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Clinical Effects Produced by a Standardized Herbal Medicinal Product of

Hibiscus sabdariffa on Patients with Hypertension. A Randomized, Double-
blind, Lisinopril-Controlled Clinica...

Article  in  Planta Medica · January 2007

DOI: 10.1055/s-2006-957065 · Source: PubMed

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 Armando Herrera-Arellano1,4
Judith Miranda-Sµnchez2
Pedro vila-Castro2
Sara Herrera-lvarez2
Clinical Effects Produced by a Standardized Herbal Jes‚s Enrique JimØnez-Ferrer1
Medicinal Product of Hibiscus sabdariffa on Patients Alejandro Zamilpa1
RubØn Romµn-Ramos3
with Hypertension. A Randomized, Double-blind, HØctor Ponce-Monter3
Lisinopril-Controlled Clinical Trial Jaime Tortoriello1
Original Paper

Abstract 12.21 %, p < 0.05). The experimental treatment showed therapeu-

Hibiscus sabdariffa L. (Malvaceae) has been used in different
countries as an antihypertensive. Pharmacological work has
demonstrated that this effect is probably produced by a diuretic
activity and inhibition of the angiotensin-converting enzyme
(ACE). Two clinical trials have confirmed the antihypertensive ef-
fect using watery infusions, in which a natriuretic effect was also
detected. To compare therapeutic effectiveness, tolerability, and
safety, as well as the effect on serum electrolytes and the ACE in-
hibitory effect of a herbal medicinal product prepared from the
dried extract of H. sabdariffa calyxes (HsHMP) with those of lisi-
nopril on patients with hypertension (HT), a randomized, con-
trolled, and double-blind clinical trial was conducted. Patients
of either sex, 25 ± 61 years of age, with hypertension stage I or II,
6 were daily treated for 4 weeks with the HsHMP, 250 mg of total
anthocyanins per dose (experimental group), or 10 mg of lisino-
pril (control group). Outcome variables included effectiveness
(diastolic blood pressure [DBP] reduction, ³ 10 mmHg), safety
(absence of pathological modifications in the biochemical tests
of hepatic and renal function), tolerability (absence of intense
side effects), effect on serum electrolytes, and effect on ACE ac-
tivity. Basal analysis included 193 subjects (100 in the experi-
mental group), while outcome variable analysis integrated 171.
Results showed that the experimental treatment decreased
blood pressure (BP) from 146.48/97.77 to 129.89/85.96 mmHg,
reaching an absolute reduction of 17.14/11.97 mmHg (11.58/
tic effectiveness of 65.12 % as well as tolerability and safety of
100 %. BP reductions and therapeutic effectiveness were lower
than those obtained with lisinopril (p < 0.05). Under the experi-
mental treatment, the serum chlorine level increased from 91.71
to 95.13 mmol/L (p = 0.0001), the sodium level showed a tend-
ency to decrease (from 139.09 to 137.35, p = 0.07), while potas-
sium level was not modified. ACE plasmatic activity was inhib-
ited by HsHMP from 44.049 to 30.1 Units (Us; p = 0.0001). In
conclusion, the HsHMP exerted important antihypertensive ef-
fectiveness with a wide margin of tolerability and safety, while
it also significantly reduced plasma ACE activity and demon-
strated a tendency to reduce serum sodium (Na) concentrations
without modifying potassium (K) levels. Further studies are nec-
essary for evaluating the dose-dependency of HsHMP and for de-
tecting lower effective doses.
Key words
Hibiscus sabdariffa ´ Malvaceae ´ antihypertensive ´ standardized
herbal medicinal product ´ complementary and alternative med-
icine
Abbreviations
ACE: angiotensin-converting enzyme
BMI: body mass index
BP: blood pressure
SBP: systolic blood pressure

Affiliation
1
Centro de Investigación BiomØdica del Sur, Instituto Mexicano del Seguro Social (IMSS), Argentina 1,
Xochitepec, Morelos, MØxico
2
Hospital General Regional No. 1 (HGR 1), IMSS, Cuernavaca, Morelos, MØxico
3
Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana (UAM). Iztapalapa, MØxico, D.F.,
MØxico
4
This work was part of the Ph.D. project of A.H.-A. at UAM, Mexico City, Mexico

