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Division of Hematology/Oncology, East Carolina University School of Medicine, Greenville, NC 27858-4354
2To whom correspondence should be addressed. E-mail: steiner{at}brody.med.ecu.edu.
ABSTRACT
Aged garlic extract (AGE) has been shown previously to have moderate
cholesterol-lowering and blood pressure–reducing effects. We have
now investigated whether platelet function, a potential risk factor for
cardiovascular disease, can be inhibited by AGE administration. In a
randomized, double-blind study of normal healthy individuals
(n = 34), both men and women, the effect of AGE was
evaluated in doses between 2.4 and 7.2 g/d vs. equal amounts of
placebo. Platelet aggregation and adhesion were measured at 2-wk
intervals throughout the study. Threshold concentrations for
epinephrine and collagen increased moderately during AGE administration
compared with the placebo and baseline periods. Only at the highest
supplementation level did AGE show a slight increase in the threshold
level of ADP-induced aggregation. Platelet adhesion to collagen,
fibrinogen and von Willebrand factor was investigated by perfusing
whole blood through a laminar flow chamber under controlled flow
conditions. Adherence of platelets was inhibited by AGE in a
dose-dependent manner when collagen was the adhesive surface
perfused at low shear rates (
30 s-1). At
high shear rates (1200 s-1), AGE also
inhibited platelet adhesion to collagen but only at higher intake
levels. Adhesion to von Willebrand factor was reduced only at 7.2 g/d
AGE, but adherence to fibrinogen was potently inhibited at all levels
of supplementation. Thus, AGE exerts selective inhibition on platelet
aggregation and adhesion, platelet functions that may be important for
the development of cardiovascular events such as myocardial infarction
and ischemic stroke. We briefly review the effect of garlic
preparations in general on cardiovascular risk factors and point out
differences between AGE and other garlic preparations that we feel are
important to explain the efficacy of AGE.
KEY WORDS: • organosulfur compounds • aged garlic extract • platelet aggregation • platelet adhesion • cardiovascular risk factors
Cardiovascular disease remains the foremost cause of death in developed countries even though a steady decline in mortality and morbidity has been recognized over the past few decades. Much of this decline is due to an effort to reduce hypercholesterolemia, a major risk factor for this group of diseases. Effective treatment of hypertension, another major risk factor, has also contributed to the decline. Of great importance as well are advances in the treatment and prevention of myocardial infarctions using a variety of techniques both medical and surgical. There has been an increasing recognition that certain natural substances have the potential to reduce the detrimental effect of a number of cardiovascular risk factors. By and large, the efficacy of such biofactors lags behind pharmaceutical intervention in the amelioration of the prevalence of risk factors. Their primary use lies in the field of prevention, i.e., before the occurrence of major cardiovascular events such as myocardial infarction or strokes as caused by cerebrovascular disease. The use of natural substances has become more widespread over the past few years, driven undoubtedly by the belief that natural substances may have fewer side effects than do pharmaceuticals and by their ready availability to the public without prescriptions or visits to health providers.
Garlic and various forms of extracts prepared from it represent an
example of such natural substances that have been claimed to possess
beneficial effects for the prevention of various aspects of
cardiovascular disease. Although a large number of intervention trials
have been reported in the literature, most studies have been small.
Meta-analyses (Silagy and Neil 1994
,
Warshafsky et al. 1993
), which combine the data of many
of the intervention trials, have sought to arrive at conclusions about
the efficacy of the preparations. However, because of the different
nature of the supplements used in these studies, the relatively short
time of their administration in most trials and the widely varying
characteristics of the study populations, it is difficult to draw
definitive conclusions.
We report here the results of a recently completed dose-finding
study on the effect of aged garlic extract (AGE), a garlic preparation
composed primarily of stable components derived from those present in
fresh garlic, on platelet function. The results of an intervention
trial using a large supplement dose of AGE in a group of moderately
hypercholesterolemic men were reported previously (Steiner et al. 1996
). Major findings of our study were AGE-induced
reduction of platelet aggregation in response to collagen and
epinephrine and a reduction of platelet adhesion to collagen and
fibrinogen, but not to von Willebrand factor. Measurement of
S-allylcysteine (SAC) levels in the blood not only provided
evidence of compliance but also showed that at least one of the major
constituents of AGE was absorbed from the human intestine.
Experimental design and methodology.
