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Comp. by: Udayasankar Stage: Proof Chapter No.: 158 Title Name: HBNP
Date:22/6/12 Time:07:51:44 Page Number: 1
1Garlic and Cardiovascular Diseases 158
2Syed Haris Omar
3Contents
41 Introduction ................................................................................. 4
52 Bioactive Constituents and Preparations .. .. . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . 4
63 Garlic and Cardio Protection .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . 7
74 Hypolipidemic Effects .. . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 8
84.1 Clinical Studies .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 9
94.2 Proposed Mechanism .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 10
10 5 Antioxidant Effects .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 10
11 6 Clinical Studies .............................................................................. 13
12 7 Proposed Mechanism .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 14
13 8 Antihypertensive Effects .. . ................................................................. 14
14 9 Clinical Studies .............................................................................. 15
15 10 Possible Mechanism .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 16
16 11 Antithrombotic and Fibrinolytic Effect .................................................... 17
17 12 Clinical Studies .............................................................................. 18
18 13 Proposed Mechanism .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 19
19 14 Antiatherosclerotic Effect ................................................................... 21
20 15 Clinical Studies .............................................................................. 22
21 16 Proposed Mechanism .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 22
22 17 Other Cardioprotective Activity .. . ......................................................... 23
23 18 Bioavailability and Metabolism . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 24
24 19 Side Effects and Toxicity ................................................................... 25
25 20 Conclusion .. ................................................................................. 26
26 References........... ........................................... .................................. 27
S.H. Omar
Faculty of Sciences, School of Biomedical Sciences, Charles Sturt University, Wagga Wagga,
NSW, Australia
e-mail: somar@csu.edu.au,syedharisomar@gmail.com
K.G. Ramawat, J.M. Merillon (eds.), Handbook of Natural Products,
DOI 10.1007/978-3-642-22144-6_158, #Springer-Verlag Berlin Heidelberg 2013
1
Comp. by: Udayasankar Stage: Proof Chapter No.: 158 Title Name: HBNP
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27 Abstract
28 Globally, there is an increasing prevalence of cardiovascular diseases (CVD)
29 and is still maintaining its apex position. It includes elevation in low density
30 lipoproteins cholesterol (LDL-C), increase in LDL-C oxidation, irregular
31 clumping of blood platelets, and increase in C-reactive proteins and homocys-
32 teine. These abnormalities are also associated with atherosclerosis, high blood
33 pressure, and hypercholesterolemia. Garlic (Allium sativum L.) is among the
34 world’s oldest cultivated plants, popular in food and for medicinal purposes.
35 Commercially available garlic preparations in the form of garlic oil, powder, and
36 pills are widely used for therapeutic purposes. The water-soluble and insoluble
37 sulfur compounds in garlic showed beneficial effects in all these cardiac abnor-
38 malities, especially for the treatment of hypercholesterolemia and prevention of
39 arteriosclerosis through antioxidant ability involving induction and inhibition of
40 various metabolic enzymes and via chelating activity. There is continuous
41 investigation being carried out to find out the other potent bioactive constituent
42 in garlic. Likewise, phenolic compounds have emerged as minor but potent
43 compounds, which are responsible for its antioxidant activity. Most of the
44 studies are in the preliminary stage and need to be clarified in clinical trials.
45 Keywords
46 Atherosclerosis • cardiovascular disease • garlic • hypercholesterolemia • sulfur
47 compounds
48 Abbreviations
49 AA Arachidonic acid
50 ACE Angiotensin converting enzyme
51 ADP Adenosine diphosphate
52 AGE Age garlic extract
53 AMS Allyl methyl sulfide
54 BC Before Christ
55 BHA Butylated hydroxyanisole
56 BHT Butylated hydroxytoluene
57 BP British Pharmacopeia
58 Ca
2+
Calcium ion
59 CAC Coronary arterial calcification
60 CETP Cholesteryl ester transfer protein
61 cNOS Endothelial nitric oxide synthase
62 CVD Cardiovascular disease
63 DADS Diallyl disulfide
64 DAS Diallyl sulfide
65 DASO Diallyl sulfoxide
66 DASO
2
Diallyl sulfone
2 S.H. Omar
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67 DBP Diastolic blood pressure
68 DNA Deoxyribose nucleic acid
69 DOX Doxorubicin
70 DPPH 1,1-Diphenyl-2-picrylhydrazyl
71 DTS Diallyl trisulfide
72 EH Essential hypertension
73 FDA Food and Drug Administration
74 GC–MS Gas chromatography–Mass spectrometry
75 GSH Glutathione
76 GTP Guanosine triphosphate
77 H
2
O
2
Hydrogen peroxide
78 H
2
S Hydrogen sulfide
79 Hcy Homocysteine
80 HDL-C High density lipoprotein cholesterol
81 HepG
2
Liver hepatocellular carcinoma cell
82 HETE Hydroxyeicosatetraenoic acid
83 HMG-CoA 3 Hydroxy-3-methylglutaryl coenzyme A
84 HOCl Hypochlorous acid
85 iNOS Inducible nitric oxide synthase
86 IP
3
Inositol phosphate
87 LDL Low density lipoprotein
88 LDL-C Low density lipoprotein cholesterol
89 L-NAME L-Arginine methyl ester
90 MDA Malondialdehyde
91 NO Nitric oxide
92 OxLDL Oxidized low density lipoprotein
93 PGG2 Prostaglandin G
2
94 PGH
2
Prostaglandin H
2
95 Ph Eur European Pharmacopeia
96 ROS Reactive oxygen species
97 SAC S-Allylcysteine
98 SACS S-Allylcysteine sulfoxide
99 SBP Systolic blood pressure
100 SBS S-Benzylcysteine
101 SPC S-Propylcysteine
102 TAS Total antioxidant status
103 TBARS Thiobarbituric acid reactive species
104 TC Total cholesterol
105 TG Triglycerides
106 TXA
2
Thromboxane A
2
107 TXB
2
Thromboxane B
2
108 USP United States Pharmacopeia
109 VF Ventricular fibrillation
110 VT Ventricular tachycardia
158 Garlic and Cardiovascular Diseases 3
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111 1 Introduction
112 Garlic, scientifically known as Allium sativum, is a close relative of onions, leeks,
113 and chives. The word Allium is derived from the Celtic word al, meaning pungent,
114 burning, or stinging and sativum meaning planted, cultivated, or sown. The English
115 name “garlic” comes from the Anglo-Saxon gar-leac or spear plant, which refers to
116 its flowering stalk. It is one of the oldest cultivated plants with its origin in central
117 Asia. It has also been found in Egyptian pyramids, ancient Greek temples, and on
118 Sumerian clay tablets dating from 2600 to 2100 BC [1,2]. Garlic was used as
119 medicine by the ancient Egyptians especially for the working class involved in
120 heavy labor and is listed in the Egyptian medical papyrus Codex Elsers (1500 BC).
121 The ancient medical manuscript of India, Charaka-Samhita, recommends garlic for
122 the treatment of heart disease and arthritis, and another ancient Indian medical
123 textbook, Bower Manuscript recommends garlic for fatigue, parasitic disease,
124 digestive disorder, and leprosy [2]. During World Wars I and II, the injured soldier
125 wounds were dressed with garlic, and it was used as an antiseptic in the prevention
126 of gangrene.
127 Garlic and its preparations are prescribed in many pharmacopeias
128 around the world, including Ph Eur 6 [3], USP 31 [4], and BP 2007 [5]. Garlic is
129 also incorporated in the list of German Commission E, which is a therapeutic
130 guide in herbal medicine, complied by a special expert commission of
131 the German Federal Institute of Medicines and Medical Inventions. German
132 Commission E recommends usage of an average dose of 4 g of fresh garlic or
133 equivalent preparations of garlic as a dietary supplement to hyperlipidemic patients
134 and in prevention of vascular alterations caused by aging. Garlic is popularly used
135 as one of the major spices, and its medicinal use is both widespread and growing
136 due to proven potential health benefits, which have been published in more than
137 3,000 research articles. Studies suggests that garlic and its components not
138 only prevent cardiovascular disease (including lowering of serum cholesterol
139 level, inhibition of platelet aggregation, and increased fibrinolysis) but
140 also other chronic diseases associated with aging, stimulation of immune
141 function through activation of macrophages, induction of T cell proliferation,
142 reduction of blood glucose level, radioprotection, improvement of memory and
143 learning deficit, and protection against microbial (viral and fungal infections) and
144 anticancer effects.
145 2 Bioactive Constituents and Preparations
146 Garlic bulbs develop and grow entirely underground and are composed of several
147 bulbils structure called cloves. Each clove is enclosed in a white or pink skin of the
148 parent bulb, mainly consists of active secondary plant metabolites, which are respon-
149 sible for taste, flavor, and health benefits. There are over 600 cultivated subvarieties
150 of garlic available in the world, and scientifically, all the true garlic comes under the
4 S.H. Omar
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151 species Allium sativum with two most common subspecies, ophioscorodon or
152 hard-necked garlic (ophios for short) and Sativum or soft-necked garlics.
