A Clinical Trial Testing The Safety And Efficacy Of A

amr
Original Research
A Clinical Trial Testing the Safety and Efficacy
of a Standardized Eucommia ulmoides Oliver
Bark Extract to Treat Hypertension
Frank Greenway, MD; Zhijun Liu, PhD; Ying Yu, MS; Alok Gupta, MD
Frank Greenway, MD –
Pennington Biomedical
Research Center, Louisiana
State University System,
Baton Rouge, LA
Correspondence address –
Pennington Biomedical
Research Center, Louisiana
State University System, 6400
Perkins Road, Baton Rouge,
LA 70808
Email:
[email protected]
Zhijun Liu, PhD – Pennington
Biomedical Research Center,
Louisiana State University
System, Baton Rouge, LA;
Louisiana State University
Agricultural Center, Baton
Rouge, LA
Ying Yu, MS – Pennington
Biomedical Research Center,
Louisiana State University
System, Baton Rouge, LA
Alok Gupta, MD – Pennington
Biomedical Research Center,
Louisiana State University
System, Baton Rouge, LA
Abstract
BACKGROUND: A tea made from Eucommia ulmoides leaves
and bark is part of the Japanese diet. Eucommia is an herbal
medicine that, by increasing nitric oxide, reduced blood
pressure (BP) in rats and humans in an uncontrolled clinical
trial. OBJECTIVE: A controlled clinical trial was conducted to
evaluate an aqueous bark extract of Eucommia standardized
to eight percent pinoresinol di-beta-D-glucoside (PG) for BP
reduction in humans. METHODS: Study 1: Twenty-four healthy
adult subjects with a BP between 120-160/80-100 mmHg
were randomized to Eucommia extract 500 mg three times
daily for eight weeks. Automatic 24-hour ambulatory blood
pressure monitoring (24-h ABPM) was utilized at baseline and
after eight weeks. Study 2: The effect of the Eucommia extract
on isoproterenol-stimulated lipolysis was evaluated in a
human fat cell assay to determine whether Eucommia was a
beta-adrenergic blocker. Study 3: Thirty healthy adult subjects
with a BP between 120-160/80-100 mmHg were randomized
to 1 g Eucommia extract three times daily for two weeks with
24-h ABPM at baseline and after two weeks. RESULTS: Study 1:
There was no toxicity or any difference in BP between the two
groups. Study 2: Eucommia at 0.5% w/v reduced isoproterenol-stimulated lipolysis from 2.67 to 1.4 times the buffer
control (p<0.001). Study 3: The Eucommia extract was
well-tolerated and reduced BP by an average of 7.5/3.9 mmHg
(p<0.008). CONCLUSION: The standardized Eucommia extract
reduced BP and has beta-adrenergic blocking activity.
Eucommia may be an appropriate nutraceutical intervention
for prehypertension.
(Altern Med Rev 2011;16(4)338-347)
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Background
Eucommia bark and leaves are used as a tea in
Japan, and this herb is part of the diet in that area
of the world.1 Eucommia tea has no known toxicity
associated with its use. Trials in rats given a water
extract of Eucommia orally at 200 mg/kg demonstrated up to 20 mmHg drop in blood pressure two
hours after dosing, without untoward effects.2 The
equivalent dose in humans is 2-6.5 g. Although this
tea is used in traditional Chinese medicine to treat
high blood pressure, and an uncontrolled Russian
trial with Eucommia ulmoides demonstrated a 25/14
mmHg drop in blood pressure in human subjects
with hypertension, no placebo-controlled, human
clinical trials have been conducted to test its safety
and efficacy.3
This trial was preceded by creation of a Eucommia
ulmoides Oliver bark extract standardized to eight
percent pinoresinol di-beta-D-glucoside (PG).
