Allii sativi bulbusGarlic

MonographsThe Scientific Foundation for Herbal Medicinal Products

2019

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The Scientific Foundation for Herbal Medicinal Products

ALLII SATIVI BULBUSGarlic

2019

ESCOP Monographs were first published in loose-leaf form progressively from 1996 to 1999 as Fascicules 1-6, each of 10 monographs

© ESCOP 1996, 1997, 1999

Second Edition, completely revised and expanded© ESCOP 2003

Second Edition, Supplement 2009© ESCOP 2009

ONLINE SERIESISBN 978-1-901964-69-1

Allii sativi bulbus - Garlic

© ESCOP 2019

Published by the European Scientific Cooperative on Phytotherapy (ESCOP)Notaries House, Chapel Street, Exeter EX1 1EZ, United Kingdom

www.escop.com

All rights reservedExcept for the purposes of private study, research, criticism or review no part of this text

may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, without the written permission of the publisher.

Important Note: Medical knowledge is ever-changing. As new research and clinical experience broaden our knowledge, changes in treatment may be required. In their efforts to provide information on the efficacy and safety of herbal drugs and herbal preparations, presented as a substantial overview together with summaries of relevant data, the authors of the material herein have consulted comprehensive sources believed to be reliable. However, in view of the possibility of human error by the authors or publisher of the work herein, or changes in medical knowledge, neither the authors nor the publisher, nor any other party involved in the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for results obtained by the use of such information. Readers are advised to check the product information included in the package of each medicinal preparation they intend to use, to be certain that the information contained in this publication is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.

Edited by Roberta Hutchins and Simon MillsCover photographs by Bernat Vanaclocha (Allium sativum) and Martin Willoughby

Cover and text design by Martin WilloughbyTypeset in Optima by Roberta Hutchins

Plant illustrated on the cover: Allium sativum

FOREWORD

On behalf of my colleagues in ESCOP it is my great pleasure here to mark the successful online programme for the publication of ESCOP Monographs. Interest in herbal medicinal products and their ingredients continues to stimulate research and the body of knowledge in this field is steadily growing. ESCOP takes full account of this in producing balanced compilations of new evidence, in the form of new ESCOP monographs and by regular revisions of previously published monographs. Our online publication, since 2011, ensures that readers and authorities are updated as rapidly as possible, and builds further on ESCOP’s endeavours in the harmonization of European standards for herbal medicinal products.

The Board of ESCOP wishes to express its sincere gratitude to all members of the Scientific Committee, to external experts and to supervising editors. All have contributed their time and scientific expertise voluntarily to ensure the high standard of the monographs.

Dr. Tankred WegenerChair of the Board of ESCOP

PREFACE

ESCOP published its first monographs in the 1990’s, initially as loose-leaf documents, then as two hardback books in 2003 and 2009. ESCOP Monographs have achieved a reputation for well-researched, comprehensive yet concise summaries of available scientific data pertaining to the efficacy and safety of herbal medicinal products.

The monograph format closely resembles the Summary of Product Characteristics (SPC) template, which is the basis for the information required for authorized/registered medicinal products, e.g. in the package leaflet, as laid down in Directive 2001/83/EC of the European Union.

Detailed work in studying the relevant scientific literature and compiling draft monographs relies on the knowledge, skills and dedication of individual project leaders and their colleagues within ESCOP Scientific Committee, as well as invited experts. After discussion and provisional acceptance by the Committee, draft monographs are reviewed by an eminent Board of Supervising Editors and all comments are taken into account before final editing and approval. In this way a wide degree of consensus is achieved.

We trust that rapid online access is helpful and convenient to all users of ESCOP Monographs. As always, ESCOP is indebted to the many contributors involved in the preparation of monographs, as well as to those who provide administrative assistance and hospitality to keep the enterprise running smoothly; our grateful thanks to them all.

NOTES FOR THE READER

From 2011 new and revised ESCOP Monographs are published as an online series only. Earlier monographs are available in two books, ESCOP Monographs Second Edition (2003) and the Second Edition Supplement 2009, but are not available online for copyright reasons.

After purchase of a single monograph, the specific items to be downloaded are:

Front cover Title page Verso Foreword and Preface Notes for the Reader Abbreviations The monograph text Back cover

Information on the member organizations and people involved in the production of ESCOP monographs and other activities can be found on the website (www.escop.com): Members of ESCOP Board of Supervising Editors ESCOP Scientific Committee Board of Directors of ESCOP

ABBREVIATIONS used in ESCOP monographs

AA arachidonic acidABTS 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)ACE angiotensin converting enzymeADP adenosine diphosphateALAT or ALT alanine aminotransferase (= SGPT or GPT)ALP alkaline phosphataseanti-IgE anti-immunoglobulin EASA acetylsalicylic acidASAT or AST aspartate aminotransferase (= SGOT or GOT)ATP adenosine triphosphateAUC area under the concentration-time curveBMI body mass indexBPH benign prostatic hyperplasiab.w. body weightcAMP cyclic adenosine monophosphateCAT catalaseCCl4 carbon tetrachlorideCI confidence intervalCmax maximum concentration of a substance in serumCNS central nervous systemCoA coenzyme ACOX cyclooxygenaseCSF colony stimulating factorCVI chronic venous insufficiencyCYP cytochrome P450d dayDER drug-to-extract ratioDHT dihydrotestosteroneDMSO dimethyl sulfoxideDNA deoxyribonucleic acidDPPH diphenylpicrylhydrazylDSM Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association)ECG electrocardiogramED50 effective dose in 50% of casesEDTA ethylenediamine tetraacetateEEG electroencephalogramEMA European Medicines AgencyENT ear, nose and throatER oestrogen receptorERE oestrogen-responsive elementFSH follicle-stimulating hormoneGABA gamma-aminobutyric acidGal galactoseGFR glomerular filtration rateGGTP gamma-glutamyl transpeptidaseGOT glutamate oxalacetate transaminase (= SGOT)GPT glutamate pyruvate transaminase (= SGPT)GSH glutathione (reduced)GSSG glutathione (oxidised)HAMA Hamilton Anxiety Scale12-HETE 12-hydroxy-5,8,10,14-eicosatetraenoic acidHDL high density lipoproteinHIV human immunodeficiency virusHMPC Committee on Herbal Medicinal Products (of the EMA)HPLC high-performance liquid chromatography 5-HT 5-hydroxytryptamine (= serotonin)IC50 concentration leading to 50% inhibitionICD-10 International Statistical Classification of Diseases and Related Health Problems, Tenth RevisionICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human UseICSD International Classification of Sleep DisordersIFN interferonIL interleukini.m. intramusculariNOS inducible nitric oxide synthaseINR International Normalized Ratio, a measure of blood coagulation (clotting) tendencyi.p. intraperitonealIPSS International Prostate Symptom Score

i.v. intravenouskD kiloDaltonKM Index Kuppermann Menopausal IndexkPa kiloPascalLC-MS liquid chromatography-mass spectrometryLD50 the dose lethal to 50% of animals tested LDH lactate dehydrogenaseLDL low density lipoproteinLH luteinizing hormone5-LOX 5-lipoxygenaseLPS lipopolysaccharideLTB4 leukotriene B4M molar (concentration)MAO monoamine oxidaseMBC minimum bactericidal concentrationMDA malondialdehydeMFC minimum fungicidal concentrationMIC minimum inhibitory concentrationMr molecularMRS Menopause Rating ScaleMRSA methicillin-resistant Staphylococcus aureusMTD maximum tolerated doseMTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideMW molecular weightNBT nitro blue tetrazoliumNF-kB nuclear factor kappa-BNO nitric oxideNOAEL no observed adverse effect levelNOS nitric oxide synthasen.s. not significantNSAID non-steroidal anti-inflammatory drugovx ovariectomy or ovariectomizedORAC oxygen radical absorbance capacityPA pyrrolizidine alkaloidPAF platelet activating factorPARP poly (ADP-ribose) polymerasePBMC peripheral blood mononuclear cellsPCR polymerase chain reactionPEG polyethylene glycolPGE prostaglandin EPgp P-glycoproteinPHA phythaemagglutininp.o. per osPOMS profile of mood statesPVPP polyvinylpolypyrrolidoneRANKL receptor activator of nuclear factor kappa-B ligandRNA ribonucleic acidROS reactive oxygen speciesRT-PCR reverse transcription polymerase chain reactions.c. subcutaneousSCI spinal cord injury SERM selective oestrogen receptor modulatorSGOT or GOT serum glutamate oxalacetate transaminase (= ASAT or AST)SGPT or GPT serum glutamate pyruvate transaminase (= ALAT or ALT)SHBG sex hormone binding globulinSOD superoxide dismutaseSSRI selective serotonin reuptake inhibitorSTAI state-trait anxiety inventoryt1/2 elimination half-lifeTBARS thiobarbituric acid reactive substancesTC total cholesterolTGF-b transforming growth factor-betaTNF tumour necrosis factorTPA 12-O-tetradecanoylphorbol-13-acetateURT upper respiratory tractURTI upper respiratory tract infectionUTI urinary tract infectionVAS visual analogue scaleVLDL very low density lipoprotein

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ALLII SATIVI BULBUS 2019

Garlic

DEFINITION

Garlic powder consists of the bulb of Allium sativum L., with the outer corneous layer removed, cut, freeze-dried or dried at a temperature not exceeding 65°C and powdered. It contains not less than 0.45 per cent of allicin (C6H10OS2; Mr 162.3), calculated with reference to the dried drug.

The material complies with the monograph of the European Pharmacopoeia [Garlic Powder].

CONSTITUENTS

Carefully dried, powdered material contains about 1 per cent of alliin [(+)-S-allyl-L-cysteine sulphoxide] as the main sulphur-containing amino acid. In the presence of the enzyme alliinase, alliin will be converted to allicin (1 mg of alliin is equivalent to 0.45 mg of allicin).

In turn, allicin is the precursor of various transformation products, including ajoenes, vinyldithiines, oligosulphides and polysulphides, depending on the conditions applied.

Material derived from garlic by steam distillation or extraction in an oily medium contains various allicin transformation products.

Other characteristic, genuine constituents are (+)-S-methyl-L-cysteine sulphoxide, gamma-L-glutamyl peptides, S-allyl-cysteine, ubiquitous amino acids, steroids, triterpenoid saponins, flavonoids, lectins and adenosine [Ackermann 2001; Benavides 2007; Blaschek 2016; Block 1985, Block 1992; Bradley 2016; Koch 1996; Lawson 1993; Sticher 1991; Wang 2015; Xiong 2015].

CLINICAL PARTICULARS

Therapeutic indications

Prophylaxis of atherosclerosis [Bordia 1989; Harenberg 1988; Kiesewetter 1991, 1993a,b; Koch 1996; Koscielny 1999; Orekhov 1995, 1996, 1997; Reuter 1991].

Treatment of elevated blood lipid levels insufficiently controlled by diet [Adler 1997; Auer 1990; Brewitt 1991; Beck 1993; De Santos 1993, 1995; Harenberg 1988; Fatima 2014; Kiesewetter 1993b; Jain 1993; Mader 1990; Orekhov 1996; Reinhard 2009; Ried 2013; Rinneberg 1989; Vorberg 1990; Schilcher 2016; Sobenin 2009b; Walper 1994; Zeng 2012].

Supportive treatment of hypertension [Ashraf 2013; Auer 1990; De Santos 1993, 1995; Holzgartner 1992; Kandziora 1988; Kiesewetter 1993b; Ried 2016; Sobenin 2009a; Vorberg 1990; Wang 2015; Xiong 2015].

Upper respiratory tract infections and catarrhal conditions [Allium BHP 1983; Andrianova 2003; Block 1992; Bradley 1992; Josling 2001; Lissiman 2009, 2014; Rafinsky 1974; Tsai 1985].

Posology and method of administration

Dosage

Prophylaxis of atherosclerosis or treatment of elevated blood lipid levelsAdults: The equivalent of 6-10 mg of alliin (approx. 3-5 mg of allicin) daily, typically contained in one clove of garlic or in 0.5-1.0 g of dried garlic powder [Adler 1997; Auer 1990; Beck 1993; Bordia 1989; Brewitt 1991; De Santos 1993, 1995; Fatima 2014; Harenberg 1988; Holzgartner 1992; Jain 1993; Kandziora 1988; Kiesewetter 1991, 1993a,b; Koch 1996; Koscielny 1999; Mader 1990; Orekhov 1995, 1996, 1997; Reuter 1991; Ried 2013; Rinneberg 1989; Schilcher 2016; Sobenin 2009b; Vorberg 1990; Walper 1994; Zeng 2012].

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Supportive treatment of hypertensionAdults: The equivalent of 6-10 mg of alliin (approx. 3-5 mg of allicin) daily, typically contained in one clove of garlic or in 0.5-1.0 g of dried garlic powder [Ashraf 2013; Auer 1990; De Santos 1993, 1995; Holzgartner 1992; Kandziora 1988; Kiesewetter 1993b; Schilcher 2016; Sobenin 2009a; Vorberg 1990].

Upper respiratory tract infectionsAdults: 2-4 g of dried bulb or 2-4 ml of tincture (1:5, 45% ethanol), three times daily or 180 mg garlic powder per day [Allium BHP 1983; Josling 2001].

Method of administrationFor oral administration.

Duration of administrationLong-term treatment is generally advised in the prevention of atherosclerosis and prophylaxis or treatment of peripheral arterial vascular diseases [Kiesewetter 1993b; Koscielny 1999].

Contra-IndicationsNone known.

Special warnings and special precautions for useCaution is advised with regard to surgical operations due to some case reports with prolonged or increased bleeding [Burnham 1995; Carden 2002; German 1995; Izzo 2007; Kilic 2014; Shakeel 2010; Woodbury 2016].

Interaction with other medicaments and other forms of interactionAn increased International Normalized Ratio (INR) has been observed in 2 patients on warfarin and in one patient on fluin-dione who had used garlic products [Sunter 1991; Pathak 2003]. The results of studies with saquinavir and ritonavir in healthy volunteers remain unclear [Piscitelli 2002; Gallicano 2003].

Pregnancy and lactationThere are no objections for use during pregnancy and lactation, because neither long term nutritional experience nor any other important circumstances give reason for concern [Ziaei 2001]. From a controlled trial it is known that major sulphur-containing volatiles from garlic are transmitted to human milk leading to improved drinking habits of the babies [Mennella 1991].

Effects on ability to drive and use machinesNone known.

Undesirable effectsIn rare cases gastro-intestinal irritation or allergic reactions [Izzo 2007; Mane 2013; Schilcher 2016; Siegers 1989; Vovolis 2010].

OverdoseNo toxic effects reported.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic propertiesGarlic exerts antiatherogenic, lipid-lowering, antihypertensive, antiaggregatory, endothelium-relaxing, vasodilatory and antioxidant effects. The effects are primarily due to allicin and its transformation products [Benavides 2007; Bradley 2016; Koch 1996; Ried 2016; Schilcher 2016; Xiong 2015].

In vitro experiments

Antiatherogenic and lipid-lowering effectsInhibitory effects of extracts and isolated fractions from garlic on

cholesterol biosynthesis were observed in chicken hepatocytes and monkey livers. At equivalent doses, both the drug and its lipophilic and hydrophilic fractions caused 50-75% inhibition of cholesterol biosynthesis [Quereshi 1983].

Inhibition of cholesterol biosynthesis by allicin and ajoene was evaluated in cultivated rat hepatocytes and the human liver cell line HepG2. In rat hepatocytes, ajoene inhibited sterol biosynthesis with an IC50 of 15 µM; alliin was almost ineffective. In HepG2 cells both allicin and ajoene inhibited sterol biosynthesis with IC50 values of 7 and 9 µM, respectively. The inhibition was exerted at the level of HMG-CoA-reductase [Gebhardt 1994].

In a study in primary rat hepatocytes, the water-soluble organo-sulphur compounds S-allyl cysteine (SAC), S-ethyl cysteine (SEC) and S-propyl cysteine (SPC) inhibited [2-14C]acetate incorporation into cholesterol in a concentration-dependent manner, achieving 42 to 55% maximal inhibition. Other sulphur compounds were less potent. Alliin, S-allyl-N-acetyl cysteine, S-allylsulphonyl alanine and S-methyl cysteine had no effect. Of the lipid-soluble compounds, diallyl disulphide (DADS), diallyl trisulphide (DATS) and dipropyl disulphide (DPDS) reduced cholesterol synthesis by 10 to 25% at low concentrations (≤ 0.5 mmol/L) and completely inhibited synthesis at high concen-trations (≥1.0 mmol/L) [Liu 2000].

Standardized garlic powder (1.3% alliin) inhibited cholesterol biosynthesis in rat hepatocytes with an IC50 of 90 µg/ml [Gebhardt 1991, 1993]. In HepG2 cells cholesterol biosynthesis was inhibited by the garlic powder with an IC50 of 35 µg/ml [Gebhardt 1993].

The mechanism of action is believed to be an interaction at the molecular level with the phosphorylation cascade of hydroxymethylglutaryl-CoA reductase. Organosulphur compounds containing an allyl disulphide or allyl sulphydryl group are capable of interacting with the thiol group of cysteine and thus forming cysteine derivatives. The antiatherogenic effects of these organosulphur compounds can be attributed to reactions that inhibit HMG-CoA reductase and other lipogenic enzymes [Gebhardt 1994; Mathew 2004; Singh 2006].

A concentration-dependent inhibition of cholesterol synthesis (3H-acetate incorporation in Hep-G2) was exerted by allyl mercaptan, a metabolite of organosulphur compounds. At concentrations between 5 and 100 µg/mL, cholesterol synthesis was inhibited by 20 to 80% in cells (approximately 50% inhibition with 25 µg/mL) and cholesterol secretion into the medium was decreased by 20 to 50% compared with control (p<0.05). In cells incubated with 1 mM of oleic acid, allyl mercaptan decreased cholesterol synthesis compared to control (19.5±1.2 x 103 dots per minute (dpm)/mg protein/4 h vs. 30.0±2.6 x 103 dpm/mg protein/4 h; p<0.05) [Xu 1999].