We recruited a group of normal individuals (n = 34), both men and women, who were in good physical health, to this 44-wk long, double-blind, crossover study. After an initial 6-wk baseline period during which no supplements were administered, the study participants were randomly selected to receive either AGE or placebo in a dosage of 3 capsules/d (each 800 mg) for a period of 6 wk. After this 6-wk period, the dosage was raised to 6 capsules/d for 6 wk, and finally to 9 capsules/d for another 6 wk. The first intervention period was followed by a 2-wk washout period. The subjects were then switched to the other supplement that they did not receive during the first arm of the study. A final 2-wk washout period concluded the study. The study was completed by 28 of 34 individuals enrolled. Reasons for dropping out of the study included complaints of gastrointestinal problems, such as heartburn, flatulence, complaints of body odor and allergy. One individual was terminated because of overt noncompliance; another had to stop because of relocating to another area of the state.
Blood was sampled every 2 wk and processed for platelet aggregation and adhesion studies. Aliquots of plasma were stored at -80°C, some for use as yet to be determined, and others for measurement of SAC levels.
Platelet function studies.
Whole blood (50 mL) was collected in 0.1 volume of 3.8% sodium citrate
in normal saline. For platelet aggregation studies, platelet-rich
plasma was prepared by previously described methods (Landolfi et al. 1984
). Aggregation was tested with the following agonists:
arachidonic acid, ADP, collagen and epinephrine. Each platelet
stimulant was used in a range of concentrations to determine threshold
levels for each agonist capable of inducing complete aggregation, which
signifies achievement of >80% maximal aggregation. Platelet
aggregation was determined in a multichannel aggregometer. Maximal
aggregation and initial slope were two parameters analyzed by the
instrument.
Measurement of platelet adhesion.
The adherence of platelets to collagen-, fibrinogen- and von Willebrand
factor–coated surfaces was evaluated in a Hele-Shaw type laminar
flow chamber perfused with whole blood at shear rates of either 1200
s-1 or 30
s-1. The low shear rate
perfusion was used only with collagen-coated surfaces. The
characteristics of the flow chamber and the experimental set-up
have been described previously (Jandak et al. 1989
).
Whole blood was perfused through the flow chamber under
temperature-controlled conditions (37°C) for 10 min. Washing
procedures as well as quantitative analysis of the adherent platelets
have been described (Steiner and Lin 1998
). Adhesion
studies to fibrinogen- or von Willebrand factor–coated surfaces were
performed in two different subsets of the study population,
n = 17 and n = 11, respectively. Both
of these adhesion measurements were done at a high shear rate (1200
s-1).
Statistical analysis.
Threshold concentrations of individual agonists were used for comparison. Aggregation data using arachidonic acid as platelet stimulant were analyzed solely to determine whether the study subjects had ingested nonsteroidal anti-inflammatory agents, inhibitors of platelet cyclooxygenase. Group means were compared by ANOVA using the statistical software program SPSS (Chicago, IL).
RESULTS
Platelet aggregation.
Aggregation studies using ADP as a stimulant showed a minimal increase
in the threshold concentration in individuals consuming AGE (Fig. 1B
). Compared with the baseline and placebo arms of the study, threshold
levels during AGE administration increased from between 4.5 and 5.2
µmol/L to 6.1–7.1 µmol/L. This increase was
significant only at the highest intake level, i.e., 7.2 g AGE/d
(P < 0.05). There was no significant difference
between supplementation levels of AGE (i.e., 2.4 and 7.2 g/d).
|
). Threshold levels for this agonist ranged between 0.41
and 0.52 µg/mL at baseline and during placebo
administration. After AGE, the threshold levels increased to 0.82
µg/mL at an intake level of 2.4 g AGE/d and rose to
1.1 µg/mL when intake was raised to 4.8 g/d. There was no
further change when the supplementation was increased to 7.2 g/d. At
all three supplementation levels, the aggregation responses were
significantly different from those under baseline and placebo
conditions.
Platelet aggregation induced by epinephrine (Fig. 1A
) was
also inhibited by AGE. With consumption of 2.4 g AGE/d, the
threshold level for this agonist increased significantly from between 4
and 4.4 µmol/L to 6.5 µmol/L. Further
increase of AGE supplementation did not produce a significant
enhancement of AGE-induced inhibition. In fact, at high doses (7.2
g AGE/d) the threshold concentration was not significantly different
from that of baseline or placebo-supplemented groups.
Platelet adhesion.