Details of this procedure are described in a prior
publication.4 The safety of acute dosing was
confirmed in rats up to a dose of 1,200 mg/kg. In
addition, repeated dosing of 200 mg/kg, 600 mg/
kg, and 1,200 mg/kg over 28 days demonstrated no
toxicity in rats as determined by clinical appearance, histopathology, and serum chemistry.4
Spontaneously hypertensive rats were given
Eucommia extract daily for 22 days, resulting in a
systolic blood pressure reduction in the male rats,
but not the female rats, of 31 mmHg and 28 mmHg
over three hours in the 600 mg/kg and 1,200 mg/
kg groups, respectively (p<0.001). This genderspecific response has been reported previously in
Volume 16, Number 4 Alternative Medicine Review 338
amr
Original Research
Key words: blood pressure,
clinical trial, Eucommia,
hypertension, human,
Eucommia ulmoides
spontaneously hypertensive rats5 and was discussed in greater detail by Lang et al.4 Since the
standardized Eucommia extract was safe and
effective in rats, the authors obtained permission
from their Institutional Review Board for testing
the same extract in hypertensive humans. This
publication will describe their controlled clinical
trials of the standardized Eucommia bark extract.
Objectives
The objectives of these studies were to conduct
controlled clinical trials to evaluate an aqueous
bark extract of Eucommia standardized to eightpercent PG for BP reduction in humans and to
explore the mechanisms by which it may act.
Methods
Study 1
The trial included 24 healthy male and female
volunteers, ages 18-60 years, with a body mass
index (BMI) ≤35 and an average blood pressure
between 120-160/80-100 (determined from three
resting weekly Pennington clinic determinations).
This level of hypertension can be safely treated
with lifestyle modification alone for six months.6
Patients with diabetes mellitus, nephropathy,
peripheral arterial disease, retinopathy, history of
stroke, or heart disease (including left ventricular
hypertrophy, prior myocardial infarction, angina
pectoris, a prior revascularization procedure, or
heart failure) were excluded from the study.
Subjects using medications that could produce
weight loss, or who were on unstable doses (stable
dose=same dose for previous three months) of
medicines that influence blood pressure, were also
excluded.
At screening, subjects signed an informed
consent approved by the Pennington Center
Institutional Review Board, provided a medical
history, and underwent a physical examination.
Testing included a fasting (10-12 hours) chemistry
panel (glucose, creatinine, potassium, uric acid,
albumin, calcium, magnesium, creatine phosphokinase, alanine-leucine transaminase, alkaline
phosphatase, iron, total cholesterol, triglycerides,
high density lipoprotein [HDL] cholesterol, and low
density lipoprotein [LDL] cholesterol) and complete blood count (CBC; hemoglobin, hematocrit,
mean cell volume, platelet count, white blood cell
count and differential), an electrocardiogram, and a
urinalysis (glucose, protein, specific gravity). Blood
pressure was taken using the validated OMRON
automated blood pressure monitor after five
minutes of rest in a sitting position with the arm at
339 Alternative Medicine Review Volume 16, Number 4
heart level, according to the Pennington Procedure
Manual.7 Patients were required to refrain from
smoking and caffeine consumption for four hours
before blood pressure measurements. They were
also provided with an ambulatory 24-hour blood
pressure monitor (24-h ABPM) that automatically
recorded blood pressure and heart rate every 30
minutes during the 24-hour period following their
screening visit.
After screening, subjects were randomized to
placebo or the standardized 500-mg Eucommia
extract, each taken three times daily for eight
weeks. A pregnancy test was conducted in women
with childbearing potential at week 0, prior to
study treatment initiation. Previous rat toxicity
studies showed safety at the equivalent daily
human dose of 21 g. This study utilized less than
one tenth of this dose. After the screening visits on
weeks -3, -2, and -1, subjects were seen in the clinic
on week 0 when the medication was started, and at
weeks 1, 3, 5, and 8. Subjects were questioned
about adverse events at each clinic visit.
Subjects did not change their baseline diet or
physical activity during the study. During clinic
visits, medication was dispensed and compliance
was monitored by pill count. Weight, pulse rate,
and blood pressure were taken. Although a subject
with a blood pressure greater than 180/110 on a
clinic visit would have been withdrawn from the
trial and referred to their treating physician, this
did not occur. A repeat 24-h ABPM was performed
during the last week of the study. At the study end,
repeat physical examinations, chemistry panels,
electrocardiograms, and CBCs were administered.