Allicin inhibits the incorporation of 14C-acetate into non-saponifiable neutral lipids at concentrations as low as 10 µM and can be regarded as the most active of the sulphur-containing metabolic products of alliin [Gebhardt 1991].

Inhibition of cholesterol biosynthesis by up to 87% was also observed with petroleum ether, methanol and water extracts of garlic, and a garlic-preparation containing S-allylcysteine [Yeh 1994].

During a 24-hour incubation period garlic powder significantly reduced the level of cholesteryl esters by 26% and free cholesterol by 32% in cells of atherosclerotic plaques of human aorta (p<0.05) and inhibited their proliferative activity by 55% at 1 mg/ml [Orekhov 1995].

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The antiatherogenic effect of egg-yolk-enriched garlic powder was determined on LDL oxidation and oxidant stress-induced cell injury models. The powder inhibited copper-induced LDL-oxidation in a dose-dependent manner. Pretreatment with the garlic powder significantly suppressed the production of peroxides in HL60 cells and protected endothelial cells from hydrogen peroxide-induced cell injury [Yamaji 2004].

Effects on vascular resistance, fibrinolysis and platelet aggregationIn isolated arterial strips from the dog, garlic at 0.2-200 g powder/litre and ajoene at 10-6 to 10-3 M hyperpolarised membrane potential by 9.3 mV and 4.2 mV, and reduced muscle tone by up to 0.33 g and 0.16 g, respectively [Siegel 1991,1992].

Similarly, in human coronary artery smooth muscle garlic at concentrations of 0.0002-0.2 g/litre caused dose-dependent hyperpolarisation (2.7 mV at maximum) and relaxation (20% at maximum); half-maximal effects were obtained at 1.15 mg/litre. Allicin and ajoene produced hyperpolarisation of up to 5.1 mV and 4.4 mV, and diminished vascular tone by 24% and 11%, respectively, with half-maximal effects at 6.2 × 10-9 M and 9.9 × 10-9 M [Siegel 1998].

In isolated rat aorta freeze-dried garlic powder dose-dependently inhibited noradrenaline-induced contractions. The EC50 values were 5.28 mg/ml in aortas with endothelia and 5.81 mg/ml in aortas without endothelia [Öztürk 1994].

A two-fold activation of endogenous nitric oxide synthesis was observed in isolated thrombocytes obtained from human volunteers after ingestion of a single dose of 4 g of fresh garlic [Das 1995; Sooranna 1996].

Garlic preparations and organosulphur compounds from garlic inhibited collagen-stimulated platelet aggregation in platelet-rich plasma with the following IC50 values (µg/ml): an aqueous garlic extract 460, total polar constituents 190, alliin 205, allicin 14.0, total thiosulphinates 13.2, adenosine 0.11, guanosine > 20. In whole blood the strongest effects were exhibited by allicin (IC50:14.0 µg/ml) and adenosine (IC50: 0.11 µg/ml) [Lawson 1992].

Diallyldisulphide (40-200 µg/mL) and diallyltrisulphide (5-100 µg/mL) dose-dependently inhibited platelet aggregation and thromboxane B2 secretion induced by arachidonic acid, adrenaline, collagen and calcium ionophore A23187 [Bordia 1998].

Antioxidant effectsAllicin inhibited lipid peroxidation induced by an ascorbic acid/Fe2+ system at a concentration of 0.18 mM [Rekka 1994].

The antioxidant effect of an aqueous garlic extract obtained from 1 mg of garlic powder was comparable to that of 30 nmol of ascorbic acid or 3.6 nmol of a-tocopherol in a chemi-luminescence assay [Lewin 1994; Popov 1994]. Radical scavenging activity of preparations containing S-allylcysteine has also been demonstrated in both chemiluminescence and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays [Imai 1994].

Garlic powder strongly inhibited superoxide production in phorbol ester-activated granulocytes with an IC50 of 390 µg/ml, whereas an alliin-enriched but alliinase-inactivated garlic extract did not inhibit superoxide production at concentrations up to 1 g/ml [Siegers 1999].

An aqueous solution of garlic powder (1.3% alliin) reduced radicals generated by the Fenton reaction and liberated by cigarette smoke [Török 1994].

Trichloromethyl and trichloromethylperoxyl free radicals were scavenged by the garlic sulphur components diallyl sulphide, diallyl disulphide and allyl mercaptan. Diallyl disulphide also inhibited CCl4-promoted liver microsomal lipid peroxidation, and diallyl sulphide was able to react with free radicals formed by UVC-activation of hydrogen peroxide or terbutyl hydroperoxide but not with those produced during UVC activation of terbutyl peroxide. However, all garlic components tested absorbed energy from UVC and became partially destroyed in the process. Allyl mercaptan was able to destroy 4-hydroxynonenal, a key reactive aldehyde produced during lipid peroxidation. Allyl mercaptan and diallyl disulphide were also able to prevent UVC and CCl4-promoted oxidation of albumin in vitro [Fanelli 1998].

Allicin reversed the effect of H2O2 on HUVEC death. The activation of PARP-cleavage and Bax expression, and the reduction of pro-caspase-3 levels, were inhibited by allicin [Chen 2014].

Other effectsIn the ischaemia-reperfusion model, garlic juice (0.01 mg/mL added to the perfusion solution) significantly (p<0.05) increased coronary flow before ischaemia in isolated rat heart. Compared to control, the released lactate dehydrogenase at the first minute, the recovery of rate pressure product, and the left ventricular-developed pressure after 45 minutes, were significantly (p<0.05) better in the garlic group [Shackebaei 2010].

An aqueous extract from fresh garlic (100-500 µg/ml) increased the proliferation and improved the morphological characteristics of cultured human fibroblasts (more thin, long and spindle cells instead of large, flat cells) [Svendson 1994].

A similar extract non-competitively and irreversibly inhibited cyclooxygenase activity in rabbit platelets and in lung and vascular aortic tissues with IC50 values of 0.35, 1.10 and 0.9 mg, respectively; boiled garlic had only modest effects [Ali 1995].

Anti-aggregatory [Mayeux 1988; Lawson 1992], antibacterial [Sharma 1977; Adetumbi 1983; Gupta 2010], antimycotic [Lutomski 1991; Li 2014], antiviral [Tsai 1985], neuroprotective [Koh 2005; Ishige 2007], anti-parasitic [Kinuthia 2014], and anti-tumour effects [Wargovich 1991; Dorant 1993; Lan 2013; Bagul 2015] of garlic have also been demonstrated.

In vivo experiments

Lipid-lowering and antiatherogenic effects, hypoglycaemic activityGarlic powder (0.6% allicin) fed to rats for 11 days at 0.25, 0.5 or 1 g/kg b.w. protected against isoprenaline-induced myocardial damage, as shown by histological examination and biochemical analysis [Ciplea 1988].

In the isolated, perfused heart (Langendorff model) from rats which had been given 1% of garlic powder (1.3% alliin) in their diet for 10 weeks, the size of the ischaemic zone (32% vs 41% of total heart tissue; p<0.05), incidence of ventricular tachycardia (0% vs 35%; p<0.05) and incidence of ventricular fibrillation (50% vs 90%; p<0.05) were significantly reduced in comparison with untreated controls [Jacob 1991; Isensee 1993].

A petroleum-ether extract of garlic (corresponding to dried garlic at 1 g/kg b.w.), fed to rats for 5 days in combination with an atherogenic diet, significantly prevented elevation of serum cholesterol and triglyceride levels (92.4 and 93 mg/dl), respectively, compared to 320 and 370 mg/dl in control animals; p<0.001), and reduced the incidence and grade of atherosclerotic lesions (p = 0.0027) compared to animals fed on the atherogenic diet alone [Lata 1991].

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Rabbits were given cholesterol in their diet at 0.5 g/kg b.w. daily for 2 months, then fed for 3 months on a normal diet with or without the addition of fresh garlic at 1 g/kg daily. Compared to rabbits receiving a normal diet over the 3-month period, those given garlic had reduced plaque areas with half as many lesions [Mand 1985].

After de-endothelialisation of the carotid artery, rats were given a diet containing 2% of cholesterol with or without the addition of 5% of garlic powder (1.3% alliin). After 4 weeks, insertion of a balloon catheter revealed only modest inhibition of the growth of neointima in the rats given garlic compared to those given cholesterol alone. However, the garlic inhibited elevation of serum cholesterol by 42% (p<0.05) and protected enzymes of the glutathione system, which were strongly impaired under hypercholesterolaemia [Heinle 1994].

In Wistar rats with induced hypercholesterolaemia, and their 1-day-old offspring, pathological changes to myocardial muscle and atherosclerosis of dorsal aorta were observed, affecting the progress of gestation and development of both morphological and skeletal abnormalities. Oral administration of 100 mg fresh garlic/kg b.w. for three weeks prior to onset of gestation as well as throughout the gestation period led to amelioration of histological heart and vessel abnormalities, serum total cholesterol, triglycerides, LDL and creatine kinase activity of both mother and their offspring. Moreover, as compared to those effects seen in animals with experimental hypercholesterolemia, the supplementation reduced the increased incidence of abortions, reduced the decrease in total number of offspring and reduced the marked depletion of body weight; additionally, congenital abnormalities induced by hypercholesterolaemia were not seen in the verum group [El-Sayyad 2010].

In guinea pigs fed a diet enriched with 2.5 and 5% garlic powder for 21 days, significant decreases were found in serum triglycerides (15 and 29%; p<0.02), total cholesterol (73 and 78%; p<0.001), VLDL (65 and 70%; p<0.001) and LDL (69 and 70%; p<0.001) when compared to control. HDL remained unchanged [Pourkabir 2010].

The effects of a single dose of an ethanolic garlic extract (250, 300 and 350 mg/kg b.w.) were compared to metformin in normal and alloxan-induced diabetic rabbits. In non-diabetic rabbits a maximum hypoglycaemic response was observed with the highest dose of garlic extract (350 mg/kg b.w.) 4 h after administration, while in diabetic rabbits, blood glucose levels (270.3 ± 0.8 mg/dl) were significantly (p<0.05) lowered as compared to control (303.8 ± 1.8 mg/dl). Triglycerides (44.0 ± 0.9 mg/dl) and cholesterol (32.8 ± 0.7 mg/dl) also significantly (p<0.05) decreased in non-diabetic rabbits [Sher 2012].

Administration of garlic juice by gavage to STZ-induced diabetic male Wistar rats (1 ml/100 g b.w. per day), resulted in a significant increase in body weight (p<0.05), together with a decrease in food intake (p<0.0001), and a decrease in glucose-, cholesterol- and TG-levels (p<0.0001) [Masjedi 2010].

In alloxan-induced diabetic rabbits, oral administration of a 1% aqueous garlic extract (300 ml three times per day) for 15 days reduced blood glucose (by 51%), cholesterol (35%) and urea (46%) [Rind 2013].

A study investigated the effects of garlic oil and gliclazide on blood glucose levels in alloxan-induced diabetic rats. Garlic oil (1 ml/kg b.w.) or a vehicle were orally administered to groups of rats for 14 days, this was followed by i.p. administration of alloxan for 2 days to induce diabetes, in all but a control group. On day 17, the diabetic rats were given single oral doses of

either vehicle, gliclazide (2 ml/kg b.w.), garlic oil (1 ml/kg b.w.) or garlic oil and gliclazide. The gliclazide and combination groups demonstrated a significantly (p<0.01) greater mean percentage blood glucose reduction (over a 12 hour period) than the diabetic control group, while the combination had a greater effect than gliclazide alone [Nandyala 2013].

Antihypertensive effectsGarlic powder given for several weeks at 1 g/kg b.w. to spon-taneously hypertensive juvenile rats, starting in their fifth week of life, inhibited the development of hypertension and reduced myocardial hypertrophy. In spontaneously hypertensive adult rats (6-7 month of age), garlic lowered blood pressure and myocardial hypertrophy (p<0.01) [Jacob 1993].

Garlic powder (1.3% alliin) added at 0.5% to the diet of hypertensive rats significantly (p<0.02) prolonged their life span by 22 days (453.2±16.2 days) compared to a control group of of hypertensive rats given the normal diet (434.5±23.5 days). During the course of the study systolic blood pressure was significantly lower in the garlic group (p<0.01) [Brändle 1997].

An aqueous garlic extract administered orally to hypertensive two-kidney-one-clip Goldblatt model rats as a single dose at 50 mg/kg b.w. or in repeated daily doses of 50 mg/kg for 2 weeks exerted a significant antihypertensive effect (p<0.05) [Al-Qattan 1999].

Other cardiovascular effectsThe oral pretreatment of female Wistar albino rats with fresh garlic (125, 250 or 500 mg/kg b.w.) for 30 days, given alone or in combination with 30 mg/kg captopril during the last seven days, showed cardioprotective effects in a modified Langendorff heart model and after isoproterenol-induced myocardial damage [Asdaq 2008a; 2010a]. Given alone, or in combination with 10 mg/kg hydrochlorothiazide, fresh garlic revealed cardioprotective effects against myocardial damage induced by ischaemia-reperfusion and isoproterenol [Asdaq 2009b]. The protective effects on the myocardium after ischaemia-reperfusion injury were also demonstrated histologically and by analysis of heart tissue [Asdaq 2008a]. However, in all studies the highest dose of 500 mg/kg b.w. of fresh garlic did not show cardioprotective effects [Asdaq 2008ab, 2009ab, 2010ab].

In male wistar rats given a high-fat diet for 12 weeks prior to treatment, a garlic extract (1% allicin; 250 or 500 mg/kg b.w. for 28 days) significantly (p<0.05) decreased the diet-induced increases in plasma insulin, total cholesterol and oxidative stress levels, and restored heart rate variability, cardiac function and cardiac mitochondrial function [Supakul 2014].

Clotting time was delayed in rats treated orally for 11 days with an ethanolic garlic extract (10 mg/kg b.w./d), and significantly (p<0.05) delayed with a combination of the garlic extract at the same dose for 10 days and a single oral dose of warfarin (3 mg/kg b.w.) on day 11, when compared to untreated controls and those given a single dose of warfarin alone. Clot retraction was also shown to be poor in rats given the combination treatment [Musubika 2015].

Antioxidant effectsPretreatment of female Wistar albino rats with an oral dose of 250 mg/kg b.w. of fresh garlic for 30 days, either alone or combined with 30 mg/kg captopril or 10 mg/kg propranolol during the last seven days of treatment, led to an increase in activities of antioxidant enzymes such as SOD and catalase (p<0.05), and retained the activities of lactate dehydrogenase and creatine phosphokinase isoenzyme [Asdaq 2008b, 2010a].

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Oral administration of fresh garlic at 125, 250 or 500 mg/kg b.w., given alone for 30 days or in combination with 10 mg/kg b.w. propranolol for the last 7 days of treatment, augmented endogenous antioxidant synthesis at the two lower doses (p<0.05), whereas at the highest dose a reduction in the synthesis of SOD and catalase was observed (p<0.05) [Asdaq 2010a].

In a study in male Albino rats, administration of fresh garlic (250 mg/kg b.w. p.o.) for 20 days significantly (p<0.05) reduced nickel- and chromium-induced increases in the lipid peroxidase (LPO) level and signficantly (p<0.05) improved SOD activity [Das 2009].

Administration of garlic oil (10 mg/kg i.p.; n=10) for 8 weeks was compared with a saline control (i.p.; n=10) in alloxan-induced diabetic rats. The garlic oil retarded lipid peroxidation of cellular membranes induced by oxidative stress associated with diabetes. Compared to the saline control, garlic oil significantly (p<0.05) decreased the levels of LPO in plasma, erythrocyte lysate and liver tissue homogenate, whereas total thiols were significantly (p<0.05) elevated in the plasma and erythrocyte lysate. SOD and GST activity were significantly (p<0.05) elevated in erythrocyte lysate and liver homogenate [Saad Abdultawab 2013].

Garlic oil (5 ml/kg b.w.), administered orally 30 minutes before each daily dose of cyclosporine A (25 mg/kg b.w. p.o.) for 3 weeks, attenuated cyclosporine-induced nephrotoxicity in rats. The significant (p<0.05) increases in renal dysfunction parameters and levels of serum NO and plasma MDA caused by cyclosporine A were significantly (p<0.05) reduced by the co-administration with garlic oil [Abdelsattar 2013].

Garlic has been shown to prevent or reduce biochemical and histological effects of methotrexate (MTX)-induced nephrotoxicity in rats. An aqueous extract (100 g crushed garlic in 100 ml water; squeezed and filtered) administered orally (1 ml/100 g b.w.) for 7 days before and after a single MTX (20 mg/kg b.w.) i.p. injection resulted in decreased urea and creatinine levels, almost normalized change of electrolytes (sodium, potassium, phosphorus, calcium), and increased concentrations of renal antioxidant stress markers such as GSH and catalase as compared to a decrease with MTX alone. Decreased oxidative stress was shown via reduction of malondialdehyde adenosine deaminase and NO levels. MTX-induced alterations in renal morphology (glomerular/tubular) were prevented by garlic [Ahmed 2015].

A study investigated the ameliorative effects of garlic on gentamicin-induced nephrotoxicity in rats. Serum creatinine and blood urea nitrogen levels were significantly increased (p<0.05) by the administration of gentamicin (100 mg/kg bw i.p.) for 10 days. When this was followed by 10 days treatment with garlic juice (20 mg/kg b.w. i.p.), these raised levels of serum creatinine and blood urea nitrogen were significantly (p<0.05) reduced [Nasri 2014].

In a study investigating cisplatin-induced nephrotoxicity in rats, oral administration of an ethanolic garlic extract (150 or 300 mg/kg b.w.) for 4 days, following a single injection of cisplatin (5 mg/kg b.w.), significantly (p<0.001) reduced the cisplatin-induced biochemical changes (increased urea, uric acid, creatinine, blood urea nitrogen) and dose-dependently (p<0.01 to p<0.001) reduced the cisplatin-induced increase in kidney weight [Anusuya 2013].

