Food and Chemical Toxicology 78 (2015) 122129

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Food and Chemical Toxicology

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / f o o d c h e m t o x

Safety and toxicological evaluation of Meratrim: An herbal

formulation for weight management
Zainulabedin M. Saiyed a, Krishanu Sengupta b, Alluri V. Krishnaraju b,
Golakoti Trimurtulu b, Francis C. Lau a, James P. Lugo a,*
a
b

InterHealth Nutraceuticals Research Center, Benicia, CA, United States

Laila Nutraceuticals, Vijayawada, India

A R T I C L E

I N F O

Article history:
Received 18 October 2014
Accepted 6 February 2015
Available online 11 February 2015
Keywords:
Meratrim
Acute oral and dermal toxicity
Primary skin and eye irritation
Ames bacterial reverse mutation assay
Mammalian erythrocyte micronucleus test
Repeated dose 13-week oral toxicity study

A B S T R A C T

Meratrim is a unique dietary ingredient consisting of extracts from Sphaeranthus indicus ower heads
and Garcinia mangostana fruit rind. Clinical studies have demonstrated that Meratrim is effective and welltolerated in weight management. Herein we assessed the broad spectrum safety of Meratrim in a battery
of in vitro and animal toxicological studies including a sub-chronic repeated-dose 13-week oral toxicity
study to determine the no-observable-adverse-effect-level (NOAEL). The LD50 levels of Meratrim in SpragueDawley (SD) rats, as determined by the acute oral and dermal toxicity studies, were >5000 and >2000 mg/
kg body weight, respectively. The primary skin and eye irritation tests classied Meratrim as nonirritating to the skin and mildly irritating to the eye. Genotoxicity studies showed that Meratrim is nonmutagenic. In the repeated-dose 13-week oral toxicity study, SD rats were orally gavaged with Meratrim
at 0, 250, 500 or 1000 mg/kg/day. No morbidity, mortality, or signicant adverse events were observed
either during the course of the study or on the 13th week. The NOAEL of Meratrim was concluded to be
1000 mg/kg of body weight/day in male and female SD rats. These results, combined with the tolerability of Meratrim in the human clinical trials, demonstrate the broad spectrum safety of Meratrim.
2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Obesity has grown into a worldwide epidemic in recent years. Accumulating evidence indicates that obesity is a risk factor for other
diseases such as type 2 diabetes, cardiovascular diseases and certain
cancers including colon cancer and breast cancer (Haslam and James,
2005; Shaw et al., 2005). In fact, it is estimated that obesity may reduce
life expectancy by 7 years at age 40 (Peeters et al., 2003). Accordingly,
the global socioeconomic burden for obesity and its related disorders
is tremendous and is expected to continue increasing.
In two clinical trials an herbal formulation (Meratrim) has been
proven to be effective in weight management (Stern et al., 2013a, 2013b).
Meratrim is a blend of extracts from the ower heads of Sphaeranthus
indicus (S. indicus) and the fruit rinds of Garcinia mangostana
(G. mangostana). The nal formulation is standardized to contain at least
3% 7-hydroxyfrullanolide and 2% -mangostin (Stern et al., 2013b).
S. indicus, a member of the aster and daisy family (Asteraceae),
is widely used in Ayurvedic system of medicine to treat various ailments including diabetes, epilepsy, hepatopathy, and many others
(Galani et al., 2010). A variety of secondary plant metabolites

including sesquiterpenoids, eudesmenolides, avonoids, glycosides and essential oils have been isolated from S. indicus (Galani
et al., 2010; Ramachandran, 2013). G. mangostana, commonly known
as mangosteen, belongs to the family of Clusiaceae. The trees
are cultivated in the tropical rainforests of Southeast Asia
(Pedraza-Chaverri et al., 2008). The pericarp (rind) of mangosteenfruit is used as an Ayurvedic medicine to treat inammation,
diarrhea, cholera and dysentery (Al-Massarani et al., 2013; Balunas
et al., 2008; Chen et al., 2008; Ee et al., 2006; Gopalakrishnan et al.,
1980; Obolskiy et al., 2009). Preclinical studies suggest that mangosteen pericarp extracts possess a wide range of biological activities
(Al-Massarani et al., 2013; Balunas et al., 2008; Chen et al., 2008;
Ee et al., 2006; Gopalakrishnan et al., 1980; Kosem et al., 2013;
Obolskiy et al., 2009; Pedraza-Chaverri et al., 2008; Sundaram et al.,
1983; Tewtrakul et al., 2009; Yoshikawa et al., 1994).
The objective of the present studies was to determine the safety
prole of Meratrim by conducting a battery of in vitro and in vivo
toxicity tests including a 13-week sub-chronic oral toxicity study.
2. Materials and methods
2.1. Test substance

* Corresponding author. InterHealth Nutraceuticals Inc., 5451 Industrial Way,

Benicia, CA 94510, United States. Tel.: +1 (707) 751 2800; fax: +1 (707) 751 2801.
E-mail address: jlugo@interhealthusa.com (J.P. Lugo).

Meratrim is an herbal blend containing the extracts of the ower heads of S. indicus
and the fruit rinds of G. mangostana. Briey, S. indicus ower heads were pulverized and extracted with 6 volumes of methanol, and then concentrated under vacuum

http://dx.doi.org/10.1016/j.fct.2015.02.010
0278-6915/ 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).

