Abstract
Globally, there is an increasing prevalence of cardiovascular diseases (CVD) and is still maintaining its apex position. It includes elevation in low density lipoproteins cholesterol (LDL-C), increase in LDL-C oxidation, irregular clumping of blood platelets, and increase in C-reactive proteins and homocysteine. These abnormalities are also associated with atherosclerosis, high blood pressure, and hypercholesterolemia. Garlic (Allium sativum L.) is among the world’s oldest cultivated plants, popular in food and for medicinal purposes. Commercially available garlic preparations in the form of garlic oil, powder, and pills are widely used for therapeutic purposes. The water-soluble and insoluble sulfur compounds in garlic showed beneficial effects in all these cardiac abnormalities, especially for the treatment of hypercholesterolemia and prevention of arteriosclerosis through antioxidant ability involving induction and inhibition of various metabolic enzymes and via chelating activity. There is continuous investigation being carried out to find out the other potent bioactive constituent in garlic. Likewise, phenolic compounds have emerged as minor but potent compounds, which are responsible for its antioxidant activity. Most of the studies are in the preliminary stage and need to be clarified in clinical trials.
Access provided by Autonomous University of Puebla. Download reference work entry PDF
Similar content being viewed by others
Keywords
1 Introduction
Garlic, scientifically known as Allium sativum, is a close relative of onions, leeks, and chives. The word Allium is derived from the Celtic word al, meaning pungent, burning, or stinging and sativum meaning planted, cultivated, or sown. The English name “garlic” comes from the Anglo-Saxon gar-leac or spear plant, which refers to its flowering stalk. It is one of the oldest cultivated plants with its origin in central Asia. It has also been found in Egyptian pyramids, ancient Greek temples, and on Sumerian clay tablets dating from 2600 to 2100 BC [1, 2]. Garlic was used as medicine by the ancient Egyptians especially for the working class involved in heavy labor and is listed in the Egyptian medical papyrus Codex Elsers (1500 BC). The ancient medical manuscript of India, Charaka-Samhita, recommends garlic for the treatment of heart disease and arthritis, and another ancient Indian medical textbook, Bower Manuscript recommends garlic for fatigue, parasitic disease, digestive disorder, and leprosy [2]. During World Wars I and II, the injured soldier wounds were dressed with garlic, and it was used as an antiseptic in the prevention of gangrene.
Garlic and its preparations are prescribed in many pharmacopeias around the world, including Ph Eur 6 [3], USP 31 [4], and BP 2007 [5]. Garlic is also incorporated in the list of German Commission E, which is a therapeutic guide in herbal medicine, complied by a special expert commission of the German Federal Institute of Medicines and Medical Inventions. German Commission E recommends usage of an average dose of 4 g of fresh garlic or equivalent preparations of garlic as a dietary supplement to hyperlipidemic patients and in prevention of vascular alterations caused by aging. Garlic is popularly used as one of the major spices, and its medicinal use is both widespread and growing due to proven potential health benefits, which have been published in more than 3,000 research articles. Studies suggests that garlic and its components not only prevent cardiovascular disease (including lowering of serum cholesterol level, inhibition of platelet aggregation, and increased fibrinolysis) but also other chronic diseases associated with aging, stimulation of immune function through activation of macrophages, induction of T cell proliferation, reduction of blood glucose level, radioprotection, improvement of memory and learning deficit, and protection against microbial (viral and fungal infections) and anticancer effects.
2 Bioactive Constituents and Preparations
Garlic bulbs develop and grow entirely underground and are composed of several bulbils structure called cloves. Each clove is enclosed in a white or pink skin of the parent bulb, mainly consists of active secondary plant metabolites, which are responsible for taste, flavor, and health benefits. There are over 600 cultivated subvarieties of garlic available in the world, and scientifically, all the true garlic comes under the species Allium sativum with two most common subspecies, ophioscorodon or hard-necked garlic (ophios for short) and Sativum or soft-necked garlics.
Fresh raw garlic bulbs contain ~65% of water, ~28% carbohydrate, ~2% proteins, ~1.2% amino acids, ~1.5% fibers, fatty acids, phenols, and trace elements, as well as more than 33 (~2.3%) sulfur (Fig. 121.1)-containing compounds [6, 7]. Hundred grams of garlic provides ~149 kcal energy, 33.07 g of carbohydrate, 6.93 g of protein, and 0.5 g of fat. It has been estimated that ~97% of chemical constituents in garlic are water soluble, and very small amounts of oil-soluble constituents which vary from 0.15–0.7% (Table 121.1). The major trace elements found in the fresh garlic cloves are shown in Table 121.2. Further compounds present in a small amount are flavonoids, steroids, and triterpene saponins from the β-sitosterol or F-gitogenin.
The sulfur-containing compounds are generally classified into nonvolatile precursor and organosulfur compound. δ-glutamyl-S-allyl-l-cysteines and S-allyl-l-cysteine sulfoxides (alliin) are abundant in intact garlic and serve as a precursor of allicin, methiin, (+)-S-(trans-1-propenyl)-l-cysteine sulfoxide, and cycloalliin. When there is any mechanical injury to the garlic bulb then, there is formation of thiosulfinate compound called allicin through enzymatic reaction of sulfur-substituted cysteine sulfoxides, which are present in the cytoplasm with alliinase in the vacuole, via sulfur-substituted sulfenic acids. Key studies by Cavallito and Bailey [9] and Stoll and Seebeck [10] identified the compound allicin. Allicin further decomposes into diallyl disulfide (DADS), diallyl sulfide (DAS), diallyl trisulfide (DTS), and sulfur dioxide. In addition, there are other thiosulfinates present in garlic homogenate, including allyl methyl, methyl allyl, and trans-1-propenyl thiosulfinate, that are also unstable like allicin.
There are various available brands of garlic products in stores/on shelves that provide a convenient way to obtain the health benefits of garlic. The most commonly used garlic preparations are raw garlic per se, aged garlic, garlic oil, allicin extract powder (Table 121.3) and commercially prepared lyophilized garlic powder, garlic oil, garlic oil macerate, and aged garlic extract (AGE) [11, 12]. Among the popular commercial garlic preparations investigated in trials are KWAI® (Lichtwer Pharma, Berlin, Germany), Garlicin® (Nature’s Way, Springville, UT, USA), and Kyolic-100® (Wakunaga of America, Mission Viejo, CA, USA).
3 Garlic and Cardio Protection
Globally, CVD remain the biggest cause of death and disability. According to WHO report 2011, 17.3 million people died from CVD in 2008, which accounts for over 80 % of deaths in low- and middle-income countries. It is estimated that by 2030, almost 23.6 million people will die from CVD [13]. CVD refers to a group of disorders of the heart and vascular system and includes coronary heart disease, congestive heart failure, stroke, congenital heart defects, myocardial infarction, and high blood pressure. Imbalance between free radicals production and scavenging leads to oxidative damage of membrane lipids, proteins, carbohydrates, and finally to DNA which brings changes in the structural, mechanical, electrical, and biochemical properties of the heart. Nowadays, natural herbal drugs are gaining greater acceptance from the researchers and public due to advances in understanding the mechanism of action, fewer side effects, and lesser cost effective therapy. Extensive in vitro, in vivo, and clinical studies showed that garlic with its sulfur and nonsulfur bioactive compounds is involved in the prevention and treatment of CVD.
4 Hypolipidemic Effects
Hyperlipidemia, which is characterized by an increase in the level of cholesterol or lipids (LDL, triglycerides) in the blood, serves as a major risk factor of atherosclerosis. The growing interest in complementary and alternative medicine has led to an increasing number of nonpharmacological therapies for lipid management and treatment of hyperlipidemia/hypercholesterolemia with dietary intervention. These include garlic, which reduces total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels; furthermore, it increases high density lipoprotein cholesterol (HDL-C), which has been confirmed in several research studies.
Preparations of garlic including garlic paste, garlic oil, allicin, and ajoene have been found to significantly reduce cholesterol biosynthesis in rat hepatocytes via inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and 14-α-demethylase [14, 15] and human HepG2 cells [16]. After measurement of the enzyme activity, it has been indicated that garlic and its constituents inhibit human squalene monooxygenase along with HMG-CoA reductase, the enzymes involved in cholesterol biosynthesis [8, 17]. In addition, garlic supplementation significantly decreased the cholesterol 7-α-hydroxylase activity [18]. Augusti et al. [19] in 2005 confirmed the inhibition of HMG-CoA reductase by garlic. Some authors postulate that garlic’s trace minerals, such as tellurium (Te), are involved in the inhibition of hepatic cholesterol synthesis [20]. It was found that the more water-soluble compounds like S-allylcysteine (SAC) present in aged garlic extract are less cytotoxic but more efficient in inhibiting cholesterol biosynthesis; in contrast the lipid-soluble sulfur compounds such as diallyl sulfide (DAS) are less efficient [16]. In rabbits that were fed with a high-cholesterol diet and supplemented with garlic or allicin, it was found that hypercholesterolemia was significantly inhibited by 50% and showed a decrease in tissue cholesterol and LDL-C concentrations and raised HDL-C concentrations along with reduced atheromatous changes [21]. Koch [22] indicated that the cholesterol-lowering effect of garlic was probably due to the nonsulfur component, saponin. In addition, another study [23] also supported the saponin fraction from methanolic raw garlic extracts, which mainly contains spirostanol saponins produced by the conversion of furostanol saponins via β-glucosidase. It lowered TC and LDL-C cholesterol without changing HDL-C levels in hypercholesterolemic animal models. A recently published animal study results showed that garlic significantly reduced TC, TG, LDL-C, very low density lipoprotein (VLDL-C), liver triglyceride, plasma malondialdehyde (MDA), and elevated plasma antioxidant in garlic-treated rats along with decrease in liver phosphatidate phosphohydrolase (PAP) activity [24].
4.1 Clinical Studies
Several clinical trials on garlic preparation have investigated, but only a few of them have showed significant hypolipidemic effects. In a meta-analysis on 28 clinical trials, Warshafsky et al. [25] found only five randomized, placebo-controlled studies that met their criteria for inclusion in the meta-analysis. The analysis result showed that treatment with garlic or garlic preparations caused decrease an approximately 9% in TC level. In addition, another meta-analysis of 16 published studies [26] in 1994, revealed that treatment with garlic preparations resulted in nearly a 12% decrease in TC and a similar decrease in LDL-C. Out of 16 studies, only 8 studies included the data on TG; when analyzed together, they revealed a 13% decrease in TG levels. A 12-week, randomized, placebo-controlled study [27] using Kwai garlic powder (900 mg/day) showed a reduction in TC and LDL-C levels by 6% and 11%, respectively, in the garlic supplement group, while TC and LDL-C levels decreased by 1% and 3%, respectively, in the placebo control group. In a long-term (10 months) randomized, double-blind, crossover study [28] in moderately hypercholesterolemic men, using AGE versus placebo, the measurements were made six times during the first intervention (AGE or placebo) and five times over the 120 days of crossover to the alternate treatment. AGE resulted in a maximum TC reduction of 6% for all study subjects compared with placebo and 7% compared with their baseline values. While the LDL-C reduction was 4.5% and 4% compared against placebo and baseline, respectively. A comparative study [29] was reported in 1997, in which garlic (900 mg powder/day) and fish oil (12 g fish oil/day) were used as dietary supplements. This was a randomized, placebo-controlled (partially double-blind) study with four arms: garlic with fish oil placebo, fish oil with garlic placebo, garlic and fish oil, and both placebos. Potential subjects began a 3-week run-in period for dietary stabilization. During this run-in period, TC level had to exceed 5.2 mmol/L (200 mg/dL). They reported that garlic significantly reduced both TC and LDL-C levels, whereas fish oil also significantly decreased TG and increased LDL-C levels as expected. An interesting outcome by Zhang et al. [30] showed that gender might be affect the action of garlic on plasma cholesterol and glucose levels of normal subjects. Alder et al. [31] in 2003 published a systematic review of the effectiveness of garlic as an antihyperlipidemic agent. They included ten studies and found that in six studies garlic was effective in reducing serum cholesterol levels. The average drop in total cholesterol was 9.9%, LDL-C 11.4%, and triglycerides 9.9%. In a study, consumption of enteric-coated garlic supplements, standardized to produce 9.6 mg allicin, significantly decreased TC (4%) and LDL-C (7%) in mild to moderated hypercholesterolemic patients when combined with a low-fat diet [32]. A clinical study confirmed the hypolipidemic effect of raw garlic in hyperlipidemic subjects and reported significantly reduction of TC and TG along with significantly increase in HDL-C [33]. Recently published meta-analysis studies, in which 13 trials including 1,056 subjects, do not produce any statistically significant reduction in serum total cholesterol level from garlic [34]. In addition, another recently published meta-analysis of 29 trials suggested intake of garlic causes significant reduction in TC and TG but does not exhibit any significant effect on LDL-C or HDL-C [35].