Other effectsPost-ischaemic neuroprotective effects of allicin were seen in a rat middle cerebral artery occlusion (MCAO) model. Treatment

with allicin (50 mg/kg b.w. i.p.) at 3 and 6 hours, but not 9 hours, after ischaemia induction significantly (p<0.05) reduced brain infarct volume, attenuated cerebral oedema and decreased the neurological deficit score when compared to vehicle only treated rats [Lin 2015].

In other studies, antiviral [Nagai 1973; Sohn 2009], antihepato-toxic [Hikino 1986; Nakagawa 1989], antidiabetic [Thomson 2007; Shariatzadeh 2008; Das 2009; Thomson 2013], anti-inflammatory [Sohn 2009; Sahbaz 2014], anti-parasitic [Khalil 2015; Kinuthia 2014], and tumour growth-inhibiting [Wargovich 1991; Dorant 1993] effects of garlic have also been demonstrated.

Pharmacological studies in humans

Rheological and antiatherosclerotic effects In a randomized, double-blind, placebo-controlled, cross-over study, the influence on cutaneous microcirculation of a single oral dose of 900 mg of garlic powder (1.3% alliin) was evaluated in 10 healthy volunteers. After 5 hours, a significant increase of 55% was observed in erythrocyte velocity in skin capillaries (p<0.01) resulting from vasodilatation of precapillary arterioles, which increased in diameter by 8.6% (p<0.01) [Jung 1991].

In a 2-week, randomized, double-blind, placebo-controlled, cross-over study involving 10 healthy volunteers, daily ingestion of 600 mg of a standardized garlic powder preparation (1.3% alliin) significantly (p<0.05) lowered susceptibility to lipoprotein oxidation by 34% [Phelps 1993].

In an open study involving 101 healthy volunteers (50 – 80 years of age), the effects of 300-900 mg of standardized garlic powder (1.3% alliin) daily on elastic properties of the aorta were investigated for at least 2 years. Compared to the results from an untreated control group, garlic intake attenuated age-related increases in aortic stiffness: significant differences were observed in pulse wave velocity (8.3 vs. 9.8 m/s, p<0.0001) and pressure-standardized elastic vascular resistance (0.63 vs. 0.9 m2/s2 × mm Hg, p<0.0001); correlation with age was significantly different (p<0.0001) for pulse wave velocity (garlic, r = 0.44; control, r = 0.52) and systolic blood pressure (garlic, r = 0.48; control, r = 0.54) [Breithaupt-Grögler 1997].

In an open study 8 healthy volunteers took 1 clove of garlic (about 3 g) daily for 16 weeks. Serum thromboxane B2 was significantly (p<0.001) reduced from 243 to 24 ng/ml [Ali 1995].

Healthy volunteers (n = 30) took 10 g of fresh garlic daily for 2 months. Clotting time increased from 4.15 to 5.02 min (p<0.001) and fibrinolytic activity (euglobulin clot lysis time) decreased from 4.17 to 3.26 hours (p<0.001). There were no changes in the control group [Gadkari 1991].

In a randomized, double-blind, placebo-controlled, cross-over study, the effect of a single dose of a dried ethyl acetate extract of garlic (55 mg pure garlic oil derived from 9.9 g fresh garlic) on ex vivo induced platelet aggregation was investigated in 14 healthy volunteers. In blood collected 4 hours after administration there was a significant (p<0.05) reduction of adrenaline-induced platelet aggregation by 12%, but no effect on platelet aggregation induced by collagen or ADP [Wojcikowski 2007].

Incubation of cultured smooth muscle cells for 24 hours with serum from patients with coronary atherosclerosis increased total cell cholesterol by 46.6%. However, incubation with serum taken from the patients 2 hours after ingestion of 300 mg of standardized garlic powder (1.3% alliin) reduced total cell cholesterol to 19.3% [Orekhov 1995].

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Lipid-lowering effectsIn a randomized, double-blind, placebo-controlled study, significant reductions of up to 30% in fasting and postprandial plasma triglycerides were observed in 24 volunteers after 6 weeks of daily treatment with 900 mg of garlic powder (p<0.05 for intergroup differences in fasting plasma triglycerides) [Rotzsch 1992].

In a randomized, double-blind, placebo-controlled study, the effects of taking 600 mg of standardized garlic powder (1.3% alliin) daily were evaluated in 68 volunteers (initial total cholesterol: verum group 222 mg/dl, placebo group 217 mg/dl). After 15 weeks total cholesterol and triglycerides showed a tendency to decrease in the verum group [Saradeth 1994].

In an open study 8 healthy volunteers (initial total cholesterol, 6.1 mmol/L) took 1 clove of garlic (about 3 g) daily for 16 weeks. Total cholesterol decreased by 21% (p<0.02) [Ali 1995]. In another open study, total cholesterol decreased by 15.5% (p<0.001) in 30 healthy volunteers who took 10 g of garlic daily for 2 months; no change was observed in an untreated control group [Gadkari 1991].

In a 12-week randomized, double-blind, placebo-controlled trial, 62 healthy volunteers received 920 mg garlic per day (corresponding to 10.8 mg alliin) or placebo. No significant differences in serum lipids (total cholesterol, LDL, HDL) were found. There was a decrease (12 %; p= 0.07) in triacylglycerol concentration [Turner 2004].

In a double-blind, randomized, placebo-controlled, cross-over study in 100 healthy volunteers, 500 mg of garlic (details and daily dosage not given) administered for up to 9 months showed no effect on blood lipid levels [Tanamai 2004].

In a randomized, placebo-controlled study involving healthy volunteers, administration of garlic oil (8.2 mg allyl sulphide daily; n=19) or garlic powder (7.8 mg allicin daily; n=20) for 11 weeks did not lead to changes in plasma lipid parameters when compared to placebo (n=21). A gender-specific analysis revealed that garlic oil exerted significant increases in HDL-cholesterol (p<0.004) and reductions in the ratio of total cholesterol:HDL-cholesterol (p<0.003) in women [Zhang 2001].

Clinical studies

Antihypertensive effects

Systematic reviews/meta-analysesIn an early meta-analysis of 8 studies, the effect of garlic on blood pressure was evaluated. The overall pooled mean difference in the absolute change from baseline to final measurement of systolic blood pressure was greater (7.7 mmHg) in subjects who were treated with garlic than those treated with placebo; the effect on diastolic blood pressure (5 mmHg) was smaller. The results suggested that garlic powder may have some clinical benefit in mild hypertension [Silagy 1994a].

A systematic review of 45 randomized trials assessing the effects of garlic on several cardiovascular-related factors revealed that inconsistent effects on blood pressure were reported in the studies. The authors noted that conclusions regarding clinical significance were limited by the low quality and short duration of many trials and by the unpredictable release and inadequate definition of active constituents in the study preparations [Ackermann 2001].

A meta-analysis of 10 randomized, controlled trials studying the effect of garlic on blood pressure in both normotensive and

hypertensive subjects, suggested that garlic is associated with blood pressure reductions only in patients with an elevated systolic blood pressure [Reinhart 2008].

A systematic review suggested that the contradictory results described in previous meta-analyses assessing the effect of garlic on blood pressure can be attributed to methodological deficiencies. The methodological quality of the selected studies (32 in all, 13 evaluated in previous meta-analyses) was considered to be poor. Only four trials had adequate allocation concealment, no trial reported an intention-to-treat analysis, and the evaluators were blinded in only three of the trials. Futhermore, half of the studies did not report any information regarding the details of blood pressure measurement. All trials fulfilling a predefined cut-off point for quality criteria (methodological and blood pressure measurement) were conducted in normotensive subjects and none of these found garlic to lower blood pressure. For these reasons, the authors conclude that the effect of garlic on blood pressure cannot be ascertained [Simons 2009].

A meta-analysis of 17 randomized controlled trials showed that garlic was superior to controls (placebo in most trials) in reducing blood pressure (BP), especially in hypertensive patients. Pooled analysis showed that garlic intake caused a 3.75-mm Hg reduction (95% CI, -5.04 to -2.45, p<0.001) in systolic BP and a 3.39-mm Hg reduction (95% CI, -4.14 to -2.65, p<0.001) in diastolic BP compared with controls. Meta-analysis of subgroups showed a significant reduction in systolic BP in hypertensive (-4.4 mm Hg; 95% CI, -7.37 to -1.42, p=0.004) but not normotensive patients. Significant diastolic BP reduction (-2.68 mm Hg, 95% CI, -4.93 to -0.42, p=0.02) was shown in hypertensive patients after sensitivity analysis [Wang 2015].

In a systematic review and meta-analysis of seven randomized, placebo-controlled trials comparing garlic with placebo in hypertensive patients, garlic had a significant lowering effect on both systolic BP (weighted mean difference (WMD): -6.71 mmHg; 95% CI: -12.44 to -0.99; p=0.02) and diastolic BP (WMD: -4.79 mmHg; 95% CI: -6.60 to -2.99; p<0.00001) [Xiong 2015].

A meta-analysis of 20 randomized, controlled trials, including 970 participants, found a mean decrease in systolic blood pressure (SBP) of 5.1 ± 2.2 mm Hg (p<0.001) and in diastolic blood pressure (DBP) of 2.5 ± 1.6 mm Hg (p<0.002) when compared with placebo. A subgroup analysis of hypertensive subjects (SBP/DBP ≥140/90 mm Hg at baseline) revealed a greater significant reduction in SBP of 8.7 ± 2.2 mm Hg (p<0.001) and in DBP of 6.1 ± 1.3 mm Hg (p<0.001) [Ried 2016].

Clinical trialsIn a randomized, double-blind, placebo-controlled study, 52 patients with hypercholesterolaemia and mild systolic hypertension were treated with 900 mg of standardized garlic powder (1.3% alliin) daily for 6 months. Systolic and diastolic blood pressure (initial values: 145 and 90 mmHg) were reduced by 17% (p<0.001) and 10% (p<0.01), respectively, in the verum group, but remained unchanged in the placebo group (p<0.001 for intergroup comparison) [De Santos 1993].

In a randomized study the effects of daily treatment with 600 mg of standardized garlic powder (1.3% alliin, equivalent to 0.6% allicin) were compared to those of 1.98 mg of garlic oil in 80 patients with mild hypercholesterolaemia and mild hypertension. By the end of 4 months of treatment, initial systolic and diastolic blood pressures of 151 and 96 mmHg had decreased by 19 and 17% respectively (both p<0.001) in the garlic powder group, whereas no effects were observed in

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the garlic oil group (p<0.001 for intergroup comparison) [De Santos 1995].

In a randomized, double-blind, placebo-controlled study the effects of 600 mg of standardized garlic powder (1.3% alliin) daily for 12 weeks were evaluated in 47 patients with mild hypertension. In the verum group, initial supine and standing diastolic blood pressures of 102 and 101 mmHg decreased by 13% and 11% respectively (p<0.05), while in the placebo group initial values of 97 and 94 mmHg decreased by 4% and 0.5% respectively (not significant). Initial systolic blood pressures of 171 and 161 mmHg in the verum and placebo groups respectively decreased by 12% (p<0.05) and 6% (not significant). Intergroup comparisons were not reported [Auer 1990].

In a 12-week randomized, reference-controlled study involving 98 normotensive patients with primary hyperlipoproteinaemia, the effects of daily administration of 900 mg of garlic powder (1.3% alliin) or 600 mg of bezafibrate were compared. Systolic blood pressures of 143.4 mmHg in the garlic group and 140.6 mmHg in the bezafibrate group were reduced by 5.5% and 2%, respectively (p<0.05 in favour of garlic). Initial diastolic blood pressures of 82.8 and 82.4 mmHg, respectively decreased by 5% in both groups [Holzgartner 1992].

In a randomized, double-blind, placebo-controlled study 40 patients with moderate hypertension (systolic blood pressure, 178 mmHg; diastolic, 100 mmHg) undergoing concomitant diuretic treatment with triamterene and hydrochlorothiazide received 600 mg of standardized garlic powder (1.3% alliin) or placebo daily. After 12 weeks systolic blood pressure had decreased by 9% in the verum group compared to 3% in the placebo group (p<0.001), while diastolic pressure had decreased by 15% in the verum group compared to 9% in the placebo group (p<0.001) [Kandziora 1988].

In a randomized, double-blind study 40 patients with hyper-cholesterolaemia and slightly elevated blood pressures received 900 mg of standardized garlic powder (1.3% alliin) or placebo daily. After 16 weeks, supine systolic and diastolic blood pressures were significantly lowered in the verum group (p<0.001 and p<0.05, respectively) compared to the placebo group [Vorberg 1990].

In a randomized, double-blind study 80 normotensive patients with peripheral arterial occlusive disease received 800 mg of standardized garlic powder (1.3% alliin) or placebo daily. After 12 weeks of therapy the initial diastolic blood pressure of 85 mmHg in the verum group had decreased by 3.5% (p<0.04), while that in the placebo group (initially 83 mmHg) remained unchanged [Kiesewetter 1993b].

In a randomized, double-blind study 42 patients with mild hypercholesterolaemia were treated with 900 mg of standardized garlic powder (1.3% alliin) or placebo daily for 12 weeks. At the end of the study systolic and diastolic blood pressures remained unchanged [Jain 1993].

In an open study, 20 patients with mild essential hypertension received two 250 mg garlic oil capsules (2.5% w/v, not clearly specified) daily for 8 weeks. A significant (p<0.05) decline in mean systolic (148±12 to 140±16 mmHg) and diastolic (94±15 to 85±23 mmHg) blood pressure was observed compared to baseline. Furthermore, significant (p<0.05) reductions in 8-hydroxy-2´-deoxyguanosine and 8-iso-prostaglandin F2a (biomarkers of oxidative stress), plasma oxidized LDL, NO levels and lipid peroxidation were observed, as well as a significant (p<0.05) increase in vitamin A, C and E levels and

total antioxidant status, when compared to baseline levels [Dhawan 2004, 2005].

An acute dose study involving 75 patients with hypertension showed no significant effects on blood pressure in any of the three patient groups: placebo; 1 clove of garlic (slightly chewed and swallowed), or 12 tablets of garlic (slightly chewed and swallowed; 2.4 mg allicin) for up to an hour after consumption [Capraz 2007].

In an open study involving 50 type 2 diabetic patients with hyperlipidaemia (total cholesterol ≥ 220 mg/dl), administration of 900 mg garlic powder daily for 6 weeks resulted in a reduction of systolic blood pressure (p<0.03) [Parastouei 2006].

In an open study, 70 hypertensive patients received an oily garlic preparation (1.6 g garlic macerate 1:1; 1.6 mg allicin derivatives) in addition to standard antihypertensive treatment for 30 days. There were no significant changes in systolic and diastolic blood pressure. A gender-specific analysis revealed a trend for better effects in women as compared to men [Duda 2008].

A placebo-controlled study involving 100 women in their third trimester of pregnancy was conducted to evaluate whether garlic (800 mg powdered garlic with 1 mg allicin daily for 8 weeks) could prevent pre-eclampsia. No difference between the garlic and control groups in the relative risk of gestational hypertension or pre-eclampsia was observed [Ziaei 2001].

In a double-blind, placebo-controlled trial, patients with mild or moderate hypertension (systolic blood pressure 150-160 mmHg, diastolic blood pressure 90-115 mmHg) received 600 mg garlic powder daily (n=30) or placebo (n=20) for 8 weeks after an 8 week placebo-run-in phase. As compared to the baseline values (after the placebo run-in-phase), garlic signifi-cantly reduced systolic and diastolic blood pressures by 7.0 mmHg and 3.8 mmHg respectively (p<0.001). There was also a significant (p<0.001) difference compared to the placebo group [Sobenin 2009a].

In a single-blind, placebo controlled, multicentre study, patients with stage 1 essential hypertension (30 per group) received garlic tablets (not further specified) for a period of 24 weeks at daily doses of 300, 600, 900, 1200 or 1500 mg, atenolol (100 mg) or placebo. Garlic demonstrated dose- and duration-dependent significant (p<0.05) reductions in systolic and diastolic blood pressure when compared to placebo; the activity was comparable with atenolol at doses of 600 mg and above at 24 weeks [Ashraf 2013].

Rheological and antiatherosclerotic effects

Systematic reviews/meta-analysesA systematic review of 45 randomized trials summarized the effects of garlic on several cardiovascular-related factors. The relevant trials reported modest but significant reductions in platelet aggregation with garlic treatment (without additional anti-platelet medication) compared with placebo. The authors noted that conclusions regarding clinical significance were limited by the low quality and short duration of many trials and by the unpredictable release and inadequate definition of active constituents in the study preparations [Ackermann 2001].

Clinical trialsIn a randomized, double-blind study, 60 young patients (average age 24 years) with constantly elevated spontaneous platelet aggregation and at increased risk of ischaemic attack were treated with 800 mg of standardized garlic powder (1.3% alliin) or placebo daily for 4 weeks. In the garlic group the ratio of

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circulating platelet aggregation decreased by 10.3% (p<0.01; placebo group unchanged) and spontaneous platelet aggregation decreased by 56.3% (p<0.01; placebo group unchanged) [Kiesewetter 1991, 1993a].

In a double-blind study 80 patients with peripheral arterial occlusive disease received 800 mg of standardized garlic powder (1.3% alliin) or placebo daily for 12 weeks. In the garlic group plasma viscosity decreased by 3.6% (p<0.0013) and spontaneous platelet aggregation dropped by 59% (p<0.01) while these parameters were unchanged in the placebo group [Kiesewetter 1993b].

In a randomized, double-blind study, 23 patients with coronary arterial disease received 900 mg of standardized garlic powder (1.3% alliin) or placebo daily for 3 weeks. The cholesterol content per mg of cell protein decreased from 40 to 28 µg, the LDL oxidation lag-time was prolonged from 133 to 176 min and the LDL-sialic acid content increased from 22 to 33 nmol/mg lipoprotein. In the control group these parameters remained unchanged [Orekhov 1996].

In an open study 20 patients with hypercholesterolaemia were treated daily for 4 weeks with 600 mg of dried garlic. Fibrinogen decreased by 10% (p<0.01) and fibrinopeptide A by 45% (p<0.01); streptokinase-activated plasminogen increased by 15% (p<0.01) and fibrinopeptide Bb 15-42 by about 42% (p<0.01) [Harenberg 1988].