Z.M. Saiyed et al./Food and Chemical Toxicology 78 (2015) 122129

followed by further extraction using ethyl acetate. The resultant product from S. indicus
extraction was a thick paste. Separately, G. mangostana fruit rinds were pulverized
and extracted with 6 volumes of 80:20 ratio of methanol to water. The G. mangostana
extract thus obtained was concentrated, washed with water, and then dried. The
resulting akes were then milled. The S. indicus paste and G. mangostana powder
extract prepared above were blended together in a 3:1 extract ratio along with approximately 55% excipients to obtain Meratrim. The S. indicus extract contains a
minimum of 12% 7-hydroxyfrullanolide while the G. mangostana extract contains
a minimum of 18% -mangostin prior to blending to ensure that the nal blend contains at least 3% 7-hydroxyfrullanolide and 2% -mangostin (Stern et al., 2013b). In
addition to 7-hydroxyfrullanolide and -mangostin, the nal blend contains other
minor constituents that include sphaeranthanolide and frullanolide derived from
S. indicus, and -mangostin, garcinone C and garcinone D derived from G. mangostana
(each at levels below 0.5%). The test substance was stored at room temperature until
use, and was provided by InterHealth Nutraceuticals (Benicia, CA) under a license
agreement with Laila Nutraceuticals (Vijayawada, India).
2.2. Animals and treatment
Acute oral toxicity, acute dermal toxicity, primary dermal toxicity and primary
eye irritation were conducted at Laila Impex Research Centre (Vijayawada, India).
A repeated dose 13-week oral toxicity study was conducted at a certied GLP facility (Bioneeds, Bangalore, India). The mammalian chromosome aberration and
erythrocyte micronucleus tests were conducted at Shriram Institute for Industrial
Research (Delhi, India). The Ames reverse mutation assay was performed at RCC Laboratories India Pvt. Ltd. (Hyderabad, India). All tests complied with Good Laboratory
Practice (GLP) regulations as dened by 21CFR58 (US Food and Drug Administration) and the specied testing procedures set by the Organisation for Economic Cooperation and Development (OECD) guidelines for the testing of chemicals. All animals
used for toxicological assessments were cared for in accordance with the Guide for
the Care and Use of Laboratory Animals DHEW (NIH). Animals were allowed free
access to standard feed and water. The animals were acclimated to facility conditions 7 or 21 days prior to use. Animal rooms were kept at 22 to 25 C, 4070%
humidity, and a 12 h lightdark cycle.
2.3. Acute oral toxicity
The single dose acute oral toxicity evaluation (up-and-down procedure) was conducted in rats. Three 10-week old Sprague-Dawley (SD) nulliparous and nonpregnant female rats (180195 g) were used for this study.
Meratrim was administered in a single dose of 5000 mg/kg using an infant feeding
tube attached to a syringe. Following administration, feed was replaced approximately 4 h after dosing. On the day of dosing, all the animals were observed for
mortality, signs of gross toxicity, and behavioral changes for several hours following dosing then at least once daily for 14 days. Individual rat body weights were
recorded before dosing (Day 0) then at weekly intervals. Animals were euthanized
using ether at the end of 14 days. Gross necropsy was performed on all animals.
2.4. Acute dermal toxicity
Ten healthy young adult SD rats (810 weeks old) were used in this test. Individual doses of the Meratrim were calculated based on the initial body weights
obtained prior to dosing at 2000 mg/kg of body weight (bw). On the day prior to
application, the hair was removed by clipping the dorsal area and the trunk. After
clipping and prior to application, the animals were examined for health, weighed
(initial) and the skin checked for any abnormalities. Meratrim was moistened with
distilled water to achieve a dry paste by preparing a 50% w/w mixture. Meratrim
(2000 mg/kg bw) was then applied to a 2 in 3 in, 4-ply gauze pad and placed on
the dorsal area of the animal (approximately 10% of the body surface). The gauze
pad and the entire trunk of each animal were wrapped with 3-inch Durapore tape
to avoid dislocation of the pad and to minimize loss of the test substance. The rats
were then returned to their designated cages. The day of application was considered day 0 of the study. After 24 h of exposure to the test substance, the pads were
removed and the test sites were gently cleansed of any residual test substance.
The body weight of each animal was recorded prior to test substance application and again on days 7 and 14. Animals were observed for mortality, signs of gross
toxicity, and behavioral changes for several hours after application and at least once
daily for 14 days. Observations included evaluation of skin and fur, eyes and mucous
membranes, respiratory, circulatory, plus autonomic and central nervous systems,
somatomotor activity, and behavior. Attention was paid to the occurrence of tremors,
convulsions, salivation, diarrhea and coma. Rats were euthanized using anesthetic
ether on day 14. Gross necropsies were performed on all animals. Tissues and organs
of the thoracic and abdominal cavities were examined.
2.5. Primary dermal irritation study in rabbits
Three New Zealand albino young adult rabbits (two male and one nulliparous,
non-pregnant female) were obtained from the animal facility at the Laila Impex R&D
Centre for this test.

123

The route of Meratrim administration was through a direct application of test

substance to clipped intact skin. On the day before application, hair was removed
by clipping the dorsal and the trunk area. On the day of dosing, but prior to application, the animals were examined for health and the skin abnormalities. No preexisting skin irritations were observed. To apply material, 500 mg of the test substance
was moistened with water then applied to a small area of the clipped skin (approximately 6 cm2) and covered with a gauze patch. The patch was loosely held in contact
with the skin by means of a suitable semi-occlusive dressing for the duration of the
exposure period. Access by the animal to the patch and ingestion or inhalation of
Meratrim was prevented.
Individual dose sites were scored according to the Draize scoring system (Draize,
1944) at approximately 1, 24, 48, and 72 h after removal of Meratrim patch. The classication of irritancy was obtained by adding the average erythema and edema scores
for 1, 24, 48, and 72 h scoring intervals and dividing by the number of evaluation
intervals. The resulting Primary Dermal Irritation Index (PDII) was classied according to the descriptive rating (Sreejayan et al., 2010). Animals were also observed
for signs of gross toxicity and behavioral changes at least once daily during the test
period. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor
activity and behavior pattern. Occurrence of tremors, convulsions, salivation, diarrhea, and coma was closely monitored.
2.6. Primary eye irritation study in rabbits
Three healthy young adult New Zealand albino (2 male and 1 nulliparous, nonpregnant female) rabbits, without pre-existing ocular irritation, were selected from
the animal facility of Laila Impex R&D Centre for this study.
The route of Meratrim administration was direct conjunctival instillation, standard for assessment of local ocular irritative potential. Prior to instillation, both eyes
of each animal were examined for gross abnormalities according to the Draize scale
for scoring eye lesions (Draize, 1944; Sreejayan et al., 2010). Meratrim was used after
thorough grinding using mortar and pestle. Meratrim (100 mg) was instilled into
the conjunctival sac of the right (test) eye of each rabbit by gently pulling the lower
lid away from the eyeball. The upper and lower lids were then gently held together for about few seconds before releasing to minimize loss of the test material. The
left (control) eye of each animal remained untreated.
Following treatment, ocular irritation was evaluated macroscopically using a highintensity white light (Maglite, Ontario, CA) in accordance with Draize (1944) at 1,
24, 48, and 72 h and daily from 4 to 10 days post-instillation. Individual eye irritation scores were recorded for each animal. Classication of eye irritation scores for
all rabbits was determined at each time point with the maximum mean total score
(MMTS) by the descriptive primary eye irritation scores system of Kay and Calandra
(1962). Ocular lesions were scored according to the Draize scale for scoring eye lesions
(Draize, 1944). The average score for all rabbits at each scoring period was calculated to aid in data interpretation. The rabbits were also observed at least once daily
for signs of gross toxicity and behavioral changes during the test period. Observations included gross evaluation of skin and fur, eyes and mucous membranes,
respiratory, circulatory, plus autonomic and central nervous systems, somatomotor
activity, and changes in behavior patterns. Occurrence of tremors, convulsions, salivation, diarrhea and coma was closely monitored.
2.7. Bacterial reverse mutation assay
The Salmonella typhimurium reverse mutation test was conducted to determine Meratrims potential to induce reverse mutation at selected histidine loci in
ve tester strains of S. typhimurium viz. TA 98, TA 100, TA 102, TA 1535 and TA 1537
(Xenometrix GmbH, Allschwil, Switzerland) in the presence and absence of metabolic activation system (Ames et al., 1975; Maron and Ames, 1983). Suspensions of
bacterial cells were exposed to Meratrim in triplicate at concentrations of 313, 625,
1250, 2500 and 5000 g/plate. The suspensions were mixed with an overlay agar
and plated immediately onto minimal medium. After 48 h incubation at 37 2 C,
revertant colonies were counted manually and compared to the number of spontaneous revertant colonies on vehicle and control plates.
2.8. Mammalian erythrocyte micronucleus test
Thirty male and thirty female healthy young (812 weeks old) Swiss albino mice
from the animal facility of Shriram Institute for Industrial Research (Delhi, India)
were randomized into three groups (n = 20/group; 10/sex). After randomization, the
animals were housed in polypropylene cages with each cage containing ve animals
per sex per group. Corn oil was used as the vehicle for oral gavage of Meratrim. Oral
administration was chosen as it is the recommended route for human
supplementation.
After acclimation, mice were orally administered either corn oil (negative group),
Meratrim (test group) at 2000 mg/kg bw (20% corn oil suspension), or cyclophosphamide (positive control) at 40 mg/kg bw. The animals were sacriced by cervical
dislocation at 24 (n = 10/group; 5/sex) and 48 (n = 10/group; 5/sex) hours after dose
administration. Two hundred erythrocytes in the bone marrow cells of each animal
were used to score the total number of mature and immature erythrocytes. The
number of micronuclei per 2000 immature erythrocytes was also recorded. The

