and onthe neonate's behaviour towards exposure to garlic-flavoured human breast milk are not known .

There are no experimental or clinical reports onadverse effects during pregnancy or lactation . (G19) Inview of this, doses of garlic greatly exceedingamounts used in foods should not be taken duringpregnancy and lactation .

Pharmaceutical CommentThere is a vast scientific literature on the chemistry,pharmacology and clinical properties of garlic .Experimental studies have focused mainly on thecardiovascular and anticancer effects of garlic andits constituents, as well as its antimicrobial proper-ties. Clinical studies have investigated mainly theanti-atherosclerotic and cholesterol- and lipid-low-ering effects of garlic preparations . Generally, thesestudies report beneficial results for garlic, althoughthe evidence at present is insufficient to recommendgarlic as routine treatment for hypercholesterolae-mia . In vitro and animal studies provide supportingevidence for some of the clinical properties of garlicand its constituents .

236

Garlic

Garlic is characterised by its sulfur-containingconstituents. Pharmacological activities documentedfor garlic are also associated with these compounds .It is recognised that allicin, the unstable compoundformed by enzymatic action of allinase on alliin whenthe garlic clove is crushed, is required for the anti-microbial activity that has been demonstrated bygarlic. However, serum concentrations of allicinachieved in humans following oral ingestion ofgarlic are unclear. The hypolipidaemic and antith-rombotic actions documented for garlic have beenattributed to many of the degradation products ofalliin .

One of the difficulties in comparing studies thathave investigated the efficacy of garlic, is establishingthe concentration of active principles present in thegarlic preparations used . It has been reported that thepercentage of active constituents in fresh garlic mayvary by a factor of 10 .43) Many commercial garlicpreparations are standardised on content of sulfur-containing constituents, particularly to alliin, or onallicin yield . Dried garlic powder contains both alliinand allinase and therefore has an allicin-releasingpotential . Garlic preparations produced by heat orsolvent extraction processes are stated to containalliin but to be devoid of allinase and thereforehave no allicin releasing potential . 143) Garlic oilmacerates and steam distillation products are richin secondary alliin metabolites, such as ajoene. How-ever, it is unclear to what extent these secondarycompounds are formed in the body following theingestion of garlic and whether, therefore, theseproducts exhibit the pharmacological actions offresh garlic. (43)

Fermented garlic preparations are considered tobe practically devoid of the active sulfur-containingcompounds.(43) Many `odourless' garlic preparationsare available : obviously one should establish if theseproducts are odourless due to the formulation of theproduct or because they are devoid of the odorifer-ous, active principles. Further randomised controlledclinical trials with standardised preparations arerequired to establish the true usefulness of garlic inreducing serum lipids, blood pressure, platelet aggre-gation and exerting an antimicrobial effect . Thera-peutic doses of garlic should not be given to thosewhose blood clots slowly and caution is recom-mended for patients on anticoagulant therapy .(G58)

References

See also General References G3, G5, G6, G9, G16,G18, G19, G20, G21, G28, G31, G32, G36, G41,G43, G50, G51, G52, G56, G58, G61, G63 and G64 .

1 Block E. The chemistry of garlic and onions . Sci

Am 1985; 252: 114-119.2 Sendl A . Allium sativum and Allium ursinum : Part

1 . Chemistry, analysis, history, botany . Phyto-medicine 1995; 4: 323-339 .

3 Koch HP, Lawson LD, eds . Garlic. The Science andTherapeutic Application of Allium sativum L. andRelated Species, 2nd edn. Baltimore, Maryland :Williams and Wilkins, 1996 .