Correspondence
Dr. Armando Herrera-Arellano ´ Centro de Investigación BiomØdica del Sur ´ Instituto Mexicano del Seguro
Social (IMSS) ´ Argentina 1 ´ 62790 Xochitepec ´ Morelos ´ MØxico ´ Phone/Fax: +52-777-361-2155 ´
E-mail: armandoha_mx@yahoo.com.mx

Received July 16, 2006 ´ Accepted November 6, 2006

Bibliography
Planta Med 2007; 73: 6±12  Georg Thieme Verlag KG Stuttgart ´ New York
DOI 10.1055/s-2006-957065 ´ Published online December 21, 2006
ISSN 0032-0943
DBP: diastolic blood pressure
f: frequencies
HsHMP: Hibiscus sabdariffa herbal medicinal product
HT: hypertension
m: means
Us: units
Introduction
Approximately 900 million patients throughout the world suffer
from hypertension (HT); of these, 420 million reside in develop-
ing countries. It has been calculated that 1.5 % (17 million) of
those patients die each year due to causes directly related with
HT: every 4 sec, an acute coronary syndrome is produced and
every 5 sec a cerebral stroke. Based on detected blood pressure
(BP) rates (mmHg), the Seventh Report of the Joint Committee
on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC 7) classifies HT in two stages: stage 1, systo-
lic blood pressure (SBP) 140 ± 159 or DBP 90 ± 99, and stage 2, SBP
³ 160 or DBP ³ 100. The main objectives of medical treatment for
HT are to avoid disease progression, prevent cardiovascular com-
plications, maintain a good quality of life, and reduce the mortal-
ity associated with this disease, while the aim is a BP of < 140/90
mmHg [1]. Different factors play a role in the pathogenesis of HT.
Among the best known factors are water and sodium retention in
the vascular compartment and increased activity of the plasmat-
ic angiotensin-converting enzyme (ACE), which results in an in-
crease in angiotensin II production and activity [2].
Hibiscus sabdariffa L. (Malvaceae), popularly known in Mexico as
ªjamaicaº or ªflor de jamaicaº, has been widely used in many cul-
tures worldwide for preparing beverages with culinary and med-
icinal objectives [3]. Based on the Complete German Commission
E Monographs, hibiscus flowers consist of the calyxes of Hibiscus
sabdariffa L. var. sabdariffa ruber and are useful to diminish the
appetite, dissolve phlegm, for colds, as a laxative, as a diuretic,
and for circulatory disorders. The phytopharmaceutical industry
in Germany considers H. sabdariffa as found among neutral pro-
ducts [4]. Different works have reported H. sabdariffa activity on
the cardiovascular system; in this manner, both an ACE inhibi-
tory effect and angioprotecting activity were measured in vitro.
The ACE inhibitory effect was attributed to flavones, while the
angioprotecting effect was attributed to anthocyanins [5]. A re-
laxing activity on the aortic rings and a hypotensive dose-depen-
dent effect on anesthetized cats and rats were also proposed. In
addition, the diuretic effect in whole animals, as well as the re-
duction of heart weight in hypertensive rats with renal artery oc-
clusion were also shown [6], [7], [8], [9]. Because of the myo-
relaxing effect on ileum smooth muscle, a calcioantagonistic ef-
fect of H. sabdariffa is proposed [10].
Hibiscus sabdariffa anthocyanins have been reported to possess
antioxidative, antitumor, and anticarcinogenic activity; delphini-
din 3-sambubioside (1) and cyanidin 3-sambubioside (2) (Fig. 1)
represent these compounds [11]. Considering Hibiscus anthocya-
nins as the active constituents, clinical studies standardized in
total content of anthocyanins must be carried out.
Herrera-Arellano A et al. Clinical Effects Produced ¼ Planta Med 2007; 73: 6 ± 12
Supporting information available online at
http://www.thieme-connect.de/ejournals/toc/plantamedica
Regarding toxicological evaluations of the H. sabdariffa aqueous
extract, two reports are available that mention an LD50 > 3.750 g/
kg on rats and that conclude that doses of £ 180 mg/kg/day p. o.
are safe [8], [12].
To date, two clinical trials support the antihypertensive effect of
Original Paper
H. sabdariffa calyces on patients suffering from HT. Recently, it
was reported that oral administration of an infusion prepared
with 10 g of dry H. sabdariffa calyxes, standardized by a colori-
metric method on 9.6 mg of anthocyanins per dose in patients di-
agnosed with stage 1 or 2 HT, was able to reduce SBP from 139.05
to 123.37 mmHg and DBP from 90.81 to 79.52 mmHg with a
therapeutic effectiveness (DBP reduction ³ 10 mmHg) and toler-
ability of 78.95 and 100 %, respectively. Moreover, a natriuretic
effect was detected without modifying potassium (K) excretion