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Z.M. Saiyed et al./Food and Chemical Toxicology 78 (2015) 122129

number of immature erythrocytes and mature erythrocytes, percent of immature

erythrocytes, and the number of micronuclei in immature erythrocytes were all analyzed by ANOVA. A p-value <0.05 was considered statistically signicant.
2.9. Mammalian chromosomal aberration test
The in vitro chromosome aberration test was conducted in cultured mammalian cells. Whole blood samples from healthy human subjects were collected in
heparinized vials. Within 4 h of sample collection, lymphocytes were cultured by
adding 0.5 mL of blood in 5 mL of RPMI 1640 medium supplemented with 20% fetal
calf serum and 0.1 mL of phytohemagglutinin. Meratrim was tested at three dose
levels (1000, 2500 and 5000 g/mL) in 1% DMSO, with and without metabolic activation. Ten percent readymade S9 fraction (Krishgen Biosystems, Mumbai, India)
was used for metabolic activation. Cyclophosphamide (20 g/mL) was used as a positive control for cultures treated with metabolic activation system while mitomycin
(0.2 g/mL) was used as a positive control for cultures treated without metabolic
activation. Cultures treated with 1% DMSO served as a negative control. Colchicine
at a concentration of 0.5 g/mL was added to the cultures 2 h prior to harvesting.
Lymphocytes were harvested at 18 h (1 cell cycles) post treatment with Meratrim
for assessment of chromosomal aberrations. Metaphase preparations were stained
with Geimsa and aberrations were classied and scored microscopically. Differences in the frequencies of structural chromosomal aberrations and mitotic indices
among the treatment groups were assessed using ANOVA. A p-value <0.05 was considered statistically signicant.

on the 17th week of the study for both recovery groups. During the examination,
each animal was observed in random order, without the observer having knowledge of the treatment group. Home cage, handling and open eld observations were
recorded for each rat. Sensory, neuromuscular and physiological observations were
recorded.
2.10.5. Clinical pathology
Blood samples were collected from 10 rats of each sex from the low, medium
and high dose groups on days 15, 45 and 91 of treatment. The animals were fasted
overnight (about 14 h) before blood collection. Blood samples were collected from
each animal into tubes containing K2-EDTA or lithium heparin for hematology and
clinical chemistry. Urine was harvested for urinalysis.
2.10.6. Gross necropsy and histology
At day 91, all animals except recovery groups were fasted overnight (about 14 h)
then weighed the next day and subjected to full necropsy. Animals were euthanized by CO2 asphyxiation followed by exsanguination. Gross pathological changes
were recorded for each rat. Necropsy included external surfaces, external orices,
abdominal, thoracic and cranial cavities, organs, and tissues. The organs were weighed
wet then preserved in 10% v/v neutral buffered formalin. Histological examination
was performed on the preserved organs and tissues for both the control and the high
dose groups. Lesions, organs and tissues were xed in 10% neutral buffered formalin, embedded in paran that was sliced 45 m thick and stained with hematoxylineosin. Bone marrow smears were xed in methanol and stained with Giemsa stain.

2.10. 13-week repeated dose oral toxicity study in rats with 4-week recovery period
Two hundred healthy young (56 weeks old) SD rats (100 males and 100 females)
obtained from Bioneeds were acclimated for a minimum of ve days before they
were randomized into four main groups (n = 40/group; 20/sex) and two recovery
groups (n = 20/group; 10/sex) (Table 1). Groups G1/G1R were orally gavaged with
vehicle (0.5% w/v carboxymethyl cellulose, Sigma Life Science, St. Louis, MO) at 0 mg/
kg/day while Groups G2, G3, and G4 plus G4R received Meratrim at 250, 500 and
1000 mg/kg/day, respectively, for 91 days. The recovery animals in the control (G1R)
and high dose (G4R) groups were observed for additional 4-weeks after the 91 day
dosing period.