Adhesion to collagen-coated surfaces was examined in all study
participants (Fig. 2A
,
C
). Two different shear rates were investigated. At low shear rates (30
s-1) (Fig. 2C
),
there was a small but significant reduction in platelet adhesion when
4.8–7.2 g AGE/d were consumed. At a daily dosage of 2.4 g AGE/d,
no significant reduction of platelet adherence was noted. The maximal
reduction obtained at the higher supplement levels was 25% below
that of baseline or placebo-supplemented groups. High shear rate
adhesion (1200 s-1) to
collagen (Fig. 2A
) showed a progressive decline with
escalating AGE dosage. Compared with low shear rate adhesion, fewer
platelets adhered to the collagen-coated surface. The maximal
reduction was 50%, which was obtained in individuals supplemented
with 7.2 g AGE/d.
|
) and von Willebrand factor
(Fig. 2B
) were both measured in a subgroup of the study
population. The former was significantly inhibited by AGE at all
concentrations used, slightly more at intake levels of 4.8 and 7.2 g than at 2.4 g/d. Even at the last-mentioned dosage, however,
adhesion was reduced by 33% compared with baseline or placebo
groups. Although the higher concentrations of AGE, i.e., 4.8 and 7.2
g/d, resulted in an increase in inhibition of 10% over that
achieved with 2.4 g AGE, the difference among the three intake
levels of AGE was not significant. Adhesion to von Willebrand
factor–coated surfaces was reduced only at the highest intake level
(7.2 g/d). The reduction was 33% compared with baseline or placebo
groups. Correlation of serum SAC levels with dietary intake of AGE.
Measurement of serum SAC levels was done in a majority of the
study participants. One study subject who showed overt noncompliance
and was eventually eliminated from the study failed to show any
increase in SAC. All other individuals consuming AGE exhibited an
increase in SAC level that peaked when they were consuming 4.8 g/d
(Fig. 3
). It was interesting to note that placebo administration also produced
an increase in SAC levels that was progressive with dose escalation.
The differences compared with baseline, however, were not significant.
After stopping AGE supplementation, i.e., during the washout period,
there was a sharp drop in SAC levels in all study subjects.
|
DISCUSSION
The results of this dose-finding study are in line with our
previous finding in a select group of hypercholesterolemic men; that
study showed that AGE supplementation can reduce platelet function
(Steiner et al. 1996
). The inhibitory effect is
selective, affecting collagen- and epinephrine-induced aggregation
more than that stimulated by ADP. To enhance discriminatory activity of
our sampling procedure, we analyzed threshold concentration levels for
each of the individual platelet agonists. In general, we found good
reproducibility of platelet responsiveness to a given stimulant over a
period of time. The exception to this rule was the intake of
nonsteroidal anti-inflammatory agents before blood collections for
our experiments. This is a problem that becomes prevalent in a
long-term study. Therefore, we tested platelet aggregation with
arachidonic acid as a stimulant in each individual to detect preceding
use of nonsteroidal anti-inflammatory agents that inhibit platelet
aggregation.
It was interesting to note that the inhibitory effect of AGE on platelet aggregation was not strictly dose dependent. At least for epinephrine and ADP as stimulants, the lowest dosage of AGE tested, i.e., 2.4 g extract/d, was as efficacious as the higher dosages given. Only for collagen was there a progressive increase at escalating dosage levels of AGE. But with this agonist as well, the highest intake level of 7.2 g AGE/d did not produce increased inhibition over and above that provided by 4.8 g AGE/d. Our studies showed clearly that the washout period of 2 wk was sufficient to eliminate the antiaggregatory activity of AGE.
Previous studies in humans and animals have shown that certain
constituents of fresh garlic or its extract have inhibitory activity on
platelet aggregation (Ali and Mohammed 1986
,
Apitz-Castro et al. 1988 and 1994a
, Ariga et al. 1981
, Bordia 1978
, Boullin 1981
,
Lawson et al. 1992
, Legnani et al. 1993
,
Makheja et al. 1980
, Mohammad and Woodward 1986
, Srivastava 1984 and 1986
,
Vanderhoek et al. 1980
). Although most of the reported
experiments used in vitro incubations with garlic or its components,
there were some ex vivo or in vivo experiments as well (De Boer and Folts 1989
, Legnani et al. 1993
) that showed
an inhibitory effect at high concentrations of the test substance.
There has been no consensus on the possible mechanism of action, but
because most of the individual components of garlic tested were
organosulfur compounds, a sulfhydryl group–mediated effect may
be responsible. Corroborating evidence has been provided in at least
one study using ajoene as the inhibitor (Apitz-Castro et al. 1994b
). AGE contains a number of organosulfur components
(Weinberg et al. 1992
), one of which, SAC, was used in
our study to monitor compliance of study participants and as
documentation of the absorption of AGE from the intestinal tract. AGE
contains a large number of other substances, including carbohydrates,
saponins and proteins; little is known concerning their effect on
platelet function, especially aggregation. For this reason, it is
premature to speculate on the mechanism of action of AGE on platelet
aggregation. However, the selectivity of platelet inhibition makes an
effect of AGE on specific receptors, e.g., that of epinephrine and
collagen, a more likely explanation for the AGE-induced reduction
of platelet aggregation than an inhibition of mediators of platelet
aggregation such as those observed with nonsteroidal
anti-inflammatory agents.