4 Al-Nagdy SA et al. Evidence for some prostaglan-dins in Allium sativum extracts . Phytother Res1988: 2: 196-197 .

5 Ernst E. Cardiovascular effects of garlic (Alliumsativuin) : a review. Pharmatherapeutica 1987; 5 :83-89.

6 Lau BHS et al. Allium sativum (garlic) andatherosclerosis : a review. Nutr Res 1983; 3: 119-128.

7 Adetumbi M, Lau BHS . Allium sativum (garlic) - anatural antibiotic. Med Hypoth 1983; 12: 227-237.

8 Fulder S. Garlic and the prevention of cardiovas-cular disease . Cardiol Pract 1989; 7: 30-35 .

9 Pizzorno JE, Murray MT. A Textbook o f NaturalMedicine . Seattle, WA : John Bastyr College Pub-lications, 1985 (looseleaf) .

10 Hamon NW. Garlic and the genus Allium. CanPharm j 1987; 120: 493-498 .

11 Fenwick GR, Hanley AB. The genus Allium. CRCCrit Rev Food Sci Nutr 1985; 22: 199-376 and 23 :1-73.

12 McEInay JC, Li Wan Po A . Garlic . Pharm j 1991 ;246: 324-326 .

13 Reuter HD . Allium sativum and Allium ursinum :Part 2. Pharmacology and medicinal application .Phytomedicine 1995; 2: 73-91 .

14 Milner JA, Garlic: its anticarcinogenic and anti-tumorigenic properties . Nutr Rev 1996; 54: S82-S86.

15 Lea MA. Organosulfur compounds and cancer . In :American Institute for Cancer Research . DietaryPhytochemicals in Cancer Prevention and Treat-ment. New York: Plenum Press, 1996 .

16 Ali M et al. Garlic and onions: their effect oneicosanoid metabolism and its clinical relevance .Prostaglandins Leukot Essent Fatty Acids 2000 :62 : 55-73 .

17 Yang CS et al. Mechanisms of inhibition ofchemical toxicity and carcinogenesis by diallylsulfide (DAS) and related compounds from garlic . JNutr 2001 ; 131(Suppl .3): S1041-S1045.

18 Borek C. Antioxidant health effects of aged garlicextract . J Nutr 2001; 131(Suppl .3): S1010-51015 .

19 Yeh Y-Y, Liu L. Cholesterol-lowering effect ofgarlic extracts and organosulfur compounds :human and animal studies . J Nutr 2001 :

131(Suppl.3): S989-S993 .20 Le Bon A-M, Siess M-H . Organosulfur compounds

from Allium and the chemoprevention of cancer .Drug Metab Drug Interact 2001 ; 17: 51-79 .Afzal M et al. Garlic and itw medicinal potential .Inflammopharmacology 2000 ; 8: 123-148 .Lachmann G et al . Unterwuchungen zur Pharma-kokinetik der mit 35S markierten Knoblauchin-haltwwtoffe Aiiiin, Allicin and Vinyldithiine .Arzneimittelforwchung 1994; 44: 734-743 .

23 Nagae S et al. Pharmacokineticw of the garliccompound S-allylcywteine . Planta Med 1994; 60 :214-217.

24 Qurewhi AA et al. Inhibition of cholewterol andfatty acid biowynthewiw in liver enzymew and chickenhepatocytew by polar fractionw of garlic . Lipidw1983; 18: 343-348 .

25 Gebhardt R. Multiple inhibitory effectw of garlicextractw on cholewterol biowynthewiw in hepatocytew .Lipdw 1993; 28: 613-619.

26 Gebhardt R et al. Inhibition of cholewterol bio-wyntheiw by allicin and ajoene in rat hepatocytewand Hep G2 cellw . Biochim Biophyw Acta 1994 ;1213: 57-62 .

27 Gebhardt R. Amplification of palmitate-inducedinhibition of cholewterol biowynthewiw in culturedrat hepatocytew by garlic-derived organowulfurcompoundw . Phytomedicine 1995; 2: 29-34 .

28 Gebhardt R, Beck H . Differential inhibitory effectwof garlic-derived organowulfur compoundw oncholewterol biowynthewiw in primary rat hepatocytew .Lipidw 1996; 31: 1269-1276 .