Lipid-lowering effects

Systematic reviews/meta-analysesThe effect of garlic on total serum cholesterol has been assessed in 9 meta-analyses [Warshafsky 1993; Silagy 1994b; Neil 1996; Stevinson 2000; Ackermann 2001; Reinhart 2009; Khoo 2009; Zeng 2012; Ried 2013]. In most of them it was concluded that the available data showed garlic to be superior to placebo in reducing total cholesterol; however, only a modest effect was indicated from one meta-analysis [Stevinson 2000] and no benefit on serum cholesterol was found in one meta-analysis [Khoo 2009].

A systematic review of 45 randomized trials summarized the effects of garlic on several cardiovascular risk-related factors. When compared with placebo, garlic preparations led to small reductions in the total cholesterol level at 1 month (range of average pooled reductions, 0.03-0.45 mmol/l [1.2-17.3 mg/dL]) and at 3 months (range of average pooled reductions 0.32-0.66 mmol/l [12.4-25.4 mg/dL]), but not at 6 months. Changes in the levels of LDL and triglycerides paralleled those of total cholesterol, while there were no significant changes in HDL levels observed. The authors noted that conclusions regarding clinical significance were limited by the low quality and short duration of many trials and by the unpredictable release and inadequate definition of active constituents in the study preparations [Ackermann 2001].

A meta-analysis of 13 trials (11-24 weeks in duration) including 1056 healthy or hypercholesterolaemic subjects showed that administration of garlic did not have any significant effects on lipid profile compared with placebo [Khoo 2009].

A meta-analysis of 29 trials studying garlic preparations revealed a significant reduction of total cholesterol (by 0.19 mmol/l (95% CI -0.33, -0.06); = 7.35 mg/dl) and triglycerides (by 0.11 mmol/l (95% CI -0.19, -0.03); = 9.7 mg/dl) as compared to placebo, but exhibited no significant effects on LDL or HDL [Reinhart 2009].

A meta-analysis of 26 randomized, double-blind, placebo-controlled trials concluded that garlic was superior to placebo

in reducing serum total cholesterol (TC) and triglyceride levels. Compared with placebo, TC levels were significantly (p=0.001) reduced by 0.28 mmol/L (95% CI, -0.45, -0.11) and triglyceride level significantly (p<0.001) reduced by 0.13 mmol/L (95% CI, -0.20, -0.06) in the garlic group. The effects of garlic were more pronounced with long-term intervention and in subjects with higher baseline cholesterol levels. Garlic powder was more effective in reducing serum cholesterol levels, while garlic oil was more effective in lowering serum triglyceride levels. However, garlic did not influence other lipid parameters, including LDL, HDL, apolipoprotein B and TC/HDL ratio [Zeng 2012].

A meta-analysis of 39 trials investigating the effect of garlic preparations on serum lipids revealed that garlic reduced total serum cholesterol compared with placebo by 15.25 mg/dL (95% CI, -20.72, -9.78; p<0.0001). The effect was stronger in individuals with elevated total cholesterol levels (>200 mg/dL) when garlic was used for more than 2 months (-17.20 mg/dL; 95% CI, -23.10, -11.30; p<0.0001). Similar results were also seen for LDL, while HDL levels improved only slightly, and triglycerides were not influenced significantly [Ried 2013].

Comparative studiesThe lipid-lowering effect of 900 mg of garlic powder (standard-ized to 1.3% alliin) daily (G) was compared to that of 600 mg of bezafibrate daily (B) in 98 patients with hyperlipoproteinaemia. After 12 weeks of treatment, both groups showed significant reductions in total cholesterol (G 25%, B 27%; p<0.001) and LDL (G 32%, B 33%; p<0.001) as well as an increase in HDL (G 51%, B 58%; p<0.001). No significant differences were found between the two groups [Holzgartner 1992].

In a randomized study the effects of daily treatment with 600 mg of standardized garlic powder (1.3% alliin) or 1.98 mg of garlic oil were compared in 80 patients with mild hypercholesterolaemia. After 4 months of treatment total cholesterol had decreased by 11% in the garlic powder group (p<0.001) and by 3% in the garlic oil group. LDL was reduced by 16% in the garlic powder group (p<0.001) and by 1% in the garlic oil group (intergroup comparison: total cholesterol, not significant; LDL, p<0.001) [De Santos 1995].

In a randomized study involving 20 hyperlipidaemic patients (serum cholesterol and triglyceride levels > 200 and 280 mg/dl respectively), the effects of garlic powder compared with clofibrate were investigated. Each patient took garlic at a dose of 900 mg (equivalent to 2.7 g of fresh garlic and 11.7 mg alliin) or 100 mg clofibrate daily for 8 weeks. After 4 and 8 weeks, total cholesterol was reduced with garlic by 9.8 and 17.5% and with clofibrate by 3.0 and 7.2%, respectively. Triglyceride levels were reduced by 34.8 and 43.7% with garlic and by 21.3 and 25.5% with clofibrate. Garlic demonstrated a significantly (p<0.01) greater effect than the clofibrate [Nouri 2008].

Placebo-controlled studiesA placebo-controlled, randomized study evaluated the effects of fresh or powdered garlic on plasma lipid concentrations in adults with moderate hypercholesterolaemia (LDL 3.36-4.91 mmol/L). The daily dosages of 4 g fresh garlic (n=49), 1.4 g powdered garlic (n=47) or placebo (n=48) were administered 6 days a week for 6 months. There were no statistically significant effects on the plasma lipids [Gardner 2007].

In a double-blind, randomized, placebo-controlled trial, the effects of a daily dose of 2.1 g garlic powder on biomarkers for inflammation, endothelial function and lipid metabolism were studied in 90 overweight subjects with cardiovascular risk factors (BMI >24.5 kg/m², >10 cigarettes/d, 40-75 years of age), in comparison to atorvastatin. The subjects were randomly

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assigned to 3 parallel treatment groups: garlic powder (2.1 g/d), atorvastatin (40 mg/d), or placebo. In contrast to atorvastatin the garlic preparation had no effect on the variables as compared to placebo [Van 2006].

In a randomized, double-blind, placebo-controlled study the effect of standardized garlic powder tablets (1.3% alliin) was investigated in 261 patients with hyperlipidaemia (initial cholesterol: verum 266, placebo 262 mg/dl). The patients received 800 mg of garlic powder or placebo daily for 16 weeks. In the garlic group mean serum total cholesterol levels dropped by 12% (p<0.001) and triglyceride values by 17% (p<0.001); both results were significant (p<0.001) compared to placebo treatment. A subgroup analysis revealed better results in patients with increased initial lipid levels [Mader 1990].

In a randomized, double-blind, placebo-controlled study, 42 patients with mild hypercholesterolaemia (serum total cholesterol: verum 262, placebo 276 mg/dl) were treated with 900 mg of standardized garlic powder (1.3% alliin) or placebo daily for 12 weeks. In the garlic group serum total cholesterol decreased by 6% (p<0.01 vs. baseline and placebo) compared to 1% in the placebo group and LDL by 11% (p<0.05 vs. baseline and placebo) compared to 3% in the placebo group [Jain 1993].

In a randomized, double-blind, placebo-controlled study, 46 patients with mild hypercholesterolaemia (6.5 mmol/dl) were assigned to one of four daily treatments: group I, 900 mg of standardized garlic powder (1.3% alliin); group II, 12 g of fish oil; group III, 12 g of fish oil + 900 mg of standardized garlic powder; group IV, placebo. After 3 weeks of treatment the changes in serum total cholesterol and LDL, respectively, were: group I, -11.5% and -14.2%; group II, 0% and + 8.8%; group III, -12.2% and -9.5%; group IV, +4.5% and -1.4%. The differences in groups I and III were significant (p<0.01) compared to those in groups II and IV [Adler 1997].

In a randomized, double-blind study 52 patients with hyper-cholesterolaemia were treated with 900 mg of standardized garlic powder (1.3% alliin) or placebo daily for 6 months. Baseline serum total cholesterol levels were 6.92 mmol/litre in the garlic group and 7.05 mmol/litre in the placebo group. Serum total cholesterol and LDL, respectively, decreased by 9% (p<0.01 vs. baseline, p<0.05 vs. placebo) and 10% (p<0.05 vs. baseline) in the verum group and by 4% and 6% in the placebo group [De Santos 1993].

In a randomized, double-blind study 40 patients with moderate hypertension (blood pressure 178/100 mmHg) and hyper-cholesterolaemia (280 mg/dl) received 600 mg of standardized garlic powder (1.3% alliin) or placebo daily. After 12 weeks serum total cholesterol had decreased by 10% (p<0.05) and triglycerides by 8% (p<0.05); no changes were observed in the placebo group [Kandziora 1988].

In a randomized, double-blind study, 40 patients with hypercholesterolaemia received 900 mg of standardized garlic powder (1.3% alliin) or placebo daily. After 16 weeks of treatment, serum total cholesterol had decreased by 21% in the verum group and 3% in the placebo group (intergroup difference p<0.001). Serum triglycerides decreased by 24% in the verum group and 3% in the placebo group (p<0.05) [Vorberg 1990].

In a randomized, double-blind study 23 patients with coronary artery disease (determined by selective coronary angiography) received 900 mg of standardized garlic powder (1.3% alliin) or placebo daily. Initial serum total cholesterol levels were 218 mg/dl in the verum group and 219 mg/dl in the placebo group. After 3 weeks of treatment HDL had increased by 16%

in the verum group (p<0.05); total cholesterol and triglycerides remained unchanged [Orekhov 1996].

In a randomized, double-blind study, 80 patients with peripheral arterial occlusive disease (determined by angiography) were assigned to treatment with 800 mg of standardized garlic powder (1.3% alliin) or placebo daily for 12 weeks. Initial serum total cholesterol levels of 266.5 and 264.4 mg/dl in the verum and placebo groups, respectively, decreased by 12% and 4% (intergroup comparison p<0.011) [Kiesewetter 1993b].

In a randomized, double-blind study the effects of 600 mg of standardized garlic powder (1.3% alliin) or placebo daily for 12 weeks were compared in 47 patients with mild hypertension. The baseline serum total cholesterol level of 268 mg/dl decreased by 14% in the garlic group (p<0.05 vs. baseline) and 6% in the placebo group (not significant). Serum triglycerides decreased by 18% in the garlic group (p<0.05) and 6% in the placebo group (not significant) [Auer 1990].

In a single-blind, placebo-controlled trial, administration of garlic tablets (not further specified) at 900 mg per day for 3 months to hyperlipidaemic patients (n=55) significantly (p<0.001) reduced total cholesterol by 9.37%, triglycerides by 1.30%, LDL by 17.59% and increased HDL-cholesterol by 5.54%, as compared to baseline values. The placebo hyperlipidaemic patient group (n=51) did not demonstrate significant changes in any of the tested parameters [Fatima 2014].

In a randomized, double-blind, placebo-controlled study 51 patients with coronary heart disease were treated with 300 mg time-released garlic powder tablets or placebo daily for 12 months. There were significant decreases in total cholesterol (-12.4 %; p=0.004) and LDL (-16.3%; p=0.001) as compared to baseline. The cholesterol lowering effects were significantly (p=0.038) greater for garlic than placebo. The most significant effects were observed in men [Sobenin 2009b].

Placebo-controlled studies in combination with defined dietIn a single-blind, randomized, placebo-controlled study the effects of garlic were studied in hyperlipidaemic patients (total cholesterol ≥ 200 mg/dl and/or LDL ≥100 mg/dl). Patients were given a garlic powder tablet (400 mg garlic,1 mg allicin; n=50) or placebo (n=50) twice daily for 6 weeks. All patients were put on the NCEP step II diet (not more than 7% of calories from saturated fat, not more than 30% of calories from total fat and less than 200 mg of cholesterol per day). Garlic had significant (p<0.001) effects on total cholesterol (12.1% reduction), LDL (17.3% reduction) and HDL (15.7 % increase), but no significant effect on triglycerides [Kojuri 2007].

After 8 weeks on an NCEP Step I diet (8-10% of calories from saturated fat, not more than 30% of calories from total fat and less than 300 mg of cholesterol per day), the effects of 900 mg of standardized garlic powder (1.3% alliin) or placebo daily for 12 weeks were compared in a randomized, double-blind study in 50 patients with hyperlipidaemia (initial serum total cholesterol: garlic group 274 mg/dl, placebo group 250 mg/dl). The diet was maintained during the course of study. There were no significant changes to lipid levels in either group and no intergroup differences were observed for serum total cholesterol or LDL [Isaacson 1998].

Over 1200 patients with hypercholesterolaemia embarked on an NCEP Step I diet. After 6 weeks, 115 patients who had not responded to the diet (serum total cholesterol 6.0-8.0 mmol/dL) maintained the diet and were enrolled in a randomized, double-blind study, assigned to 900 mg of standardized garlic powder (1.3% alliin) or placebo daily for 6 months. The baseline

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serum total cholesterol levels were 6.96 and 6.99 mmol/litre in the garlic and placebo groups respectively. At the end of this study there were no intra- nor inter-group differences in lipid parameters [Neil 1996].

In a randomized, double-blind, crossover study (2 × 12 weeks, with a wash-out period of 4 weeks) 30 patients with hyper-cholesterolaemia (serum total cholesterol 6.72 mmol/litre) were treated with 900 mg of standardized garlic powder (1.3% alliin) or placebo daily. All patients maintained an NCEP Step I diet during the study. No effects on serum lipids were observed [Simons 1995].

After following an NCEP Step II diet for 6 months, 30 children with primary familial hypercholesterolaemia participated in a randomized, double-blind study and were assigned to 900 mg of standardized garlic powder (1.3% alliin) or placebo daily for 8 weeks. Baseline serum total cholesterol levels were 6.66 and 7.06 mmol/litre in the garlic and placebo groups respectively. No effects on serum lipid levels were observed except for a 10% increase in apolipoprotein A-I in the garlic group (p = 0.03) [McCrindle 1998].

In a randomized, double-blind study, 35 renal transplant patients with serum total cholesterol levels of 290 mg/dl followed an NCEP Step I diet and were also treated with 1.36 g of an undefined garlic preparation (equivalent to 4 mg of allicin daily) or placebo daily for 12 weeks. After 6 and 12 weeks of treatment serum total cholesterol decreased by 5% in the garlic group (p<0.05) while serum levels in the placebo group remained unchanged. Serum triglycerides increased by 7.5% (not significant) and HDL decreased by 5% (not significant) in the garlic group, while in the placebo group these parameters changed by +17.3% (p<0.05) and -6% (p<0.05) respectively [Lash 1998].

After following an NCEP Step I diet for at least 2 weeks (and maintaining it during the course of study), 50 patients with moderate hypercholesterolaemia (LDL subclass pattern A or B; mean serum LDL 166 mg/dl) participated in a randomized, double-blind study, taking 900 mg of standardized garlic powder (1.3% alliin) or placebo daily for 3 months. At the end of the study no significant changes were observed in lipid parameters [Superko 2000].

In a 16 week double-blind, placebo-controlled study in 33 patients with primary hypercholesterolaemia (LDL 130-190 mg/dl after at least 4 weeks of generalized dietary modification), the effects of garlic powder (22.4 mg alliin corresponding to approx. 10 mg allicin daily) on lipid profile and various mental parameters (depression, impulsiveness, hostility and temperament) were compared with placebo. Both groups received individual dietary counseling (NCEP Step I diet). No significant effects on lipid and mental parameters were observed within or between the groups [Peleg 2003].

In a randomized, double-blind, placebo-controlled trial 136 hypercholesterolaemic patients (cholesterol concentrations ≥ 5.2 mmol/L resp. >200 mg/dl) received garlic (333 mg garlic preparation equivalent to 7 g fresh garlic, standardized to 5.6 mg allicin; n=70) or placebo (n=66) for 12 weeks. All patients were given advice to follow NCEP Step I diet for 4 weeks prior to randomization and during the study. There were no statistically significant changes in serum lipid parameters or in plasma glucose, liver or renal functions [Satitvipawee 2003].

Open studiesPatients with hyperlipoproteinaemia type IV (n = 5) and hypercholesterolaemia (n = 15) were treated daily for 4

weeks with 600 mg of garlic powder. The initial mean serum total cholesterol of 278 mg/dl decreased by 7.2% (p<0.01) [Harenberg 1988].

Patients with hyperlipidaemia (n = 44; serum total cholesterol 298 mg/dl, triglycerides > 200 mg/dl) were treated with 1.2 g of standardized garlic powder (1.3% alliin) for 18 weeks. Serum total cholesterol decreased by 11.3% (p<0.001), LDL by 15.7% (p = 0.003) and triglycerides by 13%; HDL increased by 19.9% [Rinneberg 1989].

Patients with hyperlipidaemia (n=1024; initial serum total cholesterol 297 mg/dl) took 600-900 mg of standardized garlic powder (corresponding to 3-6 mg of allicin) for 16 weeks. Serum total cholesterol decreased by 15.8%, LDL by 13.3% and tri-glycerides by 13.7%; HDL increased by 14.3% [Brewitt 1991].

Patients with hyperlipidaemia (n = 1873; serum total cholesterol > 200 mg/dl or elevated triglycerides) were treated with 900 mg of standardized garlic powder (1.3% alliin) for 16 weeks. Initial average serum total cholesterol of 290 mg/dl decreased by 16.4% (p<0.0001), LDL by 15.1% (p<0.0001) and triglycerides by 21% (p<0.0001); HDL increased by 9.4% (p<0.0001) [Beck 1993].

Patients with hypercholesterolaemia (n=917; serum total cholesterol 262 mg/dl), following a cholesterol and fat-reduced diet, were treated with 600 mg of standardized garlic powder (1.3% alliin) daily for 6-8 weeks. Serum total cholesterol decreased by 2.3% (p<0.01) [Walper 1994].

In type 2 diabetic patients with hyperlipidaemia (n=50; total cholesterol ≥ 220 mg/dL), the administration of 900 mg garlic powder daily for 6 weeks resulted in a significant reduction of total cholesterol (p<0.01) and LDL (p<0.001), and a significant increase in HDL (p<0.02). There were no significant effects on diastolic blood pressure, fasting blood sugar, serum triglycerides and HbA1c [Parastouei 2006].