This study represents the first detailed investigation of the effect of AGE on platelet adhesion to a variety of adhesive proteins. Our results showed a significant reduction of adhesion to collagen- and fibrinogen-coated surfaces. Dose escalation again provided little (for collagen only) if any greater inhibitory effect than lower levels of AGE intake (2.4 g/d). As with aggregation studies, there was specificity of inhibition of platelet adhesion. With the use of fibrinogen- and collagen-coated surfaces, significant reductions were observed, but not with von Willebrand factor–coated surfaces. Using similar reasoning as for platelet aggregation leads to the suggestion that individual receptors for these adhesive proteins may be affected differently by AGE supplementation. Although adequate for aggregation, the washout period of 2 wk was clearly not sufficient in length to evaluate the effect of AGE on platelet adhesion.
The efficacy of AGE as a means of reducing other cardiovascular risk
factors, such as total and LDL cholesterol levels and blood pressure,
was investigated in our previous study (Steiner et al. 1996
) in which the effect of a prolonged supplementation (6 mo)
with AGE was evaluated. A few meta-analyses have been published
(Silagy and Neil 1944
, Warshafsky et al. 1993
) that summarized the diverse data base on
garlic-induced alterations of lipid profiles. Notwithstanding the
negative results of recent studies using non-AGE garlic extracts,
i.e., dehydrated garlic powder or garlic oil products (Berthold et al. 1998
, Issacsohn et al. 1998
), the
majority of the published intervention trials provided evidence of a
modest but significant reduction (8–11%) in total and LDL
cholesterol levels in the blood. The magnitude of the changes observed
makes it clear that small-scale studies, such as those reported to
date, will be unable to give definitive answers on the health benefits
of the preparations when evaluated individually. The situation with
this dietary supplement is similar to that of other dietary
manipulations that have been studied for their effect on lipid
profiles. It is important to recollect that definite conclusions about
effectiveness could be obtained only after pooling large numbers of
studies to achieve the statistical power required to define
significance. These remarks also apply to the inhibition of platelet
function by dietary supplements and even pharmaceutical platelet
inhibitors.
It should be pointed out that several of the water-soluble
compounds present in AGE such as SAC, S-ethyl cysteine, and
S-propyl cysteine quite potently inhibit cholesterogenesis
by cultured hepatocytes of rats in vitro. A 40–60% inhibition of
acetate incorporation into cholesterol and fatty acids was observed
(Yeh and Yeh 1994
). Lipid-soluble organosulfurs such
as diallylsulfide, diallyldisulfides and diallyltrisulfides, as well as
dipropylsulfide, dipropyldysulfide and methylallylsulfide also decrease
cholesterol synthesis of hepatocytes but only by 10–15% and by
damaging the cells as evidenced by release of cellular lactate
dehydrogenase (Yeh and Liu, 2001). Thus, the inhibition
of cholesterol synthesis by lipid-soluble compounds may be a result
of cytotoxicity, whereas the inhibition by water-soluble compounds
appears to be the result of metabolic alterations.
The difficulty of evaluating natural substances that are prepared in a
variety of ways is clearly demonstrated for garlic-related
extracts. For AGE, detailed investigations in vitro, ex vivo and in
vivo have shown that this supplement is absorbed from the intestinal
tract and at least one major biologically important component, SAC, can
be measured in the blood. This has not or could not be done with other
garlic extracts currently on the market. Freeman and Kodera (1995)
demonstrated that allicin, one of the most effective
organosulfurs of fresh garlic in vitro, which also forms the basis of
most potency measurements of preparations made from fresh garlic, shows
rapid destruction in the blood. It appears to interact with the iron in
hemoglobin, oxidizing it to the trivalent form, thus producing
methemoglobin. Furthermore, although stable in gastric and intestinal
milieus, allicin was not absorbed (Egen-Schwind et al. 1992
). For this reason, we have the strong conviction that not
only is there a plausible basic rationale for the efficacy of AGE, but
we also have good evidence of its effectiveness upon administration.
The inhibition of individual risk factors important for the development
of cardiovascular disease is not very great, but the inhibition of
several risk factors achieved by AGE should make it a very useful
dietary supplement in the prevention of cardiovascular disease.
FOOTNOTES
1 Presented at the conference "Recent Advances on the Nutritional Benefits Accompanying the Use of Garlic as a Supplement" held November 15–17, 1998 in Newport Beach, CA. The conference was supported by educational grants from Pennsylvania State University, Wakunaga of America, Ltd. and the National Cancer Institute. The proceedings of this conference are published as a supplement to The Journal of Nutrition. Guest editors: John Milner, The Pennsylvania State University, University Park, PA and Richard Rivlin, Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, NY. 
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