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Garlic
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Allium sativum L.
[Fam. Liliaceae]
Overview
In the United States and Western Europe, garlic is one of
the most popular substances used to reduce various risks associated with
cardiovascular disease. Most of garlic’s popularity is based on the extensive
traditional use of this herb and on scientific research suggesting that
cardiovascular benefits are associated with ingesting garlic as both a
conventional food and dietary supplement (Blumenthal et al., 2000). Garlic preparations have been one of the top-selling
herbal supplements on the U.S. market for many years (Brevoort, 1998), ranking
third in retail sales in the mainstream market in 2000, and generating revenues
over $61 million (Blumenthal, 2001).
To date more than 3,000 scientific papers have been published investigating the
activities of garlic and garlic compounds, including chemical, toxicological,
pharmacological, clinical, and epidemiological studies (Amagase et al., 2001). Garlic preparations with
uniquely different chemical compositions, including powdered dried garlic
products standardized to allicin yield and aged garlic extract (AGE™) products
that are standardized to S-allylcysteine (SAC), have been the subject of
numerous clinical studies. Determining which forms are the most effective
remains controversial and is an ongoing subject of study and debate. Medical
literature includes positive outcomes in clinical studies involving several
types of garlic preparations.
Description
Garlic preparations consist of the fresh or dried bulbs (main
bulb and secondary bulbs or cloves) of Allium
sativum L. [Fam. Lilaceae], and
various dosage forms (Blumenthal et al.,
1998). Garlic oil is not present in fresh or dried garlic bulbs; instead, the
oil is produced by converting water-soluble thiosulfinates to oil-soluble
sulfides via steam distillation. Aged garlic involves long-term extraction in
dilute ethanol for up to 20 months, then drying; pickling garlic involves
immersion in vinegar (5% acetic acid) (Amagase et al., 2001; Lawson, 1998a).
Primary Uses
Cardiovascular
Hyperlipidemia (Isaacsohn et al., 1998; Lash et al., 1998; McCrindle et al.,
1998; Steiner et al.,1996a, 1996b;
Yeh et al., 1995; De A Santos and
Johns, 1995; Steiner and Lin, 1994; Jain et
al., 1993; Grünwald et al., 1992;
Holzgartner et al., 1992; Mader,
1990; Vorberg et al., 1990; Lau et al., 1987; Bordia, 1981)
Atherosclerosis (Koscielny et al., 1999)
Other Potential Uses
Cardiovascular
Hypertension, mild (Steiner et al., 1996; Auer et al., 1990)
Peripheral arterial occlusive disease (PAOD)
(Koscielny et al., 1999; ESCOP, 1997;
Kiesewetter et al., 1993b)
Hematology
Decreased platelet function (Rahman and Billington,
2000; Steiner et al., 2001; Steiner et al., 1996; Kiesewetter et al., 1991; Kiesewetter et al., 1993a)
Chemopreventative
Colon cancer preventative (Steinmetz et al, 1994; Witte et al., 1996)
Stomach cancer preventative (You et al., 1989)
Miscellaneous
Garlic has traditionally been used to relieve cough,
colds, catarrh, and rhinitis, although clinical trials do not support such uses
(ESCOP, 1997)
Dosage
Internal
Crude Preparations
Fresh herb: 4
g daily (1 clove) minced bulb or equivalent preparations (Blumenthal et al., 1998). [Note: Some authors have suggested that this
dosage level should be revised downward to approximately 2,700 mg of fresh
garlic, equivalent to the 900 mg of garlic powder used in some clinical trials
that studied the ability of garlic to prevent and/or reverse atherosclerotic
plaque build-up (Schulz et al.,
2001).]
Infusion: 4
g in 150 ml of hot water (Blumenthal et
al., 2000).
Fluid extract:
1:1 (g/ml), 4 ml (Blumenthal et al., 2000).
Tincture:
1:5 (g/ml), 20 ml (Blumenthal et al., 2000).
Standardized Preparations
Garlic powder
(Kwai®): 200–300 mg, 3 times daily (Warshafsky et al., 1993).
AGE ™
(Kyolic®) aged garlic extract: 300–800 mg, 3 times daily or 1–5 ml
daily (Steiner 2001; Steiner et al.,
1996; Rahman and Billington, 2000; USP, 2002; Lau et al., 1987).
Duration of Administration
Long-term treatment is generally advised in the prevention
of atherosclerosis (Koscielny et al.,
1999), and the prophylaxis and treatment of peripheral arterial vascular
diseases (ESCOP, 1997). Epidemiological observations support the long-term
consistent use for prevention of cancer in the stomach and intestines (You et al., 1989).
Chemistry
Crude Preparations
Fresh garlic bulbs contain about 65% water, 28%
carbohydrates (fructans), 2.3% organosulfur compounds (OSC), 2% protein, and
1.2% free amino acids. The main OSC in whole garlic are the cysteine sulfoxides
(1% alliin and 0.1% cycloalliin) and the g-glutamylcysteines
(0.6% g-glutamyl-S-trans-1-propenylcysteine
and 0.4% g-glutamyl-S-allylcysteine).
When the bulb is bruised, crushed, chewed, or minced, the alliin, in the
presence of the enzyme alliinase, is converted to allicin (ESCOP, 1997). One mg
of alliin produces 0.458 mg of allicin, which is considered to be responsible
for some of garlic’s biological activity and is a precursor to some
thiosulfinates, which also have been shown to be active (Lawson 1998a; Block,
1985; Bradley, 1992; Budavari, 1996; ESCOP, 1997). However, allicin is unstable
and decomposes to other volatile sulfur compounds (the half-life of allicin is
not more than 24 hours), so the extent of allicin’s activity has been questioned.
Intact garlic cloves (the sections that comprise the garlic bulb) also contain
S-allylcysteine (SAC), but no allicin. SAC is formed from gamma-glutamyl
cysteine catabolism and has been reported to contribute to the health benefits
of some garlic preparations (Amagase et
al., 2001). Fresh and aged garlic extract (AGE, see below) also contain
steroidal saponins (Matsuura, 2001).