4.2 Proposed Mechanism
There are four possible mechanisms through which garlic inhibit the cholesterol synthesis and enhance the cholesterol excretion from the body (Fig. 121.2). The first one is that garlic decreases cholesterol absorption in the intestine, as shown in hypercholesterolemic rat models [23]. Second, experiments using cultures of rat hepatocytes have shown that garlic inhibits the enzymes involved in cholesterol synthesis [16, 36, 37]. Third, Borek [38] has suggested that the cholesterol-lowering effect of garlic is caused by deactivation of HMG-CoA reductase, involved in the synthesis of cholesterol. Fourth, garlic also increased the excretion of cholesterol, as manifested by enhanced excretion of acidic and neutral steroids after garlic feeding [39].
5 Antioxidant Effects
There is a continuous production of free radicals from the body’s metabolic process that use oxygen, such as respiration and some cell-mediated immune functions. The LDL oxidation in the artery wall gives rise to thrombosis, atherosclerosis, and CVD. Besides reactive oxygen species (ROS) and reactive nitrogen species (RNS), hypochlorous acid (HOCl) is also a strong endogenous oxidant and is excessively produced in inflammatory, degenerative, and neoplastic disorders; thus, effective therapies and/or prophylaxes using exogenous scavengers of high specificity are required. Homeostasis and self-defense system of the body maintain a balance between the amount of generated free radicals in the body and body internal antioxidants glutathione (GSH) to quench and/or scavenge or even detoxify them and finally protect the body against their harmful effects. Nowadays, commercially available synthetic antioxidants such as BHA (butylated hydroxyanisole) and BHT (butylated hydroxytoluene) are being replaced with natural origin antioxidants because of their toxicity and carcinogenicity. Garlic and its preparations show antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, and increasing glutathione in the cells (Fig. 121.3). It has been observed that aqueous extracts from raw garlic and unpeeled cloves treated with distinct thermal processes were able to differentially scavenge HOCl and that SAC was the only effective garlic compound [40].
Alliin scavenges superoxide, while allyl cysteine and allyl disulfide do not react with superoxide. Allicin suppress the formation of superoxide by the xanthine/xanthine oxidase system, probably via a thiol exchange mechanism. It is now concluded that alliin, allyl cysteine, and allyl disulfide all scavenges hydroxyl radicals (\( {\text{O}}{{\text{H}}^{\bullet }} \)). Allyl disulfide, alliin, allicin, and allyl cysteine exhibit different patterns of antioxidant activities as protective compounds against free radical damage [41–43] and appear in fresh garlic approximately 1,000 times more potent as antioxidants than those found in aged garlic extract, while whole garlic and aqueous garlic extract exhibit direct antioxidant effects and enhance the serum levels of two antioxidant enzymes: catalase and glutathione peroxidase [44]. Several studies have been performed to test the antioxidant activity of raw and boiled garlic by using different assays: β-carotene linoleate model system (β-carotene), radical scavenging activity by 1, 1-diphenyl-2-picrylhydrazyl (DPPH), scavenging activity against nitric oxide (NO) with 2, 29-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS+), ferric-reducing/antioxidant power (FRAP), and Cu2+-induced LDL-C oxidation [45–49]. It has been investigated that an aqueous extract obtained from 1 mg of a garlic preparation was as effective as an antioxidant as 30 nmol ascorbic acid and/or 36 nmol α-tocopherol [50]. In rat liver microsomes, garlic extract prevented formation of thiobarbituric-acid-reactive substances in cell membranes during lipid peroxidation in a dose-dependent manner [51]. In an in vitro and animal study, there was a significant improvement in the plasma lipid levels in rats fed cholesterol-containing diets and an increase in the plasma antioxidant activity in groups of rats fed cholesterol-free diets supplemented with raw and boiled garlic at 100°C for 20 min [52, 53]. A concentration-dependent inhibition of LDL-C oxidation was observed with the oil-soluble garlic compound, allixin [54]. In another in vitro study, AGE significantly reduced Cu2+ and 15-lipoxygenase-mediated lipid peroxidation of isolated human LDL-C by 81% and 37%, respectively [55]. Aqueous garlic extracts have the ability to scavenge superoxide anion (\( {{\text{O}}_{{2}}}^{{ \bullet - }} \)), hydrogen peroxide (H2O2), and hydroxyl radical (\( {\text{O}}{{\text{H}}^{ \bullet }} \)) in the following aqueous preparations: (a) extracts of boiled garlic cloves (BG), (b) extracts of microwave-treated garlic cloves (MG), and (c) extracts of pickled garlic (PG) and heated extracts of (a) garlic powder (HGP) and (b) raw garlic (HRG). The data were compared with the unheated raw garlic (RG) or with the unheated garlic powder (GP). Extracts of GP and RG scavenged \( {{\text{O}}_{{2}}}^{{ \bullet - }} \), H2O2, and \( {\text{O}}{{\text{H}}^{ \bullet }} \) in a concentration-dependent way. The ROS scavenging capacity was not decreased in the aqueous garlic extracts except in MG and HRG (for \( {{\text{O}}_{{2}}}^{{ \bullet - }} \)) and in HGP and PG (for H2O2), while the heating before or after garlic cutting was unable to eliminate the capacity of the extracts to scavenge H2O2, \( {{\text{O}}_{{2}}}^{{ \bullet - }} \), and \( {\text{O}}{{\text{H}}^{ \bullet }} \) [56]. Moreover, it was also found that fresh garlic, subjected to a cooking regimen of 100 °C during 20 min, preserves its bioactivity: the decrease in the contents of the studied compounds and the decrease in the total antioxidant potential were statistically not significant [53]. Recently, Lei et al. [57] suggested that DADS and DATS protect eNOS activity against ox-LDL-C insult. This protection can be attributed partly to their mediation of phosphatidylinositol 3-kinase/protein kinase B signaling and prevention of eNOS degradation. Subsequently, another recent study [58] suggested that SAC, S-benzylcysteine (SBC), and S-propylcysteine (SPC) to be excellent hydroxyl radical (\( \bullet\! {\text{OH}} \)) scavengers, while SAC only as a modest peroxyl radical (\( {\text{HOO}}\! \bullet \)) scavenger. As described, the sulfur content in garlic responsible for antioxidant activity, furthermore some recent studies reported the abundance of phenolic compound in garlic leaves including gallic acid and quercetin, contributing the antioxidant activity [7, 59, 60].
6 Clinical Studies
In a randomized, double-blind, placebo-controlled study with three parallel arms [61], 17 participants consumed garlic oil (4 mg), 18 participants consumed garlic powder (0.5 g), and 17 participants consumed placebo for 11 weeks. Garlic oil caused a relatively rapid (4 weeks) rise in total antioxidant capacity compared with placebo or garlic powder. However, at 6 weeks, a significant rise also could be seen with garlic powder; by 11 weeks, it reached the same level as that obtained with garlic oil. Moreover, in a randomized, double-blind, placebo-controlled crossover trial [62], in which 10 normolipidemic subjects (5 males, 5 females) took six capsules each day containing either 100 mg of garlic powder/tablet or placebo followed by a 1-week washout period and then another 2 weeks on the alternate substance. The study data indicated that, for individuals taking garlic, there was increased antioxidant status as evidenced by an increase in the resistance of LDL-C to oxidative stress as compared with participants taking placebo [62]. However, the TBARS assay used in this study did not use purified LDL-C, and it is now known that the use of purified LDL-C yields more reliable data. In a small-scale preliminary double-blind, placebo-controlled, crossover study [54] involving eight subjects (4 men and 4 women), four subjects took 1.2 g AGE three times a day for 2 week, then 2 week of no garlic (washout period), followed by 2 week of placebo. The use of the garlic supplement was found to significantly increase the resistance of LDL-C to oxidation [54]. A study [63] showed that after short-term garlic supplementation in essential hypertensive patients (EH) regarding indices of oxidative stress, there is a significant reduction in ox-LDL-C and 8-iso-PGF2α levels. In a study [64] on six organosulfur compounds, derived from garlic showed marked antioxidative and antiglycative effects in partially oxidized (or glycated) LDL-C and plasma against further deterioration in 36 diabetic patients. Durak et al. [65] showed that consumption of 10 g of garlic/day for 4 months causes significant increase in blood antioxidant capacity and improved blood lipid profile in hypertensive patient. Dhawan and Jain [66] in 2005 demonstrated in a clinical trial of hypertensive patients, supplementation with garlic leads to significant reduction in 8-Hydroxy-2′-deoxyguanosine (8-OHdG), nitric oxide (NO) levels and lipid peroxidation along with an increase in vitamin levels (A, E, and C) and total antioxidant status (TAS).
7 Proposed Mechanism
Many authors suggest various possible garlic antioxidant mechanism of action, in which scavenging of ROS is most common mechanisms whereby garlic derivatives confer its important health care benefits. Vaidya et al. [67] suggested that the peroxyl-radical-trapping activity of garlic is primarily due to 2-propenesulfenic acid formed by the decomposition of allicin. Thus, sulfenic acids are very probably the most potent of all peroxyl-radical-trapping antioxidants. New insights on the antioxidant mechanism of garlic derivatives S-allylcysteine and its corresponding sulfoxide (alliin) showed the highest and lowest HOCl-scavenging capacities [68]. This scavenging activity is enhanced by increasing the number of S atoms or by the alanyl group (−CH2CH–NH2–COOH) and decreased in the absence of the C=C bond or in the presence of a sulfoxide group in the thioallyl group [68]. Recently, Miron et al. [69] showed that the allicin diffuses through cell membranes and exerts its biological effects by rapidly reacting with intracellular free thiols, such as reduced glutathione (GSH), cysteine, and sulfhydryl groups of proteins. The reaction of the allylthio group with those cellular components constitutes the major beneficial effects of allicin. The first product is most likely that of the S-allylthio-mixed disulfide (AS-SX) with GSH. Another recent study [58] suggested the mechanism by which SAC, SBC, and S-propylcysteine (SPC) scavenge \( \bullet\! {\text{OH}} \) and \( {\text{ROO}}\! \bullet \) due to amelioration when the allyl group was replaced by benzyl or propyl groups.
8 Antihypertensive Effects
Hypertension is a collective risk factor for cerebrovascular disease, ischemic heart disease, peripheral vascular disease, and renal disease characterized by systolic blood pressure of 140 mmHg or greater, and/or a diastolic blood pressure of 90 mmHg or greater, in people who are not taking antihypertensive medication. A number of studies have documented the hypotensive effect of garlic and their bioactive preparations. In 1973, Chanderkar and Jain [70] reported the hypotensive (10–50 mmHg) effect of alcoholic garlic extract (2.5–25 mg/kg) after oral administration in experimentally induced hypertension. Some studies [71, 72] showed a slight decrease in both systolic and diastolic pressures after intravenous injection of garlic extracts in experimental animals. Gastric administration of encapsuled garlic powder to anesthetized dogs induced a dose-dependent (2.5–15 mg/kg) prolonged decrease in arterial blood pressure [73]. Single or multiple doses of 0.5 mL of aqueous extract of garlic were given orally to two-kidney-one-clip (2K–1C) model rats that showed a maximum antihypertensive effect at 2–6 h after administration [74]. Experimental rats who were fed a 2% high-cholesterol diet exhibited a 23.50% increase in systolic blood pressure which was significantly reduced when the rats were fed an aqueous extract of garlic powder containing allicin on a daily basis [75]. In another study [76], chronic feeding of diets containing either AGE or raw garlic (RG) powder for 10 weeks resulted in a reduction of the increase of systolic blood pressure compared with the control group from 4 weeks after beginning the experimental diets. The effect of AGE was accompanied by a decrease of pulse pressure (PP), suggesting an improvement of the pliability of the artery, although RG did not affect PP. In a recent animal study [77], combination of fresh garlic homogenate compound S-allyl cysteine sulfoxide and captopril exerted super-additive (synergistic) interaction with respect to fall in blood pressure and angiotensin converting enzyme (ACE) inhibition and suggested the combination of garlic with captopril should be avoided. Continuous researches have been carried out on animals and have repeatedly documented the significant hypotensive activity of garlic. Another recent study [78] demonstrated that garlic homogenate in moderate dose (250 mg/kg) with added hydrochlorothiazide possesses synergistic cardioprotective and antihypertensive properties against fructose- and isoproterenol-induced toxicities in albino rats.
