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5 AUTHORS, INCLUDING:
Harish Chander Dutt
Surjeet Singh
Department of Botany
10 PUBLICATIONS 8 CITATIONS
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Bharathi Avula
University of Mississippi
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ABSTRACT Caralluma fimbriata extract has received Generally Recognized As Safe (GRAS) status for use as a nutraceutical to combat the most serious public health concern (i.e., obesity). More than 260 species grouped under the genus
Caralluma (Family Apocynaceae) are distributed in tropical Asia and Mediterranean regions of the globe. Ethnobotanically,
some species have been used as traditional and modern dietary ingredients to suppress appetite. Many species of Caralluma
are commonly used as traditional medicine for the treatment of rheumatism, diabetes, leprosy, paralysis, and inflammation and
have antimalarial, antitrypanosomal, anti-ulcer, antioxidant, antinociceptive, and antiproliferative activities. The genus is
known for compounds like pregnane glycosides, flavonoid glycoside, flavones, magastigmane glycosides, pregnane steroids,
steroidal glycosides, saturated and unsaturated hydrocarbons, aromatic and nonaromatic volatile compounds, and b-sitosterol.
An extract of C. fimbriata (Slimaluna, Gencor Nutrients, Anaheim, CA, USA) is used as an anti-obesity agent and appetite
suppressor. It is also seen that the pregnane glycosides isolated and identified from African Hoodia are reported as anti-obesity
and appetite-suppressant compounds. On reviewing the studies undertaken on the chemistry, pharmacology, and therapeutic
potential of Caralluma, it is concluded that the genus is also composed of pregnane glycosides as one of the major constituents. Availability of pregnane glycosides in Caralluma is an indication of the appetite-suppressant property of this genus.
This coupled with the GRAS status of the extract of C. fimbriata has opened the possibility of developing an anti-obesity/
appetite-suppressant product from other species of Caralluma. The main objective of this article is to review the studies
undertaken on the plant in light of further research for anti-obesity drugs and nutraceuticals from species of Caralluma.
KEY WORDS: anti-obesity appetite suppressor Caralluma Indian Hoodia pregnane glycoside
INTRODUCTION
108
109
ETHNOBOTANY
110
DUTT ET AL.
stalagmoside-V isolated from C. stalagmifera.41,43 In addition to flavonoid glycoside (luteolin neohesperidoside), the
whole plant of C. lasiantha also possesses two bisdesmosidic C-21 steroidal glycosides.44 Two novel bisdesmosidic
steroidal glycosides have also been isolated from Caralluma
indica.43 Moreover, five more steroidal glycosides have
been isolated and characterized from C. stalagmifera.43
Pregnane ester aglycones have been isolated by acidic hydrolysis of a fraction obtained from the alcoholic extract of
FIG. 2.
the aerial parts of Caralluma retrospiciens.45 Six polyoxypregnane glycosides have been isolated and characterized from leaves of C. retrospiciens.46 C. tuberculata is
characterized by the presence of boucerin, dihydroboucerin,
and caratubersides (Fig. 2).4750 Pregnane glycosides like
carumbellosides IVI and pregnane steroids including
bourcergenin, caraumbellogenin, and umbellosides IIV
have been isolated from the whole plant of Caralluma umbellata.42,5155
111
randomized clinical trial on C. fimbriata extract (Slimaluna); during the clinical trial the subjects were tested for
changes in key indicatorsnamely, weight loss, including
anthropometry, body fat composition, body mass index, net
weight, and systemic functions.20 However, based on a
safety study, the extract of C. fimbriata, was assigned
Generally Recognized As Safe (GRAS) status on June 30,
2006, which has allowed the nutraceutical industry to start
developing products with Slimaluna.76,77 The mechanism of
action for weight reduction and safety of C. fimbriata has
been reviewed and found to be similar to mechanisms proposed for Garcinia cambogia except for its direct effect on
the hypothalamus.78 The mechanism of action of G. cambogia has proven to be safe for those desiring to lose
weight.79 In addition, clues to how C. fimbriata works to
reduce weight may come from our knowledge of G. cambogia. The active component in G. cambogia is hydroxycitrate, which has been reported to cause weight loss in
humans without stimulating the central nervous system.78
Because it is a competitive inhibitor of ATP-citrate lyase, an
extramitochondrial enzyme is involved in the initial steps of
de novo lipogenesis.78 Consequently, hydroxycitrate reduces the transformation of citrate into acetyl-coenzyme A,
a step necessary for the formation of fatty acids in the liver.