Standardized Preparations
Processed garlic preparations contain a variety of sulfur-containing
compounds other than those found naturally in intact garlic cloves, depending
on the conditions applied (Lawson, 1998a; Fenwick and Henley, 1985).
Sulfur-containing compounds in commercial garlic preparations vary, depending
on their manufacturing process. Powdered preparations of dried garlic contain
alliin and compounds derived from its subsequent transformation, but no
allicin. Enteric coatings protect these powdered preparations from conversion
while in the stomach. Garlic oil yields neither alliin, nor allicin as the
converting enzyme is destroyed by heat. It does contain diallyl disulfide,
diallyl trisulfide, and allyl methyl trisulfide. Macerated garlic-derived oil
contains vinyldithiins, ajoene, and diallyl trisulfides (Lawson, 1998a). Garlic
extract and odorless AGE are listed in the United
States Pharmacopeia/National Formulary (USP, 2002). The most abundant
sulfur compound in AGE is SAC; it is standardized to not less than 0.05% SAC
(USP, 2002).
Pharmacological Actions
Human
Garlic reduces total cholesterol (TC) and serum triglycerides
(TG) and elevates high density lipoproteins (HDL) (Auer et al., 1990; Barrie et al.,
1987; Lau et al., 1987; Bordia, 1981;
De A Santos and Johns, 1995; Silagy and Neil, 1994a); prevents platelet
aggregation and thrombus formation (Rahman and Billington, 2000; Barrie et al., 1987; Kiesewetter et al., 1993a; Kiesewetter et al., 1993b; Legnani et al., 1993); stimulates fibrinolysis,
prolongs clotting time (Chutani and Bordia, 1981; Gadkari and Joshi, 1991;
Harenberg et al., 1988; Legnani et al., 1993); reduces low-density
lipoprotein (LDL) oxidation (Ide and Lau, 2001; Lau, 2001; Munday, 1999;
Steiner and Lin, 1994; Harris et al.,
1995; Phelps and Harris, 1993); reduces systolic blood pressure, diastolic
blood pressure, and mean blood pressure from baseline (Steiner et al., 1996a, 1996b; De A Santos and
Johns, 1995; Silagy and Neil, 1994b; Grünwald et al., 1992; Auer et al.,
1990;); attenuates age- and blood pressure-related increases in aortic
stiffness (Breithaupt-Grögler et al.,1997);
stimulates peripheral microcirculation (Okuhara, 1994); is antifungal and
fungistatic against Cryptococcus
neoformans, the organism that causes cryptococcal meningitis (Anon., 1980;
Davis et al., 1990); may decrease the
risk of gastrointestinal cancers (Gail et
al., 1998; You et al., 1991,
1989, 1988; Reuter et al., 1996;
Buiatti et al., 1989; Lau, 1989);
modulates immune system activity (Brosche and Platt, 1993; Kandil et al., 1988; Lawson, 1998a; Reuter et al., 1996); reduces blood glucose
levels (Kiesewetter et al., 1991).
Garlic does not inhibit H. pylori bacteria
in the stomach (Graham et al., 1999).
Although one study concluded that garlic extracts had no statistically
significant impact on how far patients with peripheral vascular disease (PVD)
can walk (Kiesewetter et al., 1993b),
AGE has been reported to exhibit stimulation of peripheral circulation in human
subjects (Okuhara, 1994; Kikuchi et al.,
1994). One pilot clinical trial (Ohnishi et
al., 2000) indicated an effect of AGE and other antioxidants in the potential
treatment of sickle cell anemia patients.
Animal
Garlic lowers elevated levels of serum homocysteine (Yeh,
1999); lowers serum cholesterol and lipids (Bordia et al., 1975; Kamanna and Chandrasekhara, 1982; Chi et al., 1982); is antithrombotic (Bordia
et al., 1975); increases fibrinolysis
and clotting time (Bordia et al.,
1975; Reuter et al., 1996); reduces
blood pressure (Sial and Ahmad, 1982; Ruffin and Hunter, 1983); is antioxidant
(Han et al., 1992; Lawson, 1998a);
modulates immune system (Kyo et al.,
1999, 1998; Lawson, 1998a; Reuter et al.,
1996); reduces blood glucose levels and increases insulin levels (Augusti,
1975; Chang and Johnson, 1980); is anti-allergenic (Kyo et al., 1997); exhibits antitumor activity against transitional
cell carcinoma of the bladder with AGE (Lau et
al., 1986; Riggs et al., 1997);
reduces breast cancer incidence (Amagase and Milner, 1993; Liu et al., 1992; Kröning, 1964); decreases
incidence of hepatic tumors in the Bufo
regularis toad (El-Mofty et al.,
1994).
In vitro
Antithrombotic
The rational clinical application of
garlic necessitates demonstrating the association between garlic consumption
and important clinical outcomes such as atherosclerosis. In vivo and in vitro
studies suggest garlic extracts and several garlic constituents have a
significant antithrombotic effect (Ariga et
al., 1981; Boullin, 1981; Srivastava, 1986; Mohammed and Woodward, 1986).
Garlic has been shown to increase fibrinolysis and prolong clotting time
(Reuter et al., 1996). Adenosine in
AGE and its constituents are the most potent antiplatelet constituents of
garlic. Allicin was thought an active compound in garlic due to its highly
reactive and oxidative characteristics, but it is rapidly metabolized in human
blood (in in vitro culture) and therefore
might not contribute to the in vivo
antithrombotic effect of garlic (Freeman and Kodera, 1995; Koch and Lawson,
1996).
Ajoene is found in small amounts in garlic oil-macerates,
but not in commercial garlic preparations and garlic powders. Bioavailability
of ajoene has not yet been established. Antithrombotic and vasodilatory actions
of garlic might be due to adenosine deaminase and cyclic AMP phosphodiesterase,
which can be found in garlic extracts. The decrease of thromboxane B2 (TXB2)
levels is another possible explanation for garlic’s antithrombotic effects.