9 Clinical Studies
Evidence has been found that people’s belief in continuing garlic use for the management of hypertension is justified and well documented. A very early research in 1921 showed the hypotensive effect of garlic tincture [79]. Allimin tablets containing 4.75 g of garlic concentrate (0.31 g of desiccated garlic and 2.375 g of desiccated parsley) administered to 26 hypertensive patients three times daily for 3 days resulted in reduction of systolic and diastolic blood pressure (12.3 mmHg and 6.5 mmHg) in 85% of the patients [80]. Intake of about 900 mg/ day garlic powder in hypercholesterolemic [81], mild hypertension patients [82], and normotensive subjects [83] resulted in reduction of diastolic blood pressures as compared to the nongarlic consuming groups. In another study [28], there was a 5.5% decrease in systolic blood pressure and a modest reduction of diastolic blood pressure in response to 900 mg/day aged garlic consumption. Short-term consumption of garlic supplementation (250 mg/day for 2 months) in essential hypertensive patients resulted significant decline in both systolic and diastolic blood pressures [63]. Garlic extract consumption for 4 months caused significant reductions in systolic and diastolic blood pressures in 13 hypertensive patient [65]. A study [84] showed that the undamaged garlic (swallowed) had no lowering effect on lipid level of serum, while crushed garlic (chewed) reduces cholesterol, triglyceride, MDA, and systolic and diastolic blood pressures. In a double-blind parallel randomized placebo-controlled trial [85] involving 50 patients, receiving four capsules of aged garlic extract (960 mg containing 2.4 mg SAC) daily for 12 weeks resulted in lowering of systolic blood pressure similar to current first-line medications in patients with treated but uncontrolled hypertension. Recently, a randomized, placebo-controlled parallel feeding trial [86] showed a significant reduction in both systolic and diastolic blood pressures in hypertensive subjects after taking two 500 mg capsules of processed garlic for 8 weeks. There was one meta-analysis performed by Silagy and Neil in 1994 [87] which included eight trials using the same dried garlic powder preparation (Kwai). The results from the data of 415 subjects after analysis showed only three of the trials were specifically conducted in hypertensive subjects, and out of the seven trials that compared the effect of garlic with that of placebo, three showed a significant reduction in systolic blood pressure (SBP) and four in diastolic blood pressure (DBP). In 2008, a study [88] searched the databases for studies published between 1955 and October 2007 in which 11 of 25 studies included in the systematic review were suitable for meta-analysis. The author suggested that garlic preparations are superior to placebo in reducing blood pressure in individuals with hypertension. Another meta-analysis study [89] was published in the same year 2008 which included ten trials in the analysis. The result showed that garlic reduced SBP by 16.3 mmHg and DBP by 9.3 mmHg compared with placebo in patients with elevated SBP in the three trials. However, the use of garlic did not reduce SBP or DBP in patients without elevated SBP. A very recently published meta-analysis [90] containing the data from January 1994 to December 2010 including 13 studies included 659 subjects. The result of all studies showed a mean decrease of 4.2 ± 2.4 mmHg for SBP in the garlic group compared to placebo, while the mean decrease in the hypertensive subgroup was 7.3 ± 2.2 mmHg for SBP and 6.7 ± 1.4 mmHg for DBP. There were no statistically significant effects of garlic (compared to placebo) observed for DBP of all subjects and the nonhypertension subgroup.
10 Possible Mechanism
Many authors proposed the possible mechanism by which garlic influences antihypertensive effects. Early investigation [72] proposed that prostaglandin-like activity responsible for antihypertensive action of garlic decreases peripheral vascular resistance. Whenever, the body increases production of angiotensin II converting enzyme (ACE), blood pressure increases. Garlic showed blood pressure reducing properties which have been linked to its hydrogen sulfide (H2S) production [91]. It has been demonstrated that garlic and garlic-derived organic polysulfides, such as diallyl trisulfide (DATS) and diallyl disulfide (DADS), induce H2S production in a thiol-dependent manner and allicin content liberated from alliin and the enzyme alliinase which has angiotensin II inhibiting and vasodilating effects in in vitro [92], animal [93] studies. Nitric oxide (NO) is a well-recognized vasodilator and vasorelaxant for endothelial and smooth muscle cells. Garlic extract and S-allyl-γ-cysteine significantly increase NO production in endothelial cells [94, 95] which results in lowering blood pressure [96]. In addition, in in vitro [97] and animal studies [98], garlic shows nitric-oxide-dependent relaxation in pulmonary arteries. Amino acid analysis of garlic powder demonstrated that it is a rich source of arginine, the precursor of NO. This was explained by the fact that NG-nitro-l-arginine methyl ester (L-NAME, a NOS inhibitor) abolished the vasodilatory effect of garlic. In a single in vitro study [99], garlic opens K+ channels, which can reduce calcium influx and cause vasodilation which was ultimately responsible for the antihypertensive activity.
11 Antithrombotic and Fibrinolytic Effect
Blood platelets are mainly responsible for maintaining the hemostatic integrity of blood vessels and to stop bleeding after injury. Due to coronary artery disease and rupture of atherosclerotic plaque, there is increase in the platelet count and activation of the coagulation cascade with platelet thrombus formation, and that finally leads to vessel embolism. Garlic inhibits the platelet aggregation and prevents the thrombosis in in vitro animal models, and clinical studies. During the 1970s, there were three animal studies which reported the antiplatelet activity of garlic. The essential oil was more effective than clofibrate in the usual clinical dose of 33 mg/kg/day prevent lipid accumulation in the rabbit aorta [100], and essential oils of garlic protect against experimental atherosclerosis by preventing the fall in the alpha lipoprotein fraction and by enhancing fibrinolytic activity [101]. Sainani et al. [102] in 1979 showed enhanced fibrinolytic activity in albino rabbits when administered with garlic juice (0.25–25 g/day) in 10 mL distilled water. Aqueous garlic extracts inhibit platelet aggregation in vivo when added to plasma rich platelet at a concentration of 10 μM, suggesting allicin as principle inhibitor [103]. ADP-, epinephrine-, collagen-, and arachidonate-induced platelet aggregation is inhibited in vitro by garlic extract in a dose-dependent manner by inhibition of the prostacyclin biosynthesis in rat aorta [104]. Diallyl disulfide and diallyl trisulfide are mainly responsible for the prevention of acute platelet thrombus formation in stenosed canine coronary arteries model [105]. Several in vitro and in vivo studies were continuously performed and have proven the previous work with proposed mechanism hypothesis. In an ex vivo study [106], infusion of different garlic extract (10, 2, 5 and 100 mg/kg) in the ear vein of the rabbit significantly inhibits serum TXB2 production in a distinct dose and time-dependent pattern. Chloroform/acetone extracts of fresh garlic have been shown to inhibit cyclooxygenase activity directly in in vitro, with the acetone extract being more effective [107]. In 1992, Lawson et al. [108] suggested that the antiaggregatory activity of garlic clove homogenates (S-allyl cysteine sulfoxide) in platelet rich plasma was due to adenosine; however, in whole blood neither adenosine nor the polar fraction had any effect, and all of the antiaggregatory activity was due to allicin and other thiosulfinates compound. Ajoene is a well-established antiplatelet agent in garlic, and its inhibitory effect on platelet aggregation has been extensively studied and documented both by in vivo and in vitro experiments [109, 110] including inhibition of baboon platelet aggregation in vitro (75 μg/mL) and in vivo (25 mg/kg) induced by adenosine diphosphate (ADP) or collagen [111]. Diallyl trisulfide inhibited platelet aggregation and Ca2+ mobilization induced by thrombin without affecting the production of IP3 [112]. Another study suggested that garlic component sodium 2-propenyl thiosulfate modulated cyclooxygenase activity in canine platelets in a dose-dependent manner, thus preventing their aggregation [113]. Administration of the garlic in a rat in situ loop model,suggested that odorless garlic not only activates fibrinolytic activity by accelerating tPA-mediated plasminogen activation but also suppresses the coagulation system by downregulating thrombin formation [114]. Recently, an in vitro study [115] suggested the alcoholic wild garlic extract is more potent, while Allium sativum and Allium ursinum exert similar antiaggregatory effects in a dose dependant manner and inhibit platelet aggregation induced via the ADP pathway.
12 Clinical Studies
Several clinical studies done by Bordia and colleagues [116, 117] in the late 1970s and early 1980s reported that a garlic oil preparation rich in vinyldithiins, sulfides, and ajoene could inhibit platelet aggregation and result in increased fibrinolytic activity. In 1977, study on 10 healthy individuals, 10 patients with old myocardial infarction, and 20 patients with acute myocardial infarction showed garlic (1 g/kg b.w.) significantly increased fibrinolytic activity in all subjects especially in healthy group [116]. Later on, Bordia et al. [118] showed that garlic oil preparation inhibits platelet function in both healthy subjects and in patients with coronary heart disease. A randomized, double-blind, placebo-controlled crossover study [119] of 12 healthy subjects reported that garlic powder (Kwai, 900 mg/day) inhibited platelet aggregation induced by ADP and collagen. Administration of garlic in a daily dose of 2 × 2 capsules (each capsule containing ethyl acetate extract from 1 g peeled and crushed raw garlic) showed antiplatelet activity and also inhibited platelet thromboxane formation [120]. In another study [121] of garlic powder, it was found that feeding 7.2 g of AGE powder/day (~25 mL/day of liquid AGE) to hypercholesterolemic men resulted in inhibition of epinephrine (another platelet aggregating agent) and collagen-induced aggregation, but not ADP-induced aggregation. A 13-week study [122] involving normolipidemic subjects who ingested 5 mL of aged garlic extract per day significantly inhibited both the total percentage and initial rate of platelet aggregation at concentrations of ADP up to 10 μmol/L. Besides sulfur containing compound, other nonsulfur compounds, such as β-chlorogenin and quercetin, have also been shown to inhibit platelet aggregation [123]. A meta-analytical survey based on 11 electronic databases study [124], which included 1,798 pertinent records, 45 randomized trials, and 73 additional studies, reported cardiovascular-related effects were limited to randomized controlled trials lasting at least 4 weeks, and it has been found that in comparison with placebo, garlic preparations lead to a significant reduction in platelet aggregation [124]. Cavagnaro et al. [125] describe the effect of cooked garlic on antiplatelet activity on the blood sample from two healthy subjects, who had abstained from eating Alliums or other known platelet inhibitory foods for at least 1 week. The result showed oven heating at 200 °C or immersing in boiling water for 3 min or less did not affect the ability of garlic to inhibit platelet aggregation (as compared to raw garlic), whereas heating for 6 min completely suppressed in vitro antiaggregatory activity in uncrushed, but not in previously crushed, samples [125]. Prolonged incubation (more than 10 min) at these temperatures completely suppressed in vitro antiaggregatory activity, while microwaved garlic had no effect on platelet aggregation. A randomized, double-blind, placebo-controlled, crossover study involving 14 healthy subjects showed one large dose of garlic oil (~9.9 g garlic) slightly but significantly affected adrenaline but not ADP or collagen-induced platelet aggregation [126]. In a recently published report, it was shown that there was reduction in adenosine-induced platelet aggregation by garlic diallyl sulfide (2.2 μg) compound in women participants with type 2 diabetes mellitus [127].