[13], [14]. At present, a herbal medicinal product has been devel-
oped that is produced from the dry aqueous extract of H.
sabdariffa, standardized by HPLC to 250 mg of total anthocyanins
(similar amount used by the traditional medicine), in a hydroso-
luble powder packed into hermetic, one-dose, aluminum enve-
lopes.
The aim of this project was to compare the antihypertensive ef-
fectiveness, tolerability, and safety, as well as the effect on serum
electrolytes and the ACE inhibitory effect of a herbal medicinal 7
product prepared from H. sabdariffa extract (250 mg of antho-
cyanins/dose) with lisinopril (10 mg) in patients with stage 1 or
2 HT. Lisinopril was the control treatment as it is known to pos-
sess an inhibitory ACE effect, analogous to what had been report-
ed in vitro for H. sabdariffa extract.
Materials and Methods
Subjects
The study was carried out with primary care out-patients of the
Regional General Hospital No. 1 (HGR 1) of the Mexican Institute
of Social Security (IMSS) in Cuernavaca, Morelos, Mexico. The
project was authorized by the Institutional Ethics Committee
and by the Mexican National Research Commission. By means
of a randomized, controlled, double-blind clinical trial, we inclu-
Fig. 1 Structure of Hi-
biscus sabdariffa antho-
cyanins: delphinidin 3-
O-(2-O-b-D-xylopyrano-
syl)-b-D-glucopyrano-
side (R = OH, 1), cya-
nidin 3-O-(2-O-b-D-xilo-
pyranosyl)-b-D-gluco-
pyranoside (R = H, 2).
 ded patients of either sex from 25 ± 61 years of age, with stages 1
or 2 HT based on the Sixth Report of the Joint National Commit-
tee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC 6) classification [15] and without antihyper-
tensive treatment (at least during the previous 30 days). Patients
with nephropathy, heart or hepatic diseases, cancer, non-con-
trolled diabetes mellitus, or pregnant or breast-feeding women,
as well as subjects with evidence of secondary hypertension,
known hypersenstivity or intolerance to ACE inhibitors or to
Hibiscus sabdariffa, were not included. All patients not conclud-
ing the study or voluntarily withdrawing from the investigation
were excluded from the analysis. Patients who showed an impor-
tant BP elevation or who presented intense or severe side effects
were also withdrawn from the study, both of these complications
Original Paper
considered as therapeutic failure.
Treatments
For the experimental treatment, H. sabdariffa calyces were ob-
tained from a controlled crop in the town of Xochitepec in
Morelos State, Mexico. A voucher specimen was prepared and
deposited at the IMSSM herbarium for reference (no. 14,290)
and identified by Abigail Aguilar, Ph. D. Calyxes were selected
and dried under dark conditions at room temperature. Dry ma-
terial was milled until < 2-mm particles were obtained. Plant
material was macerated in sterile water at 60 8C for 8 h. After-
wards, the extract was concentrated under reduced pressure.
Later, the extract was freeze-dried. A highly hygroscopic pow-
der was obtained and was stored frozen until it was used in
the HsHMP formulation. After quality control tests, the product
was packed into hermetic, one-dose, aluminum envelopes con-
taining H. sabdariffa dried extract standardized to 250 mg of to-
tal anthocyanins.
8 bioside (2).
The experimental group was treated daily for 4 weeks with one
envelope dissolved in 250 mL of water. The control group receiv-
ed lisinopril (USP, 10 mg) mixed with artificial flavor and color
and then reunited with the appropriate pharmaceutical vehicle
and packed in identical envelopes.
Extract standardization
Anthocyanin isolation: Delphinidin 3-sambubioside (1) and cya-
nidin 3-sambubioside (2) were isolated by fractionation of
Hibiscus sabdariffa dried aqueous extract. The extract (10 g)
was stirred with methanol, and the liquid phase was filtered
and concentrated to dryness using a rotavapor under vacuum
with a bath temperature maintained at 35 8C. The methanolic
fraction (2.4 g) was loaded onto a Sep-pak C18 cartridge (Wa-
ters Corp.; Milford, MA, USA), washed with 10 mL of deionized
water and eluted with a water/acetonitrile gradient. The red-
dish-purple anthocyanin fractions were lyophilized to dryness
and subjected to the preparative HPLC system consisting of a
Waters 2695 separation module and a Waters 2996 photodiode
array detector (Waters; Milford, MA, USA). Anthocyanins were
purified on an XTerraPrep RP-18 5-mm 50 ” 7.8-mm semi-pre-
parative column. The solvents utilized included 1.1 % (v/v) of
aqueous trifluoroacetic acid (solvent A) and acetonitrile (sol-