Most of the above explanations are based on in
vitro and in vivo experiments
(Berthold and Sudhop, 1998; Rahman and Billington, 2000; Bordia et al., 1996; Agarwal 1996).
Koscielny et al.
(1999) reported a slowing and reversal of atherosclerotic plaque formation. AGE
has been shown to protect vascular endothelial cells against hydrogen
peroxide-induced lipid peroxidation and biomembrane damage (Yamasaki et al., 1994); prevent oxidized
LDL-induced membrane damage, loss of cell viability, and lipid peroxidation
(Ide and Lau, 1997b); and demonstrate antihypertensive activity (Lawson, 1998a;
Steiner et al., 1996; Koch et al., 1992a; Sendl et al., 1992).
Anticancer
Garlic inhibits the induction and growth of cancer (Milner,
1996; Lea, 1996). The effect on tumor initiation and promotion has been
documented, and both the oil-soluble and water-soluble OSCs such as methyl
propyl disulfide and propylene sulfide, SAC, S-allylmercaptocysteine (SAMC),
and allicin reduce the proliferation of neoplasms and inhibit the development
of liver glutathione S-transferase placental (GST-P) positive tumor foci and
other indications of cancer in different organs. In contrast, OSCs such as
diallyl sulfide, diallyl trisulfide, and allyl methyl trisulfide enhance the
formation of liver tumor foci.
However, in rats, diallyl disulfide shows the following
activities: inhibits the potential for colon and renal tumor development
(Fukushima et al., 1997); inhibits
the growth of human prostate cancer cells (Pinto et al., 1997a); demonstrates cytotoxic activity against MBT2
bladder tumor cells (Riggs et al.,
1997); is antiallergenic (Kyo et al.,
1997); stimulates macrophage activity, natural killer cells, and LAK cells. It
may also increase production of interleukin (IL-2), tumor necrosis factor (TNF)
and interferon gamma, which are cytokines associated with beneficial antitumor
responses. AGE protects against the immunosuppression induced by chemo- and
radiation therapy (Lamm and Riggs, 2000; Lau, 1989) and UV light (Reeve et al., 1993a, 1993b).
Antimicrobial effects
Antibacterial activity against Escherichia, Salmonella, Staphylococcus, Streptococcus, Klebsiella,
Proteus, Bacillus, Mycobacterium, Clostridium, and resistant strains (Adetumbi
and Lau, 1983; Farbman et al., 1993;
Hughes and Lawson, 1991; Lawson 1998a; Reuter et al., 1996); antifungal activity against Candida and Cryptococcus (Anon.,
1980; Caporaso et al., 1983; Hughes
and Lawson, 1991; Lawson, 1998a); antiulcer/antibacterial against Helicobacter pylori (Sivam, 2001; Sivam et al., 1997); antifungal, antiparasitic
(Ankri and Mirelman, 1999). The main antimicrobial effect of allicin is limited
when in direct exposure to the microorganisms due to its chemical reaction with
enzymes (e.g., alcohol dehydrogenase, thioredoxin reductase) and RNA
polymerase. This reaction can affect the essential metabolism of cysteine
proteinase activity involved in the virulence of Entamoeba histolytica. An aqueous extract of garlic cloves, standardized
for its thiosulfinate concentration tested positively for its antimicrobial
activity against H. pylori (Sivam et al., 1997). Minimum inhibitory
concentration was 40 mcg thiosulfinate per ml. It is possible that the
sensitivity of H. pylori to garlic
extract at such low concentrations may be related to the reported low risk of
stomach cancer in those populations with high allium vegetable intake. However,
an uncontrolled trial involving 20 patients with positive urea breath tests,
taking 300 mg tablets of dried garlic powder, three times daily for eight
weeks, did not eradicate H. pylori (Fennerty
et al., 1999).
Hematology effects
In vitro
studies (and a pilot clinical trial) have indicated an effect of AGE and other
antioxidants in the potential treatment of sickle cell anemia patients (Ohnishi
et al., 2000, 2001; Ohnishi and
Ohnishi, 2001).
Mechanism of Action
Lipid-lowering
One possible mechanism is thought to be
attributed to allicin/thiosulfinates (Lawson, 1998a; Reuter et al., 1996) but a recent study
revealed water-soluble OSC, e.g., SAC and SPC, may be the active compounds
inhibiting cholesterol synthesis (Liu and Yeh, 2001). However, oil-soluble OSC,
e.g., diallyl disulfide (DADS) and others, decomposed from thiosulfinates
including allicin, actually killed the cells, thus indirectly inhibiting
cholesterol synthesis (Liu and Yeh, 2001).
Increases catabolism of fatty
acid-containing lipids, especially triglycerides (Yeh et al., 1995; Yeh and Yeh, 1994; Lawson, 1998a).
Inhibits cholesterol biosynthesis at the
level of b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) reductase (Yeh
et al., 1995; Yeh and Yeh, 1994;
Gebhardt et al., 1994; Gebhardt,
1993).
Inhibits cholesterol biosynthesis at later
steps, as evidenced by accumulation of the cholesterol precursors, lanosterol
and 7-dehydrocholesterol, although this latter effect may be of minor
therapeutic significance (Gebhardt et
al., 1994; Gebhardt, 1993).
Enhances palmitate-induced inhibition of
cholesterol biosynthesis (Gebhardt, 1995).
Inhibits cholesterol biosynthesis by
targeting squalene monooxygenase, an enzyme that catalyzes the downstream
pathway in cholesterol synthesis (in
vitro study on fresh garlic extract) (Gupta and Porter, 2001).
Lipid-lowering activity may be due to the
presence of steroid saponins in fresh garlic and AGE, which may interfere with
the absorption of total and LDL cholesterol from the intestine lumen, thereby
reducing plasma levels (40–57% in test animals), without adversely affecting
HDL levels. Saponins are known to inhibit intestinal absorption of cholesterol,
suggesting possible hypocholesterolemic effect (Matsuura, 2001).