153 Fresh raw garlic bulbs contain 65% of water, 28% carbohydrate, 2%
154 proteins, 1.2% amino acids, 1.5% fibers, fatty acids, phenols, and trace
155 elements, as well as more than 33 (2.3%) sulfur (Fig. 158.1)-containing
156 compounds [6,7]. Hundred grams of garlic provides 149 kcal energy, 33.07 g
157 of carbohydrate, 6.93 g of protein, and 0.5 g of fat. It has been estimated that 97%
158 of chemical constituents in garlic are water soluble, and very small amounts of
159 oil-soluble constituents which vary from 0.15% to 0.7% (Table 158.1). The major
Fig. 158.1 Major classification of the bioactive constituents in garlic
t1:1Table 158.1 Water-soluble and oil-soluble constituent in garlic [8]
Water soluble Oil soluble
t1:2
S-allylcysteine Diallyl disulfidet1:3
Alliin Diallyl trisulfidet1:4
S-propylcysteine Methyl allyl sulfidet1:5
S-ethylcysteine Dipropyl disulfidet1:6
S-methylcysteine Dipropyl sulfidet1:7
Se-(methyl) selenocysteine Allixint1:8
Selenomethionine Allyl mercaptant1:9
Selenocysteine Allyl methyl sulfidet1:10
158 Garlic and Cardiovascular Diseases 5
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160 trace elements found in the fresh garlic cloves are shown in Table 158.2. Further
161 compounds present in a small amount are flavonoids, steroids, and triterpene
162 saponins from the b-sitosterol or F-gitogenin.
163 The sulfur-containing compounds are generally classified into nonvolatile
164 precursor and organosulfur compound. d-glutamyl-S-allyl-L-cysteines and
165 S-allyl-L-cysteine sulfoxides (alliin) are abundant in intact garlic and serve as
166 a precursor of allicin, methiin, (+)-S-(trans-1-propenyl)-L-cysteine sulfoxide,
167 and cycloalliin. When there is any mechanical injury to the garlic bulb then,
168 there is formation of thiosulfinate compound called allicin through enzymatic
169 reaction of sulfur-substituted cysteine sulfoxides, which are present in the
170 cytoplasm with alliinase in the vacuole, via sulfur-substituted sulfenic acids.
171 Key studies by Cavallito and Bailey [9] and Stoll and Seebeck [10]
172 identified the compound allicin. Allicin further decomposes into diallyl disulfide
173 (DADS), diallyl sulfide (DAS), diallyl trisulfide (DTS), and sulfur dioxide.
174 In addition, there are other thiosulfinates present in garlic homogenate, including
175 allyl methyl, methyl allyl, and trans-1-propenyl thiosulfinate, that are also unsta-
176 ble like allicin.
177 There are various available brands of garlic products in stores/on shelves
178 that provide a convenient way to obtain the health benefits of garlic. The most
179 commonly used garlic preparations are raw garlic per se, aged garlic, garlic oil,
180 allicin extract powder (Table 158.3) and commercially prepared lyophilized garlic
t2:1Table 158.2 Important trace elements in fresh garlic bulb
Constituents Quantity per 100 g
t2:2
Aluminum 0.5–1 mgt2:3
Barium 0.2–1 mgt2:4
Boron 0.3–0.6 mgt2:5
Calcium 50–90 mgt2:6
Chromium 0.3–0.5 mgt2:7
Copper 0.02–0.03 mgt2:8
Germanium 14 mgt2:9
Iron 2.8–3.9 mgt2:10
Manganese 0.2–0.6 mgt2:11
Magnesium 43–77 mgt2:12
Nicotinic acid 0.5 mgt2:13
Phosphorus 390–460 mgt2:14
Potassium 100–120 mgt2:15
Retinal 15 mgt2:16
Riboflavin 0.08 mgt2:17
Selenium 15–35 mgt2:18
Sodium 10–22 mgt2:19
Thiamine 0.25 mgt2:20
Vitamin C 5 mgt2:21
Zinc 1.8–3.1 mgt2:22
6 S.H. Omar
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181 powder, garlic oil, garlic oil macerate, and aged garlic extract (AGE) [11,12].
182 Among the popular commercial garlic preparations investigated in trials are
183 KWAI
®
(Lichtwer Pharma, Berlin, Germany), Garlicin
®
(Nature’s Way,
184 Springville, UT, USA), and Kyolic-100
®
(Wakunaga of America, Mission Viejo,
185 CA, USA).
186 3 Garlic and Cardio Protection
187 Globally, CVD remain the biggest cause of death and disability. According to
188 WHO report 2011, 17.3 million people died from CVD in 2008, which accounts
189 for over 80 % of deaths in low- and middle-income countries. It is estimated that by
190 2030, almost 23.6 million people will die from CVD [13]. CVD refers to a group of
191 disorders of the heart and vascular system and includes coronary heart disease,
t3:1Table 158.3 Commonly available and used garlic preparations
Preparation Major sulfur constituents Preparation process Properties
t3:2
Raw garlic
per se
d-glutamyl-S-allyl-L-
cysteines, S-allyl-L-cysteine
sulfoxides, allicin,
adenosine
Intact clove with the
white or pink skin by
simple pull off
Precursor of allicin, methiin,
(+)-S-(trans-1-propenyl)-L-
cysteine sulfoxide, and
cycloalliin
t3:3
Garlic
essential
oil
Diallyl disulfide (DADS),
diallyl sulfide (DAS), diallyl
trisulfide (DTS), methyl
allyl disulfide, methyl allyl
trisulfide, vinyldithiins, and
ajoenes
Steam distillation or
ether extracted
Most potent source of garlic
odor and causes body odor,
used in perfumery and
cosmetic industry
t3:4
Garlic oil
macerate
oil
DAS, allyl methyl dimethyl,
mono-to hexasulfides, allyl
1-propenyl and methyl 1-
propenyl di-, tri-, and
tetrasulfides
Cold extraction method
(maceration) and steam
distillation
Manufactured as capsule in
diluted form for therapeutic
use
t3:5
Garlic
powder
Alliin accumulates naturally
during storage of the bulbs
at cool temperature
Simply dehydrated,
pulverized garlic clove
with (<60 C)
temperature control
Commercially available for
household use
t3:6
Allicin
powder
extract
Allicin Specialized patented
extraction process
produces allicin liquid
that is spray dried
Stable at cool temperatures
but at high temperature
allicin degraded
t3:7
Aged
garlic
extract
(AGE)
Stable and water-soluble
organosulfur compounds,
such as S-allylcysteine, S-
allylmercaptocysteine, with
allixin, selenium, and N-
alpha-(1-deoxy-D-fructos-1-
yl)-L-arginine
Sliced raw garlic is
stored in 15–20 %
ethanol, fermented bulb
of age 2 years
Highly bioavailable and
shown to be superior to raw
garlic in terms of its
antioxidant properties
t3:8
158 Garlic and Cardiovascular Diseases 7
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192 congestive heart failure, stroke, congenital heart defects, myocardial infarction, and
193 high blood pressure. Imbalance between free radicals production and scavenging
194 leads to oxidative damage of membrane lipids, proteins, carbohydrates, and finally
195 to DNA which brings changes in the structural, mechanical, electrical, and bio-
196 chemical properties of the heart. Nowadays, natural herbal drugs are gaining greater
197 acceptance from the researchers and public due to advances in understanding the
198 mechanism of action, fewer side effects, and lesser cost effective therapy. Extensive
199 in vitro, in vivo, and clinical studies showed that garlic with its sulfur and nonsulfur
200 bioactive compounds is involved in the prevention and treatment of CVD.
201 4 Hypolipidemic Effects
202 Hyperlipidemia, which is characterized by an increase in the level of cholesterol or
203 lipids (LDL, triglycerides) in the blood, serves as a major risk factor of atheroscle-
204 rosis. The growing interest in complementary and alternative medicine has led to an
205 increasing number of nonpharmacological therapies for lipid management and
206 treatment of hyperlipidemia/hypercholesterolemia with dietary intervention.
207 These include garlic, which reduces total cholesterol (TC), low density lipoprotein
208 cholesterol (LDL-C), and triglyceride (TG) levels; furthermore, it increases high
209 density lipoprotein cholesterol (HDL-C), which has been confirmed in several
210 research studies.