2.10.7. Statistics
GraphPad Prism version 5 (GraphPad Software, La Jolla, CA) was used to perform
statistical analyses. One way ANOVA followed by Dunnetts post-hoc tests were used
to analyze the difference among different dosage groups against the control group.
All values are reported as mean S.D. All comparisons were evaluated at the 95%
level of condence with statistical signicance set at p < 0.05.

3. Results
3.1. Acute oral toxicity study

2.10.1. Body weight and body weight gain

Individual body weights were recorded on Day 1 (baseline) and weekly thereafter. Mean weekly body weight gains were calculated for each sex and dose level.
Animals were weighed (fasting body weight) prior to sacrice for calculation of organto-body and organ-to-brain weights.
2.10.2. Food consumption
Food consumption was measured weekly. The net food intake per rat (g/rat/
day) was calculated using the amount of food given minus the weight of left-over
food.
2.10.3. Ophthalmologic evaluation
Ophthalmological examination was performed at pre-test and at the 13th week
for the main test groups (G1 and G4) and on the 17th week for recovery groups (G1R
and G4R).
2.10.4. Neurological and functional examination
Neurological and functional examinations were performed at the pre-test and
the 13th week of the study using the control and the high-dose animal groups, and

Table 1
Dose levels and assignment of animals.
Main groups:
Groups

G1
G2
G3
G4

Dose
(mg/kg/day)

Dose
volume
(mL/kg)

Concentration
(mg/mL)

Number/
group

Number/
sex

Control (0)
Low dose (250)
Mid dose (500)
High dose (1000)

10
10
10
10

0
25
50
100

40
40
40
40

20
20
20
20

Dose
(mg/kg/day)

Dose
volume
(mL/kg)

Concentration
(mg/mL)

Number/
group

Number/
sex

Control (0)
High dose (1000)

10
10

0
100

20
20

10
10

Recovery groups:
Groups

G1R
G4R

G = group; R = recovery.
See Materials and Methods for details.

A single oral dose of Meratrim (5000 mg/kg bw) was administered to female SD rats to assess acute toxicity. All animals survived,
gained normal body weight, appeared to be active and healthy during
the study (data not shown). Clear ocular discharge was observed
in one animal, urogenital staining was observed in one animal. These
events subsided within 24 hours. No other gross toxicities, adverse
pharmacological effects or abnormal behaviors were seen during
the 14 day observation period. No gross abnormalities were noted
for any of the animals at the conclusion of the 14-day observation
period. These results suggest that the acute oral lethal dose 50 (LD50)
of Meratrim is greater than 5000 mg/kg bw for female SD rats.
3.2. Acute dermal toxicity study
A single topical application (2000 mg/kg bw) was used to determine an acute dermal toxicity. All animals survived, gained normal
weight and appeared active and healthy (data not shown). There
were no signs of gross toxicity, dermal irritation, adverse effects or
abnormal behavior. No gross abnormalities were noted during necropsy for any of the animals at the 14-day observation point. We
conclude that the single dose acute dermal LD50 of Meratrim was
found to be greater than 2000 mg/kg body weight in male and female
SD rats.
3.3. Primary dermal irritation study
The primary dermal irritation was determined in rabbits using
a single topical application. No mortality was noted. No toxicologically relevant signs of gross toxicity, adverse pharmacologic effects
or abnormal behavior were observed. No erythema or edema was
found in any of test animals at any time. Under the conditions of
this study, the primary dermal irritation index for Meratrim was
determined as 0.0, thus classifying Meratrim to be non-irritating
to the skin.

Z.M. Saiyed et al./Food and Chemical Toxicology 78 (2015) 122129

Table 2
Incidence of positive effects, severity and reversibility of ocular irritation.
Incidence of positive effectsa

Time
post
instillation
Hours

Days

Corneal
opacity

Iritis

Conjunctivitis

0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0

3
3
3
3
3
1
1
1
1
1
0

1
24
48
72
4
5
6
7
8
9
10

Severity
(MMTS)b

14.00
14.00
12.00
7.33
2.00
0.67
0.67
0.67
0.67
0.67
0.00

Number of animals tested positive (n = 3).

Maximum mean total scores of 3 animals.
See Materials and Methods for details.
a

125

3.6. Mammalian erythrocyte micronucleus test

No signicant change was observed in the number of immature or mature erythrocytes of treated male or female animals at
the dosage level of 2000 mg/kg body weight at 24 or 48 hours compared to negative control animals (data not shown). Additionally,
these same animals did not present with any signs of systemic toxicity or any signicant increase in the number of micronucleated
immature erythrocytes at 24 or 48 hours when compared to negative controls. By contrast, the positive control cyclophosphamide
(40 mg/kg bw) induced a signicant increase in micronuclei frequency. It is concluded that Meratrim, at an oral dose of 2000 mg/
kg bw, is non-mutagenic in the mammalian erythrocyte
micronucleus test.
3.7. Mammalian chromosomal aberration test

Results indicate that Meratrim is non-mutagenic based on the

complete absence of any numerical or structural chromosomal aberration in the cultured lymphocytes (data not shown).

3.4. Primary eye irritation study

A single ocular instillation was used to determine the primary
eye irritation in rabbits. No signs of gross toxicity or adverse effects
were noted. No corneal opacity or iritis was observed in any treated
eye during the study. One hour following test substance instillation, three out of three treated eyes exhibited conjunctival discharge.
The overall incidence and severity of the observed conjunctivitis subsided within 10 days. The highest MMTS observed was 14.00
(observed as early as one hour after instillation), thus classifying
Meratrim as mildly irritating to the eye (Table 2).
3.5. Bacterial reverse mutation assay
No signicant increases in revertant colony numbers of any of
the ve tester strains were observed following treatment with
Meratrim at any concentration level (i.e. 313, 625, 1250, 2500 and
5000 g/plate) either in the presence or absence of metabolic activation (data not shown). There was no tendency of higher mutation
rates with increasing concentrations. The reference mutagens (positive controls), by contrast, showed a typical doseresponse ability
to induce revertant colonies in all ve tester strains in the presence and the absence of metabolic activation. We conclude that
Meratrim is not mutagenic according to the bacterial reverse mutation assay.