Antithrombotic
Garlic inhibits platelet aggregation and
stimulates fibrinolysis; this may be attributed to allicin/thiosulfinates at
lower garlic doses and cycloalliin at higher garlic doses (in vitro) (Lawson, 1998a; Reuter et al., 1996). However, since it is argued that
allicin/thiosulfinates may not be bioavailable, other compounds may be
responsible (Amagase et al., 2001).
Inhibits normal arachidonate metabolism
(Ariga et al., 1981; Makheja et al., 1980; Makheja et al., 1981; Reuter et al., 1996).
Inhibits the lipoxygenase and
cyclo-oxygenase pathways of the arachidonic acid cascade, thereby inhibiting
the synthesis of prostaglandins and thromboxanes (PGE2, PGD2, PGI2, TXB2)
(Rahman and Billington, 2000; Reuter et
al., 1996; Ariga et al., 1981;
Makheja et al., 1981, 1980).
Inhibits fatty acid lipoxygenase (Liu and
Yeh, 2001; Reuter et al., 1996; Ariga
et al., 1981; Makheja et al., 1981, 1980).
Ajoene affects fibrinogen-induced human
platelet aggregation and inhibits binding of fibrinogen to adenosine
diphosphate (ADP) stimulated platelets in
vitro (Reuter et al., 1996).
Antihypertensive
Action is thought to be attributed to g-glutamylcysteines and fructans; allicin is
not involved (Lawson, 1998a; Reuter et
al., 1996).
g-glutamylcysteines
can inhibit angiotensin-converting enzyme (ACE), thus inhibiting angiotensin II
(a hormone that increases vasoconstriction) (Lawson, 1998a; Sendl et al., 1992).
Fructans can inhibit adenosine deaminase in
isolated cells, thus increasing adenosine and its associated blood vessel
dilatory activity (Lawson 1998a; Koch et
al., 1992).
Increases nitric oxide through activation of
nitric oxide synthase activity (Das et
al., 1995).
Antimicrobial
Action is in vitro or externally thought to be attributed to
allicin/thiosulfinates (Lawson, 1998a; Reuter et al., 1996).
Allicin disrupts cellular metabolic
processes in vitro through
inactivation of proteins by oxidation of essential thiols to disulfide,
competitive inhibition of enzymes containing cysteine in their active sites by
reacting with the sulfhydryl (-SH) group, and noncompetitive inhibition of
enzymes by reacting with -SH groups at allosteric sites (Adetumbi and Lau,
1983; Cavallito et al., 1944; Lawson,
1998a).
Garlic extract inhibits H. pylori bacterial in vitro
at moderate concentrations, thereby suggesting mechanism for antigastric ulcer
effect (Sivam, 2001; Sivam et al.,
1997).
Anticancer
Action is thought to be attributed to any
number of garlic compounds: SAC, SAMC, thiosulfinates, g-glutamylcysteines, and other unknown compounds (Lawson, 1998a;
Pinto et al., 1997b; Reuter et al., 1996, Amagase and Milner, 1993;
Liu et al., 1992) although the
thiosulfinates (e.g., allicin) are questioned due to their instability.
Decreases the amount of nitrate-reducing
bacteria in the stomach, thus reducing the formation of carcinogenic
nitrosamines (Dion and Milner, 1996;
Mei et al., 1985, 1982).
Inhibits the induction and growth of
cancer, which may be mediated by modulation of carcinogen metabolism (Lea,
1996).
Stimulates macrophage activity, natural
killer cells, and LAK cells, and might increase the production of IL-2, TNF,
and interferon gamma, which are cytokines associated with beneficial antitumor
response (Lamm and Riggs, 2000; Lau et al.,
1991; Lau, 1989; Abdullah et al.,
1989).
Antiallergenic
Inhibits antigen-specific histamine release from mast
cells in vitro (Kyo et al., 1997); decreases
antigen-specific IgE mediated skin reactions in vivo (Kyo et al.,
1997); and reduces antigen-specific, late-phase reaction by modulating the
production and release of cytokines from activated T-lymphocytes in vivo (Kyo et al., 1997).
Antioxidant
Action is thought to be attributed to
primarily water-soluble OSC (e.g., SAC and SAMC) in addition to
fructosyl-arginine, other Maillard reaction compounds in AGE, and other
compounds (Ryu, 2001; Imai, 1994); some authors suggest action may be due to
the allicin/thiosulfinates (Lawson, 1998a; Reuter et al., 1996).
Decreases oxidation of LDL cholesterol in
humans (Ide and Lau, 2001; Lau, 2001; Munday, 1999; Steiner and Lin, 1994;
Harris et al., 1995; Phelps and
Harris, 1993).
Increases the activity of several enzymes
(including glutathione peroxidase and catalase) involved in antioxidative
processes and decreases the concentration of lipid peroxides in the blood (Ide
and Lau, 1999; Steiner and Lin, 1994; Geng and Lau, 1997; Han et al., 1992).
Increases intracellular glutathione (GSH) (a
potent intracellular antioxidant and detoxifier), modulates the activity of the
GSH redox cycle, and increases activity of superoxide dismutase (SOD, a potent
intracellular antioxidant) activity (Ide and
Lau, 2001; Wang et al., 1999; Hatono et al., 1996; Geng and Lau, 1997).
Immunomodulatory
Action thought to be attributed to protein
fraction of garlic (Moraika et al.,
1993; Lau et al., 1991; Hirao et al., 1987).
•nhibits activation of nuclear factor kappa
B (NF-kB) in human T-cells that are
involved in immune and inflammatory reactions (Geng et al., 1997).
Increases phagocytosis, natural killer cell
activity, antibody titer, and lymphocyte counts (Brosche and Platt, 1993;
Kandil et al., 1988; Lawson, 1998a;
Reuter et al., 1996).