211 Preparations of garlic including garlic paste, garlic oil, allicin, and ajoene
212 have been found to significantly reduce cholesterol biosynthesis in rat hepatocytes
213 via inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and
214 14-a-demethylase [14,15] and human HepG
2
cells [16]. After measurement of the
215 enzyme activity, it has been indicated that garlic and its constituents inhibit human
216 squalene monooxygenase along with HMG-CoA reductase, the enzymes involved
217 in cholesterol biosynthesis [8,17]. In addition, garlic supplementation significantly
218 decreased the cholesterol 7-a-hydroxylase activity [18]. Augusti et al. [19] in 2005
219 confirmed the inhibition of HMG-CoA reductase by garlic. Some authors
220 postulate that garlic’s trace minerals, such as tellurium (Te), are involved in the
221 inhibition of hepatic cholesterol synthesis [20]. It was found that the more
222 water-soluble compounds like S-allylcysteine (SAC) present in aged garlic extract
223 are less cytotoxic but more efficient in inhibiting cholesterol biosynthesis; in
224 contrast the lipid-soluble sulfur compounds such as diallyl sulfide (DAS) are less
225 efficient [16]. In rabbits that were fed with a high-cholesterol diet and supplemented
226 with garlic or allicin, it was found that hypercholesterolemia was significantly
227 inhibited by 50% and showed a decrease in tissue cholesterol and LDL-C
228 concentrations and raised HDL-C concentrations along with reduced atheromatous
229 changes [21]. Koch [22] indicated that the cholesterol-lowering effect of garlic
230 was probably due to the nonsulfur component, saponin. In addition, another
231 study [23] also supported the saponin fraction from methanolic raw garlic extracts,
232 which mainly contains spirostanol saponins produced by the conversion
233 of furostanol saponins via b-glucosidase. It lowered TC and LDL-C
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234 cholesterol without changing HDL-C levels in hypercholesterolemic animal
235 models. A recently published animal study results showed that garlic significantly
236 reduced TC, TG, LDL-C, very low density lipoprotein (VLDL-C), liver
237 triglyceride, plasma malondialdehyde (MDA), and elevated plasma antioxidant in
238 garlic-treated rats along with decrease in liver phosphatidate phosphohydrolase
239 (PAP) activity [24].
240 4.1 Clinical Studies
241 Several clinical trials on garlic preparation have investigated, but only a few
242 of them have showed significant hypolipidemic effects. In a meta-analysis on
243 28 clinical trials, Warshafsky et al. [25] found only five randomized,
244 placebo-controlled studies that met their criteria for inclusion in the meta-analy-
245 sis. The analysis result showed that treatment with garlic or garlic preparations
246 caused decrease an approximately 9% in TC level. In addition, another
247 meta-analysis of 16 published studies [26] in 1994, revealed that treatment
248 with garlic preparations resulted in nearly a 12% decrease in TC and
249 a similar decrease in LDL-C. Out of 16 studies, only 8 studies included the
250 data on TG; when analyzed together, they revealed a 13% decrease in TG levels.
251 A 12-week, randomized, placebo-controlled study [27] using Kwai garlic powder
252 (900 mg/day) showed a reduction in TC and LDL-C levels by 6% and 11%,
253 respectively, in the garlic supplement group, while TC and LDL-C levels
254 decreased by 1% and 3%, respectively, in the placebo control group. In a long-
255 term (10 months) randomized, double-blind, crossover study [28] in moderately
256 hypercholesterolemic men, using AGE versus placebo, the measurements were
257 made six times during the first intervention (AGE or placebo) and five times over
258 the 120 days of crossover to the alternate treatment. AGE resulted in a maximum
259 TC reduction of 6% for all study subjects compared with placebo and 7%
260 compared with their baseline values. While the LDL-C reduction was 4.5% and
261 4% compared against placebo and baseline, respectively. A comparative study
262 [29] was reported in 1997, in which garlic (900 mg powder/day) and fish oil (12 g
263 fish oil/day) were used as dietary supplements. This was a randomized, placebo-
264 controlled (partially double-blind) study with four arms: garlic with fish oil
265 placebo, fish oil with garlic placebo, garlic and fish oil, and both placebos.
266 Potential subjects began a 3-week run-in period for dietary stabilization. During
267 this run-in period, TC level had to exceed 5.2 mmol/L (200 mg/dL). They
268 reported that garlic significantly reduced both TC and LDL-C levels, whereas
269 fish oil also significantly decreased TG and increased LDL-C levels as expected.
270 An interesting outcome by Zhang et al. [30] showed that gender might be affect
271 the action of garlic on plasma cholesterol and glucose levels of normal subjects.
272 Alder et al. [31] in 2003 published a systematic review of the effectiveness of
273 garlic as an antihyperlipidemic agent. They included ten studies and found that in
274 six studies garlic was effective in reducing serum cholesterol levels. The average
275 drop in total cholesterol was 9.9%, LDL-C 11.4%, and triglycerides 9.9%. In
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276 a study, consumption of enteric-coated garlic supplements, standardized to pro-
277 duce 9.6 mg allicin, significantly decreased TC (4%) and LDL-C (7%) in mild to
278 moderated hypercholesterolemic patients when combined with a low-fat diet [32].
279 A clinical study confirmed the hypolipidemic effect of raw garlic in
280 hyperlipidemic subjects and reported significantly reduction of TC and TG
281 along with significantly increase in HDL-C [33]. Recently published meta-
282 analysis studies, in which 13 trials including 1,056 subjects, do not produce any
283 statistically significant reduction in serum total cholesterol level from garlic [34].
284 In addition, another recently published meta-analysis of 29 trials suggested intake
285 of garlic causes significant reduction in TC and TG but does not exhibit any
286 significant effect on LDL-C or HDL-C [35].
287 4.2 Proposed Mechanism
288 There are four possible mechanisms through which garlic inhibit the cholesterol
289 synthesis and enhance the cholesterol excretion from the body (Fig. 158.2). The first
290 one is that garlic decreases cholesterol absorption in the intestine, as shown in
291 hypercholesterolemic rat models [23]. Second, experiments using cultures of rat
292 hepatocytes have shown that garlic inhibits the enzymes involved in cholesterol
293 synthesis [16,36,37]. Third, Borek [38] has suggested that the cholesterol-lowering
294 effect of garlic is caused by deactivation of HMG-CoA reductase, involved in the
295 synthesis of cholesterol. Fourth, garlic also increased the excretion of cholesterol,
296 as manifested by enhanced excretion of acidic and neutral steroids after garlic
297 feeding [39].
298 5 Antioxidant Effects
299 There is a continuous production of free radicals from the body’s metabolic process
300 that use oxygen, such as respiration and some cell-mediated immune functions. The
301 LDL oxidation in the artery wall gives rise to thrombosis, atherosclerosis, and
302 CVD. Besides reactive oxygen species (ROS) and reactive nitrogen species (RNS),
303 hypochlorous acid (HOCl) is also a strong endogenous oxidant and is excessively
304 produced in inflammatory, degenerative, and neoplastic disorders; thus, effective
305 therapies and/or prophylaxes using exogenous scavengers of high specificity are
306 required. Homeostasis and self-defense system of the body maintain a balance
307 between the amount of generated free radicals in the body and body internal
308 antioxidants glutathione (GSH) to quench and/or scavenge or even detoxify them
309 and finally protect the body against their harmful effects. Nowadays, commercially
310 available synthetic antioxidants such as BHA (butylated hydroxyanisole) and BHT
311 (butylated hydroxytoluene) are being replaced with natural origin antioxidants
312 because of their toxicity and carcinogenicity. Garlic and its preparations show
313 antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes
314 superoxide dismutase, catalase, and glutathione peroxidase, and increasing
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315 glutathione in the cells (Fig. 158.3). It has been observed that aqueous extracts
316 from raw garlic and unpeeled cloves treated with distinct thermal processes were
317 able to differentially scavenge HOCl and that SAC was the only effective garlic
318 compound [40].