13 Proposed Mechanism
Arachidonic acid (AA) is an essential fatty acid precursor in the biosynthesis of leukotrienes, prostaglandins, and thromboxanes (Fig. 121.4). Various platelet agonists mobilize calcium through G-protein-coupled receptors. Calcium activates phospholipase A2, which liberates arachidonic acid from phosphatidylcholine and phosphatidylethanolamine. Calcium also activates myosin light-chain kinase. AA is liberated from phospholipids and, in the presence of the enzyme cyclooxygenase, incorporates oxygen to form the endoperoxide prostaglandin G2 (PGG2). PGG2 is then quickly transformed to prostaglandin H2 (PGH2). PGH2, in the presence of thromboxane synthase, produces thromboxane A2 (TXA2) which further mobilizes calcium from intracellular storage sites. TXA2 and activated myosin light-chain kinase together lead to platelet coagulant activation by stimulating secretion of products of platelet granules, allowing tenase and prothrombinase formation [128]. TXA2 is a vasoconstrictor and platelet aggregating compound which serves as precursor for inactive thromboxane-B2 (TXB2). Ajoene strongly inhibits the metabolism of arachidonic acid by both cyclooxygenase and lipoxygenase pathways [129, 130], thus inhibiting the synthesis of TXA2, AA metabolite, and 12-hydroxy-eicosatetraenoic acid (12-HETE). AGE has been shown to reduce thromboxane formation [106]. It has also been reported that N-ethylmaleimide causes the disaggregation of both ADP and thrombin-induced platelet aggregation and that this disaggregation is a result of the removal of calcium ions (Ca2+) from the platelet cytosol. Therefore, the effects of AGE on calcium mobilization were investigated in both A23187 and ADP-stimulated platelets [131]. In the presence of AGE, the initial concentration of calcium ions was significantly less than when the experiments were performed in the absence of AGE. This could be due to the metal chelation properties of AGE, as reported earlier [55]. In support of this, garlic extract has been shown to strongly inhibit calcium binding, suppressing the influx of calcium ions by chelating calcium within platelet cytosol and arteriosclerotic nanoplaque formation [132, 133]. AGE may inhibit phospholipase A2, thus reducing levels of lysophosphatidic acid, which causes platelet aggregation and increases intracellular calcium ions [131]. Antiaggregatory effect of ajoene may also be causally related to its direct interaction with the putative fibrinogen receptor (GPIIb/IIIa) in a dose-dependent manner [134]. The GPIIb–IIIa receptor has a high content of –SH groups, and binding of fibrinogen is inhibited by the organosulfur compound ajoene [135]. AGE has been reported to enhance NO production by activating cNOS, but not iNOS [136], which may increase the GTP concentration and ultimately induces platelet aggregation.
14 Antiatherosclerotic Effect
Atherosclerosis is a result of an interaction between fat and cholesterol within the cellular components of the arterial wall and buildup in the walls of arteries to form hard structures called plaques, the pathogenic substratum of many cardiovascular diseases. Various in vitro and clinical studies have shown and confirm the effect of garlic in the prevention and treatment of atherosclerosis. Early studies on experimental animals showed the reduction in aortic lipid content of garlic fed animals by 72%, while in the control group there was no significant reduction. The data suggests that cholesterol is depleted from experimentally induced atherosclerosis by garlic administration [137, 138]. Treatment with aged garlic extract reduces fatty streak development, vessel wall cholesterol accumulation, and the development of fibro fatty plaques in neointimas of cholesterol-fed rabbits, thus providing protection against the onset of atherosclerosis [139]. In cell cultures, aqueous solutions of dried garlic powder containing allicin and ajoene significantly inhibit the proliferative activity of smooth muscle cells from atherosclerotic aortic plaques [140, 141]. In hypercholesterolemic rabbits, garlic supplements significantly reduced the aortic lesions and lipid content of existing fatty plaques [142]. AGE exerts antiatherogenic effects through inhibition of smooth muscle phenotypic change and proliferation and by another (unclarified) effect on lipid accumulation in the artery wall [143]. Garlic exerts hypocholesterolemic and antiatherogenic activity by inhibition of plasma cholesteryl ester transfer protein (CETP) activity, which may delay the progression of atherosclerosis, thereby supporting the atherogenicity of CETP and the inhibitory activity of garlic supplementation against CETP [21]. An in vitro study’s results show the formation of the ternary proteoheparan sulfate HS-PG/LDL/Ca2+ complex, which is initially responsible for the “nanoplaque” composition and ultimately for the arteriosclerotic plaque generation, where the garlic extract strongly inhibits Ca2+ binding to HS-PG [132]. A notable restoration of arterial blood pressure; significantly enhanced vasorelaxant response to adenosine, acetylcholine, and isoproterenol; and reduction in atherogenic properties of cholesterol were seen in animals on garlic-supplemented diet [144]. Daily dietary supplement of allicin, 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9% and 56.8% in apolipoprotein E-deficient and low density lipoprotein (LDL) receptor knockout mice, respectively, as compared with control mice and also by using pure allicin preparation; an in vitro study results showed that allicin may affect atherosclerosis not only by acting as an antioxidant but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages [145]. A recent in vitro study suggested that AGE inhibit monocyte differentiation into macrophages, CD36 expression, and oxidized LDL-C (oxLDL-C) uptake into macrophages induced by the cardiovascular risk factor homocysteine (Hcy) [146].
15 Clinical Studies
In a randomized, placebo-controlled trial in ten healthy adults, there was a significant improvement in plasma viscosity and capillary blood flow within 5 h after taking 900 mg of standardized garlic powder [147]. Another randomized placebo-controlled double-blind crossover study in healthy volunteers showed increased erythrocyte velocity results from vasodilation of precapillary arterioles which increased diameter of erythrocyte column by an average of 8.6 % along with simultaneous inflow of interstitial fluidity accompanied by a significant decrease in hematocrit and plasma viscosity (rheoregulation) [148]. In a placebo-controlled trial of patients with stage II peripheral arterial occlusive disease, garlic powder supplements (800 mg/day) were associated with a significant increase in walking distance by 46 m; the improvement started after the fifth week of treatment mainly by simultaneous decrease in spontaneous thrombocyte aggregation [149]. A cohort study including 101 healthy adults who took at least 300 mg daily of dried garlic powder for at least 2 years were compared with 101 age and gender matched controls who were not taking supplements; pulse wave velocity and elastic vascular resistance (two measures of arterial elasticity) were significantly lower in the garlic group than in the control group, even after controlling for age and systolic blood pressure, that is, chronic garlic powder intake was associated with an attenuation in age-related increases in aortic stiffness [150]. In a prospective, 4-year clinical trial of patients treated with 900 mg daily of standardized garlic powder, there was a 9–18 % reduction in plaque volume, a 4 % decrease in LDL-C levels, an 8 % increase in HDL-C concentrations, and a 7 % decrease in blood pressure [151]. Similar results were reported in a 4-year German trial in 152 older adults; those who took high-dose garlic for 4 years, demonstrated reduced atherosclerotic plaque in both carotid and femoral arteries by 5–18 % [152]. A study of 11 atherosclerotic patients with oxidative stress showed prevention of oxidation reaction by eliminating this oxidative stress and significantly lowered plasma and erythrocyte malondialdehyde (MDA) levels after the ingestion of garlic extract [153]. A placebo-controlled, double-blind, randomized pilot study indicates the potential ability of AGE to inhibit the rate of progression of coronary calcification in 19 patients, as compared to placebo over 1 year [154]. AGE consumption increases plasma nitric oxide synthase (NOS) activity in 11 atherosclerotic patients and suggested that AGE may arise from its NOS-inducing and nitric-oxide (NO)-producing activities [155].
16 Proposed Mechanism
The exact molecular mechanism of garlic by which it shows antiatherosclerotic effect is not fully understood. The development of atherosclerotic plaque or lesions is a result of endothelial dysfunction induced by elevated and modified LDL and ox-LDL, free radicals, toxins, homocysteine, hypertension, and other unknown risk factors. It has also seen that disturbance in immune system supports the formation of atherosclerotic plaques. Diets supplemented with garlic are able to restore endothelial function in experimental laboratory animals [144] and investigations of humans [156]. It has been shown that raw garlic possibly works via its active metabolite allicin action on coronary endothelial function and vasoreactivity [157]. The electrophysiological correlation to vasodilatation in human coronary arteries under the influence of garlic extract showed decrease in the isometric wall tension. Allicin and ajoene hyperpolarized the cell membrane and relaxed the vascular strips in a concentration-dependent manner and suggested that garlic extract and its compounds can be classified as phytopharmacological K+ channel openers [99]. OxLDL-C, but not native LDL-C, contributed to atherogenesis and promoting vascular dysfunction by exerting direct cytotoxicity toward endothelial cells, by increasing chemotactic properties for monocytes, by transforming macrophages to foam cells via scavenger receptors, and by enhancing the proliferation of endothelial cells, monocytes, and smooth muscle cells. Garlic compounds can effectively suppress LDL-C oxidation in vitro and that short-term supplementation of garlic to humans increases resistance of LDL-C to oxidation [54, 158]. Hcy, a metabolite from methionine, serves as an independent cardiovascular disease risk factor, which causes thrombosis and oxidative-stress damage and is often associated with atherosclerosis and a higher risk of coronary heart disease, stroke, and peripheral vascular disease by damaging the inner lining of arteries and promoting blood clotting. Hcy has an inverse relationship with folate deficiency and decreased NO production. AGE may at least partly prevent a decrease in bioavailable NO and endothelium-derived hyperpolarizing factor during acute hyperhomocysteinemia [159] and also decrease plasma total hcy concentration by 30 % without changing the protein-bound/free hcy ratio [160]. Coronary arterial calcification (CAC), a marker of plaque formation in human coronary arteries and atherosclerosis, has been linked to an increased risk for cardiovascular events such as myocardial infarction, fatal arrhythmia, and congestive heart failure. AGE inhibits the rate of progression of coronary calcification as compared to placebo over 1 year [154]. C-reactive protein (CRP) is one of the strongest predictors for the risk of atherosclerosis and cardiovascular events in subjects with and without cardiovascular disease. But there was only one study which showed that 12 weeks of treatment with a high-dose, chemically well-characterized, production-controlled garlic powder had no significant effect on CRP protein in normolipidemic subjects with risk factors for CVD [161].
17 Other Cardioprotective Activity
Cardiac arrhythmias are any abnormality or perturbation in the normal activation sequence of the myocardium. Some earlier studies showed beneficial effects of garlic in cardiac arrhythmias. Garlic powder (1 % corresponding to Kwai/Sapec added to a standard chow for a 10-week period) significantly reduces the incidence of ventricular tachycardia (VT) and fibrillation (VF) in isolated perfused rat heart [162]. Another study in the same manner using garlic powder (1 % added to a standard chow for an 8-week period) also showed significantly reduced ischemia reperfusion-induced ventricular fibrillation (VF) in isolated perfused rat heart and suggested that an intact alliin–alliinase system is important for this activity of garlic [163]. Garlic dialysate decreased the positive inotropic and chronotropic effects of isoproterenol in a concentration-dependent manner and suggesting via β-adrenoceptor blocking action produced by the garlic dialysate [164]. Another study by same author suggested that garlic dialysate has a significant antiarrhythmic effect in both ventricular and supraventricular arrhythmias [165]. Aqueous garlic extract increased the amplitudes of atrial complex “p” wave and the ventricular complex “QRS” of the rat ECG. This is suggestive of increase in voltage output of the atria and ventricles probably in accordance with positive inotropism [166]. A recent animal study suggested that garlic cannot alter the ventricular fibrillation threshold (VFT), but it significantly decreases the upper limit of vulnerability (ULV) in a dose-dependent pattern, indicating that it can reduce the range of the stimulation strength between the VFT and ULV (vulnerability window) during the vulnerable period of a cardiac cycle [167].
A few studies have shown the beneficial effect of garlic and its active constituents in conjugation with some drugs. Allylmercaptocaptopril is an example of a conjugate of the ACE inhibitor drug captopril with garlic allicin. Allylmercaptocaptopril prevented progressive weight gain, without a detectable effect on food intake, lowered blood pressure, and improved cardiac hypertrophy, as indicated by heart weight and ventricular-wall thickness [168]. Garlic therapy in animals with myocardial infection showed improved survival and cardiac function by add-on captopril [169, 170] and propranolol [171]. Garlic juice inhibited the contractions of rabbit and guinea pig aortic rings induced by norepinephrine in Ca2+-free and Ca2+-containing Krebs–Henseleit solutions and indicated that it produces concentration-dependent synergistic effect by its calcium-blocking property [172]. Beneficial effects of combined therapy of garlic and hydrochlorothiazide were also demonstrated and confirmed in the recent past [173, 174]. The same author also reported that combination of S-allyl cysteine sulfoxide (SACS) from fresh garlic homogenate and captopril exerted super-additive (synergistic) interaction with respect to fall in blood pressure and ACE inhibition [77]. In one preliminary study, in which pretreatment with aged garlic extract for 27 days ameliorated the effect of an active anticancer agent doxorubicin (DOX) administration on cardiac tissue; cardiomyocytes looked more or less similar to those of control and suggested that aged garlic extract is potentially protective against doxorubicin-induced cardiotoxicity [175].