vent B). Flow rate was maintained at 2 mL/min with an isocratic
system consisting of 85 % of solvent A and 15 % of solvent B dur-
ing 10 min. Detection was at 520 nm; 100 mL were repetitively
injected to obtain 15 mg of 1 and 7.8 mg of 2. These compounds
Herrera-Arellano A et al. Clinical Effects Produced ¼ Planta Med 2007; 73: 6 ± 12
were identified based on their M+ (cation): m/z = 597 for 1 and
m/z = 581 for 2, respectively.
Calibration curves: Experiments were carried out on a Waters
2695 Separations Module System equipped with a Waters 996
PDA detector and Empower Chromatography Manager version 1
(Waters). Analysis was performed with a 5-mm, 250 ” 4.0-mm
Merck Lichrosphere RP-19 column. The mobile phase consisted
of 1.1 % (v/v) of aqueous trifluoroacetic acid (solvent A) and ace-
tonitrile (solvent B). An isocratic system consisted of 15 % (B) and
85 % (A) during 12 min with PDA 230 ± 600 nm and detection
wavelength 520 nm. Flow rate was maintained at 1 mL/min. Col-
umn temperature was 30 8C, and injection volume was 20 mL.
Delphinidin 3-sambubioside (1) demonstrated a retention time
of 5.96 min and cyanidin 3-sambubioside (2), 8.84 min, respec-
tively.
Previously isolated anthocyanins 1 (4 mg) and 2 (4 mg) were
separately dissolved in 0.1 % TFA/MeOH solution (v/v) (5 mL)
and used as standard stock solutions for generating calibration
curves. In addition, 250-, 500-, 1,000-, and 2,000-mg/mL concen-
trations were prepared for each anthocyanin, respectively. These
four standard solutions were injected (20 mL) to generate a cali-
bration curve for the two standard compounds separately. Stand-
ard curves were linear with R2 = 0.9966 for anthocyanin 1 and
R2 = 0.9836 for anthocyanin 2.
Sample preparation
Injection in triplicate of the H. sabdariffa extract (20 mL, 4 mg/mL)
displayed data corresponding to the concentration of anthocya-
nins 1 and 2. Total anthocyanin amount was obtained by addi-
tion of delphinidin 3-sambubioside (1) and cyanidin 3-sambu-
Biochemical tests
Serum samples from patients were immediately subjected to the
following evaluations: 1) colorimetric determination of urea,
creatinine, alkaline phosphatase (ALP), alanine aminotransferase
(ALT), and aspartate aminotransferase (AST) with diagnostic Wi-
ener reactive (Wiener Lab; Rosario, Argentina); 2) colorimetric
determination of sodium (Na), chlorine (Cl), and potassium (K)
with STANBIO reactive (Stanbio Lab; Boerne, TX, USA) and spec-
trophotometer Jenway 6305 uv/vis (Essex, UK), and 3) ACE activ-
ity. This quantified the degradation of the symmetrical substrate
of ACE (Sigma Chemical Co.; St. Louis, MO, USA), N-[3 ± 2-(2-fur-
yl)acryloyl]-Phe-Gly-Gly (FAPGG). The HPLC method was used
for FAPGG quantification contrasted with a calibration curve uti-
lizing a Chromolite column (Merck; Darmstadt, Germany) and an
isocratic solvent system consisting of acetonitrile-1.1 % trifluoro-
acetic acid (80 : 20) at a flow rate of 1.5 mL/min. FAPGG displayed
a retention time of 8.07 min. Enzymatic activity was defined in
units: one unit corresponded to 1 mmol of FAPGG transformed
during 1 min in 25 mM HEPES and 300 mM of NaCl at pH 8.3
and 37 8C
Outcome variables
Antihypertensive effectiveness was achieved when, at the end of
the study, DBP was reduced by ³ 10 mmHg, tolerability was con-
sidered as absence of intensive or severe side effects, while safety
was determined as absence of pathological modifications in bio-
chemical tests for hepatic and renal function (ALT, AST, urea, and
creatinine). When there were antihypertensive effectiveness, tol-
erability, and safety, cases were considered as therapeutic suc-
cesses; the inverse result was considered as therapeutic failure,
as well as when the patient withdrew from the study for medical
complications. Other variables measured were colorimetric de-
termination of serum Na, K, and Cl, as well as plasmatic ACE ac-
tivity.
Statistical analysis
To determine statistical differences between mean pairs of data
with normal distribution, the hypothesis test with analysis of
variance (ANOVA) was used, while the c2 test was used for com-
paring two groups of proportions. Stratified analysis was used for
dichotomized confounding variables. Values of p £ 0.05 were
considered for rejecting the nullity hypothesis.
Study description
The study was carried out from August 2004 to March 2005. Can-
didates were recruited by the institution physicians or identified
through a clinical screening in the hospital waiting room. Hyper-
tension was confirmed by a designated physician in the research