319 Alliin scavenges superoxide, while allyl cysteine and allyl disulfide do not react
320 with superoxide. Allicin suppress the formation of superoxide by the xanthine/
321 xanthine oxidase system, probably via a thiol exchange mechanism. It is now
322 concluded that alliin, allyl cysteine, and allyl disulfide all scavenges hydroxyl
323 radicals (OH). Allyl disulfide, alliin, allicin, and allyl cysteine exhibit different
324 patterns of antioxidant activities as protective compounds against free radical
325 damage [41–43] and appear in fresh garlic approximately 1,000 times more potent
326 as antioxidants than those found in aged garlic extract, while whole garlic and
Fig. 158.2 Hypolipidemic mechanism of garlic. (a) Inhibit the cholesterol biosynthesis in liver;
(b) Inhibit the rate limiting enzyme HMG-CoA reductase; (c) Inhibit intestinal absorption; (d)
Induces the rate of cholesterol excretion
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327 aqueous garlic extract exhibit direct antioxidant effects and enhance the serum
328 levels of two antioxidant enzymes: catalase and glutathione peroxidase [44]. Sev-
329 eral studies have been performed to test the antioxidant activity of raw and boiled
330 garlic by using different assays: b-carotene linoleate model system (b-carotene),
331 radical scavenging activity by 1, 1-diphenyl-2-picrylhydrazyl (DPPH), scavenging
332 activity against nitric oxide (NO) with 2, 29-azinobis (3-ethylbenzothiazoline-6-
333 sulfonic acid) radical cation (ABTS
+
), ferric-reducing/antioxidant power (FRAP),
334 and Cu
2+
-induced LDL-C oxidation [45–49]. It has been investigated that an
335 aqueous extract obtained from 1 mg of a garlic preparation was as effective as an
336 antioxidant as 30 nmol ascorbic acid and/or 36 nmol a-tocopherol [50]. In rat liver
337 microsomes, garlic extract prevented formation of thiobarbituric-acid-reactive sub-
338 stances in cell membranes during lipid peroxidation in a dose-dependent manner
339 [51]. In an in vitro and animal study, there was a significant improvement in the
340 plasma lipid levels in rats fed cholesterol-containing diets and an increase in the
341 plasma antioxidant activity in groups of rats fed cholesterol-free diets supplemented
342 with raw and boiled garlic at 100C for 20 min [52,53]. A concentration-dependent
343 inhibition of LDL-C oxidation was observed with the oil-soluble garlic compound,
344 allixin [54]. In another in vitro study, AGE significantly reduced Cu
2+
and 15-
345 lipoxygenase-mediated lipid peroxidation of isolated human LDL-C by 81% and
346 37%, respectively [55]. Aqueous garlic extracts have the ability to scavenge
Fig. 158.3 Antioxidant mechanism: garlic inhibiting oxidative modification of LDL-C, scaveng-
ing ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and
glutothione peroxidase and glutothione in the cells, thus protecting endothelial cells from the
injury by the oxidized molecules
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347 superoxide anion (O2
), hydrogen peroxide (H
2
O
2
), and hydroxyl radical (OH)in
348 the following aqueous preparations: (a) extracts of boiled garlic cloves (BG),
349 (b) extracts of microwave-treated garlic cloves (MG), and (c) extracts of pickled
350 garlic (PG) and heated extracts of (a) garlic powder (HGP) and (b) raw garlic
351 (HRG). The data were compared with the unheated raw garlic (RG) or with
352 the unheated garlic powder (GP). Extracts of GP and RG scavenged O2
,H
2
O
2
,
353 and OHin a concentration-dependent way. The ROS scavenging capacity was
354 not decreased in the aqueous garlic extracts except in MG and HRG (for O2
) and
355 in HGP and PG (for H
2
O
2
), while the heating before or after garlic cutting
356 was unable to eliminate the capacity of the extracts to scavenge H
2
O
2
,O
2
,
357 and OH[56]. Moreover, it was also found that fresh garlic, subjected to
358 a cooking regimen of 100 C during 20 min, preserves its bioactivity: the decrease
359 in the contents of the studied compounds and the decrease in the total
360 antioxidant potential were statistically not significant [53]. Recently,
361 Lei et al. [57] suggested that DADS and DATS protect eNOS activity
362 against ox-LDL-C insult. This protection can be attributed partly to their
363 mediation of phosphatidylinositol 3-kinase/protein kinase B signaling and
364 prevention of eNOS degradation. Subsequently, another recent study [58]
365 suggested that SAC, S-benzylcysteine (SBC), and S-propylcysteine (SPC) to be
366 excellent hydroxyl radical ( OH) scavengers, while SAC only as a modest
367 peroxyl radical (HOO) scavenger. Au1Besides the garlic sulfur content and
368 their antioxidant activity, some recent studies reported that the phenolic
369 compounds which are abundant in the leaves of garlic, including gallic acid and
370 quercetin, contribute to antioxidant activity [7,59,60].
371 6 Clinical Studies
372 In a randomized, double-blind, placebo-controlled study with three parallel arms
373 [61], 17 participants consumed garlic oil (4 mg), 18 participants consumed garlic
374 powder (0.5 g), and 17 participants consumed placebo for 11 weeks. Garlic oil
375 caused a relatively rapid (4 weeks) rise in total antioxidant capacity compared with
376 placebo or garlic powder. However, at 6 weeks, a significant rise also could be seen
377 with garlic powder; by 11 weeks, it reached the same level as that obtained with
378 garlic oil. Au2Another randomized, double-blind, placebo-controlled crossover trial
379 [62], in which 10 normolipidemic subjects (5 males, 5 females) took six capsules
380 each day containing either 100 mg of garlic powder/tablet or placebo followed by
381 a 1-week washout period and then another 2 weeks on the alternate substance.
382 The study data indicated that, for individuals taking garlic, there was increased
383 antioxidant status as evidenced by an increase in the resistance of LDL-C to
384 oxidative stress as compared with participants taking placebo [62]. However, the
385 TBARS assay used in this study did not use purified LDL-C, and it is now
386 known that the use of purified LDL-C yields more reliable data. In a small-scale
387 preliminary double-blind, placebo-controlled, crossover study [54] involving eight
388 subjects (4 men and 4 women), four subjects took 1.2 g AGE three times a day for
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389 2 week, then 2 week of no garlic (washout period), followed by 2 week of placebo.
390 The use of the garlic supplement was found to significantly increase the resistance
391 of LDL-C to oxidation [54]. A study [63] showed that after short-term
392 garlic supplementation in essential hypertensive patients (EH) regarding indices
393 of oxidative stress, there is a significant reduction in ox-LDL-C and 8-iso-PGF2a
394 levels. In a study [64] on six organosulfur compounds, derived from garlic showed
395 marked antioxidative and antiglycative effects in partially oxidized (or glycated)
396 LDL-C and plasma against further deterioration in 36 diabetic patients. Durak
397 et al. [65] showed that consumption of 10 g of garlic/day for 4 months causes
398 significant increase in blood antioxidant capacity and improved blood lipid profile
399 in hypertensive patient. Dhawan and Jain [66] in 2005 demonstrated in a clinical
400 trial of hypertensive patients, supplementation with garlic leads to significant
401 reduction in 8-Hydroxy-20-deoxyguanosine (8-OHdG), nitric oxide (NO) levels
402 and lipid peroxidation along with an increase in vitamin levels (A, E, and C) and
403 total antioxidant status (TAS).
404 7 Proposed Mechanism
405 Many authors suggest various possible garlic antioxidant mechanism of action, in
406 which scavenging of ROS is most common mechanisms whereby garlic derivatives
407 confer its important health care benefits. Vaidya et al. [67] suggested that the
408 peroxyl-radical-trapping activity of garlic is primarily due to 2-propenesulfenic
409 acid formed by the decomposition of allicin. Thus, sulfenic acids are very probably
410 the most potent of all peroxyl-radical-trapping antioxidants. New insights on the
411 antioxidant mechanism of garlic derivatives S-allylcysteine and its corresponding
412 sulfoxide (alliin) showed the highest and lowest HOCl-scavenging capacities [68].
413 This scavenging activity is enhanced by increasing the number of S atoms or by the
414 alanyl group (CH
2
CH–NH
2
–COOH) and decreased in the absence of the C¼C
415 bond or in the presence of a sulfoxide group in the thioallyl group [68]. Recently,
416 Miron et al. [69] showed that the allicin diffuses through cell membranes and
417 exerts its biological effects by rapidly reacting with intracellular free thiols, such
418 as reduced glutathione (GSH), cysteine, and sulfhydryl groups of proteins.
419 The reaction of the allylthio group with those cellular components constitutes the
420 major beneficial effects of allicin. The first product is most likely that of the
421 S-allylthio-mixed disulfide (AS-SX) with GSH. Another recent study [58]
422 suggested the mechanism by which SAC, SBC, and S-propylcysteine (SPC)
423 scavenge OH and ROOdue to amelioration when the allyl group was replaced
424 by benzyl or propyl groups.
425 8 Antihypertensive Effects
426 Hypertension is a collective risk factor for cerebrovascular disease, ischemic heart
427 disease, peripheral vascular disease, and renal disease characterized by systolic
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428 blood pressure of 140 mmHg or greater, and/or a diastolic blood pressure of
429 90 mmHg or greater, in people who are not taking antihypertensive medication.