18 Bioavailability and Metabolism
Very few studies have been conducted on the bioavailability of garlic compounds. An animal study [176] showed that in a very short time (10 min) after orally administering alliin (10 mg/mouse), it was observed in the stomach (7.2%), intestine (22.4%), and liver (2.5%) without the production of allicin and its degradation compounds such as DADS, vinyldithiins, and allyl-SS conjugated compounds, suggesting alliin is not metabolized to respective organosulfur compounds without an appropriate enzyme (allinase). In a pharmacokinetic study using synthesized 35S-labeled alliin, 60–70% was absorbed in rats [177]. Alliin along with DADS has been detected in the perfusate after the isolated rat liver passage, while there was absence of allicin [178] even in human serum or urine from 1 to 24 h after ingesting 25 g of raw garlic containing a significant amount of allicin [108]. These findings indicate that alliin itself is never converted to allicin in the body and metabolized into various organosulfur compounds such as DADS by liver enzymes. When allicin is added to fresh blood, it is quickly transformed into allyl mercaptan, but this compound was not found in blood or urine of people who consume garlic, also demonstrating that the level of allyl methyl sulfide (AMS) in the exhaled air depended on amount of the ingested allicin or its derivatives [179]. Vinyldithiins, 2-vinyl-4H-1,3-dithiin, and 3-vinyl-4H-1,2-dithiin, have been detected in the serum, kidney, and fat tissue >24 h after oral ingestion, while only 1,3-vinyldithiin was found in the rat liver [180]. The metabolic fate of [35S]-labeled DADS in rats after intraperitoneal injection with the maximum concentration of [35S]-labeled DADS by mice livers occurred 90 min after treatment, and about 70% of the radioactivity was distributed in the liver cytosol, of which 80% was metabolized to sulfate [181]. The pharmacokinetics of SAC is well established in animal studies, which is detected in the blood, and its pharmacokinetic parameters are well associated with oral dose administration. Significant concentration of N-acetyl-S-allyl-l-cysteine is also identified as a metabolite of SAC in the urine. This indicates that SAC could be transformed into N-acetylated metabolite by N-acetyltransferase in the body. The bioavailability of SAC is 103.0 % in mice, 98.2% in rats, and 87.2% in dogs [182]. SAC was found also in human blood after ingestion of AGE, the main component of which is SAC [183]. DAS could be metabolized by one of the cytochrome P450 isoenzymes to form diallyl sulfoxide (DASO) and then diallyl sulfone (DASO2) [184]. After GC–MS analysis, two major peaks, which were identical to allyl mercaptan and DADS after ingesting grated garlic, could be detected in human breath without other organosulfur volatiles [185]. There is a need of major clinical trial which confirm the bioavailability of sulfur and nonsulfur compounds in garlic.
19 Side Effects and Toxicity
According to the suggested doses from the studies and optimum pharmacological responses, the following doses are recommended: 2–5 g of fresh raw garlic, 0.4–1.2 g of dried garlic powder, 2–5 mg garlic oil, and 300–1,000 mg of garlic extract (as solid material). Other preparations should correspond to 4–12 mg of alliin or approximately 2–5 mg of allicin, an active constituent of garlic. Various studies have been investigated in search of toxicity from garlic, but till now there is no known toxic constituents in garlic and its preparations. Garlic is considered to have very low toxicity and is listed as Generally Recognized as Safe (GRAS) by the US Food and Drug Administration (FDA). The most common side effects produced by intake of small amounts of garlic are bad breath and body odor. When garlic is taken in a high dose by a sensitive individual, it is known to cause gastric irritation. A clinical trial showed side effects which include heartburn, nausea, vomiting, diarrhea, flatulence, bloating, mild orthostatic hypotension, flushing, tachycardia, headache, insomnia, sweating, and dizziness as well as offensive body odor [186]. In some cases, people are allergic to sulfur-based compounds and reported allergic reactions to garlic; namely, contact dermatitis, asthma, rhinitis, conjunctivitis, urticaria, anaphylaxis, and angioedema [187–189]. Garlic may be used safely in pregnant and breast-feeding mothers. Consumption of garlic enhances the pharmacological effects of anticoagulants (warfarin, fluindione) but reduces the efficacy of anti-AIDS drug saquinavir [190]. A clinical trial reported that coadministration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics [191].
20 Conclusion
Evidence from in vitro, in vivo, and clinical studies support the beneficial effects of garlic consumption in various preparations in the prevention of cardiovascular disease. The raw garlic and AGE are the most important among the available preparation and showed maximum pharmacological effect in low dose. The present report suggests that garlic has the ability to prevent excess free radical production, maintain the oxidative balance via increase in antioxidant status and increase in bioavailability of nitric oxide, prevent vascular inflammation, reduce cholesterol content and plaque formation, and inhibit platelet aggregation. Evidence suggests that garlic may produce modest but not clinically significant effects in the treatment of hyperlipidemia and hypertension via reduction in DBP. Indeed, the results from clinical trials are very few and inconsistent, probably due to differences in garlic preparations, unknown active constituents and their bioavailability, and small sample size. Systematic reviews are available for the possible antilipidemic, antihypertensive, antithrombotic, and chemopreventive effects. However, the clinical evidence is far from compelling. Garlic appears to be generally safe, although some allergic reactions may occur [192]; therefore, it would be a safe tool for the treatment and prevention of CVD. In conclusion, the proposed in vitro, in vivo, and animal models should be further verified in human studies in order to establish a causative link between molecular properties and the role of garlic active constituents in the prevention and treatment of CVD.
Abbreviations
- AA:
-
Arachidonic acid
- ACE:
-
Angiotensin converting enzyme
- ADP:
-
Adenosine diphosphate
- AGE:
-
Age garlic extract
- AMS:
-
Allyl methyl sulfide
- BC:
-
Before Christ
- BHA:
-
Butylated hydroxyanisole
- BHT:
-
Butylated hydroxytoluene
- BP:
-
British Pharmacopeia
- Ca2+ :
-
Calcium ion
- CAC:
-
Coronary arterial calcification
- CETP:
-
Cholesteryl ester transfer protein
- cNOS:
-
Endothelial nitric oxide synthase
- CVD:
-
Cardiovascular disease
- DADS:
-
Diallyl disulfide
- DAS:
-
Diallyl sulfide
- DASO:
-
Diallyl sulfoxide
- DASO2 :
-
Diallyl sulfone
- DBP:
-
Diastolic blood pressure
- DNA:
-
Deoxyribose nucleic acid
- DOX:
-
Doxorubicin
- DPPH:
-
1,1-Diphenyl-2-picrylhydrazyl
- DTS:
-
Diallyl trisulfide
- EH:
-
Essential hypertension
- FDA:
-
Food and Drug Administration
- GC–MS:
-
Gas chromatography–Mass spectrometry
- GSH:
-
Glutathione
- GTP:
-
Guanosine triphosphate
- H2O2 :
-
Hydrogen peroxide
- H2S:
-
Hydrogen sulfide
- Hcy:
-
Homocysteine
- HDL-C:
-
High density lipoprotein cholesterol
- HepG2 :
-
Liver hepatocellular carcinoma cell
- HETE:
-
Hydroxyeicosatetraenoic acid
- HMG-CoA:
-
3 Hydroxy-3-methylglutaryl coenzyme A
- HOCl:
-
Hypochlorous acid
- iNOS:
-
Inducible nitric oxide synthase
- IP3 :
-
Inositol phosphate
- LDL:
-
Low density lipoprotein
- LDL-C:
-
Low density lipoprotein cholesterol
- L-NAME:
-
l-Arginine methyl ester
- MDA:
-
Malondialdehyde
- NO:
-
Nitric oxide
- OxLDL:
-
Oxidized low density lipoprotein
- PGG2:
-
Prostaglandin G2
- PGH2 :
-
Prostaglandin H2
- Ph Eur:
-
European Pharmacopeia
- ROS:
-
Reactive oxygen species
- SAC:
-
S-Allylcysteine
- SACS:
-
S-Allylcysteine sulfoxide
- SBP:
-
Systolic blood pressure
- SBS:
-
S-Benzylcysteine
- SPC:
-
S-Propylcysteine
- TAS:
-
Total antioxidant status
- TBARS:
-
Thiobarbituric acid reactive species
- TC:
-
Total cholesterol
- TG:
-
Triglycerides
- TXA2 :
-
Thromboxane A2
- TXB2 :
-
Thromboxane B2
- USP:
-
United States Pharmacopeia
- VF:
-
Ventricular fibrillation
- VT:
-
Ventricular tachycardia
References
Rivlin RS (2001) Historical perspective on the use of garlic. J Nutr 131(3):951S–954S
Banerjee S, Maulik S (2002) Effect of garlic on cardiovascular disorders: a review. Nutr J 1(1):4
European Pharmacopoeia (2008), (6th edn). Strasbourg (France): Directorate for the Quality of Medicines and HealthCare of the Council of Europe (EDQM)
31 USP (2008) The United States pharmacopeia: the United States pharmacopeial convention, Washington
Pharmacopoeia B (2007) British pharmacopoeia commission, London
Butt MS, Sultan MT, Iqbal J (2009) Garlic: nature’s protection against physiological threats. Crit Rev Food Sci Nutr 49(6):538–551. doi:10.1080/10408390802145344
Bozin B, Mimica-Dukic N, Samojlik I, Goran A, Igic R (2008) Phenolics as antioxidants in garlic (Allium sativum L., Alliaceae). Food Chem 111(4):925–929.doi:10.1016/j.foodchem.2008.04.071
Gupta N, Porter TD (2001) Garlic and garlic-derived compounds inhibit human squalene monooxygenase. J Nutr 131(6):1662–1667
Cavallito CJ, Bailey JH (1944) Allicin, the antibacterial principle of Allium sativum. I. Isolation, physical properties and antibacterial action. J Am Chem Soc 66(11):1950–1951. doi:10.1021/ja01239a048
Stoll A, Seebeck E (1951) Chemical investigations on alliin, the specific principle of garlic. Adv Enzymol Relat Areas Mol Biol 11:377–400
Amagase H, Petesch BL, Matsuura H, Kasuga S, Itakura Y (2001) Intake of garlic and its bioactive components. J Nutr 131(3s):955S–962S
Amagase H (2006) Clarifying the real bioactive constituents of garlic. J Nutr 136(3 Suppl):716S–725S
Mendis S, Puska P, Norrving B (2011) Global atlas on cardiovascular disease prevention and control. World Health Organization, Geneva
Gebhardt R, Beck H (1996) Differential inhibitory effects of garlic-derived organosulfur compounds on cholesterol biosynthesis in primary rat hepatocyte cultures. Lipids 31(12):1269–1276
Yeh YY, Yeh SM (1994) Garlic reduces plasma lipids by inhibiting hepatic cholesterol and triacylglycerol synthesis. Lipids 29(3):189–193
Yeh YY, Liu L (2001) Cholesterol-lowering effect of garlic extracts and organosulfur compounds: human and animal studies. J Nutr 131(3s):989S–993S
Gebhardt R (1993) Multiple inhibitory effects of garlic extracts on cholesterol biosynthesis in hepatocytes. Lipids 28(7):613–619
Liu L, Yeh YY (2002) S-alk(en)yl cysteines of garlic inhibit cholesterol synthesis by deactivating HMG-CoA reductase in cultured rat hepatocytes. J Nutr 132(6):1129–1134
Augusti KT, Chackery J, Jacob J, Kuriakose S, George S, Nair SS (2005) Beneficial effects of a polar fraction of garlic (Allium sativum Linn.) oil in rats fed with two different high fat diets. Indian J Exp Biol 43(1):76–83