Hematological (AGE)
Inhibits anion transport and sickle cell
dehydration (Ohnishi et al., 2001),
restricts dense cell formation (Ohnishi and Ohnishi, 2001) and 4.0 mg/mL was
shown to inhibit dense cell formation by 50% (Ohnishi et al., 2000). A U.S. patent has been granted to Wakunaga of
America, Mission Viejo, CA for the “Therapeutic Uses of Specially Processed
Garlic for Sickle Cell Disease” (Ohnishi and Tsuyoshi, 2001).
Increased natural killer cell activity and
improved helper suppressor T-cell ratios in AIDS patients (Abdullah et al., 1989).
Contraindications
None known according to the German Commission E and other
leading European scientific bodies (Blumenthal et al., 1998; ESCOP, 1997). The World Health Organization (WHO) cautions
against the use of garlic by patients with a known allergy to garlic, and those
taking warfarin (and presumably other anticoagulants) (WHO, 1999). However, AGE
has been tested in a placebo-controlled, double-blind clinical trial in
patients taking Coumadin® (warfarin); there was no demonstrated
interaction with Coumadin® and no prolonged bleeding (Rozenfeld et al., 2000). Several case reports of
increased clotting time suggest that patients should discontinue use prior to
surgery (Brinker, 2001), usually by at least one week.
Pregnancy and Lactation: None
known (Blumenthal et al., 1998;
ESCOP, 1997). A controlled trial showed that major sulfur-containing volatiles
from garlic are transmitted to breast milk, leading to improved drinking habits
of infants (ESCOP, 1997; Mennella and Beauchamp, 1991). In Japan, AGE is an
ingredient in pharmaceutical products that are used in nutritional nourishment
for pregnant and lactating women.
Adverse Effects
The most commonly reported adverse effect of garlic is that
its odor may pervade the breath and skin (Blumenthal et al., 1998). Raw garlic has a stronger odor and higher levels of
high molecular weight sulfur compounds than cooked garlic, but malodorous
breath tested in humans who ingested raw garlic showed higher levels of low
molecular weight sulfur compounds and different constituents than those
associated with common halitosis (Tamaki and Sonoki, 1999). Differences in the
frequency of other adverse effects caused by various garlic preparations have
not been completely determined (Mulrow
et al., 2000), such adverse effects
being dependent upon the method of preparation. Gastrointestinal symptoms and
changes to the intestinal flora or allergic reactions are rare but are
occasionally reported (Lembo et al.,
1991). In separate, single-case reports, garlic was associated with
postoperative bleeding (Burnham, 1995), spontaneous spinal epidural hematoma,
and platelet dysfunction from excessive ingestion (Rose et al., 1990). Occupational exposure to crushed garlic products
and the topical application of garlic to treat wounds or skin infections may
cause allergic contact dermatitis (Lee and Lam, 1991; Bojs and Svensson, 1998).
Allergic reactions including burns (Roberge et
al., 1997), zosteriform dermatitis (Farrell and Staughton, 1996), induction
of pemphigus (blisters) (Brenner and Wolf, 1994), allergic asthma and rhinitis,
contact urticaria, and protein contact dermatitis have been reported for garlic
and various generic garlic preparations (WHO, 1999; DeSmet, 1992), but no
adverse effects were reported for AGE according to toxicological and clinical
studies (Miyoshi et al., 1984;
Nakagawa et al., 1984, 1980;
Sumiyoshi et al., 1984).
Cross-sensitivity may occur with onions and tulips (Siegers, 1992; WHO, 1999).
Garlic preparations can increase clotting time (Chutani and Bordia, 1981;
Gadkari and Joshi, 1991; Harenberg et
al., 1988; Legnani et al., 1993),
which is sometimes beneficial, but in some cases, can contribute to an adverse
event.
Drug Interactions
Concurrent use of garlic and antiplatelet agents (e.g.,
aspirin) and anticoagulants (e.g., warfarin) might increase the potential for
prolonged bleeding. One report showed that clotting time (International
Normalization Ratio) doubled for two patients taking warfarin and garlic
simultaneously (Sunter, 1991); how-ever, this report lacks adequate data to
assess causality (Rotblatt and Ziment, 2001). Further, a controlled clinical
trial on AGE
showed no interactions with warfarin (Rozenfeld,
2000). Another trial on nine HIV-negative individuals produced significant
decreases in serum levels of the anti-HIV drug saquinavir (Piscitelli et al., 2002); however,
this study has design problems rendering the results uninterpretable.
American Herbal Products Association (AHPA) Safety Rating
Class 2c: Not to be used
while nursing (McGuffin et al.,
1997). However, a controlled trial indicated a positive therapeutic use during
lactation (ESCOP, 1997; Mennella and Beauchamp, 1991).
Regulatory Status
Canada: Drug
or possibly “New Drug” if claims made. Food in absence of claims (HPB, 1993).
Schedule OTC “Herbal and Natural Products” and “Homoeopathic Products” have
marketing authorization with Drug Identification Numbers (DIN) assigned (Health
Canada, 2001).
European Union: Powder,
freeze-dried, or low temperature dried (<65°C), containing not less than
0.45% allicin, official in European
Pharmacopoeia 3rd ed. Suppl. 2001 (Ph.Eur., 2001).
France: Traditional
Herbal Medicine (THM) permitted for treatment of minor circulatory disorders
(Bradley, 1992). Essential oil is dispensed as an aromatherapy drug (Goetz,
1999).
Germany: Fresh
or carefully dried bulb is approved by Commission E as non-prescription drug
(Blumenthal et al., 1998). Fresh bulb
for preparation of mother tincture official in the German Homoeopathic Pharmacopoeia (GHP, 1993).
Ghana: Monograph
for fresh whole bulb occurs in Ghana
Herbal Pharmacopoeia (GHP, 1992).
India: Bulb
and oil are approved single drugs dispensed in Unani system of medicine (CCRUM,
1997).