430 A number of studies have documented the hypotensive effect of garlic and their
431 bioactive preparations. In 1973, Chanderkar and Jain [70] reported the hypotensive
432 (10–50 mmHg) effect of alcoholic garlic extract (2.5–25 mg/kg) after oral admin-
433 istration in experimentally induced hypertension. Some studies [71,72] showed
434 a slight decrease in both systolic and diastolic pressures after intravenous injection
435 of garlic extracts in experimental animals. Gastric administration of encapsuled
436 garlic powder to anesthetized dogs induced a dose-dependent (2.5–15 mg/kg)
437 prolonged decrease in arterial blood pressure [73]. Single or multiple doses of
438 0.5 mL of aqueous extract of garlic were given orally to two-kidney-one-clip
439 (2K–1C) model rats that showed a maximum antihypertensive effect at 2–6 h
440 after administration [74]. Experimental rats who were fed a 2% high-cholesterol
441 diet exhibited a 23.50% increase in systolic blood pressure which was significantly
442 reduced when the rats were fed an aqueous extract of garlic powder containing
443 allicin on a daily basis [75]. In another study [76], chronic feeding of
444 diets containing either AGE or raw garlic (RG) powder for 10 weeks resulted in
445 a reduction of the increase of systolic blood pressure compared with the control
446 group from 4 weeks after beginning the experimental diets. The effect of AGE
447 was accompanied by a decrease of pulse pressure (PP), suggesting an improvement
448 of the pliability of the artery, although RG did not affect PP. In a recent
449 animal study [77], combination of fresh garlic homogenate compound S-allyl
450 cysteine sulfoxide and captopril exerted super-additive (synergistic) interaction
451 with respect to fall in blood pressure and angiotensin converting enzyme (ACE)
452 inhibition and suggested the combination of garlic with captopril should be
453 avoided. Continuous researches have been carried out on animals and have
454 repeatedly documented the significant hypotensive activity of garlic. Another
455 recent study [78] demonstrated that garlic homogenate in moderate dose
456 (250 mg/kg) with added hydrochlorothiazide possesses synergistic cardioprotective
457 and antihypertensive properties against fructose- and isoproterenol-induced
458 toxicities in albino rats.
459 9 Clinical Studies
460 Evidence has been found that people’s belief in continuing garlic use for the
461 management of hypertension is justified and well documented. A very early
462 research in 1921 showed the hypotensive effect of garlic tincture [79]. Allimin
463 tablets containing 4.75 g of garlic concentrate (0.31 g of desiccated garlic and
464 2.375 g of desiccated parsley) administered to 26 hypertensive patients three times
465 daily for 3 days resulted in reduction of systolic and diastolic blood pressure
466 (12.3 mmHg and 6.5 mmHg) in 85% of the patients [80]. Intake of about 900 mg/
467 day garlic powder in hypercholesterolemic [81], mild hypertension patients [82],
468 and normotensive subjects [83] resulted in reduction of diastolic blood pressures as
469 compared to the nongarlic consuming groups. In another study [28], there was a
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470 5.5% decrease in systolic blood pressure and a modest reduction of diastolic blood
471 pressure in response to 900 mg/day aged garlic consumption. Short-term consump-
472 tion of garlic supplementation (250 mg/day for 2 months) in essential hypertensive
473 patients resulted significant decline in both systolic and diastolic blood pressures
474 [63]. Garlic extract consumption for 4 months caused significant reductions in
475 systolic and diastolic blood pressures in 13 hypertensive patient [65].
476 A study [84] showed that the undamaged garlic (swallowed) had no lowering
477 effect on lipid level of serum, while crushed garlic (chewed) reduces cholesterol,
478 triglyceride, MDA, and systolic and diastolic blood pressures. In a double-blind
479 parallel randomized placebo-controlled trial [85] involving 50 patients, receiving
480 four capsules of aged garlic extract (960 mg containing 2.4 mg SAC) daily for
481 12 weeks resulted in lowering of systolic blood pressure similar to current first-line
482 medications in patients with treated but uncontrolled hypertension.
483 Recently, a randomized, placebo-controlled parallel feeding trial [86] showed
484 a significant reduction in both systolic and diastolic blood pressures in hypertensive
485 subjects after taking two 500 mg capsules of processed garlic for 8 weeks.
486 There was one meta-analysis performed by Silagy and Neil in 1994 [87] which
487 included eight trials using the same dried garlic powder preparation (Kwai).
488 The results from the data of 415 subjects after analysis showed only three of the
489 trials were specifically conducted in hypertensive subjects, and out of the
490 seven trials that compared the effect of garlic with that of placebo, three
491 showed a significant reduction in systolic blood pressure (SBP) and four in diastolic
492 blood pressure (DBP). In 2008, a study [88] searched the databases for
493 studies published between 1955 and October 2007 in which 11 of 25 studies
494 included in the systematic review were suitable for meta-analysis. The
495 author suggested that garlic preparations are superior to placebo in reducing
496 blood pressure in individuals with hypertension. Another meta-analysis study [89]
497 was published in the same year 2008 which included ten trials in the analysis. The
498 result showed that garlic reduced SBP by 16.3 mmHg and DBP by 9.3 mmHg
499 compared with placebo in patients with elevated SBP in the three trials. However,
500 the use of garlic did not reduce SBP or DBP in patients without elevated SBP.
501 A very recently published meta-analysis [90] containing the data from January
502 1994 to December 2010 including 13 studies included 659 subjects. The result of all
503 studies showed a mean decrease of 4.2 2.4 mmHg for SBP in the garlic group
504 compared to placebo, while the mean decrease in the hypertensive subgroup was
505 7.3 2.2 mmHg for SBP and 6.7 1.4 mmHg for DBP. There were no statistically
506 significant effects of garlic (compared to placebo) observed for DBP of all subjects
507 and the nonhypertension subgroup.
508 10 Possible Mechanism
509 Many authors proposed the possible mechanism by which garlic influences
510 antihypertensive effects. Au3Early investigation [72] proposed that prostaglandin-like
511 activity responsible for antihypertensive action of garlic decreases peripheral
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512 vascular resistance. Whenever, the body increases production of angiotensin II
513 converting enzyme (ACE), blood pressure increases. Garlic showed blood
514 pressure reducing properties which have been linked to its hydrogen sulfide (H
2
S)
515 production [91]. It has been demonstrated that garlic and garlic-derived organic
516 polysulfides, such as diallyl trisulfide (DATS) and diallyl disulfide (DADS), induce
517 H
2
S production in a thiol-dependent manner and allicin content liberated from alliin
518 and the enzyme alliinase which has angiotensin II inhibiting and vasodilating
519 effects in in vitro [92], animal [93] studies. Nitric oxide (NO) is a well-recognized
520 vasodilator and vasorelaxant for endothelial and smooth muscle cells. Garlic
521 extract and S-allyl-g-cysteine significantly increase NO production in endothelial
522 cells [94,95] which results in lowering blood pressure [96]. In addition, in in vitro
523 [97] and animal studies [98], garlic shows nitric-oxide-dependent relaxation in
524 pulmonary arteries. Amino acid analysis of garlic powder demonstrated that it is
525 a rich source of arginine, the precursor of NO. This was explained by the fact that
526 NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor) abolished the
527 vasodilatory effect of garlic. In a single in vitro study [99], garlic opens K
+
528 channels, which can reduce calcium influx and cause vasodilation which was
529 ultimately responsible for the antihypertensive activity.
530 11 Antithrombotic and Fibrinolytic Effect
531 Blood platelets are mainly responsible for maintaining the hemostatic integrity of
532 blood vessels and to stop bleeding after injury. Due to coronary artery disease and
533 rupture of atherosclerotic plaque, there is increase in the platelet count and
534 activation of the coagulation cascade with platelet thrombus formation, and that
535 finally leads to vessel embolism. Garlic inhibits the platelet aggregation and
536 prevents the thrombosis in in vitro animal models, and clinical studies. During
537 the 1970s, there were three animal studies which reported the antiplatelet activity of
538 garlic. The essential oil was more effective than clofibrate in the usual clinical dose
539 of 33 mg/kg/day prevent lipid accumulation in the rabbit aorta [100], and essential
540 oils of garlic protect against experimental atherosclerosis by preventing the fall in
541 the alpha lipoprotein fraction and by enhancing fibrinolytic activity [101]. Sainani
542 et al. [102] in 1979 showed enhanced fibrinolytic activity in albino rabbits when
543 administered with garlic juice (0.25–25 g/day) in 10 mL distilled water. Aqueous
544 garlic extracts inhibit platelet aggregation in vivo when added to plasma rich
545 platelet at a concentration of 10 mM, suggesting allicin as principle inhibitor [103].
546 ADP-, epinephrine-, collagen-, and arachidonate-induced platelet aggregation is
547 inhibited in vitro by garlic extract in a dose-dependent manner by inhibition of
548 the prostacyclin biosynthesis in rat aorta [104]. Diallyl disulfide and diallyl
549 trisulfide are mainly responsible for the prevention of acute platelet thrombus
550 formation in stenosed canine coronary arteries model [105]. Several in vitro and
551 in vivo studies were continuously performed and have proven the previous work
552 with proposed mechanism hypothesis. In an ex vivo study [106], infusion of
553 different garlic extract (10, 2, 5 and 100 mg/kg) in the ear vein of the rabbit
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554 significantly inhibits serum TXB
2
production in a distinct dose and time-dependent
555 pattern. Chloroform/acetone extracts of fresh garlic have been shown to inhibit
556 cyclooxygenase activity directly in in vitro, with the acetone extract being more
557 effective [107]. In 1992, Lawson et al. [108] suggested that the antiaggregatory
558 activity of garlic clove homogenates (S-allyl cysteine sulfoxide) in platelet
559 rich plasma was due to adenosine; however, in whole blood neither adenosine nor
560 the polar fraction had any effect, and all of the antiaggregatory activity was
561 due to allicin and other thiosulfinates compound. Ajoene is a well-established
562 antiplatelet agent in garlic, and its inhibitory effect on platelet aggregation has
563 been extensively studied and documented both by in vivo and in vitro experiments
564 [109,110] including inhibition of baboon platelet aggregation in vitro (75 mg/mL)
565 and in vivo (25 mg/kg) induced by adenosine diphosphate (ADP) or collagen [111].