3.8. 13-week repeated dose oral gavage toxicity study in rats with
four week recovery period
3.8.1. Body weight and body weight gain
Table 3 summarizes the change in body weight over the study
period. Results showed no treatment related changes in mean body
weight in any of the Meratrim groups compared to the control group
with one exception. There was a statistically signicant (p < 0.05)
decrease in mean body weight on days 29, 36 and 43 in high-dose
male animals (1000 mg/kg/day) compared to the control group. A
trend in lower weights was also noted in male animals for all three
doses between day 50 and day 90. These differences did not achieve
statistical signicance but may be related to treatment with Meratrim
as they appear to demonstrate a doseresponse pattern.
3.8.2. Food consumption
Statistically signicant decreases in feed consumption (weeks
1 and 3) were noted in males supplemented with the highest dose
(1000 mg/kg/day) of Meratrim (12% reduction; data not shown). Similarly, there were decreases in food consumption in low dose
(250 mg/kg/day) and mid dose (500 mg/kg/day) female animals at
week 11 (11% reduction). These variations may be considered inconclusive due to the lack of data justifying a sustained dose or time
dependency.

Table 3
Summary of average weekly body weight.
Days

Group (Male)

Group (Female)

Control

Low-dose

Mid-dose

High-dose

Control

Low-dose

Mid-dose

High-dose

1
8
15
22
29
36
43
50
57
64
71
78
85
91

145.27 8.79
178.08 13.17
199.72 19.53
225.32 20.52
244.37 21.86
261.82 23.01
273.99 24.42
285.44 25.85
295.34 26.90
306.47 28.98
318.77 30.43
322.49 33.36
326.87 38.11
331.94 43.77

144.89 8.82
173.31 15.90
191.72 20.19
214.41 24.60
230.98 26.75
248.54 27.57
262.95 26.84
273.45 28.59
285.43 29.19
297.27 28.65
309.79 29.54
312.52 30.52
316.52 31.67
320.56 32.97

143.76 8.50
173.19 10.70
189.91 14.62
214.42 19.74
233.42 22.51
248.11 25.68
260.60 25.84
272.57 28.78
284.28 29.01
296.47 30.55
308.11 31.46
311.16 32.29
314.50 33.29
317.25 34.80

144.96 7.49
168.81 15.05
187.92 20.14
209.29 22.72
224.62 24.26*
241.16 26.24*
254.38 25.57*
264.90 26.50
277.74 28.03
290.15 27.74
302.51 28.02
307.03 29.78
311.09 31.65
315.18 34.10

134.42 7.87
150.48 6.96
157.97 8.02
169.30 9.00
179.21 10.61
188.85 12.64
197.58 13.30
205.24 13.57
212.13 14.42
217.97 13.71
223.46 13.55
220.42 15.55
218.40 17.78
217.13 19.67

135.20 7.63
148.17 7.04
157.13 11.95
167.98 10.24
178.70 8.70
187.81 9.70
196.52 10.93
203.91 11.59
210.37 11.65
216.11 11.45
221.82 11.24
216.79 14.18
213.88 14.94
211.63 16.91

137.73 6.89
153.58 11.16
162.29 12.32
176.64 16.96
187.30 20.08
198.14 21.99
208.58 22.40
215.65 23.05
221.85 23.72
227.44 23.01
232.19 23.33
232.26 24.07
231.80 24.52
231.23 25.39

133.60 5.96
149.01 8.10
157.28 8.84
170.95 11.69
178.43 15.62
188.99 17.06
197.62 17.33
204.72 16.90
210.94 16.55
217.23 16.47
222.25 16.13
217.84 17.24
214.36 18.78
211.28 20.33

Values are the Mean SD (n = 20).

* Statistically signicant difference from control values (P < 0.05). See Materials and Methods for details.

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Z.M. Saiyed et al./Food and Chemical Toxicology 78 (2015) 122129

Table 4
Summary of mean hematology values at day 91.
Parameter (Units)

Group (Male)

WBC (10 cells/L)

RBC (106 cells/L)
Hemoglobin (g/dL)
Hematocrit (%)
MCV (fL)
MCH (pg)
MCHC (g/dL)
Platelets (103 cells/L)
Clotting time (sec)
Neutrophils (%)
Lymphocytes (%)
Monocytes (%)
Eosinophils (%)
Basophils (%)

Group (Female)

Control

Low-dose

Mid-dose

High-dose

Control

Low-dose

Mid-dose

High-dose

7.76 2.47
8.37 0.66
13.70 1.23
43.54 3.70
52.06 2.62
16.38 0.86
31.48 0.36
605.70 164.99
121.10 3.28
20.77 4.50
72.46 4.80
2.72 1.03
2.93 2.22
0.10 0.05

9.10 1.83
8.33 0.95
13.82 1.71
43.78 5.06
52.55 1.32
16.59 0.40
31.55 0.28
612.20 104.29
125.20 3.22*
17.68 2.62
75.91 3.37
2.65 1.09
2.40 1.23
0.11 0.03

9.53 1.69
8.10 0.65
13.26 0.80
42.86 2.97
53.04 2.59
16.38 0.69
30.90 0.71
639.50 114.33
124.00 2.98
17.07 4.16
78.72 5.52*
2.20 1.23
1.13 0.63
0.10 0.07

8.95 3.20
7.99 0.67
13.33 1.05
43.12 4.61
54.00 3.85
16.70 0.80
31.01 1.02
668.20 142.89
124.70 2.58*
17.81 3.60
76.07 6.56
3.01 2.04
2.23 1.78
0.10 0.05

6.05 1.19
7.65 0.70
12.83 1.03
41.62 3.36
54.47 1.88
16.79 0.59
30.85 0.87
658.80 99.58
124.10 3.14
21.20 3.20
72.48 3.65
2.97 0.35
2.49 1.77
0.10 0.05

6.62 0.96
6.90 0.48
11.98 0.75
39.34 2.26
57.08 2.53
17.37 0.74
30.49 1.13
649.30 160.28
124.30 2.45
22.05 5.57
72.03 6.53
2.95 0.97
1.99 1.95
0.08 0.04

6.73 2.07
7.20 0.78
12.51 1.44
40.55 3.88
56.46 2.48
17.39 0.54
30.82 1.23
682.90 90.83
124.60 1.84
17.62 8.16
75.99 9.99
2.71 1.42
2.82 2.87
0.10 0.05

6.01 1.52
7.00 0.77
12.22 1.13
39.20 3.49
56.26 3.49
17.52 1.03
31.18 1.21
689.30 125.99
124.80 2.90
20.52 4.68
72.95 5.73
3.11 1.07
2.49 1.40
0.11 0.07

Values are the Mean SD (n = 10).