group and was based on the mean of two pressure measure-
ments obtained under resting conditions with a 5-min interval.
Blood samples were obtained for biochemical tests of hepatic
and renal function for approval of patient inclusion after they
signed informed consent for participation in the study. Treat-
ment-group assignment was performed based on a random-
ized-number table. During the initial interview, measurement
of basal conditions was conducted and 1 week's worth of medi-
cation was handed out, along with oral and written instructions
for the medication (dilute the envelope's content in a glass of
clear water and drink daily before breakfast for 4 weeks). For all
patients, clinical evaluation, variables outcome, and treatment
adherence (counting the number of empty envelopes) were eval-
uated weekly, when the endowment of new treatment was car-
ried out. All patients were treated and followed up for 4 weeks.
Blood samples for biochemical analysis were obtained at the be-
ginning and the end of treatment.
Supporting information
The comparison of the basal conditions between treatment
groups are available as Supporting Information.
Results and Discussion
Basal conditions: A total of 193 subjects were included in the
study, 100 of these corresponding to the experimental group
(Supporting Information, Tables S1 to S3). It was observed that,
after comparing both treatments groups, no differences were
found in any of the analyzed parameters (p ³ 0.11). At the begin-
ning of the study, BP in the experimental group was 146.38/97.73
mmHg and the control group showed 145.67/97.74 mmHg;
56.99 % of the patients suffered from stage 1 HT.
Excluded patients: During the study period, three patients with-
drew from the study due to medical complications (considered
therapeutic failure), two of these because of a hypertensive
emergency (one per group) and an additional patient (from the
Herrera-Arellano A et al. Clinical Effects Produced ¼ Planta Med 2007; 73: 6 ± 12
control group) due to angioneurotic edema. Twenty-two pa-
tients were eliminated due to lack of treatment adherence and
another one for non-medical reasons. Causes of patient withdraw-
al from the study showed no differences between the two treat-
ment groups. One hundred and sixty-eight subjects concluded
the study, their results were included in the antihypertensive ef-
fect and safety analysis. An additional patient, the case of angio-
neurotic edema, was included in the tolerability analysis, while
two additional patients with hypertensive emergencies were in-
cluded in the effectiveness analysis. Finally, therapeutic success
analysis comprised 171 patients.
Anti-hypertensive effect: Fig. 2 shows the effect of both treat-
ments on the reduction of SBP and DBP along the 4-week treat-
Original Paper
ment. At the beginning of the study, these parameters were not
changed significantly, while at the end of the administration
period both treatments resulted in reduced BP rates (ANOVA
p = 0.0001). Nevertheless, the antihypertensive effect was more
pronounced under control treatment (p < 0.002). The H.
sabdariffa-derived medicine was able to reduce BP to 129.89/
85.96 mmHg, while control treatment reduced this parameter
to 122.32/82.33. At the end of the study, the HsHMP reduced BP
by 17.14/11.97 mmHg (11.58/12.21 %) and the control treatment
by 23.31/15.39 mmHg (15.79/15.68 %) (p < 0.001). Two previous
clinical trials reported the H. sabdariffa's antihypertensive effect;
in both studies, BP was reduced significantly [13], [14]. The pres-
ent study confirms the antihypertensive effect of HsHMP. The
antihypertensive effect was better than that obtained in the
ALLHAT study: after 4 years of treatment, chlorthalidone de-
creased the BP by 12.3/7.6, amlodipine by 12.3/8.7 and lisinopril
by 12.0/8.0 mmHg [21].
Outcomes: Table 1 compares outcome variables between the two 9
treatments. We observed 100 % safety for both; tolerability per-
centages were better in the case of HsHMP (100 vs. 98.81 %, p >
0.31). This is explained by the observation that a patient from
the lisinopril group suffered from facial angioneurotic edema;
Fig. 2 Effect of H. sabdariffa herbal medicinal product (u) or lisinopril
(n) on SBP (systolic blood pressure; top of the figure) and DBP (dias-
tolic blood pressure; bottom part), along the 4-week treatment. Val-
ues are mmHg; points represent means and bars SD. * Comparison be-
tween treatments, ANOVA p £ 0.05.
 Table 1 Outcome variables obtained after the 4-week treatment. Values are absolute frequencies (f) and percentages