At the completion of the study, subjects were
instructed in the appropriate dietary and lifestyle
recommendations for hypertension, and were
advised to follow-up with their treating physicians.
The primary outcome variable was the difference
in blood pressure between the Eucommia and
placebo groups from baseline to eight weeks by
24-h ABPM. Secondary outcome variables included
the differences in pulse rate, clinic OMRON blood
pressures, and safety measures (electrocardiograms, physical examination, and laboratory
testing).
Study 2
To determine whether blocking of beta-adrenergic receptors contributes to the blood pressurelowering effect of Eucommia, the effect of 0.5
percent w/v Eucommia standardized extract and
10-4 M propranolol was tested on 10-7 M isoproterenol-stimulated lipolysis in a human fat-cell assay,
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
amr
using glycerol generation as a measure of lipolysis.
Briefly, differentiated human adipocytes in 96-well
plates were obtained from the cell biology core
facility of the Clinical Nutrition Research Unit
Center, Grant # 1P30 DK072476 awarded to the
Pennington Biomedical Research Center. On the
day of the assay, 150 µL of medium was removed
from each well of the 96-well plate, and 200 µL of
wash buffer was then added to each well. Next, 200
µL of medium and wash buffer were removed, and
another 200 µL of wash buffer was added to each
well; then the medium and wash buffer were
removed from each well. The cells were then
treated with 150 µL of the test compounds and
controls, eight wells at a time. The diluted isoproterenol was treated as a positive control, and the
assay buffer was treated as the vehicle control. The
plate was incubated for five hours at 37o C (5%
CO2). After incubation, 100 µL of the test compounds were removed and added to a sterile
96-well plate. Glycerol reagent (100 µL) was then
added to create a colorimetric assay, dependent on
the amount of glycerol released during incubation
with the test compounds. A series of glycerol
standards were also run with each assay to create a
standard curve upon which the results were based.
The plates were then read in a spectrophotometer
plate reader at 540 nm, and the results were
plotted based on the standard curve. The results
were analyzed by t-test and expressed as the mean
± the standard deviation, with the number of wells
(observations) noted.
Study 3
A second clinical trial was performed using a
Eucommia dose of 1 g three times daily for two
weeks. The design modifications in this second
clinical trial were prompted by lack of a statistically
significant drop in blood pressure in the first
clinical trial, the safety of Eucommia at much
higher doses in animals, the safety of the first
clinical trial, and evidence in animals that the effect
on blood pressure is apparent in eight days.
The trial included 30 healthy male and female
volunteers (n=30; ages 18-70 years) with a BMI
<40 kg/m2 and an average blood pressure between
120-160/80-100 mmHg, tested on three occasions
in the Pennington Center clinic (each separated by
one week). Pregnant or lactating women and
individuals who had smoked within the six months
preceding the trial were excluded. Patients with
diabetes mellitus, nephropathy, peripheral arterial
disease, retinopathy, history of stroke, or heart
disease (including left ventricular hypertrophy,
Original Research
prior myocardial infarction, angina pectoris, a prior
revascularization procedure, and heart failure)
were also excluded from the study. Subjects using
beta-adrenergic blocking medications, medications
that could produce weight loss, or on unstable
doses of medicines that influence blood pressure
were excluded.
At screening, subjects provided a medical history
and underwent a physical examination, blood
chemistry panel, CBC, electrocardiogram, and a
24-h ABPM. Blood pressure was also measured at
each visit using the validated OMRON automated
blood pressure monitor after five minutes of rest in
a sitting position with the arm at heart level,
according to the Pennington Center procedure
manual.7 Patients were required to refrain from
caffeine for six hours prior to blood pressure
measurements. The ambulatory blood pressure
monitor recorded blood pressure automatically
every 30 minutes during the 24-hour period and
was the primary endpoint of the trial. Secondary
endpoints included the OMRON blood pressure,
lab tests, electrocardiograms, physical examinations, and adverse events.