Hypertensive patients (n=70) received 6 capsules of an oily garlic preparation daily, in addition to standard antihypertensive medications, for 30 days. Each capsule contained 270 mg garlic macerate in rapeseed oil (1:1) with 0.27 mg of allicin derivatives standardized for allicin. Total cholesterol and LDL were significantly (p<0.05) reduced, while HDL increased nonsignificantly. There was also a slight increase of 7 to 10% in the proportion of patients with normal total serum cholesterol levels at the end of the study [Duda 2008].

Prophylaxis of atherosclerosisPatients homogenous in all demographic data except age (verum > placebo, p<0.001), with advanced atherosclerotic plaques (measured by ultrasound in the carotid bifurcation and/or femoral arteries) and at least one risk factor (high systolic blood pressure, hypercholesterolaemia, diabetes mellitus, smoking), participated in a randomized, double-blind, placebo-controlled study. They were assigned to treatment with 900 mg of standardized garlic powder (1.3% alliin; n = 140) or placebo (n = 140) daily for 48 months; 152 patients (61 in the garlic group and 91 in the placebo group) completed the study; 38% of patients in the verum group dropped out because of annoyance with odour. In the remaining patients plaque volume decreased by 2.6% in the verum group and increased by 15.6% in the placebo group. The strongest effects (in both directions) were observed in women. There was a strong correlation (p<0.0001) of inhibition of the increase in plaque volume with increasing age [Koscielny 1999].

In a 3-year randomized study, 432 patients with a history of myocardial infarction were assigned to an oily extract of garlic (n = 222) or placebo (n = 210) daily, in addition to other necessary

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medication. Significant reductions in the non-fatal reinfarction rate (44%; p<0.001) and mortality (31%; p<0.01) were observed in patients taking the oily extract of garlic compared to those taking placebo [Bordia 1989].

Respiratory Tract Infections / Common coldA systematic review revealed insufficient evidence for the use of garlic in preventing or treating the common cold. Of the eight studies identified, only one (Josling 2001) met the inclusion criteria and suggested that garlic may prevent the common cold [Lissiman 2014].

In a randomized, double-blind, placebo-controlled study, a daily dose of 180 mg of stabilized allicin or placebo were given to 146 volunteers for 12 weeks. There were significantly (p<0.001) fewer occurrences of common cold in the garlic group (24) than in the placebo group (65). Symptoms lasted significantly (p<0.001) longer in the placebo group (5.01 days) compared to the garlic group (1.52 days) and there were fewer days of illness in the garlic group (n=111) compared with the placebo group (n=366) [Josling 2001].

In a randomized, double-blind, placebo-controlled, 5-month trial, garlic tablets (300 mg/day; not further specified; n=42) reduced acute respiratory disease morbidity 1.7-fold in children aged 10 to 12 years compared to placebo (n=41) [Andrianova 2003].

Other clinical effectsOther clinical studies of garlic preparations have reported antimycotic and antibacterial effects, such as in women with bacterial vaginosis [Ledezma 2000; Sabitha 2005; Mohammadzadeh 2014].

In a randomized, placebo-controlled study involving 41 patients suffering from hepatopulmonary syndrome, the effect of garlic oil capsules (n=21) was compared to placebo (n=20) over a period of 9 to 18 months. Each garlic capsule contained 250 mg oil and the mean daily garlic dose was 1.55±0.29 g. After 9 months there was a significant (p<0.001) increase in baseline arterial oxygen levels of 24.66% in the garlic group compared to only 7.37% in the placebo group (p=0.02), and a significant (p<0.001) decrease in the alveolar-arterial oxygen gradient in the garlic group (28.35%) compared to placebo (10.73%; p=0.12). The arterial oxygen level and alveolar-arterial oxygen level were also significantly (p<0.001) higher and lower, respectively, in the garlic group compared to the placebo group. Two of 21 patients in the garlic group and 7 of 20 patients in the placebo group died during the follow-up period of up to 18 months [De 2010].

In a randomized, double-blind, placebo-controlled trial, 40 women with metabolic syndrome according to NCEP ATPIII (Adult Treatment Panel III) criteria, and 10 healthy female controls, were treated with 1.8 g garlic tablets per day or placebo for 6 weeks. Compared to placebo, the garlic treatment resulted in a significantly lower weight (p=0.04) and waist circumference (p<0.001) in the women with metabolic syndrome, while no effect was seen in healthy women [Sharifi 2010].

In an open, two phase study involving 30 patients with type-II diabetes, both dry powdered garlic and a dried aqueous extract (dried filtrate of an aqueous macerate), at a dose of 45 mg/kg/d orally for 14 days, significantly (p<0.05) decreased blood glucose levels in patients taking no other medications as well as in patients taking oral hypoglycaemics but with an inadequate control of blood glucose. Lower doses (20 and 30 mg/kg/d) had no significant effect. Glycosuria, found only in the patients not also taking oral hypoglycaemics, was reversed by both garlic preparations at the 45 mg/kg/d dose. There was

no significant activity found in a healthy control group (n=15) for either garlic preparation [Waheed 2014].

Various epidemiologic studies have found a negative correlation between the intake or use of garlic and the incidence of cancer [Gao 1999; Munoz 2001; Setiawan 2005; Galeone 2006; Galeone 2007; Zhou 2013; Galeone et al. 2015; Kodali 2015]. A systematic review found 4 randomized controlled trials on the effectiveness of garlic extract for reducing cancer risk. The analyzed studies were of mixed quality, and the findings from these trials were not uniformly positive [Ernst 2012].

In a randomized, placebo-controlled, double-blind trial, the preventive effect of garlic against nosocomial infections was studied in 94 patients in intensive care units. A powdered and dissolved garlic tablet (400 mg/day) or placebo were administered by gavage through nasogastric intubation for 6 days. There were no cases of venous catheter infection in the garlic group and the frequency of positive venous catheter tip cultures was significantly (p=0.03) higher in the placebo group than in the garlic group. There was no significant difference in urinary catheter cultures between the groups [Madineh 2017].

Pharmacokinetic propertiesThe absorption and excretion of orally administered radio-actively-labelled 35S-alliin, allicin and vinyldithiine were studied in rats. Alliin was absorbed and eliminated much faster than the other compounds. After administration of 35S-alliin at 8 mg/kg b.w. maximum blood concentration was reached after 10 minutes (allicin 30-60 minutes, vinyldithiine 120 minutes). The excretion of alliin equivalents was mainly renal [Lachmann 1991].

The metabolism of allicin was analyzed in perfusion experiments using isolated rat liver. Allicin could be identified after passage through the liver only after administration of high doses (1.2 mg allicin/minute). After administration of 400 µg allicin/minute 95% was metabolized after the first hepatic passage; in this case allicin metabolites such as diallyl disulphide and allyl mercaptan were detected in the liver and gall bladder [Egen-Schwind 1991].

S-allylcysteine orally administered to rats, mice and dogs was rapidly and easily absorbed, and distributed mainly in plasma, liver and kidney; the bioavailability was 98.2% in rats, 103.0% in mice and 87.2% in dogs. It was mainly excreted in the urine as the N-acetyl metabolite in rats, while mice excreted both unchanged and N-acetyl forms [Nagae 1994].

Interactions in animalsPharmacokinetic interactions between orally administered metformin (320 mg/kg b.w.) and garlic (500 mg/kg b.w.) were studied in rats. Compared to metformin alone, administration of the garlic with metformin for 8 days produced a significant (p-value not given) increase in the Cmax and AUC0-12h, as well as a slightly higher t1/2, of metformin. Furthermore, blood glucose was decreased more with the combination than with metformin alone [Chourey 2011].

Oral pre-treatment of rats with a garlic homogenate (250 mg/kg b.w.) for 30 days enhanced the bioavailabilty of a single oral dose of propranolol (10 mg/kg b.w.). Significant increases in the half-life (p<0.001) and Cmax (p<0.05) were demonstrated, as well as a significant (p<0.001) reduction in clearance, when compared to propranolol given alone [Asdaq 2011].

Interactions in humansAn increased INR in 2 patients on warfarin was attributed to garlic products as there were no other changes of medication

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or habits (no further data) [Sunter 1991]. A decreased INR was reported in a patient on fluindione with concurrent use of garlic (600 mg, no further details) for 12 days [Pathak 2003].

A preparation of garlic (equivalent to approx. 8 g/day; not further defined) was given to 10 healthy volunteers on study days 5-25. Saquinavir was administered on days 1-4, 22-25 and 36-39, and blood samples were obtained on study days 4, 25 and 39. At day 25 as compared to day 4, the mean area under the curve (AUC) of saquinavir was reduced by 51%, the trough levels by 49% and the mean maximum concentrations (Cmax) by 54%. After a 10-day washout period from garlic (day 39), the AUC, trough, and Cmax values returned to 60-70% of their values at baseline. However, the decrease was only seen in 6 of the patients; in 3 of the patients an increase was observed. A control group as well as information on nutrition which could influence the bioavailability of saquinavir are missing [Piscitelli 2002].

A garlic preparation (equivalent to 1 g fresh garlic daily), administered for 4 days to 10 volunteers, decreased the AUC0-∞ of a single dose of 400 mg ritonavir by 17% and peak plasma concentration by 1%. The authors concluded that the results should not be extrapolated to steady-state conditions [Gallicano 2003].

Another study in healthy volunteers revealed no significant effects on pharmacokinetic parameters of probe substrates of the CYP2D6 (dextromethorphan) or CYP3A4 (alprazolam) pathway of metabolism after administration of 1800 mg of a garlic extract (1800 µg “potential” allicin) twice daily for 14 days [Markowitz 2003].

The effect of dried garlic powder on blood pressure was studied in a 12-week randomized, double-blind, placebo-controlled trial in 62 healthy volunteers assigned to garlic (920 mg daily, corresponding to 10.8 mg alliin) or placebo. No significant differences in blood pressure were measured between the groups [Turner 2004].

In an open study, 70 hypertensive patients received an oily garlic preparation (1.6 g garlic macerate 1:1; 1.6 mg allicin derivatives) in addition to standard antihypertensive pharmacotherapy for 30 days. A significantly lower level of lipid peroxidation products reacting with thiobarbituric acid (from 4.9±0.9 to 2.8±0.9 µmol/l, p<0.05), as compared to the initial values, was measured in the blood [Duda 2008].

In an open pilot study involving 13 elderly healthy adults, daily consumption of garlic (0.1 g/kg b.w.) for one month resulted in significantly lower plasma and erythrocyte malondialdehyde levels (from 381.7±39.8 to 352.2±38.4 nmol/ml, p<0.05) and increased activities of the antioxidant enzymes glutathione peroxidase (from 8.34±1.07 to 9.32±0.78 IU/ml) and SOD (from 1,668±495 to 2,065±298 IU/ml, p<0.05) as compared to the initial values [Avci 2008].

Preclinical safety data

Acute toxicityThe LD50 of an aqueous extract of garlic applied s.c. to rabbits (3 per group) was 3034 mg/kg b.w. and the maximum tolerated dose was 2200 mg/kg b.w. At doses of 3200 and 4200 mg/kg b.w. the extract induced behavioural signs such as loss of appetite, depression, partial paralysis and death (2 of 3 animals at 3200 mg/kg b.w.; 3 of 3 animals at 4200 mg/kg b.w.) [Mikail 2010].

Other investigators, using various non-standardized garlic extracts, reported the lowest oral LD50 value in rats and mice as 30 ml/kg

for a 14.5% ethanolic extract from fresh bulbs [Nagakawa 1984].

The LD50 of an aqueous suspension of powdered garlic admin-istered by oral gavage to mice was determined to be 25 g/kg b.w. [Alqasoumi 2012].

Repeated dose toxicityFresh garlic juice orally administered to rats at 5 ml/kg b.w. daily for 3 weeks resulted in reduced weight gain, gastric mucosal damage and in some cases death [Nagakawa 1980].

Daily administration of a raw garlic extract to rats at 200 mg/kg b.w. for 4 weeks resulted in weight loss and a drop in serum protein levels [Shashikanth 1986].

An aqueous extract administered by gavage to rats at doses of 1000, 3000 and 5000 mg/kg b.w. for 14 days did not induce mortality. The increased levels of liver enzymes and bilirubin, and reduced levels of urea and creatinine, were non-significant compared to control. Whereas the low and high doses demonstrated a significant (p<0.005) increase in white blood cells. Neither gross pathology nor histopathological analysis revealed any adverse effects [Asiedu-Gyekye 2014].

An aqueous suspension of powdered garlic administered by oral gavage to mice for 90 days, at doses of 37.5 and 75 mg/kg b.w., induced mild to moderate autonomic symptoms such as changes of respiration rate, heart rate and hypothermia, in addition to causing itching, alopecia, agressive behavior and excitation [Alqasoumi 2012].

MutagenicityThe genotoxicity of orally administered garlic was assessed using the micronucleus test in mice; compared to controls no significant changes were found in the bone marrow cells [Abraham 1984]. No mutagenicity was evident in the Ames test [Yoshida 1984].

In the micronucleus test an aqueous suspension of powdered garlic administered to mice by oral gavage at doses of 250 and 500 mg/kg b.w. did not reveal any significant activity as compared to the control [Alqasoumi 2012].

Clinical safety dataSystematic reviews and meta-analyses have concluded that garlic preparations were well tolerated in all trials with minimal side effects [Ried 2013] and that no serious adverse events were reported in any of the included trials [Xiong 2015].

In a 5-month, open study involving 172 children with acute respiratory disease, there was no difference in the prevalence of gastrointestinal side effects between the groups receiving garlic tablets (not further specified), benzimidazole or placebo [Andrianova 2003].

In published studies involving consumption of up to 1.2 g of garlic powder daily, garlic odour was the most common side effect, with an incidence of up to 50%. However, this effect is not considered to be adverse. Gastrointestinal discomfort was a common adverse effect reported and there have been rare cases of allergic reactions [Hughes 2002; Pires 2002; Izzo 2007; Polat 2007].

In healthy volunteers 10 g of raw garlic consumed daily for 2 months induced no adverse events [Gadkari 1991].

Daily administration of high doses of garlic oil (approx. 120 mg, equivalent to 60 g/day fresh garlic) over a period of 3 months did not result in any toxic effects or adverse events [Bordia 1978].

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In 4 cases reduced platelet aggregation and prolonged bleeding time have been reported after intake of raw garlic or garlic powder [Rose et al. 1990; Burnham 1995; German 1995; Carden 2002; Woodbury & Sniecinski 2016], and in one further case also in combination with acetyl salicylic acid and milk thistle tablets (no further details) [Shakeel 2010].

In an 8 week, randomized, single-blind, placebo-controlled study involving 100 women in the third trimester of pregnancy, given either garlic (n=50; 800 mg garlic powder per day, 2 mg allicin) or placebo (n=50), no serious side effects were reported. A slight feeling of nausea was reported in 8 of the garlic group patients and 2 of the placebo patients. An “odour due to garlic” was reported by 34% of the garlic group and 4% of the placebo group [Ziaei 2001].

In a case report, consumption of approx. 6 stir-fried garlic cloves three times per week was associated with HIV virologic failure during treatment with boosted atazanavir [Duncan 2013].

REFERENCES

Abdelsattar MH. Garlic oil as an effective protective agent against cyclosporine-induced nephrotoxicity in rats. International Journal of Medicinal and Aromatic Plants 2013;3:85-92.

Abraham SK, Kesavan PC. Genotoxicity of garlic, turmeric and asafoetida in mice. Mutat Res 1984;136:85-8. http://dx.doi.org/10.1016/0165-1218(84)90138-1

Ackermann R, Mulrow C, Ramirez G, Gardner C, Morbidoni L, Lawrence V. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med 2001;161:813-24. http://dx.doi.org/10.1001/archinte.161.6.813

Adetumbi MA, Lau BHS. Allium sativum (garlic) - a natural antibiotic. Med Hypotheses 1983;12:227-37. http://dx.doi.org/10.1016/0306-9877(83)90040-3s

Adler AJ, Holub BJ. Effect of garlic and fish-oil supplementation on serum lipid and lipoprotein concentrations in hypercholesterolemic men. Am J Clin Nutr 1997;65:445-50. https://doi.org/10.1093/ajcn/65.2.445

Ahmed W, Zaki A, Nabil T. Prevention of methotrexate-induced nephro-toxicity by concomitant administration of garlic aqueous extract in rat. TURK J MED SCI 2015;45:507-516. Ali M, Thomson M. Consumption of a garlic clove a day could be beneficial in preventing thrombosis. Prostagland Leukotr Essent Fatty Acids 1995;53:211-2. http://dx.doi.org/10.1016/0952-3278(95)90118-3

Allium. In: British Herbal Pharmacopoeia 1983. Bournemouth: British Herbal Medicine Association 1983:20-1.

Alqasoumi S, Khan TH, Al-Yahya M, Al-Mofleh I, Rafatullah S. Effect of acute and chronic treatment of common spices in swiss albino mice: A safety assessment study. INT J PHARMACOL 2012;8:80-90. https://doi.org/10.3923/ijp.2012.80.90

Al-Qattan KK, Alnaqeeb MA, Ali M. The antihypertensive effect of garlic (Allium sativum) in the rat two-kidney-one-clip Goldblatt model. J Ethnopharmacol 1999;66:217-22. http://dx.doi.org/10.1016/S0378-8741(98)00173-1

Andrianova I. Vliianie chesnochnykh tabletok prolongirovannogo deistviia 'allikor' na zabolevaemost' ostrymi respiratornymivirusnymi infektsiiami u detei.Effect of long-acting garlic tablets 'allicor' on the incidence of acute respiratory viral infections in children. Terapevticheskii arkhiv 2003;75:53-6. (Article in Russian, quoted after Lissiman 2014).

Anusuya N, Durgadevi P, Dhinek A, Mythily S. Nephroprotective effect of ethanolic extract of garlic (Allium sativum L.) on cisplatin induced nephrotoxicity in male wistar rats. Asian Journal of Pharmaceutical and Clinical Research 2013;6:97-100.