* Statistically signicant difference from control values (P < 0.05).
Abbreviations: WBC = White Blood Cells; RBC = Red Blood Cells; MCV = Mean Corpuscular Volume; MCH = Mean Corpuscular Hemoglobin; MCHC = Mean Corpuscular Hemoglobin Concentration.

3.8.3. Ophthalmologic evaluation

No changes were observed in any aspect of the eyes either at
the start or end of the study at any of the doses of Meratrim tested
(data not shown). We conclude that Meratrim is not an ocular
toxicant.
3.8.4. Neurological and functional observation
No toxicologically signicant treatment related changes were observed in neurological or functional examination at any of the doses
tested during experimental period. However, statistically signicant decrease in excessive grooming in high-dose male animals and
increase in body temperature in high-dose female animals were
noted. These observations were not found in recovery groups. Hence
these changes were considered to be incidental.

3.8.5. Clinical pathology and observation

3.8.5.1. Hematology. The following sporadic but statistically signicant hematological changes were found in males: (1) increase
in platelet count (Day 15: mid dose); (2) clotting time (Day 91: low
dose and high dose, Table 4); and (3) lymphocyte % (Day 91: mid
dose, Table 4). In females, a statistically signicant increase in MCHC
(Day 45: high dose) was noted. These changes do not appear to be
related to the treatment since they were not dose dependent.
3.8.5.2. Clinical chemistry. Clinical chemistry parameters revealed
normal values except a few sporadic changes at various time points.
In the male cohort, a slight but statistically signicant drop in ALP
and ALT enzyme levels were observed on day 91 in high dose group
(Table 5). However, these values are within the normal range of SD

Table 5
Mean clinical biochemistry values at day 91.
Parameter
(Units)

Group (Male)
Control

Low-dose

Mid-dose

High-dose

Control

Group (Female)
Low-dose

Mid-dose

High-dose

AST (IU/L)
ALT (IU/L)
ALP (U/L)
GGT (U/L)
BILT (mg/dL)
BUN (mg/dL)
CREA (mg/dL)
CHE (U/L)
GLDH (U/L)
TPR (g/dL)
CHOL (mg/dL)
TRIG (mg/dL)
GLUC (mg/dL)
ALB (g/dL)
GLOB (g/dL)
CALC (mg/dL)
PHOS (mg/dL)
Na (mmol/L)
K (mmol/L)
CHL (mmol/L)

115.00 21.10
46.40 10.80
262.80 76.30
2.15 2.07
0.10 0.07
21.50 4.93
0.76 0.10
412.90 151.00
7.73 2.79
6.68 0.68
62.60 13.01
103.20 22.66
103.10 10.99
3.50 0.37
3.18 0.93
8.78 0.39
5.49 1.58
138.28 4.36
3.85 0.42
111.30 3.62

110.80 14.15
47.90 8.74
255.70 88.88
2.13 2.11
0.15 0.13
19.30 2.11
0.76 0.05
410.00 142.01
9.71 3.78
6.98 0.71
63.30 12.90
89.50 28.59
91.70 10.97
3.42 0.18
3.56 0.72
8.72 0.52
5.01 0.73
138.16 1.69
3.80 0.29
111.80 1.81

121.90 20.06
48.20 5.59
231.40 65.82
1.26 0.92
0.13 0.08
19.10 2.18
0.73 0.05
352.20 82.31
8.98 1.93
6.96 0.61
60.10 11.71
87.80 23.06
92.20 12.42
3.50 0.24
3.46 0.76
8.63 0.37
6.12 1.43
138.41 1.08
4.01 0.63
112.10 2.18

108.80 17.62
36.20 7.44*
177.10 20.67*
2.39 1.88
0.17 0.11
20.10 2.42
0.76 0.07
295.20 111.07
8.47 2.22
6.96 0.56
65.90 14.49
94.70 21.27
104.40 23.49
3.57 0.29
3.39 0.65
8.74 0.39
5.09 0.86
139.73 2.22
3.78 0.25
112.70 2.54

123.40 11.39
40.10 6.57
189.40 49.94
1.76 0.97
0.14 0.08
23.40 5.58
0.82 0.06
632.50 121.92
10.57 3.24
6.87 0.96
64.10 12.38
74.10 21.39
113.30 20.63
3.74 0.17
3.13 1.03
8.79 0.66
3.86 1.09
138.55 2.41
3.55 0.22
113.60 2.59

132.20 20.15
41.20 9.03
158.00 28.98
1.31 0.92
0.17 0.09
23.10 2.38
0.80 0.08
631.70 140.11
10.40 3.85
7.21 0.75
70.90 10.13
73.30 12.71
95.60 16.53
3.74 0.21
3.47 0.69
8.63 0.44
4.42 1.48
139.85 1.97
3.64 0.22
114.50 2.17

117.80 12.81
41.00 11.87
187.20 58.58
1.44 1.57
0.18 0.09
24.40 2.72
0.80 0.07
642.80 93.21
10.16 1.48
7.54 0.92
75.00 13.53
80.30 19.93
102.70 19.30
3.72 0.25
3.82 0.96
8.47 0.68
4.48 1.72
141.53 1.27*
3.85 0.36
114.40 3.44

137.40 18.35
45.00 8.06
200.70 65.78
1.35 0.96
0.12 0.09
25.80 3.22
0.79 0.065
632.40 115.06
11.48 2.14
6.86 1.01
73.40 9.61
83.00 25.76
101.10 28.66
3.70 0.41
3.16 0.92
8.50 1.21
4.17 1.03
141.18 1.72*
3.74 0.41
115.50 2.42

Values are the Mean SD (n = 10).

* Statistically signicant difference from control values (P < 0.05).
Abbreviations: AST = Aspartate Aminotransferase; ALT = Alanine Aminotransferase; ALP = Alkaline Phosphatase; GGT = Gamma-Glutamyl Transferase; BILT = Total Bilirubin;
BUN = Blood Urea Nitrogen; CREA = Creatinine; CHE = Cholinesterase; GLDH = Glutamate Dehydrogenase; TPR = Total Protein; CHOL = Cholesterol; TRIG = Triglycerides;
GLUC = Glucose; ALB = Albumin; GLOB = Globulin; CALC = Calcium; PHOS = Phosphorus; NA = Sodium; K = Potassium; CHL = Chloride.