29 Yeh Y-Y, Yeh S-M. Garlic reducew plawma lipidw byinhibiting hepatic cholewterol and triacylglycerolwynthewiw . Lipidw 1994; 29: 189-193 .

30 Liu L, Yeh Y-Y . Water-woluble organowulfurcompoundw of garlic inhibit fatty acid and trigly-ceride wynthewiw in cultured rat hepatocytew . Lipidw2001 ; 36: 395-400 .

31 Adoga GI. The mechaniwm of the hypolipidemiceffect of garlic oil extract in ratw fed on highwucrowe and alcohol dietw. Biochem Biophyw RewCommun 1987; 142: 1046-1052 .

32 Gupta N, Porter TD. Garlic and garlic-derivedcompoundw inhibit human wqualene monooxygen-awe . J Nutr 2001 ; 131 : 1662-1667 .

33 Kamanna VS, Chandrawekhara N . Effect of garlic(Allium wativum Linn.) on werum lipoproteinw andlipoprotein cholewterol levelw in Albino ratw ren-dered hypercholewterolemic by feeding cholewterol .Lipidw 1982; 17: 483-488 .

34 Campbell JH et al. Molecular bawiw by which garlicwuppewwew atherowclerowiw . J Nutr 2001 ;131(Suppl .3): S1006-51009.

35 Abramowitz D . Allicin-induced decreawe in forma-tion of fatty wtreakw (atherowclerowiw) in mice fed acholewterol-rich diet. Coronary Artery Diw 1999 ;10: 515-519 .

36 Boullin DJ. Garlic aw a platelet inhibitor . Laticet

21

22

Garlic

237

1981;i:776-777.37 Gaffen JD et a! . The effect of garlic extractw on

contractionw of rat gawtric funduw and humanplatelet aggregation . J Pharm Pharmacol 1984 ;36:272-274 .

38 Srivawtava KC, Winwloww JB. Evidence for themechaniwm by which garlic inhibitw platelet aggre-gation . Prowtaglandinw Leukot Med 1986; 22: 313-321 .

39 Apitz-Cawtro A et al . Effectw of garlic extract and ofthree pure componentw iwolated from it on humanplatelet aggregation, arachidonate metaboliwm,releawe reaction and platelet ultrawtructure .Thromb Rew 1983; 32: 155-169 .

40 Wagner H et al . Effectw of garlic conwtituentw onarachidonate metaboliwm . Planta Med 1987; 53 :305-306 .

41 Sharma CP, Nirmala NV . Effectw of garlic extractand of three pure componentw iwolated from it onhuman platelet aggregation, arachidonate metabo-liwm, releawe reaction and platelet ultrawtructure -commentw . Thromb Rew 1985; 37: 489-490 .

42 Mohammad SF, Woodward SC. Characterizationof a potent inhibitor of platelet aggregation andreleawe reaction iwolated from Allium wativum(garlic) . Thromb Rew 1986; 44: 793-806 .

43 Sympowium on the chemiwtry, pharmacology andmedicinal applicationw of garlic . Cardiol Pract1989; 7: 1-15 .

44 Srivawtava KC, Tyagi OD . Effectw of a garlic-derived principle (aioene) on aggregation andarachidonic acid metaboliwm in human bloodplateletw . Prowtaglandinw Leukot Ewwent Fatty Acidw1993; 49: 587-S95.

45 Jamaluddin MP et a!. Ajoene inhibition of plateleraggregation: powwible mediation by a hemoprotein .Biochem Biophyw Rew Commun 1988; 153 : 479-486 .

46 Block E et al. Antithrombotic organowulfur com-poundw from garlic: wtructural, mechaniwtic, andwynthetic wtudiew . J Am Chem Soc 1986; 108 :7045-70SS.

47 Rendu F et al . Ajoene, the antiplatelet compoundderived from garlic, wpecifically inhibitw plateletreleawe reaction by affecting the plawma membraneinternal microviwcowity . Biochem Pharmacol 1989 ;38:1321-1328 .