Asdaq S, Inamdar M, Asad M, Nanjundan P. Interaction of propranolol with garlic in isoproterenol induced myocardial infarction in rat. J Pharmacol Toxicol 2008a;3:414-24.http://dx.doi.org/10.3923/jpt.2008.414.424

Asdaq S, Inamdar M, Asad M. Pharmacodynamic interaction of garlic with propranolol in ischemia-reperfusion induced myocardial damage. Pak J Pharm Sci 2010a;23:42-7.

Asdaq S, Inamdar M. Interaction of propranolol with garlic on bio-chemical and histological changes in rat. Iran J Pharm Res 2009a;8:201-7.

Asdaq S, Inamdar M. Pharmacodynamic interaction of captopril with garlic in isoproterenol-induced myocardial damage in rat. Phytother Res 2010b;24:720-5.

Asdaq S, Inamdar M. Pharmacodynamic interaction of garlic with captopril in ischemia-reperfusion induced myocardial damage in rats. Pharmacology online 2008b;2:875-88.

Asdaq S, Inamdar M. Pharmacodynamic interaction of garlic with hydrochlorothiazide in rats. Indian J Physiol Pharmacol 2009b;53:127-36.

Asdaq SMB, Inamdar MN. Pharmacodynamic and pharmacokinetic interactions of propranolol with garlic (Allium sativum) in rats. Evid Based Complement Alternat Med 2011;2011:824042. http://dx.doi.org/10.1093/ecam/neq076

Ashraf R, Khan RA, Ashraf I, Qureshi AA. Effects of Allium sativum (garlic) on systolic and diastolic blood pressure in patients with essential hypertension. Pak J Pharm Sci 2013;26:859-63.

Asiedu-Gyekye I, Awortwe C, Antwi D. Absence of visible toxic effects accompanying the short-term administration of an aqueous extract of Allium sativa linn. in male sprague-dawley rats. American J Pharmacology and Toxicology 2014;9:53-67. https://doi.org/10.3844/ajptsp.2014.53.67

Auer W, Eiber A, Hertkorn E, Hoehfeld E, Koehrle U, Lorenz A et al. Hypertension and hyperlipidaemia: garlic helps in mild cases. Br J Clin Pract 1990;44(Suppl 69):3-6.

Avci A, Atli T, Ergüder IB, Varli M, Devrim E, Aras S, et al. Effects of garlic consumption on plasma and erythrocyte antioxidant parameters in elderly subjects. Gerontology 2008;54:173-6. http://dx.doi.org/10.1159/000130426

Bagul M, Kakumanu S, Wilson TA. Crude Garlic Extract Inhibits Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis of Cancer Cells in Vitro. J Med Food 2015;18:731-737. http://dx.doi.org/10.1089/jmf.2014.0064

Beck E, Grünwald J. Allium sativum in der Stufentherapie der Hyper-lipidämie. Med Welt 1993;44:516-20.

Benavides GA, Squadrito GL, Mills RW, Patel HD, Isbell TS, Patel RP, Darley-Usmar VM, Doeller JE, Kraus DW. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci U S A 2007;104:17977-82. https://doi.org/10.1073/pnas.0705710104

Blaschek W, Wichtl M, Loew D. Alli sativi pulvis - Knoblauchpulver. In: Blaschek W, editor. Teedrogen und Phytopharmaka. Ein Handbuch für die Praxis. 6th ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft 2016;58-60.

Block E. Die Organoschwefelchemie der Gattung Allium und ihre

14

ALLII SATIVI BULBUS

Bedeutung für die organische Chemie des Schwefels. Angew Chem 1992;104:1158-203. Translated into English as: The organosulphur chemistry of the genus Allium: implications for the organic chemistry of sulfur. Angew Chem Int Ed Engl 1992;31:1135-78. http://dx.doi.org/10.1002/anie.199211351

Block E. The chemistry of garlic and onions. Sci Am 1985;252:114-9. http://dx.doi.org/10.1038/scientificamerican0385-114

Bordia A, Joshi HK, Sanadhya YK, Bhu N. Effect of essential oil of garlic on serum fibrinolytic activity in patients with coronary artery disease. Atherosclerosis 1978;28:155-9. http://dx.doi.org/10.1016/0021-9150(77)90152-6

Bordia A, Verma SK, Srivastava KC. Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronary artery disease. Prostagland Leukotr Essent Fatty Acids 1998;58:257-63. http://dx.doi.org/10.1016/S0952-3278(98)90034-5

Bordia A. Knoblauch und koronare Herzkrankheit. Wirkungen einer dreijährigen Behandlung mit Knoblauchextrakt auf die Reinfarkt- und Mortalitätsrate. Dtsch Apoth Ztg 1989;129(Suppl 15):16-7.

Bradley JM, Organ CL, Lefer DJ. Garlic-Derived Organic Polysulfides and Myocardial Protection. J Nutr 2016;146:403S-409S. https://doi.org/10.3945/jn.114.208066

Bradley PR, editor. Garlic. In: British Herbal Compendium. Volume 1. Bournemouth: British Herbal Medicine Association 1992;105-8.

Brändle M, Al Makdessi S, Weber RK, Dietz K, Jacob R. Prolongation of life span in hypertensive rats by dietary interventions. Effects of garlic and linseed oil. Basic Res Cardiol 1997;92:223-32. http://dx.doi.org/10.1007/BF00788517

Breithaupt-Grögler K, Ling M, Boudculas H, Belz GG. Protective effect of chronic garlic intake on elastic properties of aorta in the elderly. Circulation 1997;96:2649-55. https://doi.org/10.1161/01.CIR.96.8.2649

Brewitt B, Lehmann B. Lipidregulierung durch standardisierte Naturarzneimittel. Multizentrische Langzeitstudie an 1209 Patienten. Der Kassenarzt 1991;5:47-55.

Burnham BE. Garlic as a possible risk for postoperative bleeding. Plastic Reconstr Surg 1995;95:213. http://dx.doi.org/10.1097/00006534-199501000-00060

Capraz M, Dilek M, Akpolat T. Garlic, hypertension and patient education. Int J Cardiol 2007;121:130-1. http://dx.doi.org/10.1016/j.ijcard.2006.08.060

Carden S, Good W, Carden P, Good R. Garlic and the strabismus surgeon. Clin Experiment Ophthalmol 2002;30:303-4. http://dx.doi.org/10.1046/j.1442-9071.2002.00540.x

Chen S, Tang Y, Qian Y, Chen R, Zhang L. Allicin prevents H2O2-induced apoptosis of HUVECs by inhibiting an oxidative stress pathway. BMC Complement Altern Med 2014;14:321. https://doi.org/10.1186/1472-6882-14-321

Chourey S, Narsinghani T, Soni LK. Effect of Allium sativum on the pharmacokinetic of Metformin in rat plasma: A herb-drug interaction study. Der Pharma Chemica 2011;3:287-291.

Ciplea AG, Richter KD. The protective effect of Allium sativum and Crataegus on isoprenaline-induced tissue necroses in rats. Arzneim-Forsch/Drug Res 1988;38:1583-92.

Das GA, Dhara P, Dhundasi S, Das K. Effect of garlic (Allium sativum) on nickel II or chromium VI induced alterations of glucose homeostasis and hepatic antioxidant status under sub-chronic exposure conditions. J

Basic Clin Physiol Pharmacol 2009;20:1-14. http://dx.doi.org/10.1515/JBCPP.2009.20.1.1

Das I, Khan NS, Sooranna SR. Potent activation of nitric oxide synthase by garlic: a basis for its therapeutic applications. Curr Med Res Opin 1995;13:257-63. http://dx.doi.org/10.1185/03007999509111550

De B, Dutta D, Pal S, Gangopadhyay S, Das Baksi S, Pani A. The role of garlic in hepatopulmonary syndrome: a randomized controlled trial. Can J Gastroenterol 2010;24:183-8. https://doi.org/10.1155/2010/349076

De Santos OS, Grünwald J. Effect of garlic powder tablets on blood lipids and blood pressure - a six month placebo controlled double blind study. Br J Clin Res 1993;4:37-44.

De Santos OS, Johns RA. Effects of garlic powder and garlic oil preparations on blood lipids, blood pressure and well-being. Br J Clin Res 1995;6:91-100.

Dhawan V, Jain S. Effect of garlic supplementation on oxidized low density lipoproteinsand lipid peroxidation in patients of essential hypertension. Mol Cell Biochem 2004;266:109-15. http://dx.doi.org/10.1023/B:MCBI.0000049146.89059.53

Dhawan V, Jain S. Garlic supplementation prevents oxidative DNA damage in essential hypertension. Mol Cell Biochem 2005;275:85-94. http://dx.doi.org/10.1007/s11010-005-0824-2

Dorant E, van den Brandt PA, Goldbohm RA, Hermus RJJ, Sturmans F. Garlic and its significance for the prevention of cancer in humans: a critical view. Br J Cancer 1993;67:424-9. http://dx.doi.org/10.1038/bjc.1993.82

Duda G, Suliburska J, Pupek-Musialik D. Effects of short-term garlic supplementation on lipid metabolism and antioxidant status in hypertensive adults. Pharmacol Rep 2008;60:163-70.

Duncan A, Mills J. An unusual case of HIV virologic failure during treatment with boosted atazanavir. AIDS 2013;27:1361-2. http://dx.doi.org/10.1097/QAD.0b013e32835fac84

Egen-Schwind C, Eckard R, Kemper FH. Stoffwechsel von Allicin in der isoliert perfundierten Rattenleber. Hoher First-pass-Effekt von Allicin nachgewiesen. Med Welt 1991;42(Suppl 7a):49.

El-Sayyad HI, Abou-El-Naga AM, Gadallah AA, Bakr IH. Protective effects of Allium sativum against defects of hypercholesterolemia on pregnant rats and their offspring. Int J Clin Exp Med 2010;3:152-63.

Ernst E, Posadzki P. Can garlic-intake reduce the risk of cancer? A systematic review of randomised controlled trials. Focus on Alternative and Complementary Therapies 2012;17:192-196. http://dx.doi.org/10.1111/fct.12000

Fanelli S, Castro G, de T, Castro J. Mechanisms of the preventive properties of some garlic components in the carbon tetrachloride-promoted oxidative stress. Diallyl sulfide; diallyl disulfide; allyl mercaptan and allyl methyl sulfide. Res Commun Mol Pathol Pharmacol 1998;102:163-74.

Fatima A, Niaz K, Qudoos A, Murad S. Single blind placebo-controlled study on effects of Garlic tablets to reduce serum lipids. Pakistan Journal of Medical and Health Sciences 2014;8:302-305.

Gadkari JV, Joshi VD. Effect of ingestion of raw garlic on serum cholesterol level, clotting time and fibrinolytic activity in normal subjects. J Postgrad Med 1991;37:128-31.

Galeone C, Pelucchi C, Levi F, Negri E, Franceschi S, Talamini R, et al. Onion and garlic use and human cancer. Am J Clin Nutr 2006;84:1027-32. https://doi.org/10.1093/ajcn/84.5.1027

Galeone C, Pelucchi C, Talamini R, Negri E, Dal Maso L, Montella

15

ALLII SATIVI BULBUS

M, et al. Onion and garlic intake and the odds of benign prostatic hyperplasia. Urology 2007;70:672-6. http://dx.doi.org/10.1016/j.urology.2007.06.1099

Gallicano K, Foster B, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. Br J Clin Pharmacol 2003;55:199-202. http://dx.doi.org/10.1046/j.1365-2125.2003.01736.x

Gao C, Takezaki T, Ding J, Li M, Tajima K. Protective effect of allium vegetables against both esophageal and stomach cancer: a simultaneous case-referent study of a high-epidemic area in Jiangsu Province, China. Jpn J Cancer Res 1999;90:614-21. http://dx.doi.org/10.1111/j.1349-7006.1999.tb00791.x

Gardner C, Lawson L, Block E, Chatterjee L, Kiazand A, Balise R, et al. Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: A randomized clinical trial. Arch Intern Med 2007;167:346-53. http://dx.doi.org/10.1001/archinte.167.4.346

Garlic Powder - Allii sativi bulbi pulvis. European Pharmacopoeia. Council of Europe.

Gebhardt R, Beck H, Wagner KG. Inhibition of cholesterol biosynthesis by allicin and ajoene in rat hepatocytes and HepG2 cells. Biochim Biophys Acta 1994;1213:57-62. https://doi.org/10.1016/0005-2760(94)90222-4

Gebhardt R. Inhibition of cholesterol biosynthesis by a water-soluble garlic extract in primary cultures of rat hepatocytes. Arzneim-Forsch/Drug Res 1991;41:800-4.

Gebhardt R. Multiple inhibitory effects of garlic extracts on cholesterol biosynthesis in hepatocytes. Lipids 1993;28:613-9. http://dx.doi.org/10.1007/BF02536055

German K, Kumar U, Blackford HN. Garlic and the risk of TURP bleeding. Br J Urol 1995;76:518. http://dx.doi.org/10.1111/j.1464-410X.1995.tb07766.x

Gupta R, Thakur B, Singh P, Singh HB, Sharma VD, Katoch VM, et al.. Anti-tuberculosis activity of selected medicinal plants against multi-drug resistant Mycobacterium tuberculosis isolates. Indian J Med Res 2010;131:809-13.

Harenberg J, Giese C, Zimmermann R. Effect of dried garlic on blood coagulation, fibrinolysis, platelet aggregation and serum cholesterol levels in patients with hyperlipoproteinemia. Atherosclerosis 1988; 74:247-9. http://dx.doi.org/10.1016/0021-9150(88)90244-4

Heinle H, Betz E. Effects of dietary garlic supplementation in a rat model of atherosclerosis. Arzneim-Forsch/Drug Res 1994;44:614-7.

Hikino H, Tohkin M, Kiso Y, Namiki T, Nishimura S, Takeyama K. Antihepatotoxic actions of Allium sativum bulbs. Planta Med 1986; 52:163-8. http://dx.doi.org/10.1055/s-2007-969111

Holzgartner H, Schmidt U, Kuhn U. Comparison of the efficacy and tolerance of a garlic preparation vs. bezafibrate. Arzneim-Forsch/Drug Res 1992;42:1473-7.

Hughes T, Varma S, Stone N. Occupational contact dermatitis from a garlic and herb mixture. Contact Dermatitis 2002;47:48. http://dx.doi.org/10.1034/j.1600-0536.2002.470110.x

Imai J, Ide N, Nagae S, Moriguchi T, Matsuura H, Itakura Y. Antioxidant and radical scavenging effects of aged garlic extract and its constituents. Planta Med 1994;60:417-20. http://dx.doi.org/10.1055/s-2006-959522

Isaacsohn JL, Moser M, Stein E, Dudley K, Davey JA, Liskov E, Black HR. Garlic powder and plasma lipids and lipoproteins. Arch Int Med 1998;158:1189-94. http://dx.doi.org/10.1001/archinte.158.11.1189

Isensee H, Rietz B, Jacob R. Cardioprotective actions of garlic (Allium sativum). Arzneim-Forsch/Drug Res 1993;43:94-8.

Ishige K, Takagi N, Imai T, Rausch W, Kosuge Y, Kihara T, et al. Role of Caspase-12 in Amyloid beta-Peptide-Induced Toxicity in Organotypic Hippocampal Slices Cultured for Long Periods. J Pharmacol Sci 2007;104:46-55. http://dx.doi.org/10.1254/jphs.FP0061533

Izzo A. Efficacy and safety of Allium sativum (garlic). Focus on Alternative and Complementary Therapies 2007;12:162-6.

Jacob R, Ehrsam M, Ohkubo T, Rupp H. Antihypertensive und kardioprotektive Effekte von Knoblauchpulver (Allium sativum). Med Welt 1991;42(Suppl 7a):39-41.

Jacob R, Isensee H, Rietz B, Makdessi S, Sweidan H. Cardioprotection by dietary interventions in animal experiments. Pharm Pharmacol Lett 1993;3:131-4.

Jain AK, Vargas R, Gotzkowsky S, McMahon FG. Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med 1993;94:632-5. http://dx.doi.org/10.1016/0002-9343(93)90216-C

Josling P. Preventing the common cold with a garlic supplement: a double-blind, placebo-controlled survey. Adv Ther 2001;18:189-193. https://doi.org/10.1007/BF02850113

Jung EM, Jung F, Mrowietz C, Kiesewetter H, Pindur G, Wenzel E. Influence of garlic powder on cutaneous microcirculation. A randomized placebo-controlled double-blind cross-over study in apparently healthy subjects. Arzneim-Forsch/Drug Res 1991;41:626-30.

Kandziora J. Blutdruck- und lipidsenkende Wirkung eines Knoblauch-Präparates in Kombination mit einem Diuretikum. Ärztl Forsch 1988; 35:1-8.

Khalil AM, Yasuda M, Farid AS, Desouky MI, Mohi-Eldin MM. Immunomodulatory and antiparasitic effects of garlic extract on Eimeria vermiformis-infected mice. Parasitology Research 2015;114:2735-2742 http://dx.doi.org/10.1007/s00436-015-4480-5

Khoo Y, Aziz Z. Garlic supplementation and serum cholesterol: A meta-analysis. J Clin Pharm Ther 2009;34:133-45. http://dx.doi.org/10.1111/j.1365-2710.2008.00998.x

Kiesewetter H, Jung EM, Mrowietz C, Koscielny J, Wenzel E. Effect of garlic on platelet aggregation in patients with increased risk of juvenile ischaemic attack. Eur J Clin Pharmacol 1993a;45:333-6. http://dx.doi.org/10.1007/BF00265950

Kiesewetter H, Jung F, Jung EM, Blume J, Mrowietz C, Birk A et al. Effects of garlic coated tablets in peripheral arterial occlusive disease. Clin Invest 1993b;71:383-6. http://dx.doi.org/10.1007/BF00186628

Kiesewetter H, Jung F, Pindur G, Jung EM, Mrowietz C, Wenzel E. Effect of garlic on thrombocyte aggregation, microcirculation and other risk factors. Int J Clin Pharmacol Ther Toxicol 1991;29:151-5.