566 Diallyl trisulfide inhibited platelet aggregation and Ca
2+
mobilization induced
567 by thrombin without affecting the production of IP
3
[112]. Another study
568 suggested that garlic component sodium 2-propenyl thiosulfate modulated
569 cyclooxygenase activity in canine platelets in a dose-dependent manner, thus
570 preventing their aggregation [113]. Administration of the garlic in a rat in situ
571 loop model,suggested that odorless garlic not only activates fibrinolytic
572 activity by accelerating tPA-mediated plasminogen activation but also suppresses
573 the coagulation system by downregulating thrombin formation [114]. Recently,
574 an in vitro study [115] suggested the alcoholic wild garlic extract is more potent,
575 while Allium sativum and Allium ursinum exert similar antiaggregatory effects
576 in a dose dependant manner and inhibit platelet aggregation induced via the
577 ADP pathway.
578 12 Clinical Studies
579 Several clinical studies done by Bordia and colleagues [116,117] in the late 1970s
580 and early 1980s reported that a garlic oil preparation rich in vinyldithiins, sulfides,
581 and ajoene could inhibit platelet aggregation and result in increased fibrinolytic
582 activity. In 1977, study on 10 healthy individuals, 10 patients with old myocardial
583 infarction, and 20 patients with acute myocardial infarction showed garlic (1 g/kg
584 b.w.) significantly increased fibrinolytic activity in all subjects especially
585 in healthy group [116]. Later on, Bordia et al. [118] showed that garlic oil
586 preparation inhibits platelet function in both healthy subjects and in patients
587 with coronary heart disease. A randomized, double-blind, placebo-controlled
588 crossover study [119] of 12 healthy subjects reported that garlic powder (Kwai,
589 900 mg/day) inhibited platelet aggregation induced by ADP and collagen.
590 Administration of garlic in a daily dose of 2 2 capsules (each capsule containing
591 ethyl acetate extract from 1 g peeled and crushed raw garlic) showed antiplatelet
592 activity and also inhibited platelet thromboxane formation [120]. In another study
593 [121] of garlic powder, it was found that feeding 7.2 g of AGE powder/day
594 (25 mL/day of liquid AGE) to hypercholesterolemic men resulted in inhibition
595 of epinephrine (another platelet aggregating agent) and collagen-induced
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596 aggregation, but not ADP-induced aggregation. A 13-week study [122] involving
597 normolipidemic subjects who ingested 5 mL of aged garlic extract per day
598 significantly inhibited both the total percentage and initial rate of platelet aggre-
599 gation at concentrations of ADP up to 10 mmol/L. Besides sulfur containing
600 compound, other nonsulfur compounds, such as b-chlorogenin and quercetin,
601 have also been shown to inhibit platelet aggregation [123]. A meta-analytical
602 survey based on 11 electronic databases study [124], which included 1,798
603 pertinent records, 45 randomized trials, and 73 additional studies, reported car-
604 diovascular-related effects were limited to randomized controlled trials lasting at
605 least 4 weeks, and it has been found that in comparison with placebo, garlic
606 preparations lead to a significant reduction in platelet aggregation [124].
607 Cavagnaro et al. [125] describe the effect of cooked garlic on antiplatelet activity
608 on the blood sample from two healthy subjects, who had abstained from eating
609 Alliums or other known platelet inhibitory foods for at least 1 week. The result
610 showed oven heating at 200 C or immersing in boiling water for 3 min or less did
611 not affect the ability of garlic to inhibit platelet aggregation (as compared to raw
612 garlic), whereas heating for 6 min completely suppressed in vitro antiaggregatory
613 activity in uncrushed, but not in previously crushed, samples [125]. Prolonged
614 incubation (more than 10 min) at these temperatures completely suppressed
615 in vitro antiaggregatory activity, while microwaved garlic had no effect on platelet
616 aggregation. A randomized, double-blind, placebo-controlled, crossover study
617 involving 14 healthy subjects showed one large dose of garlic oil (9.9 g garlic)
618 slightly but significantly affected adrenaline but not ADP or collagen-induced
619 platelet aggregation [126]. In a recently published report, it was shown that there
620 was reduction in adenosine-induced platelet aggregation by garlic diallyl sulfide
621 (2.2 mg) compound in women participants with type 2 diabetes mellitus [127].
622 13 Proposed Mechanism
623 Arachidonic acid (AA) is an essential fatty acid precursor in the biosynthesis of
624 leukotrienes, prostaglandins, and thromboxanes (Fig. 158.4). Various platelet ago-
625 nists mobilize calcium through G-protein-coupled receptors. Calcium activates
626 phospholipase A
2
, which liberates arachidonic acid from phosphatidylcholine and
627 phosphatidylethanolamine. Calcium also activates myosin light-chain kinase. AA is
628 liberated from phospholipids and, in the presence of the enzyme cyclooxygenase,
629 incorporates oxygen to form the endoperoxide prostaglandin G
2
(PGG
2
). PGG
2
is
630 then quickly transformed to prostaglandin H
2
(PGH
2
). PGH
2
, in the presence of
631 thromboxane synthase, produces thromboxane A
2
(TXA
2
) which further mobilizes
632 calcium from intracellular storage sites. TXA
2
and activated myosin light-chain
633 kinase together lead to platelet coagulant activation by stimulating secretion of
634 products of platelet granules, allowing tenase and prothrombinase formation [128].
635 TXA
2
is a vasoconstrictor and platelet aggregating compound which serves
636 as precursor for inactive thromboxane-B
2
(TXB
2
). Ajoene strongly inhibits
637 the metabolism of arachidonic acid by both cyclooxygenase and lipoxygenase
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638 pathways [129,130], thus inhibiting the synthesis of TXA
2
, AA metabolite, and
639 12-hydroxy-eicosatetraenoic acid (12-HETE). AGE has been shown to reduce
640 thromboxane formation [106]. It has also been reported that N-ethylmaleimide
641 causes the disaggregation of both ADP and thrombin-induced platelet aggregation
642 and that this disaggregation is a result of the removal of calcium ions (Ca
2+
) from
643 the platelet cytosol. Therefore, the effects of AGE on calcium mobilization were
644 investigated in both A23187 and ADP-stimulated platelets [131]. In the presence of
645 AGE, the initial concentration of calcium ions was significantly less than when the
646 experiments were performed in the absence of AGE. This could be due to the metal
647 chelation properties of AGE, as reported earlier [55]. In support of this, garlic
648 extract has been shown to strongly inhibit calcium binding, suppressing the influx
649 of calcium ions by chelating calcium within platelet cytosol and arteriosclerotic
650 nanoplaque formation [132,133]. AGE may inhibit phospholipase A
2
, thus reduc-
651 ing levels of lysophosphatidic acid, which causes platelet aggregation and increases
652 intracellular calcium ions [131]. Antiaggregatory effect of ajoene may also be
653 causally related to its direct interaction with the putative fibrinogen receptor
654 (GPIIb/IIIa) in a dose-dependent manner [134]. The GPIIb–IIIa receptor has
655 a high content of –SH groups, and binding of fibrinogen is inhibited by the
Fig. 158.4 Proposed antiplatelet mechanism of garlic: 1-directly inhibit the phospholipase A2; 2-
modulate the TXA
2
and decrease the production; 3-directly inhibit the TXB
2
function; 4-inhibit
the ADP, collagen and arachidonate induced platelet aggregation; 5-effect on Ca
2+
mobilization
via scavenging the available Ca
2+
;6-directly enhance the nitric oxide production
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656 organosulfur compound ajoene [135]. AGE has been reported to enhance NO
657 production by activating cNOS, but not iNOS [136], which may increase the GTP
658 concentration and ultimately induces platelet aggregation.
659 14 Antiatherosclerotic Effect
660 Atherosclerosis is a result of an interaction between fat and cholesterol within the
661 cellular components of the arterial wall and buildup in the walls of arteries to form
662 hard structures called plaques, the pathogenic substratum of many cardiovascular
663 diseases. Various in vitro and clinical studies have shown and confirm the effect of
664 garlic in the prevention and treatment of atherosclerosis. Early studies on experi-
665 mental animals showed the reduction in aortic lipid content of garlic fed animals by
666 72%, while in the control group there was no significant reduction. The data
667 suggests that cholesterol is depleted from experimentally induced atherosclerosis
668 by garlic administration [137,138]. Treatment with aged garlic extract reduces fatty
669 streak development, vessel wall cholesterol accumulation, and the development of
670 fibro fatty plaques in neointimas of cholesterol-fed rabbits, thus providing protec-
671 tion against the onset of atherosclerosis [139]. In cell cultures, aqueous solutions of
672 dried garlic powder containing allicin and ajoene significantly inhibit the prolifer-
673 ative activity of smooth muscle cells from atherosclerotic aortic plaques [140,141].