Variable Total population H. sabdariffa Lisinopril X2 test

f % f % f % p

Effectiveness 0.01
Positive 125 73.53 56 65.12 69 82.14
Negative 45 26.47 30 34.88 15 17.86
Safety 1.00
Positive 168 100.0 85 100.0 83 100.0
Negative 0 0.0 0 0.0 0 0.0
Tolerability 0.31
Positive 168 99.41 85 100.00 83 98.81
Negative 1 0.59 0 0.00 1 1.19
Original Paper

Successes 0.01
Positive 125 73.09 56 65.12 69 81.18
Negative 46 26.90 30 34.88 16 18.82

in this case, it was necessary to withdraw the patient from the
study. This infrequent side effect has been previously reported
and can affect the face, tongue, trachea, intestine, and penis
[16]. After comparison of the data obtained from the HsHMP-
treated group with those of the lisinopril-treated group, there
was evidence of better effectiveness (65.12 vs. 82.14 %) and of
better therapeutic success (65.12 vs. 81.18 %) (p < 0.01) in the lisi-
nopril group. The therapeutic effectiveness of the H. sabdariffa
herbal product (65.12 %) was slightly less than the one obtained
in the ALLHAT study, in which chlorthalidone reached 68.9 %, am-
lodipine 68.6 % and lisinopril 67.4 % [17].
10 It is important to mention that two cases (one from each group)
were considered as therapeutic failures because they produced
hypertensive crises requiring emergency-room treatment. With
respect to mild side effects, all were transient; the most fre-
quently side effects reported in both groups included headache
and blurred vision, both symptoms observed during the first 2
weeks of the study. Moreover, two cases of nervousness were re-
ported in the experimental group, while in the lisinopril group
we observed one case of dry cough and one of dry mouth.
Stratified analysis (to ascertain the confounding effect of demo-
graphic variables on outcome variables observed under experi-
mental treatment): This statistical analysis demonstrated that al-
coholism and smoking reduced the antihypertensive effect by
roughly 4 to 5 mmHg (p < 0.02). These two habits negatively influ-
enced the antihypertensive response; those findings agree with
other previously published reports [18]. On the other hand, as sup-
posed, the HT stage also significantly influenced the HsHMP's ther-
apeutic effectiveness because treatment was 18.86 % more effec-
tive in patients with stage I HT than in patients with stage 2 HT.
Effects on serum electrolytes and ACE activity: As illustrated in Ta-
ble 2, the herbal medicinal product increased serum Cl by 3.42
meq/L (p = 0.0001) and decreased plasma Na by 2.04 meq/L,
reaching a borderline p value (p = 0.07), while the K level was
not affected (p = 0.18). Control treatment solely increased plas-
ma Cl by 2.87 meq/L (p = 0.0001). These effects agree with the
observations from our previous clinical trial, in which patients
treated with the H. sabdariffa infusion (10 mg colorimetric meth-
od-quantified anthocyanins) after 4 weeks of administration
showed significantly increased Na excretion to 19.31 meq/L,
with a tendency of decreased Cl and without modification of K
excretion [14]. The diuretic effect consists of eliminating water,