Larner AJ (1995) How does garlic exert its hypocholesterolaemic action? The tellurium hypothesis. Med Hypotheses 44(4):295–297
Kwon MJ, Song YS, Choi MS, Park SJ, Jeong KS, Song YO (2003) Cholesteryl ester transfer protein activity and atherogenic parameters in rabbits supplemented with cholesterol and garlic powder. Life Sci 72(26):2953–2964. doi:10.1016/s0024-3205(03)00234-0
Koch HP (1993) Saponins of garlic and onion. Chemistry, analytics, therapeutic and toxic activities [Saponine in knoblauch und kuchenzwiebel chemie, analytik, therapeutische und toxische wirkungen]. Dtsch Apoth Ztg 133(41):63–75
Matsuura H (2001) Saponins in garlic as modifiers of the risk of cardiovascular disease. J Nutr 131(3s):1000S–1005S
Heidarian E, Jafari-Dehkordi E, Seidkhani-Nahal A (2011) Effect of garlic on liver phosphatidate phosphohydrolase and plasma lipid levels in hyperlipidemic rats. Food Chem Toxicol 49(5):1110–1114. doi:10.1016/j.fct.2011.02.001
Warshafsky S, Kamer RS, Sivak SL (1993) Effect of garlic on total serum cholesterol. A meta-analysis. Ann Intern Med 119(7 Pt 1):599–605
Silagy C, Neil A (1994) Garlic as a lipid lowering agent – a meta-analysis. J R Coll Physicians Lond 28(1):39–45
Jain AK, Vargas R, Gotzkowsky S, McMahon FG (1993) Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med 94(6):632–635
Steiner M, Khan AH, Holbert D, Lin RI (1996) A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids. Am J Clin Nutr 64(6):866–870
Adler AJ, Holub BJ (1997) Effect of garlic and fish-oil supplementation on serum lipid and lipoprotein concentrations in hypercholesterolemic men. Am J Clin Nutr 65(2):445–450
Zhang XH, Lowe D, Giles P, Fell S, Connock MJ, Maslin DJ (2001) Gender may affect the action of garlic oil on plasma cholesterol and glucose levels of normal subjects. J Nutr 131(5):1471–1478
Alder R, Lookinland S, Berry JA, Williams M (2003) A systematic review of the effectiveness of garlic as an anti-hyperlipidemic agent. J Am Acad Nurse Pract 15(3):120–129
Kannar D, Wattanapenpaiboon N, Savige GS, Wahlqvist ML (2001) Hypocholesterolemic effect of an enteric-coated garlic supplement. J Am Coll Nutr 20(3):225–231
Mahmoodi M, Islami MR, Asadi Karam GR, Khaksari M, Sahebghadam Lotfi A, Hajizadeh MR, Mirzaee MR (2006) Study of the effects of raw garlic consumption on the level of lipids and other blood biochemical factors in hyperlipidemic individuals. Pak J Pharm Sci 19(4):295–298
Khoo YS, Aziz Z (2009) Garlic supplementation and serum cholesterol: a meta-analysis. J Clin Pharm Ther 34(2):133–145. doi:10.1111/j.1365-2710.2008.00998.x
Reinhart KM, Talati R, White CM, Coleman CI (2009) The impact of garlic on lipid parameters: a systematic review and meta-analysis. Nutr Res Rev 22(1):39–48. doi:10.1017/S0954422409350003
Spigelski D, Jones PJ (2001) Efficacy of garlic supplementation in lowering serum cholesterol levels. Nutr Rev 59(7):236–241
Sovova M, Sova P (2004) Pharmaceutical importance of Allium sativum L. 5. Hypolipemic effects in vitro and in vivo. Ceska Slov Farm 53(3):117–123
Borek C (2006) Garlic reduces dementia and heart-disease risk. J Nutr 136(3 Suppl):810S–812S
Chi MS, Koh ET, Stewart TJ (1982) Effects of garlic on lipid metabolism in rats fed cholesterol or lard. J Nutr 112(2):241–248
Pedraza-Chaverri J, Arriaga-Noblecia G, Medina-Campos ON (2007) Hypochlorous acid scavenging capacity of garlic. Phytother Res 21(9):884–888. doi:10.1002/ptr.2175
Prasad K, Laxdal VA, Yu M, Raney BL (1995) Antioxidant activity of allicin, an active principle in garlic. Mol Cell Biochem 148(2):183–189
Imai J, Ide N, Nagae S, Moriguchi T, Matsuura H, Itakura Y (1994) Antioxidant and radical scavenging effects of aged garlic extract and its constituents. Planta Med 60(5):417–420. doi:10.1055/s-2006-959522
Borek C (2001) Antioxidant health effects of aged garlic extract. J Nutr 131(3s):1010S–1015S
Kumaraguruparan R, Chandra Mohan KVP, Abraham SK, Nagini S (2005) Attenuation of N-methyl-N′-nitro-N-nitrosoguanidine induced genotoxicity and oxidative stress by tomato and garlic combination. Life Sci 76(19):2247–2255. doi:10.1016/j.lfs.2004.11.006
Lewin G, Popov I (1994) Antioxidant effects of aqueous garlic extract. 2nd communication: inhibition of the Cu(2+)-initiated oxidation of low density lipoproteins. Arzneimittelforschung 44(5):604–607
Ide N, Nelson AB, Lau BH (1997) Aged garlic extract and its constituents inhibit Cu(2+)-induced oxidative modification of low density lipoprotein. Planta Med 63(3):263–264. doi:10.1055/s-2006-957668
Munday JS, James KA, Fray LM, Kirkwood SW, Thompson KG (1999) Daily supplementation with aged garlic extract, but not raw garlic, protects low density lipoprotein against in vitro oxidation. Atherosclerosis 143(2):399–404
Ho SE, Ide N, Lau BH (2001) S-allyl cysteine reduces oxidant load in cells involved in the atherogenic process. Phytomedicine 8(1):39–46
Pedraza-Chaverri J, Gil-Ortiz M, Albarran G, Barbachano-Esparza L, Menjivar M, Medina-Campos ON (2004) Garlic’s ability to prevent in vitro Cu2+-induced lipoprotein oxidation in human serum is preserved in heated garlic: effect unrelated to Cu2+-chelation. Nutr J 3:10. doi:10.1186/1475-2891-3-10
Popov I, Blumstein A, Lewin G (1994) Antioxidant effects of aqueous garlic extract. 1st communication: direct detection using the photochemiluminescence. Arzneimittelforschung 44(5):602–604
Horie T, Murayama T, Mishima T, Itoh F, Minamide Y, Fuwa T, Awazu S (1989) Protection of liver microsomal membranes from lipid peroxidation by garlic extract. Planta Med 55(6):506–508. doi:10.1055/s-2006-962081
Gorinstein S, Leontowicz M, Leontowicz H, Najman K, Namiesnik J, Park Y-S, Jung S-T, Kang S-G, Trakhtenberg S (2006) Supplementation of garlic lowers lipids and increases antioxidant capacity in plasma of rats. Nutr Res 26(7):362–368
Gorinstein S, Drzewiecki J, Leontowicz H, Leontowicz M, Najman K, Jastrzebski Z, Zachwieja Z, Barton H, Shtabsky B, Katrich E, Trakhtenberg S (2005) Comparison of the bioactive compounds and antioxidant potentials of fresh and cooked Polish, Ukrainian, and Israeli garlic. J Agric Food Chem 53(7):2726–2732. doi:10.1021/jf0404593
Lau BH (2001) Suppression of LDL oxidation by garlic. J Nutr 131(3s):985S–988S
Dillon SA, Burmi RS, Lowe GM, Billington D, Rahman K (2003) Antioxidant properties of aged garlic extract: an in vitro study incorporating human low density lipoprotein. Life Sci 72(14):1583–1594. doi:10.1016/s0024-3205(02)02475-x
Pedraza-Chaverri J, Medina-Campos ON, Avila-Lombardo R, Berenice Zuniga-Bustos A, Orozco-Ibarra M (2006) Reactive oxygen species scavenging capacity of different cooked garlic preparations. Life Sci 78(7):761–770. doi:10.1016/j.lfs.2005.05.075
Lei YP, Liu CT, Sheen LY, Chen HW, Lii CK (2010) Diallyl disulfide and diallyl trisulfide protect endothelial nitric oxide synthase against damage by oxidized low-density lipoprotein. Mol Nutr Food Res 54(Suppl 1):S42–S52. doi:10.1002/mnfr.200900278
Maldonado PD, Alvarez-Idaboy JR, Aguilar-Gonzalez A, Lira-Rocha A, Jung-Cook H, Medina-Campos ON, Pedraza-Chaverri J, Galano A (2011) Role of allyl group in the hydroxyl and peroxyl radical scavenging activity of S-allylcysteine. J Phys Chem B 115(45):13408–13417. doi:10.1021/jp208233f
Nencini C, Menchiari A, Franchi GG, Micheli L (2011) In vitro antioxidant activity of aged extracts of some Italian Allium species. Plant Foods Hum Nutr 66(1):11–16. doi:10.1007/s11130-010-0204-2
Tuan PA, Li X, Park NI, Lee SY, Kim HH, Park SU (2011) Molecular cloning of 4-coumarate: CoA ligase and total phenolic content in garlic (Allium sativum). Plant OMICS 4(1):25–28
Zhang XH, Maxwell SR, Thorpe GH, Thomason H, Rea CA, Connock MJ, Maslin DJ (1997) The action of garlic upon plasma total antioxidant capacity. Biochem Soc Trans 25(3):523S
Phelps S, Harris WS (1993) Garlic supplementation and lipoprotein oxidation susceptibility. Lipids 28(5):475–477
Dhawan V, Jain S (2004) Effect of garlic supplementation on oxidized low density lipoproteins and lipid peroxidation in patients of essential hypertension. Mol Cell Biochem 266(1–2):109–115
Huang CN, Horng JS, Yin MC (2004) Antioxidative and antiglycative effects of six organosulfur compounds in low-density lipoprotein and plasma. J Agric Food Chem 52(11):3674–3678. doi:10.1021/jf0307292
Durak I, Kavutcu M, Aytac B, Avci A, Devrim E, Ozbek H, Ozturk HS (2004) Effects of garlic extract consumption on blood lipid and oxidant/antioxidant parameters in humans with high blood cholesterol. J Nutr Biochem 15(6):373–377. doi:10.1016/j.jnutbio.2004.01.005
Dhawan V, Jain S (2005) Garlic supplementation prevents oxidative DNA damage in essential hypertension. Mol Cell Biochem 275(1–2):85–94
Vaidya V, Ingold KU, Pratt DA (2009) Garlic: source of the ultimate antioxidants–sulfenic acids. Angew Chem Int Ed Engl 48(1):157–160. doi:10.1002/anie.200804560
Arguello-Garcia R, Medina-Campos ON, Perez-Hernandez N, Pedraza-Chaverri J, Ortega-Pierres G (2010) Hypochlorous acid scavenging activities of thioallyl compounds from garlic. J Agric Food Chem. doi:10.1021/jf102423w
Miron T, Listowsky I, Wilchek M (2010) Reaction mechanisms of allicin and allyl-mixed disulfides with proteins and small thiol molecules. Eur J Med Chem 45(5):1912–1918. doi:10.1016/j.ejmech.2010.01.031
Chanderkar A, Jain P (1973) Analysis of hypotensive action of Allium sativum (garlic). Indian J Physiol Pharmacol 17:132–133
Sial AY, Ahmad SI (1982) Study of the hypotensive action of garlic extract in experimental animals. J Pak Med Assoc 32(10):237–239
Rashid A, Khan HH (1985) The mechanism of hypotensive effect of garlic extract. J Pak Med Assoc 35(12):357–362
Pantoja CV, Chiang LC, Norris BC, Concha JB (1991) Diuretic, natriuretic and hypotensive effects produced by Allium sativum (garlic) in anaesthetized dogs. J Ethnopharmacol 31(3):325–331
Al-Qattan KK, Alnaqeeb MA, Ali M (1999) The antihypertensive effect of garlic (Allium sativum) in the rat two-kidney – one-clip Goldblatt model. J Ethnopharmacol 66(2):217–222. doi:10.1016/s0378-8741(98)00173-1
Ali M, Al-Qattan KK, Al-Enezi F, Khanafer RMA, Mustafa T (2000) Effect of allicin from garlic powder on serum lipids and blood pressure in rats fed with a high cholesterol diet. Prostaglandins Leukot Essent Fatty Acids 62(4):253–259. doi:10.1054/plef.2000.0152
Harauma A, Moriguchi T (2006) Aged garlic extract improves blood pressure in spontaneously hypertensive rats more safely than raw garlic. J Nutr 136(3 Suppl):769S–773S
Asdaq SM, Inamdar MN (2010) Potential of garlic and its active constituent, S-allyl cysteine, as antihypertensive and cardioprotective in presence of captopril. Phytomedicine 17(13):1016–1026. doi:10.1016/j.phymed.2010.07.012
Asdaq SM, Inamdar MN (2011) The potential benefits of a garlic and hydrochlorothiazide combination as antihypertensive and cardioprotective in rats. J Nat Med 65(1):81–88. doi:10.1007/s11418-010-0467-9