Japan: OTC
drug for fatigue (Okada and Miyagaki, 1983). AGE approved for nourishment of
pregnant and lactating women.
Sweden: Classified
as ‘Natural Remedy’ for self-medication requiring pre-marketing authorization
from Medical Products Agency (MPA). One product (e.g. Bio-Garlic Pharma Nord)
is listed in the “Authorised Natural Remedies” with the approved indication
“Traditionally used for the relief of cold symptoms” (MPA, 2001a; Tunón, 1999).
Homoeopathic dilutions (e.g., Radiotron AB) are also registered drugs (MPA,
2001b).
Switzerland: Powdered
garlic in tablets, standardized powdered extract in tablets, oily macerate in
capsules, and multiple-herb preparations containing standardized garlic extract
have positive classification (List D) by the Interkantonale Konstrollstelle für Heilmittel (IKS) and
corresponding sales category D, with sales limited to pharmacies and
drugstores, without prescription (Morant and Ruppanner, 2001). Twenty-eight
garlic phytomedicines and two homoeopathic medicines are listed in the Swiss Codex 2000/01 (Ruppanner and
Schaefer, 2000).
U.K: Herbal
medicine on the General Sale List
(GSL), Table A (internal or external use), Schedule 1 (requires full product
license) (GSL, 1989).
U.S.: Dietary
Supplement (USC, 1994). Fresh or dried compound bulbs, powdered garlic,
fluidextract and extract are official in the U.S. National Formulary 19th edition (USP, 2002). Tincture of mature
bulb, 1:10 (w/v) in 55% alcohol (v/v), is a Class C OTC drug of the Homoeopathic Pharmacopoeia of the United
States (HPUS, 1989).
Clinical Review
Thirty-two studies, including 45,694 participants, are
outlined in the following table, “Clinical Studies on Garlic.” All but four of
the studies (Berthold et al., 1998;
Isaacsohn et al., 1998; McCrindle et al., 1998; Simons et al., 1995) demonstrated positive
effects on conditions including cardiovascular and arterial health, cancer,
immunity, and circulation. Studies from the table are categorized and discussed
in the following six sections. In addition to the studies in the table, this
Clinical Review discusses numerous reviews and meta-analyses that are not
listed in the table.
Based on the Agency for Healthcare Research and Quality’s
(AHRQ) review and summary of clinical studies on garlic (Mulrow et al., 2000), researchers concluded that
garlic preparations may have small, positive, short-term effects (less than
three months) on lipids, and promising antithrombic effects. However, the data
was insufficient to draw conclusions about certain clinical cardiovascular
outcomes (e.g., myocardial infarction), antithrombic activity, or cancer
prevention. No effects on glucose or insulin sensitivity, or consistent
decreases in blood pressure were found. Case-control studies suggest that
consuming large amounts of garlic in the diet may reduce the risks of
laryngeal, gastric, colorectal, and endometrial cancers, and adenomatous
colorectal polyps (Mulrow, et al.,
2000). A subsequent review of 45 randomized trials by some of the same
researchers concluded that the trials suggest possible small short-term
benefits of garlic preparations on some lipid and antiplatelet factors,
insignificant effects on blood pressure, and no effect on glucose levels
(Ackermann et al., 2001). Conclusions
regarding clinical significance are limited due to the marginal quality and
short duration of many trials, as well as the unpredictable release and
inadequate definition of active constituents in many of the garlic preparations
used in the studies.
Lipid-lowering effect
Thirteen trials involving a total of 795 participants
demonstrated a positive correlation between garlic oil, powder, or capsule
intake and lipid-lowering effects. Six randomized, double-blind,
placebo-controlled (R, DB, PC) studies (Yeh et
al., 1995; Jain et al., 1993;
Rotzsch et al., 1992; Auer et al., 1990; Mader et al., 1990; Vorberg et al.,
1990), as well as two DB, multi-center studies (Grünwald et al., 1992; Holzgartner et
al., 1992) supported the use of garlic in treating elevated lipid
conditions including hyperlipidemia and hypercholesterolemia. Three studies
showed the positive impact of taking Kyolic® capsules specifically
for improving hypercholesterolemia conditions (Steiner et al., 1996; Steiner and Lin, 1994; Lau et al., 1987). One R, open, parallel group, comparison (O, PG, Cm)
found garlic powder to have a significant impact over garlic oil on lowering
blood lipid counts and blood pressure, as well as increasing the overall sense
of well-being in 70 subjects (De A Santos and Johns, 1995). An R, PC study
involving 35 renal transplant patients found the garlic product, Pure-Gar®,
to have positive effects on hyperlipidemia (Lash et al., 1998). One O study involving 82 subjects (Bordia, 1981)
found garlic to have, in conjunction with the lipid-lowering effects, a
positive impact on patients with coronary heart disease.