Table 2 Effect produced by treatments administered on serum electrolytes. Values are meq/L expressed as means (m) and standard deviation
(SD)

Variable Initial Final ANOVA

m SD m SD p

Hibiscus sabdariffa
Chlorine 91.71 10.19 95.13 9.62 0.0001
Sodium 139.09 8.43 137.35 9.31 0.07
Potassium 3.67 0.63 3.54 0.46 0.18
Lisinopril
Chlorine 91.66 9.44 94.53 10.94 0.0001
Sodium 139.17 14.62 139.57 8.82 0.60
Potassium 3.79 0.69 3.59 0.45 0.17

Herrera-Arellano A et al. Clinical Effects Produced ¼ Planta Med 2007; 73: 6 ± 12

Table 3 Inhibition produced by administered treatments on angiotensin converting enzyme (ACE) activity. Data are units, and values are means
(m) and standard deviation (SD)
Variable Initial Final
m SD m SD
Hibiscus sabdariffa
ACE Activity 44.04 14.85 30.100 13.23
Lisinopril
ACE Activity 42.57 13.35 22.24 10.47
ANOVA p 0.51 0.0001
sodium and, except of the aldosterone antagonists, potassium.
The prolonged administration of diuretics tends to modify the
serum concentrations of these electrolytes [19]. This diuretic ef-
fect, natriuresis without modification of K excretion, is similar to
the effect produced by the aldosterone antagonists (potassium-
saving diuretics) spironolactone and eplerenone. Spironolactone
is rarely used in long-term treatment of HT due to its mineralocor-
ticoid effects [20]. Eplerenone, a non-mineralocorticoid aldoster-
one antagonist, is proposed for long-term treatment of HT because
it possesses the same antihypertensive effect as spironolactone,
achieving up to 74.4 % therapeutic effectiveness [21]. Finally, the
treatments reproducibly reduced ACE activity (p < 0.02). This find-
ing confirms the ACE inhibitory effect previously observed in
vitro[5]. Nonetheless, after comparing absolute and percentage
treatment reduction, the ACE inihibitory effect was significantly
higher (p < 0.004) in the lisinopril-treated group (Table 3).
Based on the data reported herein, it is possible to conclude that
the H. sabdariffa plant-derived medicine exerts antihypertensive
action at least through two modes of action that are complemen-
tary and synergic: diuretic (probably as the aldosterone antago-
nist) and ACE inhibitory, which is in agreement with reported sci-
entific works [5], [8]. On the other hand, the extract of H. sabdariffa
possesses hypocholesterolemic and antiatherosclerotic effects,
which are also useful in the treatment of hypertension [22], [23].
In summary, we are able to say that H. sabdariffa includes ± in
one product ± the properties of the two most frequently prescri-
bed drug groups for long-term treatment of HT, ACE inhibitory
and diuretic, namely. In addition, it has the advantage that the
diuretic activity did not modify plasma K levels and did not pos-
sess the spirolactone's mineralocorticoid effects.
Further trials are necessary for evaluating the dose-dependency
of the HsHMP in patients with hypertension.
Acknowledgements
This work was partially supported by CONACyT MØxico (SALUD
2002-COI/6448) and IMSS (FOFOI 2002 ± 062) grants. A.A.-H. re-
ceived a doctoral fellowship from CONACyT, MØxico (#172 485)
Herrera-Arellano A et al. Clinical Effects Produced ¼ Planta Med 2007; 73: 6 ± 12
Difference Difference (%) ANOVA
m SD m SD p
13.94 12.58 29.75 25.11 0.0001
20.32 14.71 45.54 26.41 0.02
0.004 0.0002
Original Paper
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