After screening, subjects were randomized to
placebo or 1 g Eucommia extract three times daily
for two weeks. This represents only one-seventh
the dose used in rat toxicity studies, which showed
safety at the human equivalency dose of 21 g. A
pregnancy test was conducted on females with
childbearing potential at week 0 prior to initiating
study treatment. Subjects were questioned about
adverse events on each visit.
Subjects made no change in baseline diet or
physical activity during the study. During weekly
clinic visits, medication was dispensed, compliance
was monitored by pill count, and blood pressure
and weight were measured. Subjects with a blood
pressure greater than 180/110 mmHg on a clinic
visit were to be withdrawn from the trial and
referred to their physician, but this did not occur. A
repeat ambulatory blood pressure monitoring was
done during the last week of the study, and
subjects were administered a repeat physical
examination, chemistry panel, CBC, and electrocardiogram. At completion of the study, subjects were
instructed in the appropriate dietary and lifestyle
changes for hypertension, and were advised to
follow up with their personal physicians.
Statistical Analysis
Blood pressure and pulse were compared using a
mixed procedure model with a Tukey-Kramer
adjustment for multiple comparisons.
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Volume 16, Number 4 Alternative Medicine Review 340
amr
Original Research
Non-normally distributed variables like demographics were analyzed using the Tukey test.
Serum glucose increased by 3.00±1.67 mg/dL
from a baseline of 94.82±2.56 mg/dL in the
Eucommia group and fell by 1.72±1.65 mg/dL from
a baseline of 97.33±3.20 mg/dL in the placebo
group (p=0.043). Serum creatinine increased by
0.02±0.01 mg/dL from a baseline of 0.87±0.03 mg/
dL in the Eucommia group and fell by 0.03±0.02
mg/dL from a baseline of 0.97±0.05 mg/dL in the
placebo group (p=0.018). There were no other
significant differences between groups on blood
tests or adverse events observed on physical exams
or electrocardiograms.
At the request of the sponsor, an interim
analysis was performed for efficacy when 11
subjects (approximately half of the subjects
randomized to the study) had completed the trial.
Mean 24-h ABPM decreased by 3.2/1.2 mmHg in
the Eucommia group and increased by 2.0/3.3
mmHg in the placebo group. The decreases in
systolic and diastolic blood pressures in the
Eucommia group compared to the placebo group
were marginally significant, (p=0.048) and
(p=0.028), respectively; by the end of the trial,
however, the statistical significance was lost. This
Results
Study 1
Of the 24 subjects randomized into the study, 20
subjects completed the trial. Three of five subjects
on antihypertensive medication were in the
Eucommia group. Two subjects withdrew from the
study – one in the placebo group, who developed a
rash, and one in the Eucommia group, who developed headaches. Two subjects, one in the
Eucommia group and one in the placebo group,
stopped participation by not following through.
There were five adverse events in the Eucommia
group (two colds, one headache, one dizziness, and
one edema) and, with the exception of the moderately severe headache that resulted in discontinuation, all adverse events were mild and resolved
during the study. There were eight adverse events in
the placebo group (one diarrhea, one nausea, one
anorexia, one headache, one anxiety, one fatigue,
and two rashes). The reactions in this group were
classified as mild (3), moderate (2), and severe (3).
Figure 1. The Difference in Pulse Rate from Baseline to Week 8 at the Interim Analysis
20
Eucommia
Placebo
DIFFERENCE
15
10
5
0
-5
30
5:
4
HR
HR
30
2:
1
HR
HR
0
23
:3
22
HR
HR
30
19
20
:
0
HR
HR
:3
17
0
16
HR
HR
14
:3
13
HR
0
HR
11
:3
10
HR
30
HR
8:
HR
HR
7
-10
TIME
341 Alternative Medicine Review Volume 16, Number 4
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
amr
Original Research
Figure 2. Eucommia (0.5% w/v) and Propranolol (10-4 M) Inhibit Lipolysis Stimulated by Isoproterenol (10-7 M)
3
Fold Induction of Glycerol
2.67
2.5
2
1.4
1.5
1
1.06
1
0.5
0
Buffer
Iso
Iso + Pro
Iso + Euc
Key: Iso=isoproterenol; Pro=propranolol; Euc=Eucommia
suggested to the researchers that the dose of
Eucommia extract was just at the threshold of
efficacy. Although the heart rate was not significantly different in the Eucommia and placebo
groups in the interim analysis, there appeared to
be a trend in the Eucommia group to have a lower
pulse rate during waking hours, suggesting the
possibility that Eucommia might be acting as a
beta-adrenergic blocking drug (Figure 1).