674 In hypercholesterolemic rabbits, garlic supplements significantly reduced the aortic
675 lesions and lipid content of existing fatty plaques [142]. AGE exerts antiatherogenic
676 effects through inhibition of smooth muscle phenotypic change and proliferation
677 and by another (unclarified) effect on lipid accumulation in the artery wall [143].
678 Garlic exerts hypocholesterolemic and antiatherogenic activity by inhibition of
679 plasma cholesteryl ester transfer protein (CETP) activity, which may delay the
680 progression of atherosclerosis, thereby supporting the atherogenicity of CETP and
681 the inhibitory activity of garlic supplementation against CETP [21]. An in vitro
682 study’s results show the formation of the ternary proteoheparan sulfate HS-PG/LDL/
683 Ca
2+
complex, which is initially responsible for the “nanoplaque” composition and
684 ultimately for the arteriosclerotic plaque generation, where the garlic extract strongly
685 inhibits Ca
2+
binding to HS-PG [132]. A notable restoration of arterial blood
686 pressure; significantly enhanced vasorelaxant response to adenosine, acetylcholine,
687 and isoproterenol; and reduction in atherogenic properties of cholesterol were seen in
688 animals on garlic-supplemented diet [144]. Daily dietary supplement of allicin,
689 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9% and 56.8%
690 in apolipoprotein E-deficient and low density lipoprotein (LDL) receptor knockout
691 mice, respectively, as compared with control mice and also by using pure allicin
692 preparation; an in vitro study results showed that allicin may affect atherosclerosis
693 not only by acting as an antioxidant but also by other mechanisms, such as lipopro-
694 tein modification and inhibition of LDL uptake and degradation by macrophages
695 [145]. A recent in vitro study suggested that AGE inhibit monocyte differentiation
696 into macrophages, CD36 expression, and oxidized LDL-C (oxLDL-C) uptake into
697 macrophages induced by the cardiovascular risk factor homocysteine (Hcy) [146].
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698 15 Clinical Studies
699 In a randomized, placebo-controlled trial in ten healthy adults, there was
700 a significant improvement in plasma viscosity and capillary blood flow within 5 h
701 after taking 900 mg of standardized garlic powder [147]. Another randomized
702 placebo-controlled double-blind crossover study in healthy volunteers showed
703 increased erythrocyte velocity results from vasodilation of precapillary arterioles
704 which increased diameter of erythrocyte column by an average of 8.6 % along with
705 simultaneous inflow of interstitial fluidity accompanied by a significant decrease in
706 hematocrit and plasma viscosity (rheoregulation) [148]. In a placebo-controlled
707 trial of patients with stage II peripheral arterial occlusive disease, garlic powder
708 supplements (800 mg/day) were associated with a significant increase in walking
709 distance by 46 m; the improvement started after the fifth week of treatment mainly
710 by simultaneous decrease in spontaneous thrombocyte aggregation [149]. A cohort
711 study including 101 healthy adults who took at least 300 mg daily of dried garlic
712 powder for at least 2 years were compared with 101 age and gender matched
713 controls who were not taking supplements; pulse wave velocity and elastic vascular
714 resistance (two measures of arterial elasticity) were significantly lower in the garlic
715 group than in the control group, even after controlling for age and systolic blood
716 pressure, that is, chronic garlic powder intake was associated with an attenuation in
717 age-related increases in aortic stiffness [150]. In a prospective, 4-year clinical
718 trial of patients treated with 900 mg daily of standardized garlic powder, there
719 was a 9–18 % reduction in plaque volume, a 4 % decrease in LDL-C levels, an 8 %
720 increase in HDL-C concentrations, and a 7 % decrease in blood pressure [151].
721 Similar results were reported in a 4-year German trial in 152 older adults; those who
722 took high-dose garlic for 4 years, demonstrated reduced atherosclerotic plaque in
723 both carotid and femoral arteries by 5–18 % [152]. A study of 11 atherosclerotic
724 patients with oxidative stress showed prevention of oxidation reaction by eliminat-
725 ing this oxidative stress and significantly lowered plasma and erythrocyte
726 malondialdehyde (MDA) levels after the ingestion of garlic extract [153].
727 A placebo-controlled, double-blind, randomized pilot study indicates the potential
728 ability of AGE to inhibit the rate of progression of coronary calcification in 19
729 patients, as compared to placebo over 1 year [154]. AGE consumption increases
730 plasma nitric oxide synthase (NOS) activity in 11 atherosclerotic patients
731 and suggested that AGE may arise from its NOS-inducing and nitric-oxide
732 (NO)-producing activities [155].
733 16 Proposed Mechanism
734 The exact molecular mechanism of garlic by which it shows antiatherosclerotic
735 effect is not fully understood. The development of atherosclerotic plaque or lesions
736 is a result of endothelial dysfunction induced by elevated and modified LDL and
737 ox-LDL, free radicals, toxins, homocysteine, hypertension, and other unknown risk
738 factors. It has also seen that disturbance in immune system supports the formation
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739 of atherosclerotic plaques. Diets supplemented with garlic are able to restore
740 endothelial function in experimental laboratory animals [144] and investigations
741 of humans [156]. It has been shown that raw garlic possibly works via its active
742 metabolite allicin action on coronary endothelial function and vasoreactivity [157].
743 The electrophysiological correlation to vasodilatation in human coronary arteries
744 under the influence of garlic extract showed decrease in the isometric wall tension.
745 Allicin and ajoene hyperpolarized the cell membrane and relaxed the vascular strips
746 in a concentration-dependent manner and suggested that garlic extract and its
747 compounds can be classified as phytopharmacological K
+
channel openers [99].
748 OxLDL-C, but not native LDL-C, contributed to atherogenesis and promoting
749 vascular dysfunction by exerting direct cytotoxicity toward endothelial cells, by
750 increasing chemotactic properties for monocytes, by transforming macrophages
751 to foam cells via scavenger receptors, and by enhancing the proliferation of
752 endothelial cells, monocytes, and smooth muscle cells. Garlic compounds can
753 effectively suppress LDL-C oxidation in vitro and that short-term supplementation
754 of garlic to humans increases resistance of LDL-C to oxidation [54,158]. Hcy,
755 a metabolite from methionine, serves as an independent cardiovascular disease
756 risk factor, which causes thrombosis and oxidative-stress damage and is often
757 associated with atherosclerosis and a higher risk of coronary heart disease, stroke,
758 and peripheral vascular disease by damaging the inner lining of arteries and
759 promoting blood clotting. Hcy has an inverse relationship with folate deficiency
760 and decreased NO production. AGE may at least partly prevent a decrease in
761 bioavailable NO and endothelium-derived hyperpolarizing factor during acute
762 hyperhomocysteinemia [159] and also decrease plasma total hcy concentration by
763 30 % without changing the protein-bound/free hcy ratio [160]. Coronary arterial
764 calcification (CAC), a marker of plaque formation in human coronary arteries and
765 atherosclerosis, has been linked to an increased risk for cardiovascular events such
766 as myocardial infarction, fatal arrhythmia, and congestive heart failure. AGE
767 inhibits the rate of progression of coronary calcification as compared to placebo
768 over 1 year [154]. C-reactive protein (CRP) is one of the strongest predictors for
769 the risk of atherosclerosis and cardiovascular events in subjects with and
770 without cardiovascular disease. But there was only one study which showed that
771 12 weeks of treatment with a high-dose, chemically well-characterized, production-
772 controlled garlic powder had no significant effect on CRP protein in
773 normolipidemic subjects with risk factors for CVD [161].
774 17 Other Cardioprotective Activity
775 Cardiac arrhythmias are any abnormality or perturbation in the normal activation
776 sequence of the myocardium. Some earlier studies showed beneficial effects of
777 garlic in cardiac arrhythmias. Garlic powder (1 % corresponding to Kwai/Sapec
778 added to a standard chow for a 10-week period) significantly reduces the incidence
779 of ventricular tachycardia (VT) and fibrillation (VF) in isolated perfused rat heart
780 [162]. Another study in the same manner using garlic powder (1 % added to
158 Garlic and Cardiovascular Diseases 23
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781 a standard chow for an 8-week period) also showed significantly reduced ischemia
782 reperfusion-induced ventricular fibrillation (VF) in isolated perfused rat heart and
783 suggested that an intact alliin–alliinase system is important for this activity of garlic
784 [163]. Garlic dialysate decreased the positive inotropic and chronotropic effects
785 of isoproterenol in a concentration-dependent manner and suggesting via
786 b-adrenoceptor blocking action produced by the garlic dialysate [164]. Another
787 study by same author suggested that garlic dialysate has a significant antiarrhythmic
788 effect in both ventricular and supraventricular arrhythmias [165]. Aqueous garlic
789 extract increased the amplitudes of atrial complex “p” wave and the ventricular
790 complex “QRS” of the rat ECG. This is suggestive of increase in voltage output of
791 the atria and ventricles probably in accordance with positive inotropism [166].