Z.M. Saiyed et al./Food and Chemical Toxicology 78 (2015) 122129

127

Table 6
Mean urine analysis values at day 91.
Parameter (Units)

Volume (mL)
Specic Gravity (SG)
pH
Urobilinogen (EU/dL)

Group (Male)

Group (Female)

Control

Low-dose

Mid-dose

High-dose

Control

Low-dose

Mid-dose

High-dose

6.0 3.3
1.021 0.008
7.5 1.2
0.4 0.4

6.2 4.6
1.026 0.006
7.0 1.0
0.3 0.3

5.3 3.5
1.023 0.008
7.2 1.1
0.7 0.6

5.8 4.0
1.024 0.006
7.2 1.0
0.4 0.4

6.0 4.7
1.024 0.010
7.2 1.2
0.4 0.4

5.5 4.0
1.019 0.008
7.3 0.9
0.3 0.3

5.4 3.7
1.020 0.007
7.3 0.8
0.4 0.3

5.1 3.6
1.021 0.009
7.5 1.1
0.5 0.4

Values are the Mean SD (n = 10). No signicant difference from control values.

rats at similar age point. Such change in ALP and ALT was not observed in low dose, mid dose and recovery groups. Other statistically
signicant changes observed in clinical chemistry of the male cohort
(data not shown) are: (1) an increase in glucose (day 45, mid and
high dose); (2) an increase in sodium (day 45, high dose); and (3)
a decrease in creatinine (day 45, low dose). However these changes
were transient and not observed on day 91 evaluation.
In the female cohort, a statistically signicant increase in sodium
(day 91, mid and high dose) was observed (Table 5). The slight
hypernatremia noted is correlated with a slight reduction in urine
output that was not statistically signicant (Table 6). These changes,
like those seen in the male cohort, may be sporadic by nature. Other
statistically signicant changes observed in the female cohort (data
not shown) during this study included: (1) a decrease in AST (day
15, low, mid and high dose); (2) an increase in total bilirubin (day
45, low dose), and (3) a decrease in ALT (day 15, mid dose). However
these changes were transient and not observed on day 91.
None of the changes noted above for both cohorts were either
treatment duration dependent or dose-dependent, and no microscopic or gross pathological changes were noted in any organ or
tissue. Hence the above mentioned changes noted in clinical chemistry parameters were considered not related to the treatment. Other
than the slight reduction in female urine output at day 91, there
were no further changes in the urinalysis data (Table 6).
3.8.5.3. Absolute and relative organ weight. At study conclusion, the
absolute and relative organ weights (Table 7) at each dose level were
not signicantly different from the control group with the following sporadic, but statistically signicant, exceptions: (1) the absolute
thymus weights were reduced in the low-dose male and female
animals; (2) the absolute thyroidparathyroid weights were lower
in the mid-dose male animals but higher in the low-dose and middose female animals; (3) the relative thymus weight ratios were
reduced in the low-dose female animals, whereas the relative
thyroidparathyroid weight ratios were higher in the

low-dose female cohort (Table 8). Since these changes were not dosedependent they were considered incidental and not related to
supplementation.
3.8.6. Recovery group
No treatment related changes were noted at pre-test and on the
17th week (day 119) for recovery group animals (data not shown).
The statistically signicant exceptions for the G4R, high dose group
include; (1) an increase in chloride (1.7%, male and female); (2) a
sodium increase (2.0%, female); (3) a decrease in glutamate dehydrogenase (23%, male), and (4) a decrease in urinary pH coupled
with an increase in specic gravity in the female G4R cohort. The
above observations were considered not related to treatment for
the following two reasons: (1) they were not observed in main group
animals including those treated with up to 1000 mg/kg/day of
Meratrim; (2) the resulting values for all these biochemical markers
fell within the normal range of the main group controls. We therefore conclude that Meratrim treatment over a 91 day period does
not result in any toxicologically relevant effects.
3.8.7. No-observable-adverse-effect-level (NOAEL)
Daily administration of Meratrim by oral gavage at dose levels
up to 1000 mg/kg/day for 13-weeks did not produce any toxicologically signicant adverse effects. Based on clinical and
histopathological evaluations, and under the conditions of this study,
a dose level of 1000 mg/kg/day was identied as the NOAEL.
4. Discussion
The main goal of the current study was to demonstrate the broadspectrum safety of Meratrim when ingested orally. Acute oral toxicity
studies did not reveal any signicant changes for all examined tissues.
Based on these results and under the conditions of this study, the
oral LD50 of Meratrim was concluded to be >5000 mg/kg in female
rats. In the acute dermal toxicity study, there were no signs of dermal

Table 7
Summary of absolute mean organ weight (g) after 91 days of supplementation.
Organ

Epididymides
PSC
Testes
Adrenals
Brain
Heart
Kidneys
Liver
Spleen
Thymus
ThyroidParathyroid
Ovaries
Uterus

Group (Male)

Group (Female)

Control

Low-dose

Mid-dose

High-dose

Control

Low-dose

Mid-dose

High-dose

1.17 0.13
2.40 0.74
3.19 0.42
0.041 0.009
1.95 0.10
1.05 0.13
2.68 0.44
10.08 1.27
1.06 0.25
0.32 0.11
0.036 0.008

1.12 0.11
2.48 0.61
3.12 0.43
0.043 0.007
1.90 0.13
1.02 0.12
2.52 0.47
9.77 1.17
1.07 0.26
0.25 0.09*
0.036 0.006

1.24 0.14
2.38 0.41
3.17 0.38
0.044 0.007
1.93 0.10
0.99 0.24
2.52 0.24
9.78 1.12
1.15 0.35
0.31 0.07
0.030 0.005*

1.17 0.08
2.35 0.38
3.20 0.32
0.043 0.007
1.93 0.11
1.04 0.14
2.51 0.32
10.19 1.43
1.01 0.23
0.32 0.07
0.033 0.007

0.072 0.056
1.96 0.37
0.79 0.09
1.68 0.28
6.82 0.72
0.90 0.21
0.30 0.05
0.028 0.004
0.11 0.03
0.61 0.37

0.061 0.011
1.94 0.45
0.77 0.08
1.77 0.31
7.05 0.94
0.91 0.17
0.24 0.07*
0.032 0.006*
0.11 0.10
0.55 0.20

0.063 0.011
1.92 0.31
0.83 0.13
1.76 0.28
7.29 0.93
0.85 0.20
0.32 0.08
0.032 0.007*
0.11 0.03
0.58 0.24

0.059 0.011
1.93 0.42
0.76 0.08
1.61 0.22
6.94 0.81
0.92 0.23
0.27 0.06
0.028 0.006
0.14 0.13
0.51 0.24

Values are the Mean SD (n = 20 per group).