48 Apitz-Cawtro R et al . Ajoene. The antiplateletprinciple of garlic, wynergiwtically potentiatew theantiaggregatory action of prowtacyclin, forwkolin,indomethacin and dypiridamole on human plate-letw . Thromb Rew 1986; 42: 303-311 .

49 Siegerw C-P et al. Effectw of garlic preparationw onwuperoxide production by phorbol ewter activatedgranulocytew . Phytomedicine 1999; 6: 13-16 .

50 Ide N, Lau BHS . Garlic compoundw protectvawcular endothelial cellw from oxidiwed low

238

Garlic

density lipoprotein-induced injury .] Pharm Phar-niacol 1997; 49: 908-911 .

51 ide N, Lau BHS . Aged garlic extract attentuatesintracellular oxidative stress . Phytomedicine 1999;6: 125-131 .

52 Rashid A, Khan HH. The mechanism of hypoten-sive effect of garlic extract . J Pak Med Ass 1974;35: 357-362 .

53 Jacob j et a!. Antihypertensive and Kardioprotek-tive Effekte von Knoblaucherpulver (Allium sati-vum). Med Welt 1991; 42: 39-41 .

54 Kiviranta j et al. Effects of onion and garlicextracts on spontaneously hypertensive rats . Phyt-other Res 1989; 3 : 132-135 .

55 Kyo E et al . Immunomodulation and antitumouractivities of aged garlic extract . Phytomedicine1998; 5 : 259-267 .

56 Schaffer EM et al. Garlic and associated allyl sulfurcomponents inhibit N-methyl-N-nitrosoureainduced rat mammary carcinogenesis . Cancer Lett1996;102:199-204 .

57 Balasenthil S et al. Prevention of 4-nitroquinoline-1-oxide-induced rat tongue carcinogenesis bygarlic. Fitoterapia 2001; 72: 524-531 .

58 Sparnins VL et al. Effects of organosulfur com-pounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferaseactivity in the mouse . Carcinogenesis 1988; 9:131-134 .

59 Siegers C-P et al. The effects of garlic preparationsagainst human tumor cell proliferation . Phyto-medicine 1999; 6: 7-11 .

60 Nakagawa H et al. Growth inhibitory effects ofdiallyl disulphide on human breast cancer celllines . Carcinogenesis 2001; 22: 891-897 .

61 Liu JZ et al . Inhibition of 7,12-dimethylbenz(a)an-thracene induced mammary tumours and DNAadducts by garlic powder . Carcinogenesis 1992;13 : 1847-1851 .

62 Lin X-Y et al. Dietary garlic suppresses DNAadducts caused by N-nitroso compounds . Carci-nogenesis 1994; 15: 349-352.

63 Fujita K-I, Kamataki T: Screening of organosulfurcompounds as inhibitors of human CYP2A6 . DrugMetab Disposition 2001; 29: 983-989 .

64 Guyonnet D et al . Antimutagenic activity oforganosulfur compounds from Allium is associatedwith phase II enzyme induction . Mutat ResGenet Toxicol Environ Mutagen 2001; 495: 135-145.

65 Moon D-G et al. Allium sativum potentiatessuicide gene therapy for murine transitional cellcarcinoma . Nutr Cancer 2000; 38: 98-105 .

66 Hirao Y et al. Activation of immunoresponder cellsby the protein fraction from aged garlic extract .Phytother Res 1987; 1 : 161-164 .

67 Lamm DL, Riggs DR . Enhanced immunocompe-

tence by garlic : role in bladder cancer and othermalignancies . J Nutr 2001; 131(Suppl.3): S1067-S1070.

68 Burger RA et al . Enhancement of in vitro humanimmune function by-Allium sativum L . (garlic)fractions . Int J Pharmacog 1993; 31 : 169-174 .