A meta-analysis on the effect of garlic on total serum
cholesterol levels found a statistically significant reduction in total
cholesterol levels (Warshafsky et al.,
1993). Another analysis assessed clinical data from 952 patients and 16 trials,
indicating a decrease in total cholesterol levels (Silagy and Neil, 1994b). A
subsequent reanalysis of all data still demonstrated a significant reduction of
total cholesterol compared to placebo (Warshafsky et al., 1993). Three studies on the allicin-standardized garlic
powder tablets (Kwai®) failed to show a significant reduction in
elevated serum cholesterol (Isaacsohn et
al., 1998; McCrindle et al.,
1998; Simons et al., 1995). It was
later determined that the allicin release from the tablets varied
significantly, and that negative studies were possibly due to the lack of
expected allicin release (Lawson et al.,
2001). A study of 24 brands of enteric-coated tablets found that 83% of the
brands released less than 15% of their allicin potential (Lawson and Wang,
2001). Therefore, the researchers recommend that manufacturers standardize
supplements to dissolution of allicin release, not to allicin potential. (For
non-allicin releasing products, e.g., AGE, the standardization is to other
compounds, e.g., SAC.) In a recent, comprehensive meta-analysis of 13 R, DB, PC
trials researchers demonstrated a significant difference (p<0.01) in the
reduction of total cholesterol levels between baseline and placebo, equivalent
to a 5.8% reduction in total cholesterol levels. The authors concluded that
current evidence indicates that any specific lipid-lowering effect is small,
and the clinical outcome may not be meaningful (Stevinson et al., 2000). However, there were several problems identified with
the meta-analysis, indicating that the conclusions can only be attributed to
the specific brands tested and not the effectiveness of garlic in general. In
particular, the brand used in 10 of the trials did not protect allinase from
exposure to gastric acid. Another tested supplement was spray-dried, resulting
in the loss of alliin. The study on the garlic oil that showed no effect
utilized a form that has demonstrated low bioavailability; therefore the
conclusions of the meta-analysis need to be considered within this context
(Lawson, 2001). Several of these products are not standardized to a
bioavailable marker compound. Clinical studies with positive outcomes using AGE
standardized with bioavailable SAC have shown significant levels of SAC in
human blood during the study period (Steiner and Li, 2001).
Antihypertensive effect
Two R, DB, PC studies and one R, O, PG, Cm study (159 total
participants) demonstrated the antihypertensive effects of garlic (De A Santos
and Johns, 1995; Jain et al., 1993;
Auer et al., 1990). A systematic
review and meta-analysis of randomized controlled trials was conducted to
determine the effect of garlic on blood pressure. Eight trials, including 415
participants, were identified. Of the seven trials that compared the effect of
garlic with a placebo, three demonstrated a significant reduction in systolic
blood pressure (SBP), and 4 in diastolic blood pressure (DBP). The authors
concluded that more rigorously designed trials can provide evidence to
recommend the clinical application of garlic in the treatment of hypertension
(Silagy and Neil, 1994b).
Antiplatelet effects
One R, DB, PC, crossover (CO) study and 2 DB, PC studies
involving a total of 214 subjects indicate the potential use of garlic as a
coronary disease preventative due to its positive impact on platelet functions
(Steiner and Li, 2001; Kiesewetter et
al., 1991; 1993a).
Anti-atherosclerotic effect
In the longest clinical trial on garlic to date, garlic’s
ability to prevent and possibly reverse atherosclerosis was tested in a R, DB,
PC, four-year study in which 152 men and women were given 900 mg garlic powder
as tablets (Kwai®) per day (Koscielny et al., 1999). The subjects possessed significant plaque buildup
and at least one additional cardiovascular risk factor (e.g., high LDL levels,
hypertension, diabetes, and/or history of smoking). After the four years,
garlic subjects had an average 2.6% reduction in plaque volume while the
placebo group’s plaque increased 15.6%. Researchers concluded that garlic has a
preventive and possibly curative role in arteriosclerosis therapy. In one
epidemiological, cross-sectional, observational (E, CS, OB) study with 202
participants, standardized garlic powered was found to have positive effects on
arterial activities including elastic vascular resistance, pulse wave velocity,
and systolic blood pressure (Breithaupt-Grogler, 1997).
Anticancer/Chemoprevention
Anti-cancer and chemopreventative qualities of garlic were
demonstrated in five studies involving a total of 44,044 subjects. One E study
spanning over a period of 15 years, demonstrated that raw and cooked garlic use
had a significant impact on decreasing stomach cancer incidents (You et al., 1989). Two other E studies found
that garlic intake significantly decreased the risk of colon cancer in 42,325
participants (Witte et al., 1996;
Steinmetz et al., 1994). Garlic’s
chemopreventative potential was demonstrated in two OB studies through the
improvement of arachidonic acid and acetaminophen metabolism (Dimitrov and
Bennink, 1997; Gwilt et al., 1994).
Case-control studies suggest that consuming large amounts of garlic in the diet
may reduce the risks of laryngeal, gastric, colorectal, and endometrial cancers
and adenomatous colorectal polyps (Mulrow, et
al., 2000).
Several reviews of E studies have examined the
cancer-preventive effect of garlic, including garlic ingested as a food (Dorant
et al., 1993; Fleischauer et al., 2000). A meta-analysis of the
epidemiological evidence on the association between garlic consumption and risk
of stomach, colon, head and neck, lung, breast, and prostate cancers concluded
that raw and cooked garlic consumption might have a protective effect against
stomach and colorectal cancers (Fleischauer et
al., 2000). An earlier review of in
vitro, in vivo, epidemiologic,
and case-control studies suggested that the evidence is not conclusive to
support chemoprevention in humans, but further research is warranted (Dorant et al., 1993); however, this review
preceded much of the salient research in this area.
Other
One pilot study involving 7 HIV+ patients demonstrated a
positive impact on natural killer cell activity as well as improvement in
conditions such as diarrhea, genital herpes, and candidiasis (Abdullah et al., 1989). One R, DB, PC study
showed that garlic did not negatively impact bleeding potential in patients
undergoing warfarin therapy (Rozenfeld, et
al., 2000). Two studies involving 92 subjects demonstrated garlic’s
positive impact on peripheral circulation: one R, CO, Cm study showed an
immediate improvement in hand and foot circulation (Okuhara, 1994); and one DB,
PC study involving 80 subjects with peripheral arterial occlusive disease
(PAOD) showed a significant increase in walking distance (Kiesewetter et al., 1993b). This last study was the
only study to meet the inclusion criteria established by the Cochrane Library
for its review on the use of garlic for PAOD. The Cochrane Review concluded
that further trials on garlic’s effectiveness on PAOD are warranted because the
one study reviewed was small, of short duration (12 weeks), and found no
significant overall improvement in patients with PAOD. The discrepancy between
the conclusions of the study and those of the review is a result of the study’s
analysis of the mean difference between the garlic and placebo groups instead
of analyzing the mean change within the groups’ pre- and post-treatment.