Kiliç R, Çetin AB, Demir S, Göktolga G. A case of Intraretinal and preretinal hemorrhages thought to develop due to garlic extract. Retina-Vitreus 2014;22:236-238.

Kinuthia GK, Kabiru EW, Anjili CO, Kigondu EM, Ngure VN. Efficacy of crude methanolic extracts of Allium sativum L. and Moringa stenopetala (Baker f.) cufod. against Leishmania major. International Journal of Medicinal and Aromatic Plants 2014;4:16-25.

Koch HP, Lawson LD, editors. Garlic - The science and therapeutic application of Allium sativum L. and related species. 2nd ed. Baltimore-Philadelphia-London: Williams & Wilkins 1996.

Koh S, Kwon H, Park K, Ko J, Kim J, Hwang M, et al. Protective effect

16

ALLII SATIVI BULBUS

of diallyl disulfide on oxidative stress-injured neuronally differentiated PC12 cells. Brain Res Mol Brain Res 2005;133:176-86. http://dx.doi.org/10.1016/j.molbrainres.2004.10.006

Kojuri J, Vosoughi A, Akrami M. Effects of anethum graveolens and garlic on lipid profile in hyperlipidemic patients. Lipids Health Dis 2007;6:5. http://dx.doi.org/10.1186/1476-511X-6-5

Koscielny J, Klüßendorf D, Latza R, Schmitt R, Radtke H, Siegel G, Kiesewetter H. The antiatherosclerotic effect of Allium sativum. Atherosclerosis 1999;144:237-49. http://dx.doi.org/10.1016/S0021-9150(99)00060-X

Lachmann G, Radeck W. Pharmakokinetik von 35S-Alliin bei Ratten. Med Welt 1991;42(Suppl 7a):48.

Lan X, Sun H, Liu J, Lin Y, Zhu Z, Han X. Effects of garlic oil on pancreatic cancer cells. Asian Pac. J. Cancer Prev. 2013;14:5905-10. https://doi.org/10.7314/APJCP.2013.14.10.5905

Lash JP, Cardoso LR, Mesler PM, Walczak DA, Pollak R. The effect of garlic on hypercholesterolemia in renal transplant patients. Transplant Proceed-ings 1998;30:189-91. https://doi.org/10.1016/S0041-1345(97)01227-X

Lata S, Saxena KK, Bhasin V, Saxena RS, Kumar A, Srivastava VK. Beneficial effects of Allium sativum, Allium cepa and Commiphora mukul on experimental hyperlipidemia and atherosclerosis - a comparative evaluation. J Postgrad Med 1991;37:132-5.

Lawson LD, Ransom DK, Hughes BG. Inhibition of whole blood platelet aggregation by compounds in garlic clove extracts and commercial garlic products. Thromb Res 1992;65:141-56. http://dx.doi.org/10.1016/0049-3848(92)90234-2

Lawson LD. Bioactive organosulfur compounds of garlic and garlic products: role in reducing blood lipids. In: Kinghorn AD, Balandrin MF, editors. Human Medicinal Agents from Plants. ACS Symp Ser 534. Washington DC: American Chemical Society 1993:306-30. https://doi.org/10.1021/bk-1993-0534.ch021

Ledezma E, Marcano K, Jorquera A, De S, Padilla M, Pulgar M, et al. Efficacy of ajoene in the treatment of tinea pedis: a double-blind and comparative study with terbinafine. J Am Acad Dermatol 2000;43:829-832. http://dx.doi.org/10.1067/mjd.2000.107243

Lewin G, Popov I. Antioxidant effects of aqueous garlic extract. 2nd communication: inhibition of the Cu2+-initiated oxidation of low density lipoproteins. Arzneim-Forsch/Drug Res 1994;44:604-7.

Li WR, Shi QS, Liang Q, Huang XM, Chen YB. Antifungal effect and mechanism of garlic oil on Penicillium funiculosum. Appl Microbiol Biotechnol 2014. http://dx.doi.org/10.1007/s00253-014-5919-9

Lin JJ, Chang T, Cai WK, Zhang Z, Yang YX. Post-injury administration of Allicin attenuates ischemic brain injury through sphingosine kinase 2: in vivo and in vitro studies. Neurochem Int 2015;89:92-100. https://doi.org/10.1016/j.neuint.2015.07.022

Lissiman E, Bhasale AL, Cohen M. Garlic for the common cold. Cochrane database of systematic reviews (Online) 2009;CD006206.

Lissiman E, Bhasale AL, Cohen M. Garlic for the common cold. Cochrane Database Syst Rev 2014;11:CD006206. http://dx.doi.org/10.1002/14651858

Liu L, Yeh Y. Inhibition of cholesterol biosynthesis by organosulfur compounds derived from garlic. Lipids 2000;35:197-203. http://dx.doi.org/10.1007/BF02664770

Lutomski J, Maleszka R. Mycostatic properties of garlic preparation. II. International Garlic Symposium: Pharmacy, pharmacology and clinical application of Allium sativum. Berlin, 7-10 March 1991.

Mader FH. Treatment of hyperlipidaemia with garlic-powder tablets. Evidence from the German Association of General Practitioners’ multicentric placebo-controlled double-blind study. Arzneim-Forsch/Drug Res 1990;40:1111-6.

Madineh H, Yadollahi F, Yadollahi F, Mofrad EP, Kabiri M. Impact of garlic tablets on nosocomial infections in hospitalized patients in intensive care units. Electron Physician 2017;9:4064-4071. https://doi.org/10.19082/4064

Mand JK, Gupta PP, Soni GL, Singl R. Effect of garlic on experimental atherosclerosis in rabbits. Indian Heart J 1985;37:183-8.

Mane SK, Jordan PA, Bahna SL. Eosinophilic esophagitis to unsuspected rare food allergen. Ann Allergy Asthma Immunol 2013;111:64-5. http://dx.doi.org/10.1016/j.anai.2013.04.004

Markowitz JS, DeVane CL, Chavin KD, Taylor RM, Ruan Y, Donovan JL. Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Therap 2003;74:170-177. http://dx.doi.org/10.1016/S0009-9236(03)00148-6

Masjedi F, Gol A, Dabiri Sh. Preventive effect of garlic juice on food intake and serum levels of glucose, cholesterol and triglycerides in streptozotocin-induced diabetic rats. Journal of Medicinal Plants 2010;9:124-135+204. (Article in Arabian)

Mathew B, Prasad N, Prabodh R. Cholesterol-lowering effect of organosulphur compounds from garlic: a possible mechanism of action. Kathmandu Univ Med J 2004;2:100-102.

Mayeux PR, Agrawal KC, Tou J-SH, King BT, Lippton HL, Hyman AL et al. The pharmacological effects of allicin, a constituent of garlic oil. Agents Actions 1988;25:182-90. http://dx.doi.org/10.1007/BF01969110

McCrindle BW, Helden E, Conner WT. Garlic extract therapy in children with hypercholesterolemia. Arch Pediatr Adolesc Med 1998;152:1089-94. https://doi.org/10.1001/archpedi.152.11.1089

Mennella JA, Beauchamp GK. Maternal diet alters the sensory qualities of human milk and the nursling’s behavior. Pediatrics 1991;88:737-44.

Mikail H. Phytochemical screening, elemental analysis and acute toxicity of aqueous extract of Allium sativum L. bulbs in experimental rabbits. J Med Plant Res 2010;4:322-6.

Mohammadzadeh F, Dolatian M, Jorjani M, Majd HA, Borumandnia N. Comparing the therapeutic effects of garlic tablet and oral metronidazole on bacterial vaginosis: A randomized controlled clinical trial. Iran Red Crescent Me 2014;16(7):e19118. http://dx.doi.org/10.5812/ircmj.19118

Munoz N, Plummer M, Vivas J, Moreno V, De S, Lopez G, et al. A case-control study of gastric cancer in Venezuela. Int J Cancer 2001;93:417-23. http://dx.doi.org/10.1002/ijc.1333

Musubika B, Domínguez Montero G, Betancourt Valladares M, Nkwangu D. Efecto antihemostático del extracto alcohólico de Allium sativum L. combinado con warfarina en ratas Wistar. Antihaemostatic effect of combination of Allium sativum L. ethanol extract and warfarin in Wistar rats. Revista Cubana de Plantas Medicinales 2015;20:301-312.

Nagae S, Ushijima M, Hatono S, Imai J, Kasuga S, Matsuura H et al. Pharmacokinetics of the garlic compound S-allylcysteine. Planta Med 1994;60:214-7. http://dx.doi.org/10.1055/s-2006-959461

Nagai K. Experimental studies on preventive effect of garlic extract against infections with influenza and Japanese encephalitis viruses in mice. J Jap Assoc Infect Dis 1973;47:111-5. [Japanese].https://doi.org/10.11150/kansenshogakuzasshi1970.47.111

17

ALLII SATIVI BULBUS

Nakagawa S, Kasuga S, Matsuura H. Prevention of liver damage by aged garlic extract and its components in mice. Phytotherapy Res 1989;3:50-3. http://dx.doi.org/10.1002/ptr.2650030203

Nakagawa S, Masamoto K, Sumiyoshi H, Harada H. Acute toxicity test of garlic extract. J Toxicol Sci 1984;9:57-60. [Japanese]. http://dx.doi.org/10.2131/jts.9.57

Nakagawa S, Masamoto K, Sumiyoshi H, Kunihiro K, Fuwa T. Effect of raw and extracted garlic juice on growth of young rats and their organs after peroral administration. J Toxicol Sci 1980;5:91-112. [Japanese]. http://dx.doi.org/10.2131/jts.5.91

Nandyala S, Vijaya Kumar G, Srinivasu M, Sravani B. Influence of garlic oil on anti diabetic activity of gliclazide in diabetic rats. International Journal of Pharma and Bio Sciences 2013;4:871-876.

Nasri H, Rafieian-Kopaei M. Preventive and curative effect of garlic on nephrotoxic effect of gentamicin in rat. Journal of Babol University of Medical Sciences 2014;16:42-48.

Neil A, Silagy C, Lancaster 1, Hodgeman J, Moore JW, Jones L, Fowler GH. Garlic powder in the treatment of moderate hyperlipidaemia: a controlled trial and meta-analysis. J Royal Coll Physicians London 1996; 30:329-34.

Nouri M, Pipelzadeh M, Badiei A. A comparative study on the effectiveness of garlic with clofibrate in the treatment of hyperlipidemia. J Med Sci 2008;8:85-9. http://dx.doi.org/10.3923/jms.2008.85.89

Orekhov AN, Grünwald J. Effects of garlic on atherosclerosis. Nutrition 1997;13:656-63. http://dx.doi.org/10.1016/S0899-9007(97)83010-9

Orekhov AN, Pivovarova EM, Tertov VV. Garlic powder tablets reduce atherogenicity of low density lipoprotein. A placebo-controlled double-blind study. Nutr Metab Cardiovasc Dis 1996;6:21-31.

Orekhov AN, Tertov VV, Sobenin IA, Pivovarova EM. Direct anti-atherosclerosis–related effects of garlic. Ann Med 1995;27:63-5. http://dx.doi.org/10.3109/07853899509031938

Öztürk Y, Aydin S, Kosar M, Hüsnü Can Baser K. Endothelium-dependent and independent effects of garlic on rat aorta. J Ethnopharmacol 1994;44:109-16. http://dx.doi.org/10.1016/0378-8741(94)90076-0

Parastouei K, Ravanshad S, Mostaphavi H, Setoudehmaram E. Effects of garlic tablet on blood sugar, plasma lipids and blood pressure in type 2 diabetic patients with hyperlipidemia. J Med Plants 2006;5:48-54. (Article in Persian; referenced by database abstract only).

Pathak A, Leger P, Bagheri H, Senard J, Boccalon H, Montastruc J. Garlic interaction with fluindione: a case report. Therapie 2003;58:380-1. http://dx.doi.org/10.2515/therapie:2003060

Peleg A. Effect of garlic on lipid profile and psychopathologic parameters in people with mild to moderate hypercholesterolemia. Isr Med Assoc J 2003;5:637-40.

Phelps S, Harris WS. Garlic supplementation and lipoprotein oxidation susceptibility. Lipids 1993;28:475-7. http://dx.doi.org/10.1007/BF02535949

Pires G, Pargana E, Loureiro V, Almeida M, Pinto J. Allergy to garlic. Allergy 2002;57:957-8. http://dx.doi.org/10.1034/j.1398-9995.2002.23832_2.x

Piscitelli S, Burstein A, Welden N, Gallicano K, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 2002;34:234-8. http://dx.doi.org/10.1086/324351

Polat M, Oztas P, Yalcin B, Tamer E, Gur G, Alli N. Contact dermatitis due to Allium sativum and Ranunculus illyricus: two cases. Contact

Dermatitis 2007;57:279-80. http://dx.doi.org/10.1111/j.1600-0536.2007.01120.x

Popov I, Blumstein A, Lewin G. Antioxidant effects of aqueous garlic extract. 1st communication: direct detection using the photo-chemiluminescence. Arzneim-Forsch/Drug Res 1994;44:602-4.

Pourkabir M, Shomali T, Asadi F. Alterations in serum lipid, lipoprotein and visceral abdominal fat pad parameters of hypercholesterolemic guinea pigs in response to short term garlic consumption. African Journal of Biotechnology 2010;9:7930-7933. https://doi.org/10.5897/AJB09.1795

Quereshi AA, Abiurmeileh N, Din ZZ, Elson CE, Burger WC. Inhibition of cholesterol and fatty acid biosynthesis in liver enzymes and chicken hepatocytes by polar fractions of garlic. Lipids 1983;18:343-8. http://dx.doi.org/10.1007/BF02537229

Reinhart KM, Coleman CI, Teevan C, Vachhani P, White CM. Effects of garlic on blood pressure in patients with and without systolic hypertension: a meta-analysis. Ann Pharmacother 2008;42:1766-71. http://dx.doi.org/10.1345/aph.1L319

Reinhart KM, Talati R, White CM, Coleman CI. The impact of garlic on lipid parameters: a systematic review and meta-analysis. Nutr Res Rev 2009;22:39-48. http://dx.doi.org/10.1017/S0954422409350003

Rekka EA, Kourounakis PN. Investigation of the molecular mechanism of the antioxidant activity of some Allium sativum ingredients. Pharmazie 1994;49:539-40.

Reuter HD. Spektrum Allium sativum L., 2nd ed. Basel: Aesopus Verlag, 1991.

Ried K. Garlic Lowers Blood Pressure in Hypertensive Individuals, Regulates Serum Cholesterol, and Stimulates Immunity: An Updated Meta-analysis and Review. J Nutr 2016;146:389-396. https://doi.org/10.3945/jn.114.202192

Ried K, Toben C, Fakler P. Effect of garlic on serum lipids: an updated meta-analysis. Nutr Rev 2013;71:282-99. http://dx.doi.org/10.1111/nure.12012

Rind NA, Dahot MU, Malik SA, Kumar M, Bhutto MA. Comparative antihyperglycemic activity of aqueous extracts of garlic (Allium sativum) and ginger (Zingiber officinale) in alloxan-induced male rabbits. Pakistan Journal of Biotechnology 2013;10:53-62.

Rinneberg AL, Lehmann B. Therapie der Hyperlipoproteinämie mit einem standardisierten Knoblauchpulver-Arzneimittel. Der Kassenarzt 1989;45:40-7.

Rose KD, Croissant PD, Parliament CF, Levin MB. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: a case report. Neurosurgery 1990;26:880-2. http://dx.doi.org/10.1227/00006123-199005000-00026

Rotzsch W, Richter V, Rassoul F, Walper A. Postprandiale Lipämie unter Medikation von Allium sativum. Arzneim Forsch/Drug Res 1992; 42:1223-7.

Saad Abdultawab H, Ayuob NN. Can garlic oil ameliorate diabetes-induced oxidative stress in a rat liver model? A correlated histological and biochemical study. Food Chem Toxicol 2013;59:650-656. http://dx.doi.org/10.1016/j.fct.2013.07.009

Sabitha P, Adhikari P, Shenoy S, Kamath A, John R, Prabhu M, et al. Efficacy of garlic paste in oral candidiasis. Trop Doct 2005;35:99-100. http://dx.doi.org/10.1258/0049475054037084

Sahbaz A, Isik H, Aynioglu O, Gungorduk K, Gun BD. Effect of intraabdominal administration of Allium sativum (garlic) oil on

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postoperative peritoneal adhesion. Eur J Obstet Gyn R B 2014;177:44-47. http://dx.doi.org/10.1016/j.ejogrb.2014.03.018

Saradeth T, Seidl S, Resch KL, Ernst E. Does garlic alter the lipid pattern in normal volunteers? Phytomedicine 1994;1:183-5. http://dx.doi.org/10.1016/S0944-7113(11)80062-0

Satitvipawee P, Rawdaree P, Indrabhakti S, Ratanasuwan T, Getn-gern P, Viwatwongkasem C. No effect of garlic extract supplement on serum lipid levels in hypercholesterolemic subjects. J Med Assoc Thai 2003;86:750-7.

Schilcher H, Fischer M, Frank B, Kammerer S, Wegener T. Knoblauchzwiebel (Allii sativi bulbus). In: Leitfaden Phytotherapie. 5th ed. München: Elsevier Urban & Fischer 2016;189-191.

Setiawan V, Yu G, Lu Q, Lu M, Yu S, Mu L, et al. Allium vegetables and stomach cancer risk in China. Asian Pac J Cancer Prev 2005;6:387-95.

Shackebaei D, Ghazvineh S, Godini A, Pilehvarian A, Reshadat S. Cardioprotective effect of garlic juice on the isolated rat heart in ischemia- reperfusion. Journal of Medicinal Plants 2010;9:71-79.