* Statistically signicant from control value (P < 0.05).
PSC = Prostate and Seminal vesicles with Coagulation.

128

Z.M. Saiyed et al./Food and Chemical Toxicology 78 (2015) 122129

Table 8
Summary of mean relative organ weight (organ-to-body weight ratio) after 91 days of supplementation.
Organ

Epididymides
PSC
Testes
Adrenals
Brain
Heart
Kidneys
Liver
Spleen
Thymus
ThyroidParathyroid
Ovaries
Uterus

Group (Male)

Group (Female)

Control

Low-dose

Mid-dose

High-dose

Control

Low-dose

Mid-dose

High-dose

0.38 0.07
0.77 0.26
1.02 0.20
0.013 0.003
0.63 0.10
0.34 0.06
0.86 0.16
3.22 0.54
0.34 0.10
0.10 0.04
0.012 0.003

0.36 0.04
0.81 0.21
1.01 0.15
0.014 0.002
0.62 0.08
0.33 0.05
0.81 0.12
3.16 0.39
0.35 0.09
0.08 0.03
0.012 0.003

0.42 0.06
0.80 0.16
1.06 0.13
0.015 0.003
0.65 0.07
0.33 0.07
0.84 0.10
3.26 0.35
0.39 0.13
0.10 0.03
0.010 0.002

0.39 0.04
0.78 0.12
1.07 0.12
0.014 0.003
0.65 0.06
0.35 0.03
0.84 0.09
3.39 0.29
0.34 0.07
0.11 0.02
0.011 0.002

0.036 0.03
0.98 0.24
0.39 0.04
0.83 0.15
3.38 0.30
0.45 0.11
0.15 0.03
0.014 0.002
0.052 0.013
0.30 0.18

0.031 0.005
1.00 0.26
0.39 0.04
0.90 0.15
3.58 0.44
0.46 0.08
0.12 0.03*
0.016 0.003*
0.055 0.051
0.28 0.10

0.029 0.006
0.91 0.24
0.38 0.05
0.82 0.12
3.39 0.42
0.40 0.09
0.15 0.04
0.015 0.003
0.050 0.015
0.27 0.11

0.030 0.005
0.99 0.23
0.39 0.05
0.82 0.11
3.54 0.43
0.47 0.13
0.14 0.03
0.015 0.003
0.069 0.061
0.26 0.11

Values are the Mean SD (n = 20 per group).

* Statistically signicant difference from control value (P < 0.05).
PSC = Prostate and Seminal vesicles with Coagulation.

irritation, adverse pharmacological effects or abnormal behavior.

Based on these results, the acute dermal LD50 of Meratrim was determined to be >2000 mg/kg. The primary dermal irritation assay
using a single 500 mg dose of Meratrim applied directly to the skin
of rabbits for four hours did not cause any dermal irritation, thereby
allowing Meratrim to be classied as non-irritating to the skin. In
the primary eye irritation study, one hour after Meratrim instillation, treated eyes exhibited conjunctival discharge. The overall
incidence and severity decreased with time and became zero on day
10. Based on these results, Meratrim was classied as mildly irritating to the eye.
In the Ames Bacterial Reverse Mutation Assay conducted using
ve strains of S. typhimurium TA 98, TA 100, TA102, TA 1535, and
TA 1537, Meratrim was determined to be non-mutagenic. Similarly, Meratrim was concluded to be non-mutagenic in the mammalian
erythrocyte micronucleus test. The mammalian chromosomal aberration tests showed no evidence of numerical or structural
aberrations further classifying Meratrim as non-mutagenic.
The results from the 13-week sub-chronic oral toxicity study with
4-week recovery period did not show any dose or time dependent
adverse effects in test animals. Absence of toxicologically relevant
changes in body weight, percent change in body weight, feed consumption, ophthalmoscopic examination, neurological-functional
examination, hematology, clinical chemistry, urine analysis and organ
weight (both absolute and relative) were noted up to 1000 mg/kg/
day of Meratrim. Therefore, under the conditions of this study, the
NOAEL for male and female SD rats was considered to be
1000 mg/kg/day.
To the best of our knowledge, this is the rst report that supports the safety of S. indicus ower head extract (albeit in
combination with G. mangostana fruit rind) through systematic in
vitro and in vivo toxicological evaluations. On the other hand, multiple G. mangostana pericarp extracts have been the subject of
multiple safety investigations. Hutadilok-Towatana and coworkers
(Hutadilok-Towatana et al., 2010) reported that intragastric administration of a hydroalcoholic extract of mangosteen pericarp, at doses
up to 1200 mg/kg body weight/day in rats for 12 weeks, produced
no relevant toxicological effects. In a chronic toxicity study in rats,
an ethanolic extract of mangosteen pericarp, given orally at doses
of 10 to 1000 mg/kg for 6-months, showed no overt pharmacotoxicity
or abnormal hematological effects (Chivapat et al., 2011). However,
animals receiving doses of 500 mg/kg/day onward showed reduction in body weight and alterations in select blood biomarkers
including alanine transaminase, blood urea nitrogen and creatinine (Chivapat et al., 2011). In a report by Wong and Klemmer (2008),

a case of severe lactic acidosis was putatively attributed to the use

of mangosteen juice. However, because this study fails to provide
specics on the quantity or quality of the mangosteen juice consumed per day, it is uncertain if a cause-and-effect relationship can
be established (Wong and Klemmer, 2008). In the case of Meratrim,
a daily dose of 800 mg (~90 mg G. mangostana extract) has been clinically tested and shown to be well-tolerated (Stern et al., 2013a,
2013b). Taking the 13-week oral toxicity study NOAEL into account,
the margin of safety for Meratrim is estimated to be 75-fold.
To conclude, the results presented herein, when combined with
tolerability in the human trials (Stern et al., 2013a, 2013b), demonstrate the broad-spectrum safety of Meratrim.
Conict of interest
Dr. Lau was a past employee of InterHealth Nutraceuticals Inc.
Drs. Sengupta, Krishnaraju and Trimurtulu are employees of Laila
Nutraceuticals and have pending patents led. Drs. Saiyed and Lugo
are employees of InterHealth Nutraceuticals Inc.
Transparency document
The Transparency document associated with this article can be
found in the online version.
Acknowledgements
We thank Weiman Xu, Ph.D. for her helpful comments and for
her extensive support in the preparation of this manuscript.
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