Branded Products*
AGE™ (Aged Garlic Extract): Wakunaga of America Co., Ltd. /
23501 Madero / Mission Viego, CA 92691 / U.S.A. / Tel: (800) 421-2998 /
www.kyolic.com. This refers to a
proprietary garlic extract with stable sulfure compounds standardized to
bioavailable components (e.g., SAC) in various types of formulations. See
Kyolic® below.
Höfel’s® Garlic Pearles One-A-Day: Seven Seas
Ltd., a division of the Merck Group / Hedon Road / Marfleet / Hull / England /
HU9 5NJ / U.K. / Tel.: +44-1482-37-5234 / Fax: +44-1482-37-4345 / Email:
info@hofels.com or Info@Seven-Seas.ltd.uk / www.hofels.com. A gelatin or
glycerin capsule containing 2 mg garlic oil, and soybean oil.
Kwai® forte 300 mg LI 111: 1. Lichtwer Pharma AG
/ Wallenroder Strasse 8-14 / 13435 Berlin / Germany / Tel: +49-30-40-3700 /
Fax: +49-30-40-3704-49 / www.lichtwer.de. One sugar-coated tablet (dragée)
contains: garlic bulb powder 300 mg. Other components: lactose monohydrate,
cellulose, highly dispersive silicon dioxide, magnesium stearate, castor oil,
Macrogol 6000, Hypromellose, saccharose, talcum, gelatin, Povidon K25, carnauba
wax, bleached wax, yellow quinoline E104, indigo carmine E132.
KwaiâN LI
111: Lichtwer Pharma AG. One tablet contains 100 mg dried powder from Allium sativum (garlic bulb)
standardized to contain 1.3% allicin (yielding 0.6% allicin). Inactive
ingredients: lactose, magnesium stearate, powdered cellulose, colloidal
anhydrous silica, methylhydroxypropylcellulose, polyethylene glycol 6000,
castor oil, talc, polyvinylpyrrolidone 25, sucrose, gelatin, quinoline yellow E
104, indigotine E 132, carnauba wax, cera alba.
Kyolic® Liquid: Wakunaga of America Co., Ltd.
Aged Garlic Extract™ in water and residual alcohol from extraction.
Kyolic® Reserve: Wakunaga of America Co., Ltd.
600 mg Aged Garlic Extract™ per capsule.
Kyolic® Super Formula 100: Wakunaga of America
Co., Ltd. 300 mg Aged Garlic Extract™ per capsule plus whey.
Kyolic® Super Formula 101: Wakunaga of America
Co., Ltd. 270 mg Aged Garlic Extract™ per capsule, plus brewer’s yeast, kelp,
and whey.
Kyolic® Super Formula 102: Wakunaga of America
Co., Ltd. 350 mg Aged Garlic Extract™ per capsule, plus food enzymes: amylase, protease,
lipase, and cellulase (30 mg).
Kyolic® Super Formula 103: Wakunaga of America
Co., Ltd. 220 mg Aged Garlic Extract™ per capsule, plus Ester C® (105
mg), Astragalus membranaceous (100
mg), and calcium (23 mg).
Kyolic® Super Formula 104: Wakunaga of America
Co., Ltd. 300 mg Aged Garlic Extract™ per capsule, plus 190 mg lecithin.
Kyolic® Super Formula 105: Wakunaga of America
Co., Ltd. 200 mg Aged Garlic Extract™ per capsule, plus beta-carotene (6 mg),
vitamin C (120 mg), vitamin E (60 IU), selenium (25 mg), and green tea (45 mg).
Kyolic® Super Formula 106: Wakunaga of America
Co., Ltd. 300 mg Aged Garlic Extract™ per capsule, plus hawthorn berry (50 mg),
cayenne pepper (10 mg), and vitamin E (100 IU).
Pure-Gar® Garlic Powder A-2000: Essentially Pure
Ingredients™, c/o Pure Gar L.P. / 21411 Prairie Street / Chatsworth, CA 91311 /
U.S.A. / Tel: (800) 537-7695 / www.essentiallypure.com. Dried powder from Allium sativum (garlic bulb): allicin
yield 2,000 ppm min.; total thiosulfinates yield 2,100 ppm minimum; allian
7,500 ppm minimum; gamma-glutamylcysteines 10,000 ppm minimum.
Pure-Gar® Garlic Powder A-5000: Essentially Pure
Ingredients™ / 21411 Prairie Street / Chatsworth, CA 91311 / U.S.A. / Tel:
818-739-6046 / www.essentiallypure.com. Dried powder from Allium sativum (garlic bulb): allicin yield 5,000 ppm minimum;
total thiosulfinates yield 5,000 ppm minimum; allian 11,000 ppm minimum;
gamma-glutamylcysteines 10,000 ppm minimum; total sulfur 6,500 ppm minimum.
Pure-Gar® Garlic Powder A-8000: Essentially Pure
Ingredients™. Dried powder from Allium
sativum (garlic bulb): allicin yield 8,000 ppm minimum; total
thiosulfinates yield 8,000 ppm minimum; allian 18,000 ppm minimum;
gamma-glutamylcysteines 8,000 ppm minimum.
Pure-Gar® Garlic Powder A-10000: Essentially Pure
Ingredients™. Dried powder from Allium
sativum (garlic bulb): allicin yield 10,000 ppm minimum; total
thiosulfinates yield 10,000 ppm minimum; allian 23,000 ppm minimum;
gamma-glutamylcysteines 8,000 ppm minimum.
Sapec®: Lichtwer Pharma AG. 300 mg tablet of
dried garlic powder standardized to contain 1.3% allicin (yielding 0.6%
allicin).
Tegra®: Hermes Fabrick Pharma / Georg-Kalb-Str.
5-8 / 82049 Grosshesselohe / Germany. Steam-distilled garlic oil (does not
contain allicin, fructans, agrinine, or gamma-glutamylcysteines).
*American equivalents, if any, are found in the Product
Table beginning on page 398.
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