Loeper M, DeBray M (1921) Hypotensive effect of tincture of garlic. Progr Med 36:391–392
Damrau F (1941) The use of garlic concentrate in vascular hypertension. Med Rec 153:249–251
Vorberg G, Schneider B (1990) Therapy with garlic: results of a placebo-controlled, double-blind study. Br J Clin Pract Suppl 69:7–11
Auer W, Eiber A, Hertkorn E, Hoehfeld E, Koehrle U, Lorenz A, Mader F, Merx W, Otto G, Schmid-Otto B et al (1990) Hypertension and hyperlipidaemia: garlic helps in mild cases. Br J Clin Pract Suppl 69:3–6
Kiesewetter H, Jung F, Pindur G, Jung EM, Mrowietz C, Wenzel E (1991) Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxicol 29(4):151–155
Jabbari A, Argani H, Ghorbanihaghjo A, Mahdavi R (2005) Comparison between swallowing and chewing of garlic on levels of serum lipids, cyclosporine, creatinine and lipid peroxidation in renal transplant recipients. Lipids Health Dis 4:11. doi:10.1186/1476-511X-4-11
Ried K, Frank OR, Stocks NP (2010) Aged garlic extract lowers blood pressure in patients with treated but uncontrolled hypertension: a randomised controlled trial. Maturitas 67(2):144–150. doi:10.1016/j.maturitas.2010.06.001
Han CH, Liu JC, Chen KH, Lin YS, Chen CT, Fan CT, Lee HL, Liu DZ, Hou WC (2011) Antihypertensive activities of processed garlic on spontaneously hypertensive rats and hypertensive humans. Bot Stud 52(3):277–283
Silagy CA, Neil HA (1994) A meta-analysis of the effect of garlic on blood pressure. J Hypertens 12(4):463–468
Ried K, Frank OR, Stocks NP, Fakler P, Sullivan T (2008) Effect of garlic on blood pressure: a systematic review and meta-analysis. BMC Cardiovasc Disord 8:13. doi:10.1186/1471-2261-8-13
Reinhart KM, Coleman CI, Teevan C, Vachhani P, White CM (2008) Effects of garlic on blood pressure in patients with and without systolic hypertension: a meta-analysis. Ann Pharmacother 42(12):1766–1771. doi:10.1345/aph.1L319
Yan J, Fan Z (2011) Meta-analysis of the effect of garlic on blood pressure. Int J Cardiol 152:S84–S85
Benavides GA, Squadrito GL, Mills RW, Patel HD, Isbell TS, Patel RP, Darley-Usmar VM, Doeller JE, Kraus DW (2007) Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA 104(46):17977–17982. doi:10.1073/pnas.0705710104
Rietz B, Isensee H, Strobach H, Makdessi S, Jacob R (1993) Cardioprotective actions of wild garlic (Allium ursinum) in ischemia and reperfusion. Mol Cell Biochem 119(1–2):143–150
Hosseini M, Shafiee SM, Baluchnejadmojarad T (2007) Garlic extract reduces serum angiotensin converting enzyme (ACE) activity in nondiabetic and streptozotocin-diabetic rats. Pathophysiology 14(2):109–112. doi:10.1016/j.pathophys.2007.07.002
Kim KM, Chun SB, Koo MS, Choi WJ, Kim TW, Kwon YG, Chung HT, Billiar TR, Kim YM (2001) Differential regulation of NO availability from macrophages and endothelial cells by the garlic component S-allyl cysteine. Free Radic Biol Med 30(7):747–756
Pedraza-Chaverri J, Tapia E, Medina-Campos ON, de los Angeles Granados M, Franco M (1998) Garlic prevents hypertension induced by chronic inhibition of nitric oxide synthesis. Life Sci 62(6):PL 71–PL 77
Bruckdorfer R (2005) The basics about nitric oxide. Mol Aspects Med 26(1–2):3–31. doi:10.1016/j.mam.2004.09.002
Fallon MB, Abrams GA, Abdel-Razek TT, Dai J, Chen SJ, Chen YF, Luo B, Oparil S, Ku DD (1998) Garlic prevents hypoxic pulmonary hypertension in rats. Am J Physiol 275(2 Pt 1):L283–L287
Kim-Park S, Ku DD (2000) Garlic elicits a nitric oxide-dependent relaxation and inhibits hypoxic pulmonary vasoconstriction in rats. Clin Exp Pharmacol Physiol 27(10):780–786
Siegel G, Nuck R, Schnalke F, Michel F (1998) Molecular evidence for phytopharmacological K+ channel opening by garlic in human vascular smooth muscle cell membranes. Phytother Res 12(suppl 1):S149–S151
Bordia A, Arora SK, Kothari LK, Jain KC, Rathore BS, Rathore AS, Dube MK, Bhu N (1975) The protective action of essential oils of onion and garlic in cholesterol-fed rabbits. Atherosclerosis 22(1):103–109
Bordia A, Verma SK, Vyas AK, Khabya BL, Rathore AS, Bhu N, Bedi HK (1977) Effect of essential oil of onion and garlic on experimental atherosclerosis in rabbits. Atherosclerosis 26(3):379–386
Sainani GS, Desai DB, Natu MN, Katrodia KM, Valame VP, Sainani PG (1979) Onion, garlic, and experimental atherosclerosis. Jpn Heart J 20(3):351–357
Mohammad SF, Woodward SC (1986) Characterization of a potent inhibitor of platelet aggregation and release reaction isolated from Allium sativum (garlic). Thromb Res 44(6):793–806
Srivas KC (1984) Effects of aqueous extracts of onion, garlic and ginger on platelet aggregation and metabolism of arachidonic acid in the blood vascular system: in vitro study. Prostaglandins Leukot Med 13(2):227–235
DeBoer LW, Folts JD (1989) Garlic extract prevents acute platelet thrombus formation in stenosed canine coronary arteries. Am Heart J 117(4):973–975
Thomson M, Mustafa T, Ali M (2000) Thromboxane-B(2) levels in serum of rabbits receiving a single intravenous dose of aqueous extract of garlic and onion. Prostaglandins Leukot Essent Fatty Acids 63(4):217–221. doi:10.1054/plef.2000.0212
Sendl A, Elbl G, Steinke B, Redl K, Breu W, Wagner H (1992) Comparative pharmacological investigations of Allium ursinum and Allium sativum. Planta Med 58(1):1–7. doi:10.1055/s-2006-961378
Lawson LD, Ransom DK, Hughes BG (1992) Inhibition of whole blood platelet-aggregation by compounds in garlic clove extracts and commercial garlic products. Thromb Res 65(2):141–156
Apitz-Castro R, Badimon JJ, Badimon L (1992) Effect of ajoene, the major antiplatelet compound from garlic, on platelet thrombus formation. Thromb Res 68(2):145–155
Apitz-Castro R, Badimon JJ, Badimon L (1994) A garlic derivative, ajoene, inhibits platelet deposition on severely damaged vessel wall in an in vivo porcine experimental model. Thromb Res 75(3):243–249
Teranishi K, Apitz-Castro R, Robson SC, Romano E, Cooper DK (2003) Inhibition of baboon platelet aggregation in vitro and in vivo by the garlic derivative, ajoene. Xenotransplantation 10(4):374–379
Qi R, Liao F, Inoue K, Yatomi Y, Sato K, Ozaki Y (2000) Inhibition by diallyl trisulfide, a garlic component, of intracellular Ca2+ mobilization without affecting inositol-1,4,5-trisphosphate (IP3) formation in activated platelets. Biochem Pharmacol 60(10):1475–1483. doi:10.1016/s0006-2952(00)00467-6
Chang HS, Yamato O, Yamasaki M, Maede Y (2005) Modulatory influence of sodium 2-propenyl thiosulfate from garlic on cyclooxygenase activity in canine platelets: possible mechanism for the anti-aggregatory effect. Prostaglandins Leukot Essent Fatty Acids 72(5):351–355. doi:10.1016/j.plefa.2005.01.003
Fukao H, Yoshida H, Tazawa Y, Hada T (2007) Antithrombotic effects of odorless garlic powder both in vitro and in vivo. Biosci Biotechnol Biochem 71(1):84–90
Hiyasat B, Sabha D, Grotzinger K, Kempfert J, Rauwald JW, Mohr FW, Dhein S (2009) Antiplatelet activity of Allium ursinum and Allium sativum. Pharmacology 83(4):197–204. doi:10.1159/000196811
Bordia AK, Joshi HK, Sanadhya YK, Bhu N (1977) Effect of essential oil of garlic on serum fibrinolytic activity in patients with coronary artery disease. Atherosclerosis 28(2):155–159. doi:10.1016/0021-9150(77)90152-6
Chutani SK, Bordia A (1981) The effect of fried versus raw garlic on fibrinolytic activity in Atherosclerosis 38(3–4):417–421. doi:10.1016/0021-9150(81)90058-7
Bordia A, Verma SK, Srivastava KC (1996) Effect of garlic on platelet aggregation in humans: a study in healthy subjects and patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids 55(3):201–205
Legnani C, Frascaro M, Guazzaloca G, Ludovici S, Cesarano G, Coccheri S (1993) Effects of a dried garlic preparation on fibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung 43(2):119–122
Bordia A, Verma SK, Srivastava KC (1998) Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids 58(4):257–263
Steiner M, Lin RS (1998) Changes in platelet function and susceptibility of lipoproteins to oxidation associated with administration of aged garlic extract. J Cardiovasc Pharmacol 31(6):904–908
Rahman K, Billington D (2000) Dietary supplementation with aged garlic extract inhibits ADP-induced platelet aggregation in humans. J Nutr 130(11):2662–2665
Allison GL, Lowe GM, Rahman K (2006) Aged garlic extract and its constituents inhibit platelet aggregation through multiple mechanisms. J Nutr 136(3 Suppl):782S–788S
Ackermann RT, Mulrow CD, Ramirez G, Gardner CD, Morbidoni L, Lawrence VA (2001) Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med 161(6):813–824
Cavagnaro PF, Camargo A, Galmarini CR, Simon PW (2007) Effect of cooking on garlic (Allium sativum L.) antiplatelet activity and thiosulfinates content. J Agric Food Chem 55(4):1280–1288. doi:10.1021/jf062587s
Wojcikowski K, Myers S, Brooks L (2007) Effects of garlic oil on platelet aggregation: a double-blind placebo-controlled crossover study. Platelets 18(1):29–34. doi:10.1080/09537100600800636
Abhaykumar NK, Prasad MPR, Panpatil VV, Prasanna Krishna T, Sesikeran B, Polasa K (2011) Reduction in platelet aggregation (in vitro) by diallyl sulphide in female participants with type 2 diabetes mellitus. J Pharmacol Toxicol 6(4):381–390
Clemetson KJ, Clemetson JM (2001) Platelet collagen receptors. Thromb Haemost 86(1):189–197
Wagner H, Wierer M, Fessler B (1987) Effects of garlic constituents on arachidonate metabolism. Planta Med 53(3):305–306. doi:10.1055/s-2006-962719
Srivastava KC, Tyagi OD (1993) Effects of a garlic-derived principle (ajoene) on aggregation and arachidonic acid metabolism in human blood platelets. Prostaglandins Leukot Essent Fatty Acids 49(2):587–595
Srivastava KC (1986) Evidence for the mechanism by which garlic inhibits platelet aggregation. Prostaglandins Leukot Med 22(3):313–321. doi:10.1016/0262-1746(86)90142-3
Siegel G, Malmsten M, Pietzsch J, Schmidt A, Buddecke E, Michel F, Ploch M, Schneider W (2004) The effect of garlic on arteriosclerotic nanoplaque formation and size. Phytomedicine 11(1):24–35
Allison GL, Lowe GM, Rahman K (2006) Aged garlic extract may inhibit aggregation in human platelets by suppressing calcium mobilization. J Nutr 136(3 Suppl):789S–792S
Apitz-Castro R, Ledezma E, Escalante J, Jain MK (1986) The molecular basis of the antiplatelet action of ajoene: direct interaction with the fibrinogen receptor. Biochem Biophys Res Commun 141(1):145–150
Apitz-Castro R, Jain MK, Bartoli F, Ledezma E, Ruiz MC, Salas R (1991) Evidence for direct coupling of primary agonist-receptor interaction to the exposure of functional IIb-IIIa complexes in human blood platelets. Results from studies with the antiplatelet compound ajoene. Biochim Biophys Acta 1094(3):269–280
Morihara N, Sumioka I, Moriguchi T, Uda N, Kyo E (2002) Aged garlic extract enhances production of nitric oxide. Life Sci 71(5):509–517
Jain RC (1976) Onion and garlic in experimental cholesterol induced atherosclerosis. Indian J Med Res 64(10):1509–1515