Study 2
Isoproterenol at 10-7 M stimulated lipolysis as
measured by glycerol generation 2.67±0.0066 (SD)
times the buffer control in our human fat cell assay.
The addition of propranolol at 10-4 M to the
isoproterenol reduced lipolysis to 1.06±0.00273
times the buffer control. The addition of Eucommia
(0.5% w/v) to the isoproterenol reduced lipolysis to
1.4±0.2081 times the buffer control. The difference
between the isoproterenol and isoproterenol plus
propranolol or isoproterenol plus Eucommia was
significantly different (p<0.001, Figure 2). This
suggests that Eucommia, like propranolol, may act
as a beta-adrenergic blocker.
Study 3
Of the 30 subjects randomized to the study, 29
completed the study. The subjects were well
matched at baseline for weight, age, BMI, gender,
and race (Table 1). Starting blood pressure was
137/87 mmHg in the Eucommia group and 136/89
mHg in the placebo group, which was not significantly different. One subject in the placebo group
dropped out of the trial due to a pruritic rash and
joint pain. There were six subjects who experienced
adverse events and all resolved by the end of the
trial. All were mild to moderate with the exception
of the subject who dropped from the trial due to a
rash. There was one subject in the Eucommia group
who experienced two adverse events and five
subjects in the placebo group who experienced a
total of eleven adverse events (Table 2). There were
no adverse events observed on blood tests, physical
exams, or electrocardiograms.
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Volume 16, Number 4 Alternative Medicine Review 342
amr
Original Research
Table 1. Demographic Characteristics of the Eucommia and
Placebo Subjects
Variable
Number enrolled
Eucommia
Placebo
14
15
Gender
Table 2. Number of Subjects Reporting Adverse
Events in the Second Eucommia Trial
P-value
Group
0.8759 (ns)
Female
8
9
Male
6
6
Race
0.8328 (ns)
Caucasian
8
7
Black
5
7
Other
1
1
Weight (kg)
84.0
84.7
SD
16.0
12.4
29.8
29.9
5.2
3.0
50.5
49.2
6.4
9.1
Body mass index
(kg/m2)
SD
Age
SD
0.8853 (ns)
0.9595 (ns)
0.6784 (ns)
Eucommia
Placebo
Respiratory
Cold
Sinus infection
0
1
1
0
Gastrointestinal
Diarrhea
1
0
Neurological
Headache
0
3
Oral complaints
Sore throat
Other
0
1
1
0
Cardiovascular
Chest pain
0
1
Nonspecific
Other
0
1
Dermatologic
Pruritis
Rash
0
0
1
1
Musculoskeletal
Joint pain
0
1
Values are means and standard deviation (SD)
Systolic blood pressure on 24-h ABPM decreased
an average of 3.6 mmHg in the Eucommia group
and increased by an average of 3.7 mmHg in the
placebo group (p<0.0001, Figure 3). Diastolic blood
pressure decreased by an average of 0.9 mmHg in
the Eucommia group and increased by an average
of 2.0 mmHg in the placebo group (p<0.008, Figure
4). Although the difference between the Eucommia
and placebo groups in diastolic pressure was a
significant 3 mmHg, the actual reduction in
diastolic blood pressure from baseline in the
Eucommia group was not statistically significant.