69 Kyo E et al. Immunomodulatory effects of agedgarlic extract . J Nutr 2001; 131(Suppl .3): S1075-S1079.

70 Ahsan M, Islam SN . Garlic: a broad spectrumantibacterial agent effective against commonpathogenic bacteria . Fitoterapia 1996; 67: 374-376.

71 Tsao S-M, Yin M-C. In vitro activity of garlic oiland four diallyl sulphides against antibiotic-resis-tant Pseudomonas aeruginosa and Klebsiella pneu-moniae. J Antimicrob Chemother 2001; 47: 665-670.

72 Tsao S-M, Yin M-C. In vitro antimicrobial activityof four diallyl sulphides occurring naturally ingarlic and Chinese leek oils . J Med Microbiol 2001;50:646-649 .

73 Delaha ED, Garagusi VF. Inhibition of mycobac-teria by garlic extract (Allium sativum). Antimi-crob Agents Chemother 1985; 27: 485-486 .

74 Deshpande RG et al. Inhibition of Mycobacteriumavium complex isolates from AIDS patients bygarlic (Allium sativum). J Antimicrob Chemother1993; 32: 623-626 .

75 Cellini L et al. Inhibition of Helicobacter pylori bygarlic extract (Allium sativum). FEMS ImmunolMed Microbiol 1996; 13: 273-277 .

76 Chung JG et al. Effects of garlic compounds diallylsulfide and diallyl disulfide on arylamine N-acetyltransferase activity in strains of Helicobacterpylori from peptic ulcer patients . Am J Chin Med1998; 26: 353-364 .

77 Feldberg RS et al. In vitro mechanism of inhibitionof bacterial cell growth by allicin . AntimicrobAgents Chemother 1988; 32: 1763-1768 .

78 Adetumbi M et a!. Allium sativum (garlic) inhibitslipid synthesis by Candida albicans. AntimicrobAgents Chemother 1986; 30: 499-501 .

79 Graham HD, Graham EJF . Inhibition of Aspergil-lus parasiticus growth and toxin production bygarlic . J Food Safety 1987; 8: 101-108 .

80 Ankri S et al. Allicin from garlic strongly inhibitscysteine proteinases and cytopathic effects ofEntamoeba histolytica . Antimicrob AgentsChemother 1997; 41 : 2286-2288 .

81 Harris JC et al. The microaerophilic flagellateGiardia intestinalis : Allium sativum (garlic) is aneffective antigiardial . Microbiology 2000; 146 :3119-3127.

82 Hughes BG et al. Antiviral constituents fromAllium sativum. Planta Med 1989; 55: 114 .

83 Tsai Y et al. Antiviral properties of garlic : In vitro

effects on influenza B, Herpes simplex andCoxsackie viruses . Planta Med 1985; 51 : 460-461 .Joshi DJ et al. Gastrointestinal actions of garlic oil .Phytother Res 1987; 1 : 140-141 .Hikino H et al. Antihepatotoxic actions of Alliumsativum bulbs . Planta Med 1986; 52: 163-168 .

86 Nakagawa S et al. Prevention of liver damage byaged garlic extract and its components in mice .Phytother Res 1989; 3: 50-53 .

87 Sheen L-Y et al. Effect of diallyl sulfide and diallvldisulfide, the active principles of garlic, on theaflatoxin Bt-induced DNA damage in primary rathepatocytes . Toxicol Lett 2001 ; 122 : 45-52 .

88 Saxena KK et al . Effect of garlic pretreatment onisoprenaline-induced myocardial necrosis in albinorats . Indian J Physiol Pharmacol 1980; 24: 233-236 .

89 Senapati SK et al. Effect of garlic (Allium sativumL.) extract on tissue lead level in rats . J Ethno-pharmacol 2001 ; 76: 229-232 .

90 Horie T et al. Alleviation by garlic of antitumordrug-induced damage to the intestine . J Nutr 2001 ;131(Suppl .3): S1071-S1074 .

91 Nishiyama N et al. Ameliorative effect of S-allylcysteine, a major thioallyl constituent in agedgarlic extract, on learning deficits in senescence-accelerated mice . J Nutr 2001 ; 131(Suppl.3) :51093-S1095 .