Shakeel M, Trinidade A, McCluney N, Clive B. Complementary and alternative medicine in epistaxis: A point worth considering during the patient's history. Eur J Emerg Med 2010;17:17-9. http://dx.doi.org/10.1097/MEJ.0b013e32832b1679

Shariatzadeh S, Mehranjani M, Mamoodi M, Abnosi M, Momeni H, Dezfulian A, et al. Effects of garlic (Allium sativum) on blood sugar and nephropathy in diabetic rats. J Biol Sci 2008;8:1316-21. http://dx.doi.org/10.3923/jbs.2008.1316.1321

Sharifi F, Sheikhi A, Behdad M, Mousavinasab N. Effect of garlic on serum adiponectin and interleukin levels in women with metabolic syndrome. International Journal of Endocrinology and Metabolism 2010;8:68-73.

Sharma VD, Sethi MS, Kumar A, Rarotra JR. Antibacterial property of Allium sativum Linn.: in vivo & in vitro studies. Indian J Exp Biol 1977;15:466-8.

Shashikanth KN, Basappa SC, Murthy VS. Effect of feeding raw and boiled garlic extracts on the growth, cecal microflora and serum proteins of albino rats. Nutr Rep Int 1986;33:313-9.

Sher A, Fakhar-Ul-Mahmood M, Shah SNH, Bukhsh S, Murtaza G. Effect of garlic extract on blood glucose level and lipid profile in normal and alloxan diabetic rabbits. Adv Clin Exp Med 2012;21:705-711.

Siegel G, Emden J, Schnalke F, Walter A, Rückborn K, Wagner KG. Wirkungen von Knoblauch auf die Gefäßregulation. Med Welt 1991;42(Suppl 7a):32-4.

Siegel G, Nuck R, Schnalke F, Michel F. Molecular evidence for phytopharmacological K+ channel opening by garlic in human vascular smooth muscle cell membranes. Phytother Res 1998;12:149-151. http://dx.doi.org/10.1002/(SICI)1099-1573(1998)12:1+<S149::AID-PTR279>3.0.CO;2-T

Siegel G, Walter A, Schnalke F, Rückborn K, Emden J, Wagner KG. Knoblauch und Senkung des Gefäßtonus. Vasomed 1992;4:8-12.

Siegers CP, Röbke A, Pentz R. Effects of garlic preparations on superoxide production by phorbol ester activated granulocytes. Phytomedicine 1999;6:13-6. http://dx.doi.org/10.1016/S0944-7113(99)80029-4

Siegers C-P. Toxicology, side effects and allergenicity. In: Symposium on the chemistry, pharmacology and medical applications of garlic. Lüneburg, Germany, 23-25 February 1989. Cardiology in Practice 1989; September (Suppl):14-5.

Silagy C, Neil A. Garlic as a lipid lowering agent - a meta-analysis. J Royal Coll Physicians London 1994b;28:39-45.

Silagy CA, Neil HAW. A meta-analysis of the effect of garlic on blood pressure. J Hypertension 1994a;12:463-8. http://dx.doi.org/10.1097/00004872-199404000-00017

Simons LA, Balasubramaniam S, von Königsmark M, Parfitt A, Simons J, Peters W. On the effect of garlic on plasma lipids and lipoproteins in mild hypercholesterolaemia. Atherosclerosis 1995;113:219-25. http://dx.doi.org/10.1016/0021-9150(94)05449-S

Simons S, Wollersheim H, Thien T. A systematic review on the influence of trial quality on the effect of garlic on blood pressure. Neth J Med 2009;67:212-9.

Singh D, Porter T. Inhibition of Sterol 4{alpha}-Methyl Oxidase Is the Principal Mechanism by Which Garlic Decreases Cholesterol Synthesis. J Nutr 2006;136:1156-1161. https://doi.org/10.1093/jn/136.3.759S

Sobenin IA, Andrianova IV, Fomchenkov IV, Gorchakova TV, Orekhov AN. Time-released garlic powder tablets lower systolic and diastolic blood pressure in men with mild and moderate arterial hypertension. Hypertens Res 2009a;32:433-7. http://dx.doi.org/10.1038/hr.2009.36

Sobenin IA, Pryanishnikov VV, Kunnova LM, Rabinovich YA, Martirosyan DM, Orekhov AN. The effects of time-released garlic powder tablets on multifunctional cardiovascular risk in patients with coronary artery disease. Lipids in Health and Disease 2009b;9/2010/ANR. https://doi.org/10.1186/1476-511X-9-119

Sohn D, Han C, Jung Y, Kim S, Kim S, Cho Y. Anti-inflammatory and antimicrobial effects of garlic and synergistic effect between garlic and ciprofloxacin in a chronic bacterial prostatitis rat model. Int J Antimicrob Ag 2009;34:215-9. http://dx.doi.org/10.1016/j.ijantimicag.2009.02.012

Sooranna S, Hirani J, Khan N, Das I. Garlic and nitric oxide metabolism: the implications during pregnancy. Eur J Clin Res 1996;8:22-3.

Stabler SN, Tejani AM, Huynh F, Fowkes C. Garlic for the prevention of cardiovascular morbidity and mortality in hypertensive patients. Cochrane Database Syst Rev 2012;8:CD007653. http://dx.doi.org/10.1002/14651858

Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia. A meta-analysis of randomized clinical trials. Ann Intern Med 2000;133: 420-9. https://doi.org/10.7326/0003-4819-133-6-200009190-00009

Sticher O. Beurteilung von Knoblauchpräparaten. Dtsch Apoth Ztg 1991;131:403-13.

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

Supakul L, Pintana H, Apaijai N, Chattipakorn S, Shinlapawittayatorn K. Protective effects of garlic extract on cardiac function, heart rate variability, and cardiac mitochondria in obese insulin-resistant rats. Eur J Nutr 2014;53:919-928. http://dx.doi.org/10.1007/s00394-013-0595-6

Superko HR, Krauss RM. Garlic powder, effect on plasma lipids, postprandial lipemia, low-density lipoprotein particle size, high-density lipoprotein subclass distribution and lipoprotein (a). J Am Coll Cardiol 2000;35:321-6. http://dx.doi.org/10.1016/S0735-1097(99)90541-7

Svendson L, Rattan SIS, Clark BFC. Testing garlic for possible anti-aging effects on long-term growth characteristics, morphology and macromolecular synthesis of human fibroblasts in culture. J Ethnopharmacol 1994;43:125-33. http://dx.doi.org/10.1016/0378-8741(94)90009-4

Tanamai J. The efficacy of cholesterol-lowering action and side effects of garlic enteric coated tablets in man. J Med Assoc Thailand 2004;87:1156-61.

19

ALLII SATIVI BULBUS

Thomson M, Al-Amin Z, Al-Qattan K, Shaban L, Ali M. Anti-diabetic and hypolipidaemic properties of garlic (Allium sativum) in streptozotocin-induced diabetic rats. Int J Diabetes Metab 2007;15:108-15. https://doi.org/10.3923/ijp.2013.501.512

Thomson M, Al-Qattan KK, Divya JS, Ali M. Ameliorative actions of garlic (Allium sativum) and ginger (Zingiber officinale) on biomarkers of diabetes and diabetic nephropathy in rats: Comparison to aspirin. Int J Pharmacol 2013;9:501-512.

Török B, Belagyi J, Rietz B, Jacob R. Effectiveness of garlic on the radical activity in radical generating systems. Arzneim-Forsch/Drug Res 1994;44:608-11.

Tsai Y, Cole LL, Davis LE, Lockwood SJ, Simmons V, Wild GC. Antiviral properties of garlic: in vitro effects on influenza B, Herpes simplex and Coxsackie viruses. Planta Med 1985;51:460-1. http://dx.doi.org/10.1055/s-2007-969553

Turner B. Effect of garlic (Allium sativum) powder tablets on serum lipids, blood pressure and arterial stiffness in normo-lipidaemic volunteers: A randomised, double-blind, placebo-controlled trial. Brit J Nutr 2004;92:701-6. http://dx.doi.org/10.1079/BJN20041255

Van D, Espirito S, Meijer P, Kamerling I, Schoemaker R, Dirsch V, et al. Effect of garlic powder on C-reactive protein and plasma lipids in overweight and smoking subjects. American J Clin Nutr 2006;84:1324-9. https://doi.org/10.1093/ajcn/84.6.1324

Vorberg G, Schneider B. Therapy with garlic: results of a placebo-controlled, double-blind study. Br J Clin Pract 1990;44(Suppl 69):7-11.

Vovolis V, Kalogiros L, Ivanova D, Koutsostathis N. Garlic-induced severe anaphylaxis in a nonatopic patient. J Investig Allergol Clin Immunol 2010;20:356.

Waheed A, Nawaz U, Miana GA. Antidiabetic actions of powdered plant and aqueous extract of Allium sativum (garlic) bulbs in type-II diabetic patients. Medical Forum Monthly 2014;25:27-31.

Walper A, Rassoul F, Purschwitz K, Schulz V. Effizienz einer Diätempfehlung und einer zusätzlichen Phytotherapie mit Allium sativum bei leichter bis mäßiger Hypercholesterinämie. Medwelt 1994; 45:327-32.

Wang H-P, Yang J, Qin L-Q, Yang X-J. Effect of Garlic on Blood Pressure: A Meta-Analysis. J Clin Hypertens 2015;17:223-231. http://dx.doi.org/10.1111/jch.12473.

Wargovich MJ. Cancer chemoprevention: organosulphur components of garlic. In: II. International Garlic Symposium. Pharmacy, pharmacology and clinical application of Allium sativum. Berlin, 7-10 March 1991. Cardiology in Practice 1991;June (Suppl):7.

Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol. A meta-analysis. Ann Intern Med 1993;119:599-605. https://doi.org/10.7326/0003-4819-119-7_Part_1-199310010-00009

Watson CJ, Grando D, Fairley CK, Chondros P, Garland SM. The effects of oral garlic on vaginal candida colony counts: A randomised placebo controlled double-blind trial. BJOG: An International Journal of Obstetrics and Gynaecology 2014;121:498-506. http://dx.doi.org/10.1111/1471-0528

Wojcikowski K, Myers S, Brooks L. Effects of garlic oil on platelet aggregation: a double blind placebo controlled crossover study. Platelets 2007;18:29-34. http://dx.doi.org/10.1080/09537100600800636

Woodbury A, Sniecinski R. Garlic-Induced Surgical Bleeding: How Much Is Too Much? A Case Rep 2016;7:266-269.

Xiong XJ, Wang PQ, Li SJ, Li XK, Zhang YQ. Garlic for hypertension: A systematic review and meta-analysis of randomized controlled trials. Phytomedicine 2015;22:352-361. http://dx.doi.org/10.1016/j.phymed.2014.12.013

Xu S, Simon C. Allyl mercaptan, a major metabolite of garlic compounds, reduces cellular cholesterol synthesis and its secretion in Hep-G2 cells. J Nutr Biochem 1999;10:654-9. http://dx.doi.org/10.1016/S0955-2863(99)00056-X

Yamaji K, Sarker K, Abeyama K, Maruyama I. Anti-atherogenic effects of an egg yolk-enriched garlic supplement. Int J Food Sci Nutr 2004;55:61-6. http://dx.doi.org/10.1080/09637480310001642493

Yeh YY, Yeh S-M. Garlic reduces plasma lipids by inhibiting hepatic cholesterol and triacylglycerol synthesis. Lipids 1994;29:189-93. http://dx.doi.org/10.1007/BF02536728

Yoshida S, Hirao Y, Nakagawa S. Mutagenicity and cytotoxicity tests of garlic. J Toxicol Sci 1984;9:77-86. http://dx.doi.org/10.2131/jts.9.77

Zeng T, Guo FF, Zhang CL, Song FY, Zhao XL, Xie KQ. A meta-analysis of randomized, double-blind, placebo-controlled trials for the effects of garlic on serum lipid profiles. J SCi Food Agric 2012;92:1892-1902. http://dx.doi.org/10.1002/jsfa.5557

Zhang X, Lowe D, Giles P, Fell S, Connock M, Maslin D. Gender may affect the action of garlic oil on plasma cholesterol and glucose levels of normal subjects. J Nutr 2001;131:1471-8. https://doi.org/10.1093/jn/131.5.1471

Ziaei S, Hantoshzadeh S, Rezasoltani P, Lamyian M. The effect of garlic tablet on plasma lipids and platelet aggregation in nulliparous pregnants at high risk of preeclampsia. Eur J Obstet Gynecol Reprod Biol 2001;99:201-6. http://dx.doi.org/10.1016/S0301-2115(01)00384-0

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ABSINTHII HERBA Wormwood Second Edition, 2003AGNI CASTI FRUCTUS Agnus Castus Second Edition, 2003AGRIMONIAE HERBA Agrimony Online Series, 2019ALCHEMILLAE HERBA Lady's Mantle Online Series, 2013ALLII SATIVI BULBUS Garlic Online Series, 2019ALOE BARBADENSIS Barbados Aloes Online Series, 2014ALOE CAPENSIS Cape Aloes Online Series, 2014ALTHAEAE RADIX Marshmallow Root Online Series, 2018ANGELICAE RADIX Angelica Root Supplement 2009ANISI FRUCTUS Aniseed Online Series, 2014ARNICAE FLOS Arnica Flower Second Edition, 2003ARCTII RADIX Burdock Root Online Series, 2016BALLOTAE NIGRAE HERBA Black Horehound Online Series, 2015BETULAE FOLIUM Birch Leaf Online Series, 2015BOLDI FOLIUM Boldo Leaf Second Edition, 2003CALENDULAE FLOS Calendula Flower Second Edition, 2003CAPSICI FRUCTUS Capsicum Supplement 2009CARVI AETHEROLEUM Caraway Oil Online Series, 2019CARVI FRUCTUS Caraway Fruit Second Edition, 2003CARYOPHYLLI AETHEROLEUM Clove Oil Online Series, 2014CENTAURII HERBA Centaury Online Series, 2015CENTELLAE ASIATICAE HERBA Centella Supplement 2009CHAMOMILLAE ROMANAE FLOS Roman Chamomile Flower Online Series, 2019CHELIDONII HERBA Greater Celandine Second Edition, 2003CIMICIFUGAE RHIZOMA Black Cohosh Online Series, 2011CINNAMOMI CORTEX Cinnamon Second Edition, 2003COLAE SEMEN Cola Online Series, 2014CRATAEGI FOLIUM CUM FLORE Hawthorn Leaf and Flower Second Edition, 2003CRATAEGI FRUCTUS Hawthorn Berries Supplement 2009CUCURBITAE SEMEN Pumpkin Seed Supplement 2009CURCUMAE LONGAE RHIZOMA Turmeric Second Edition, 2003CURCUMAE XANTHORRHIZAE RHIZOMA Javanese Turmeric Supplement 2009CYNARAE FOLIUM Artichoke Leaf Supplement 2009ECHINACEAE ANGUSTIFOLIAE RADIX Narrow-leaved Coneflower Root Online Series, 2019ECHINACEAE PALLIDAE RADIX Pale Coneflower Root Online Series, 2018ECHINACEAE PURPUREAE HERBA Purple Coneflower Herb Supplement 2009ECHINACEAE PURPUREAE RADIX Purple Coneflower Root Supplement 2009ELEUTHEROCOCCI RADIX Eleutherococcus Supplement 2009EQUISETI HERBA Equisetum stem Online Series, 2018EUCALYPTI AETHEROLEUM Eucalyptus Oil Second Edition, 2003FILIPENDULAE ULMARIAE HERBA Meadowsweet Online Series, 2015FOENICULI AETHEROLEUM Fennel Oil Online Series, 2019FOENICULI FRUCTUS Fennel Fruit Online Series, 2019FRANGULAE CORTEX Frangula Bark Online Series, 2017FUMARIAE HERBA Fumitory Online Series, 2018GENTIANAE RADIX Gentian Root Online Series, 2014GINKGO FOLIUM Ginkgo Leaf Second Edition, 2003GINSENG RADIX Ginseng Second Edition, 2003GRAMINIS RHIZOMA Couch Grass Rhizome Online Series, 2016GRINDELIAE HERBA Grindelia Online Series, 2015HAMAMELIDIS AQUA Hamamelis Water Online Series, 2012HAMAMELIDIS CORTEX Hamamelis Bark Online Series, 2012HAMAMELIDIS FOLIUM Hamamelis Leaf Online Series, 2012HARPAGOPHYTI RADIX Devil’s Claw Root Supplement 2009HEDERAE HELICIS FOLIUM Ivy Leaf Second Edition, 2003HIPPOCASTANI SEMEN Horse-chestnut Seed Second Edition, 2003HYDRASTIS RHIZOMA Goldenseal rhizome Online Series, 2013HYPERICI HERBA St. John’s Wort Online Series, 2018

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The second edition of ESCOP Monographs, published as a hardback book in 2003 with a Supplement in 2009, has been widely acclaimed for its authoritative information on the therapeutic uses of herbal medicines. Monographs covering a total of 107 herbal substances include extensive summaries of pharmacological, clinical and toxicological data, and copious references to scientific literature form an important part of each text.

Although publication in the form of books was convenient in the past, ESCOP recognizes that online publication now offers a number of advantages, not least in facilitating rapid publication of individual monographs as soon as all stages of preparation have been completed. Commencing from 2011, therefore, new and revised monographs will be published online only.

The European legislative framework for herbal medicines has advanced considerably over the past decade. Directive 2004/24/EC introduced a simplified registration procedure for traditional herbal medicinal products in EU member states and imposed a 2011 deadline for the registration of certain products on the market. The Committee on Herbal Medicinal Products (HMPC), established in 2004 as part of the European Medicines Agency, has made substantial progress in the preparation of Community Herbal Monographs and associated documentation to provide a more harmonized approach to the scientific assessment of herbal medicinal products throughout the European Community

Whether the evaluation of a herbal medicine is based on evidence of clinical efficacy (well-established use) or on experience and historical use of that product (traditional use) those involved at all levels of the regulatory process need access to detailed, reliable and structured summaries of the available efficacy and safety data. ESCOP monographs meet that requirement and offer an invaluable source of scientific information on herbal medicines to regulators, manufacturers, academics, researchers, health professionals and numerous others.

MonographsThe Scientific Foundation for Herbal Medicinal Products

www.escop.com ISBN 978-1-901964-69-1

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