Bordia A, Verma SK (1980) Effect of garlic feeding on regression of experimental atherosclerosis in rabbits. Artery 7(5):428–437
Efendy JL, Simmons DL, Campbell GR, Campbell JH (1997) The effect of the aged garlic extract, ‘Kyolic’, on the development of experimental atherosclerosis. Atherosclerosis 132(1):37–42
Orekhov AN, Tertov VV, Sobenin IA, Pivovarova EM (1995) Direct anti-atherosclerosis-related effects of garlic. Ann Med 27(1):63–65
Orekhov AN, Tertov VV (1997) In vitro effect of garlic powder extract on lipid content in normal and atherosclerotic human aortic cells. Lipids 32(10):1055–1060
Ismail MF, Gad MZ, Hamdy MA (1999) Study of the hypolipidemic properties of pectin, garlic and ginseng in hypercholesterolemic rabbits. Pharmacol Res 39(2):157–166. doi:10.1006/phrs.1998.0421
Campbell JH, Efendy JL, Smith NJ, Campbell GR (2001) Molecular basis by which garlic suppresses atherosclerosis. J Nutr 131(3s):1006S–1009S
Zahid Ashraf M, Hussain ME, Fahim M (2005) Antiatherosclerotic effects of dietary supplementations of garlic and turmeric: restoration of endothelial function in rats. Life Sci 77(8):837–857. doi:10.1016/j.lfs.2004.11.039
Gonen A, Harats D, Rabinkov A, Miron T, Mirelman D, Wilchek M, Weiner L, Ulman E, Levkovitz H, Ben-Shushan D, Shaish A (2005) The antiatherogenic effect of allicin: possible mode of action. Pathobiology 72(6):325–334. doi:10.1159/000091330
Morihara N, Ide N, Weiss N (2011) Aged garlic extract inhibits homocysteine-induced scavenger receptor CD36 expression and oxidized low-density lipoprotein cholesterol uptake in human macrophages in vitro. J Ethnopharmacol 134(3):711–716. doi:10.1016/j.jep. 2011.01.021
Jung F, Jung EM, Mrowietz C, Kiesewetter H, Wenzel E (1990) Influence of garlic powder on cutaneous microcirculation: a randomised, placebo-controlled, double-blind, crossover study in apparently healthy subjects. Br J Clin Pract Suppl 69:30–35
Jung EM, Jung F, Mrowietz C, Kiesewetter H, Pindur G, Wenzel E (1991) Influence of garlic powder on cutaneous microcirculation. A randomized placebo-controlled double-blind cross-over study in apparently healthy subjects. Arzneimittelforschung 41(6):626–630
Kiesewetter H, Jung F, Jung EM, Blume J, Mrowietz C, Birk A, Koscielny J, Wenzel E (1993) Effects of garlic coated tablets in peripheral arterial occlusive disease. Clin Investig 71(5):383–386
Breithaupt-Grogler K, Ling M, Boudoulas H, Belz GG (1997) Protective effect of chronic garlic intake on elastic properties of aorta in the elderly. Circulation 96(8):2649–2655
Siegel G, Walter A, Engel S, Walper A, Michel F (1999) Pleiotropic effects of garlic. Wien Med Wochenschr 149(8–10):217–224
Koscielny J, Klussendorf D, Latza R, Schmitt R, Radtke H, Siegel G, Kiesewetter H (1999) The antiatherosclerotic effect of Allium sativum. Atherosclerosis 144(1):237–249
Durak I, Aytac B, Atmaca Y, Devrim E, Avci A, Erol C, Oral D (2004) Effects of garlic extract consumption on plasma and erythrocyte antioxidant parameters in atherosclerotic patients. Life Sci 75(16):1959–1966. doi:10.1016/j.lfs.2004.04.015
Budoff MJ, Takasu J, Flores FR, Niihara Y, Lu B, Lau BH, Rosen RT, Amagase H (2004) Inhibiting progression of coronary calcification using aged garlic extract in patients receiving statin therapy: a preliminary study. Prev Med 39(5):985–991. doi:10.1016/j.ypmed.2004.04.012
Durak I, Atmaca Y, Aytac B, Devrim E, Avci A, Ozdol C, Erol C, Oral D (2007) Aged garlic extract consumption causes significant increases in plasma nitric oxide synthase activity and nitric oxide levels in atherosclerotic patients. Vasc Dis Prev 4(4):278–280
Williams MJ, Sutherland WH, McCormick MP, Yeoman DJ, de Jong SA (2005) Aged garlic extract improves endothelial function in men with coronary artery disease. Phytother Res 19(4):314–319. doi:10.1002/ptr.1663
Sun X, Ku DD (2006) Allicin in garlic protects against coronary endothelial dysfunction and right heart hypertrophy in pulmonary hypertensive rats. Am J Physiol Heart Circ Physiol 291(5):H2431–H2438. doi:10.1152/ajpheart.00384.2006
Lau BH (2006) Suppression of LDL oxidation by garlic compounds is a possible mechanism of cardiovascular health benefit. J Nutr 136(3 Suppl):765S–768S
Weiss N, Ide N, Abahji T, Nill L, Keller C, Hoffmann U (2006) Aged garlic extract improves homocysteine-induced endothelial dysfunction in macro- and microcirculation. J Nutr 136(3 Suppl):750S–754S
Yeh YY, Yeh SM (2006) Homocysteine-lowering action is another potential cardiovascular protective factor of aged garlic extract. J Nutr 136(3 Suppl):745S–749S
van Doorn MB, Espirito Santo SM, Meijer P, Kamerling IM, Schoemaker RC, Dirsch V, Vollmar A, Haffner T, Gebhardt R, Cohen AF, Princen HM, Burggraaf J (2006) Effect of garlic powder on C-reactive protein and plasma lipids in overweight and smoking subjects. Am J Clin Nutr 84(6):1324–1329
Isensee H, Rietz B, Jacob R (1993) Cardioprotective actions of garlic (Allium sativum). Arzneimittelforschung 43(2):94–98
Rietz B, Belagyi J, Torok B, Jacob R (1995) The radical scavenging ability of garlic examined in various models. Boll Chim Farm 134(2):69–76
Martín N, Bardisa L, Pantoja C, Román R, Vargas M (1992) Experimental cardiovascular depressant effects of garlic (Allium sativum) dialysate. J Ethnopharmacol 37(2):145–149. doi:10.1016/0378-8741(92)90072-y
Martín N, Bardisa L, Pantoja C, Vargas M, Quezada P, Valenzuela J (1994) Anti-arrhythmic profile of a garlic dialysate assayed in dogs and isolated atrial preparations. J Ethnopharmacol 43(1):1–8. doi:10.1016/0378-8741(94)90109-0
Tongia SK (1984) Effects of intravenous garlic juice Allium sativum on rat electrocardiogram. Indian J Physiol Pharmacol 28(3):250–252
Sungnoon R, Kanlop N, Chattipakorn SC, Tawan R, Chattipakorn N (2008) Effects of garlic on the induction of ventricular fibrillation. Nutrition 24(7–8):711–716. doi:10.1016/j.nut.2008.03.003
Ernsberger P, Johnson JL, Rosenthal T, Mirelman D, Koletsky RJ (2007) Therapeutic actions of allylmercaptocaptopril and captopril in a rat model of metabolic syndrome. Am J Hypertens 20(8):866–874. doi:10.1016/j.amjhyper.2007.02.015
Asdaq SMB, Inamdar MN (2008) Pharmacodynamic interaction of garlic with captopril in ischemia-reperfusion induced myocardial damage in rats. Pharmacology Online 2:875–888
Asdaq SM, Inamdar MN (2010) Pharmacodynamic interaction of captopril with garlic in isoproterenol-induced myocardial damage in rat. Phytother Res 24(5):720–725. doi:10.1002/ptr.3009
Asdaq SMB, Inamdar MN, Asad M, Nanjundan PK (2008) Interaction of propanolol with garlic in isoproterenol induced myocardial infarction in rat. J Pharmacol Toxicol 3(6):414–424
Aqel MB, Gharaibah MN, Salhab AS (1991) Direct relaxant effects of garlic juice on smooth and cardiac muscles. J Ethnopharmacol 33(1–2):13–19
Asdaq SM, Inamdar MN (2009) The potential for interaction of hydrochlorothiazide with garlic in rats. Chem Biol Interact 181(3):472–479. doi:10.1016/j.cbi.2009.07.022
Asdaq SM, Inamdar MN (2009) Pharmacodynamic interaction of garlic with hydrochlorothiazide in rats. Indian J Physiol Pharmacol 53(2):127–136
Alkreathy H, Damanhouri ZA, Ahmed N, Slevin M, Ali SS, Osman AM (2010) Aged garlic extract protects against doxorubicin-induced cardiotoxicity in rats. Food Chem Toxicol 48(3):951–956. doi:10.1016/j.fct.2010.01.005
Guo Z, Muller D, Pentz R, Kress G, Siegers CP (1990) Bioavailability of sulphur-containing ingredients of garlic in the rat. Planta Med 56(6):692
Lachmann G, Lorenz D, Radeck W, Steiper M (1994) The pharmacokinetics of the S35 labeled labeled garlic constituents alliin, allicin and vinyldithiine. Arzneimittelforschung 44(6):734–743
Egen-Schwind C, Eckard R, Kemper FH (1992) Metabolism of garlic constituents in the isolated perfused rat liver. Planta Med 58(4):301–305. doi:10.1055/s-2006-961471
Lawson LD, Wang ZJ (2005) Allicin and allicin-derived garlic compounds increase breath acetone through allyl methyl sulfide: use in measuring allicin bioavailability. J Agric Food Chem 53(6):1974–1983. doi:10.1021/jf048323s
Egen-Schwind C, Eckard R, Jekat FW, Winterhoff H (1992) Pharmacokinetics of vinyldithiins, transformation products of allicin. Planta Med 58(1):8–13. doi:10.1055/s-2006-961379
Pushpendran CK, Devasagayam TP, Chintalwar GJ, Banerji A, Eapen J (1980) The metabolic fate of [35S]-diallyl disulphide in mice. Experientia 36(8):1000–1001
Nagae S, Ushijima M, Hatono S, Imai J, Kasuga S, Matsuura H, Itakura Y, Higashi Y (1994) Pharmacokinetics of the garlic compound S-allylcysteine. Planta Med 60(3):214–217. doi:10.1055/s-2006-959461
Steiner M, Li W (2001) Aged garlic extract, a modulator of cardiovascular risk factors: a dose-finding study on the effects of AGE on platelet functions. J Nutr 131(3s):980S–984S
Davenport DM, Wargovich MJ (2005) Modulation of cytochrome P450 enzymes by organosulfur compounds from garlic. Food Chem Toxicol 43(12):1753–1762. doi:10.1016/j.fct.2005.05.018
Minami T, Boku T, Inada K, Morita M, Okazaki Y (1989) Odor components of human breath after the ingestion of grated raw garlic. J Food Sci 54(3):763–765. doi:10.1111/j.1365-2621.1989.tb04703.x
Desai HG, Kalro RH, Choksi AP (1990) Effect of ginger & garlic on DNA content of gastric aspirate. Indian J Med Res 92:139–141
Kanerva L, Estlander T, Jolanki R (1996) Occupational allergic contact dermatitis from spices. Contact Dermatitis 35(3):157–162. doi:10.1111/j.1600-0536.1996.tb02334.x
Armentia A, Vega JM (1996) Can inhalation of garlic dust cause asthma? Allergy 51(2):137–138
Morbidoni L, Arterburn JM, Young V, Mullins D, Mulrow C, Lawrence V (2001) Garlic. J Herb Pharmacother 1(1):63–83. doi:doi:10.1080/J157v01n01_06
Borrelli F, Capasso R, Izzo AA (2007) Garlic (Allium sativum L.): adverse effects and drug interactions in humans. Mol Nutr Food Res 51(11):1386–1397. doi:10.1002/mnfr.200700072
Mohammed Abdul MI, Jiang X, Williams KM, Day RO, Roufogalis BD, Liauw WS, Xu H, McLachlan AJ (2008) Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects. Br J Pharmacol 154(8):1691–1700. doi:10.1038/bjp. 2008.210
Aviello G, Abenavoli L, Borrelli F, Capasso R, Izzo AA, Lembo F, Romano B, Capasso F (2009) Garlic: empiricism or science? Nat Prod Commun 4(12):1785–1796
Acknowledgments
I wish to thank CSU library for databases, Kathryn Koromilas for valuable suggestion and Dr. Basit Iqbal for abstract drafting. I can’t finish without my family inspiration, including My Parents, Saba and Ariba.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer-Verlag Berlin Heidelberg
About this entry
Cite this entry
Omar, S.H. (2013). Garlic and Cardiovascular Diseases. In: Ramawat, K., Mérillon, JM. (eds) Natural Products. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-22144-6_158
Download citation
DOI: https://doi.org/10.1007/978-3-642-22144-6_158
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-22143-9
Online ISBN: 978-3-642-22144-6
eBook Packages: Chemistry and Materials ScienceReference Module Physical and Materials ScienceReference Module Chemistry, Materials and Physics