92 Brahmachari HD, Augusti KT. Orally effectivehypoglycaemic agents from plants . J Pharm Phar-macol 1962; 14: 254-255 .

93 Dirsch VM, Voilmar AM . Ajoene, a naturalproduct with non-steroidal anti-inflammatory drug(NSAID)-like properties? . Biochem Pharmacol2001; 61: 587-593 .

94 Koch HP. Metabolismus and pharmakokinetik derInhaltsstoffe des Knoblauchs : was Wissen wirdarUber? . Z Phytother 1992; 13: 83-90 .

95 Jandke J, Spiteller G . Unusual conjugates inbiological profiles originating from consumptionof onions and garlic . J Chromatog 1987; 421 : 1-8 .

96 De Rooij BM et al. Urinary excretion of N-acetyl-S-allyl-L-cysteine upon garlic consumption byhuman volunteers. Arch Toxicol 1996; 70: 635-639 .

97 Mennella JA, Beauchamp GK . Maternal diet altersthe sensory qualities of human milk and thenursling's behavior. Pediatrics 1991 ; 88: 737-744 .

98 Mennella JA et al Garlic ingestion by pregnantwomen alters the odor of amniotic fluid . ChemSenses 1995; 20: 207-209 .

99 Bordia A et a! . Effect of garlic (Allium sativum) onblood lipids, blood sugar, fibrinogen and fibrino-lytic activity in patients with coronary arterydisease . Prostaglandins Leukot Essent Fatty Acids1998; 58: 257-263 .

100 Steiner M, Lin RS . Changes in platelet function

84

85

Garlic

239

and susceptibility of lipoproteins to oxidationassociated wirh administration of aged garlicextract. J Cardiovasc Pharmacol 1998; 31 : 904-908 .

101 Warrshafsky S et al. Effect of garlic on totalserum cholesterol . A meta-analysis . Ann InternMed 1993; 119: 599-605 .

102 Silagy C, Neil A . Garlic as a lipid lowering agent- a meta-analysis. j R Coll Phys Lond 1994; 28 :2-8 .

103 Neil HAW et al . Garlic powder in the treatmentof moderate hyperlipidaemia: a controlled trialand meta-analysis . J R Coll Phys Lond 1996; 30 :329-334 .

104 Stevinson C et al . Garlic for treating hypercho-lesterolaemia . A meta-analysis of randomizedclinical trials . Ann Intern Med 2000; 133 : 420-429 .

105 Berthold HK et al. Effect of a garlic oil prepara-tion on serum lipoproteins and cholesterolmetabolism . A randomized controlled trial .JAMA 1998; 279: 1900-1902 .

106 Issacsohn JL et al. Garlic powder and plasmalipids and lipoproteins. A multicenter, rando-mized, placebo-controlled trial . Arch Intern Med1998; 158: 1189-1194 .

107 Adler AJ, Holub BJ . Effect of garlic and fish-oilsupplementation on serum lipid and lipoproteinconcentrations in hypercholesterolaemic men .Am J Clin Nutr 1997; 65: 445-450 .

108 Gardner CD et a! . The effect of a garlicpreparation on plasma lipid levels in moderatelyhypercholesterolaemic adults . Atherosclerosis2001 ;154:213-220 .

109 Lawson LD. Effect of garlic on serum lipids .JAMA 1998; 280: 1568 .

110 Ackermann RT et a!. Garlic shows promise forimproving some cardiovascular risk factors . ArchIntern Med 2001; 161 : 813-824 .

111 Koscielny j et al. The anti-atherosclerotic effect ofAllitim sativum . Atherosclerosis 1999; 144: 237-249 .

112 Jepson RG et a! Garlic for peripheral arterialocclusive disease (Cochrane review). In : TheCochrane Library, Issue 3, 2001 . Oxford : UpdateSoftware .