There was no significant difference in heart rate
between the two groups. Heart rate decreased by
an average of 0.4 beats per minute (bpm) in the
343 Alternative Medicine Review Volume 16, Number 4
Eucommia group and increased by an average of 1.1
bpm in the placebo group. There were no significant differences in the OMRON blood pressures
taken at the clinic visits. The compliance by pill
count was >90 percent, with no significant difference between the Eucommia and placebo groups.
Note: In both Figures 3 and 4, the time points
from the 24-hour blood pressure monitoring at the
end of the study were subtracted from the same
time points as the 24-hour blood pressure monitoring at baseline. This difference was plotted on the
vertical axis and the time points of the 24-hour
monitoring were plotted on the horizontal axis.
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
amr
Original Research
Figure 3. Difference in 24-Hour Ambulatory Systolic Blood Pressure between Eucommia and Placebo Groups
20
Eucommia
15
Placebo
DIFFERENCE
10
5
0
-5
-10
-15
-20
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
HOUR
Figure 4. Difference in 24-Hour Ambulatory Diastolic Blood Pressure between Eucommia and Placebo Groups
12
Eucommia
10
Placebo
8
DIFFERENCE
6
4
2
0
-2
-4
-6
-8
-10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
HOUR
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Volume 16, Number 4 Alternative Medicine Review 344
amr
Original Research
Discussion
The seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation
and Treatment of High Blood Pressure (JNC 7)
created a new category called “prehypertension,”
defined as systolic blood pressure of 120-139
mmHg and diastolic blood pressure of 80-89
mmHg. The report suggests that individuals in this
category should be treated with dietary and
lifestyle modification.8 Since Eucommia is consumed as a tea in some Asian cultures, it could be
considered a food or a dietary herbal supplement.
Thus, Eucommia ulmoides might be employed as a
“dietary measure” to maintain a healthy blood
pressure in individuals with prehypertension and
for whom blood pressure medications may not yet
be indicated. Given that the prevalence of prehypertension in U.S. adults is 36.3 percent and these
adults demonstrate an adverse cardiometabolic
profile that places them at higher cardiovascular
disease risk compared to those with lower blood
pressure (<120/80 mmHg),9 Eucommia may
represent a non-pharmaceutical method to reduce
that risk.
In uncontrolled studies, Eucommia has been
reported to decrease blood pressure in humans and
animals. Prior studies have attempted to define the
mechanism by which Eucommia reduces blood
pressure. Kwan et al, using rat aortic rings and dog
carotid rings contracted with phenylephrine,
showed that Eucommia bark extract relaxed the
rings in an endothelium-dependent manner, which
involved nitric oxide and potassium channels.10
They then extended these observations by showing
that, in large elastic arteries like the aorta, vasorelaxation was entirely endothelium-dependent and
nitric oxide-mediated, but in smaller muscular
arteries like the mesenteric artery, vasorelaxation
was mediated by both nitric oxide and endothelium-derived hyperpolarizing factor.11 Jin et al,
using an aqueous extract of Eucommia leaves in an
intact rodent model, confirmed the involvement of
endothelium-derived hyperpolarizing factor as a
mediator of vasorelaxation in mesenteric resistance arteries. They confirmed endothelium
dependency and involvement of potassium
channels and gap junctions, but found that the
vasorelaxation was nitric oxide-independent.12 In
spontaneously hypertensive rats, Luo et al demonstrated that Eucommia ulmoides Oliver extract
lowered blood pressure while increasing nitric
oxide and reducing rennin and angiotensin II. They
also demonstrated that the vascular relaxation was
345 Alternative Medicine Review Volume 16, Number 4
endothelium-independent, suggesting that
Eucommia extract had a direct effect on the
vessels.13
Thus, prior studies into the mechanism of action
of Eucommia to reduce blood pressure are conflicted. Most studies, however, appear to agree that
nitric oxide plays a role in the vasodilatation seen
with Eucommia. We noticed the apparent reduction of heart rate during 24-h ABPM in the first
Eucommia trial, which was consistent with the
effect of a beta-adrenergic blocker. Testing the
effect of Eucommia on isoproterenol-stimulated
lipolysis in the human fat cell assay confirmed that
Eucommia does indeed have beta-adrenergic
blocking properties. Thus, it appears that there
may be at least two separate mechanisms by which
Eucommia reduces blood pressure. Nipradilol, a
beta-adrenergic blocking drug with the ability to
stimulate nitric oxide, is thought to have a similar
ability to reduce blood pressure to propranolol,
which does not increase nitric oxide, but has a
renal protective effect that propranolol does not
have.14 Thus, Eucommia might act as a beta-adrenergic blocker, but due to its seeming potential to
stimulate nitric oxide, could have renal protective
advantages in the treatment of prehypertension
over a pure beta-blocking drug.