792 A recent animal study suggested that garlic cannot alter the ventricular fibrillation
793 threshold (VFT), but it significantly decreases the upper limit of vulnerability
794 (ULV) in a dose-dependent pattern, indicating that it can reduce the range of the
795 stimulation strength between the VFT and ULV (vulnerability window) during the
796 vulnerable period of a cardiac cycle [167].
797 A few studies have shown the beneficial effect of garlic and its active constit-
798 uents in conjugation with some drugs. Allylmercaptocaptopril is an example of
799 a conjugate of the ACE inhibitor drug captopril with garlic allicin. Allylmercapto-
800 captopril prevented progressive weight gain, without a detectable effect on food
801 intake, lowered blood pressure, and improved cardiac hypertrophy, as indicated by
802 heart weight and ventricular-wall thickness [168]. Garlic therapy in animals with
803 myocardial infection showed improved survival and cardiac function by add-on
804 captopril [169,170] and propranolol [171]. Garlic juice inhibited the contractions
805 of rabbit and guinea pig aortic rings induced by norepinephrine in Ca
2+
-free and
806 Ca
2+
-containing Krebs–Henseleit solutions and indicated that it produces concen-
807 tration-dependent synergistic effect by its calcium-blocking property [172].
808 Beneficial effects of combined therapy of garlic and hydrochlorothiazide were
809 also demonstrated and confirmed in the recent past [173,174]. The same author
810 also reported that combination of S-allyl cysteine sulfoxide (SACS) from fresh
811 garlic homogenate and captopril exerted super-additive (synergistic) interaction
812 with respect to fall in blood pressure and ACE inhibition [77]. In one preliminary
813 study, in which pretreatment with aged garlic extract for 27 days ameliorated the
814 effect of an active anticancer agent doxorubicin (DOX) administration on cardiac
815 tissue; cardiomyocytes looked more or less similar to those of control and suggested
816 that aged garlic extract is potentially protective against doxorubicin-induced
817 cardiotoxicity [175].
818 18 Bioavailability and Metabolism
819 Very few studies have been conducted on the bioavailability of garlic compounds.
820 An animal study [176] showed that in a very short time (10 min) after orally
821 administering alliin (10 mg/mouse), it was observed in the stomach (7.2%), intes-
822 tine (22.4%), and liver (2.5%) without the production of allicin and its degradation
24 S.H. Omar
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823 compounds such as DADS, vinyldithiins, and allyl-SS conjugated compounds,
824 suggesting alliin is not metabolized to respective organosulfur compounds without
825 an appropriate enzyme (allinase). In a pharmacokinetic study using synthesized
826 35S-labeled alliin, 60–70% was absorbed in rats [177]. Alliin along with DADS has
827 been detected in the perfusate after the isolated rat liver passage, while there was
828 absence of allicin [178] even in human serum or urine from 1 to 24 h after ingesting
829 25 g of raw garlic containing a significant amount of allicin [108]. These findings
830 indicate that alliin itself is never converted to allicin in the body and metabolized
831 into various organosulfur compounds such as DADS by liver enzymes. When
832 allicin is added to fresh blood, it is quickly transformed into allyl mercaptan, but
833 this compound was not found in blood or urine of people who consume garlic, also
834 demonstrating that the level of allyl methyl sulfide (AMS) in the exhaled air
835 depended on amount of the ingested allicin or its derivatives [179]. Vinyldithiins,
836 2-vinyl-4H-1,3-dithiin, and 3-vinyl-4H-1,2-dithiin, have been detected in the
837 serum, kidney, and fat tissue >24 h after oral ingestion, while only 1,3-vinyldithiin
838 was found in the rat liver [180]. The metabolic fate of [
35
S]-labeled DADS in rats
839 after intraperitoneal injection with the maximum concentration of [
35
S]-labeled
840 DADS by mice livers occurred 90 min after treatment, and about 70% of
841 the radioactivity was distributed in the liver cytosol, of which 80% was
842 metabolized to sulfate [181]. The pharmacokinetics of SAC is well established in
843 animal studies, which is detected in the blood, and its pharmacokinetic
844 parameters are well associated with oral dose administration. Significant concen-
845 tration of N-acetyl-S-allyl-L-cysteine is also identified as a metabolite of SAC in the
846 urine. This indicates that SAC could be transformed into N-acetylated metabolite
847 by N-acetyltransferase in the body. The bioavailability of SAC is 103.0 % in mice,
848 98.2% in rats, and 87.2% in dogs [182]. SAC was found also in human blood after
849 ingestion of AGE, the main component of which is SAC [183]. DAS could be
850 metabolized by one of the cytochrome P
450
isoenzymes to form diallyl sulfoxide
851 (DASO) and then diallyl sulfone (DASO
2
)[184]. After GC–MS analysis, two major
852 peaks, which were identical to allyl mercaptan and DADS after ingesting grated
853 garlic, could be detected in human breath without other organosulfur volatiles
854 [185]. There is a need of major clinical trial which confirm the bioavailability of
855 sulfur and nonsulfur compounds in garlic.
856 19 Side Effects and Toxicity
857 According to the suggested doses from the studies and optimum pharmacological
858 responses, the following doses are recommended: 2–5 g of fresh raw garlic,
859 0.4–1.2 g of dried garlic powder, 2–5 mg garlic oil, and 300–1,000 mg of garlic
860 extract (as solid material). Other preparations should correspond to 4–12 mg of
861 alliin or approximately 2–5 mg of allicin, an active constituent of garlic. Various
862 studies have been investigated in search of toxicity from garlic, but till now there is
863 no known toxic constituents in garlic and its preparations. Garlic is considered to
864 have very low toxicity and is listed as Generally Recognized as Safe (GRAS) by the
158 Garlic and Cardiovascular Diseases 25
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865 US Food and Drug Administration (FDA). The most common side effects produced
866 by intake of small amounts of garlic are bad breath and body odor. When garlic is
867 taken in a high dose by a sensitive individual, it is known to cause gastric irritation.
868 A clinical trial showed side effects which include heartburn, nausea, vomiting,
869 diarrhea, flatulence, bloating, mild orthostatic hypotension, flushing, tachycardia,
870 headache, insomnia, sweating, and dizziness as well as offensive body odor [186].
871 In some cases, people are allergic to sulfur-based compounds and reported
872 allergic reactions to garlic; namely, contact dermatitis, asthma, rhinitis, conjuncti-
873 vitis, urticaria, anaphylaxis, and angioedema [187–189]. Garlic may be used safely
874 in pregnant and breast-feeding mothers. Consumption of garlic enhances the
875 pharmacological effects of anticoagulants (warfarin, fluindione) but reduces the
876 efficacy of anti-AIDS drug saquinavir [190]. A clinical trial reported that
877 coadministration of garlic did not significantly alter warfarin pharmacokinetics or
878 pharmacodynamics [191].
879 20 Conclusion
880 Evidence from in vitro, in vivo, and clinical studies support the beneficial effects of
881 garlic consumption in various preparations in the prevention of cardiovascular
882 disease. The raw garlic and AGE are the most important among the available
883 preparation and showed maximum pharmacological effect in low dose. The present
884 report suggests that garlic has the ability to prevent excess free radical production,
885 maintain the oxidative balance via increase in antioxidant status and increase in
886 bioavailability of nitric oxide, prevent vascular inflammation, reduce cholesterol
887 content and plaque formation, and inhibit platelet aggregation. Evidence suggests
888 that garlic may produce modest but not clinically significant effects in the treatment
889 of hyperlipidemia and hypertension via reduction in DBP. Indeed, the results from
890 clinical trials are very few and inconsistent, probably due to differences in
891 garlic preparations, unknown active constituents and their bioavailability, and
892 small sample size. Systematic reviews are available for the possible antilipidemic,
893 antihypertensive, antithrombotic, and chemopreventive effects. However, the
894 clinical evidence is far from compelling. Garlic appears to be generally safe,
895 although some allergic reactions may occur [192]; therefore, it would be
896 a safe tool for the treatment and prevention of CVD. In conclusion, the proposed
897 in vitro, in vivo, and animal models should be further verified in human studies in
898 order to establish a causative link between molecular properties and the role of
899 garlic active constituents in the prevention and treatment of CVD.
900 Acknowledgments I wish to personally thank the following people and library for their
901 contributions to my inspiration and knowledge and other help in creating this book: Charles
902 Sturt University Library (database), Kathryn Koromilas, Dr. Basit Iqbal, and Saba Nabi.
26 S.H. Omar
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36 S.H. Omar
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