113 Breithaupt-Grogler K et al . Protective effect ofchronic garlic intake on elastic properties of aortain the elderly. Circulation 1997; 96: 2649-2655 .

114 All M, Thomson M . Consumption of a garlicclove a day could be beneficial in preventingthrombosis . Prostaglandins Leitkot Essent FattyAcids 1995; 53 : 211-212 .

115 Byrne DJ et al. A pilot study of garlic consump-tion shows no significant effect on markers ofoxidation or sub-fraction composition of low-density lipoprotein including lipoprotein(a) after

240

Garlic

allowance for non-compliance and the placeboeffect. Clin Chim Acta 1999; 285: 21-33 .

116 Orekhov AN et al. Garlic powder tablets reduceatherogenicity of low density lipoprotein . Aplacebo-controlled double-blind study . NutrMetab Cardiovasc Dis 1996; 6 : 21-31 .

117 Grune T et al. Influence of Allium sativum onoxidative stress status - a clinical investigation .Phytomedicine 1996; 2: 205-207.

118 Silagy CA, Neil HAW. A meta-analysis of theeffect of garlic on blood pressure . J Hypertens1994; 12: 463-468 .

119 Ernst E. Can Allium vegetables prevent cancer? .Phytomedicine 1997; 4: 79-83 .

120 You W-C et a!. Helicobacter pylori infection,garlic intake and precancerous lesions in aChinese population at low risk of gastric cancer.Int J Epidemiol 1998; 27: 941-944 .

121 Ledezma E et al . Efficacy of ajoene, an organo-sulphur compound from garlic, in the short-termtherapy of tinea pedis. Mycoses 1996; 39: 393-395.

122 Stjernberg L, Berglund J. Garlic as an insectrepellant. JAMA 2000; 284: 831 .

123 Abrams GA, Fallon MB. Treatment of hepato-pulmonary syndrome with Allium sativum L .(Garlic) : a pilot trial . J Clin Gastroenterol 1998 ;27:232-235 .

124 Nakagawa S et al. Acute toxicity test of garlicextract . J Toxicol Sci 1984; 9: 57-60 .

125 Papageorgiou C et al. Allergic contact dermatitisto garlic (Allium sativum L.) Identification of theallergens: The role of mono-, di-, and trisulfides

present in garlic . Arch Derinatol Res 1983; 275 :229-234.

126 Laurier R, Wendt V . Contact allergy to Alliaceae/case-report and literature survey . Dermatosen1985; 33 : 213-215 .

127 Asero R et a! . A case of garlic allergy . J AllergyClin Immunol 1998; 101: 427-428 .

128 Hallel-Halevy D et al. Multifaceted dermatitiscaused by garlic . J Eur Acad Dermatol Venereol1997; 9: 185-187 .

129 Farrell AM, Staughton RCD. Garlic burnsmimicking herpes zoster . Lancet 1996; 347:1195.

130 Rafaat M, Leung AKC. Garlic burns . PediatrDertnatol 2000; 17: 475-476 .

131 Sunter W. Warfarin and garlic . Pharm j 1991;246: 722 .

132 Stockley IH . Drug Interactions, 5th edn. London :Pharmaceutical Press, 1999 .

133 Ruffin J, Hunter SA . An evaluation of the sideeffects of garlic as an antihypertensive agent.Cytobios 1983; 37: 85-89.

134 Sumiyoshi H et al. Chronic toxicity test of garlicextract in rats . J Toxicol Sci 1984; 9: 61-75 .

135 Yoshida S et al. Mutagenicity and cytotoxicitytests of garlic . J Toxicol Sci 1984; 9: 77-86.

136 Abraham SK, Kesavan PC. Genotoxicity of garlic,turmeric and asafoetida in mice . Mutat Res 1984;136: 85-88 .

137 Mennella JA, Beauchamp GK . The effects ofrepeated exposure to garlic-flavoured milk on thenursling's behavior. Pediatr Res 1993; 34: 805-808 .