The adverse effects seen in both trials, including
colds, diarrhea, dizziness, edema, and headache,
resolved prior to the end of the trial and were
consistent with the safety of Eucommia as a food.
Although the subjects taking Eucommia in the first
trial had a statistically significant increase in blood
sugar and creatinine, the changes were not clinically significant and were not seen in the second
trial that used twice the dose. In fact, Eucommia
has been reported to reduce blood sugar in C57BL/
KsJ-db-db mice and improve insulin sensitivity in
fructose-drinking rats.15,16 Eucommia has also been
demonstrated, along with light training, to
enhance the ability of muscle to resist fatigue.17
Since creatinine is a breakdown product of muscle
metabolism, one would expect Eucommia to reduce
rather than increase creatinine.
To demonstrate the potential importance of the
blood pressure reduction of 7.5/3.9 mmHg in this
study using an oral standardized aqueous extract of
Eucommia ulmoides, one can look to the dietary
intervention used in the DASH study, which is the
recommended dietary intervention for the treatment of prehypertension or high blood pressure.
The DASH study participants had hypertension
while the Eucommia trial participants had a
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
amr
mixture of hypertension and prehypertension.
Recognizing those differences and the much larger
number of subjects in the DASH trial, the DASH
diet reduced blood pressure by an average of
5.5/3.0 mmHg.18 That reduction in blood pressure
was estimated to reduce coronary heart disease by
15 percent and stroke by 27 percent. The second
Eucommia study gave a larger reduction in blood
pressure and suggests that it also might be
effective in reducing cardiovascular risk. Eucommia
deserves consideration as a potential nutraceutical
intervention to maintain a healthy blood pressure
in those with prehypertension who do not achieve
the desirable blood pressure of 120/80 or less with
the use of the DASH diet alone.
Original Research
3.
4.
5.
6.
7.
Conclusion
A standardized aqueous bark extract of
Eucommia ulmoides Oliver appears to be a safe and
effective botanical intervention to reduce blood
pressure in the prehypertensive and mildly
hypertensive range. The current study demonstrates that Eucommia acts as a beta-adrenergic
blocker, while other studies have shown it stimulates nitric oxide. Since the Eucommia extract
effectively reduces blood pressure, it deserves
consideration as a nutraceutical intervention in
people with prehypertension, as defined by the
JNC7, who do not respond to the DASH diet alone.
8.
9.
10.
Acknowledgements
The Eucommia standardization, preclinical
studies, and clinical trial were supported by the
Louisiana Educational Quality Support Fund
(LEQSF(2000-02)-RD-B-01) and Sage
Pharmaceuticals in Shreveport, Louisiana. The
mechanistic in vitro studies were partially supported by a CNRU Center Grant #1P30 DK072476
entitled, “Nutritional Programming:
Environmental and Molecular Interactions,”
sponsored by NIDDK, with the assistance of
Jeffrey Gimble, MD, PhD, and Ying Yu, MS.
References
Sasaki YF, Chiba A, Murakami M, et al.
Antimutagenicity of Tochu tea (an aqueous extract
of Eucommia ulmoides leaves): 2. Suppressing effect
of Tochu tea on the urine mutagenicity after
ingestion of raw fish and cooked beef. Mutat Res
1996;371:203-214.
2. Hu J. Progress in Eucommia ulmoides research. Chin
Herb Med 1999;30:394-396.
11.
12.
13.
1.
14.
Shchepotin BM, Shchulipenko IM. Treatment of
patients with hypertension with an extract of the
leaves of Eucommia ulmoides. Vrach Delo 1983;(1):3033. [Article in Russian]
Lang C, Liu Z, Taylor HW, Baker DG. Effect of
Eucommia ulmoides on systolic blood pressure in the
spontaneous hypertensive rat. Am J Chin Med
2005;33:215-230.
Freis ED, Ragan D, Pillsbury H 3rd, Mathews M.
Alteration of the course of hypertension in the
spontaneously hypertensive rat. Circ Res
1972;31:1-7.
No authors listed. The Sixth Report of the Joint
National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure.
Arch Intern Med 1997;157:2413-2446.
Coleman A, Freeman P, Steel S, Shennan A.
Validation of the Omron 705IT (HEM-759-E)
oscillometric blood pressure monitoring device
according to the British Hypertension Society
protocol. Blood Press Monit 2006;11:27-32.
Chobanian AV, Bakris GL, Black HR, et al. The
Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure: the JNC 7 report. JAMA
2003;289:2560-2572.
Gupta AK, McGlone M, Greenway FL, Johnson WD.
Prehypertension in disease-free adults: a marker for
an adverse cardiometabolic risk profile. Hypertens
Res 2010;33:905-910.
Kwan CY, Chen CX, Deyama T, Nishibe S.
Endothelium-dependent vasorelaxant effects of the
aqueous extracts of the Eucommia ulmoides Oliv. leaf
and bark: implications on their antihypertensive
action. Vascul Pharmacol 2003;40:229-235.
Kwan CY, Zhang WB, Deyama T, Nishibe S.
Endothelium-dependent vascular relaxation
induced by Eucommia ulmoides Oliv. bark extract is
mediated by NO and EDHF in small vessels. Naunyn
Schmiedebergs Arch Pharmacol 2004;369:206-211.
Jin X, Otonashi-Satoh Y, Sun P, et al. Endotheliumderived hyperpolarizing factor (EDHF) mediates
endothelium-dependent vasodilator effects of
aqueous extracts from Eucommia ulmoides Oliv.
leaves in rat mesenteric resistance arteries. Acta
Med Okayama 2008;62:319-325.
Luo LF, Wu WH, Zhou YJ, et al. Antihypertensive
effect of Eucommia ulmoides Oliv. extracts in
spontaneously hypertensive rats. J Ethnopharmacol
2010;129:238-243.
Takamitsu Y, Nakanishi T, Nishihara F, et al. A nitric
oxide-generating beta-blocking agent prevents renal
injury in the rat remnant kidney model.
Comparative study of two beta-blocking drugs,
nipradilol and propranolol. Nephron Physiol
2003;93:P42-P50.
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Volume 16, Number 4 Alternative Medicine Review 346
amr
Original Research
15. Park SA, Choi MS, Kim MJ, et al.
Hypoglycemic and hypolipidemic action
of Du-zhong (Eucommia ulmoides Oliver)
leaves water extract in C57BL/KsJ-db/
db mice. J Ethnopharmacol
2006;107:412-417.
16. Jin X, Amitani K, Zamami Y, et al.
Ameliorative effect of Eucommia
ulmoides Oliv. leaves extract (ELE) on
insulin resistance and abnormal
perivascular innervation in fructosedrinking rats. J Ethnopharmacol
2010;128:672-678.
17. Li Y, Koike K, Che Q, et al. Changes in
lactate dehydrogenase and 3-hydroxyacetyl-CoA dehydrogenase activities in
rat skeletal muscle by the administration of Eucommia ulmoides OLIVER leaf
with spontaneous running-training.
Biol Pharm Bull 1999;22:941-946.
18. Appel LJ, Moore TJ, Obarzanek E, et al.
A clinical trial of the effects of dietary
patterns on blood pressure. DASH
Collaborative Research Group. N Engl J
Med 1997;336:1117-1124.
347 Alternative Medicine Review Volume 16, Number 4
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.