It is believed that the pregnane glycoside blocks the activity
of citrate lyase enzyme, thereby inhibiting fatty acid biosynthesis. Furthermore, it also blocks formation of malonylcoenzyme A, thereby encouraging stored fatty acid oxidation (Fig. 3). Therefore, this is more effective than other
such compounds that block the fat biosynthesis at one step
PHARMACOLOGY
Caralluma species have been used for centuries in semiarid areas of Pakistan as an emergency food, and these
species are also known for their antihyperglycemic activity.
In this context, C. edulis has been evaluated for its antidiabetic properties.7375 The medicinal properties of Caralluma species have been attributed to their glycosides. C.
fimbriata is an edible vegetable in the semi-arid regions of
Western India and is well known as a famine food, appetite
suppressant, and a thirst quencher when its green follicles
are boiled and salted.73 It is surprising that no significant
weight loss was seen in a double-blind, placebo-controlled,
FIG. 3. Schematic diagram showing the effect of pregnane glycosides on the formation of fatty acid. CoA, coenzyme A; iP, inorganic
phosphate; OAA, oxaloacetic acid.
112
C. arabica N.E.Br.
C. attenuata Wight
C. burchardii N.E.Br.
C. dalzielii N.E.Br.
C. flava N.E.Br.
C. indica N.E.Br.
6
7
9
10
11
12
C. adscendens R.Br.
Study number
Antioxidant27
NA
NA
Antioxidant, antidiabetic26,75
b-Sitosterol, hydrocarbons,
fatty acids63
Essential oils65,66
n-Pentatriacontane and other
hydrocarbons5659
Anti-obesity23,24
NA
Antiproliferative36
Antinociceptive, anti-inflammatory,
antigastric ulcer, and cytoprotective
properties8991
Antihyperglycemic, anti-inflammatory,
and antinociceptive28,74,92
NA
NA
NA
Bioactivity
3,4-Secotriterpene60
Steroidal glycosides, pregnane
glycosides36,61,62
Hydrocarbons58,59
Flavonoids19
NA
NA
Ethnobotany
(continued)
NA
Beside use as an appetite suppressant in
India since the Vedic times, it is also
used to treat various conditions such
as diabetes, pain, fever, and
inflammation4
NA
NA
Table 1. Summary of Chemical Constituents, Bioactivity, and Ethnobotanical Uses of Caralluma Species
113
C. penicillata N.E.Br.
C. quadrangula N.E.Br.
C. retrospiciens N.E.Br.
C. stalagmifera C.E.C.Fisch.
C. tuberculata N.E.Br.
C. umbellata Haw.
14
15
16
17
18
20
21
22
19
C. lasiantha N.E.Br.
13
Study number
Carumbellosides, pregnene-type
steroid, bourcergenin,
caraumbellogenin5154
Luteolin neohesperidoside
bisdesmosidic C-21 steroidal
glycoside44
Megastigmane glycosides,
flavones18,21
Pregnane glycosides, penicilloside93
NA
NA
Bioactivity
NA
Antimalarial, antitrypanosomal,
antiplasmodial, hypoglycemic, and
gastric mucosa protective93,94,99101
NA
NA
NA
It is used as a general tonic27
NA
NA
Ethnobotany
Antitrypanosomal, antiplasmodial93,94
Antitrypanosomal, antiplasmodial93,94
NA
NA
Table 1. (Continued)
114
DUTT ET AL.
parable to that of a 100 mg/kg tolbutamide dose.103 C. attenuate contains luteolin-4-O-neohesperidoside with a
significant anti-inflammatory and antinociceptive activity;
similarly, C. umbellata has also been evaluated for
anti-inflammatory and antinociceptive activity (Tables 1
and 3).15,24
Several members of the genus Caralluma have been
found to be medicinally active in the treatment of rheumatism, diabetes, and leprosy and as antiseptics and disinfectants.104 In several pharmacological studies on species of
Caralluma, some of the isolated pregnane glycosides or
their esters showed antitumor activity, and others were
postulated to be precursors of cardenolides.55,105108 Combined treatment with C. tuberculata and cyclophosphamide
showed that the species diminished the effect of cyclophosphamide on DNA levels; however, RNA levels were
further suppressed, resulting in increased cytotoxicity.102
Steroidal glycosides and pregnane glycosides isolated from
C. dalzielii were tested for their antiproliferative activity on
murine monocyte/macrophage cell lines ( J774.A1), human
epithelial kidney cell lines (HEK-293), and murine fibrosarcoma cell lines (WEHI-164) cell lines; moderate to high
potency of cytotoxicity was found in almost all tested
compounds, confirming the significant cytotoxic activity of
pregnane glycosides (Tables 1 and 2).31,43 Antifungal and
anthelmintic activities of C. fimbriata Wall. has also been
studied in detail.109
CONCLUSIONS
The genus Caralluma is composed of about 260 species,
the ethnobotanical properties of some of which have been
described. Caralluma species have been extensively used
for the treatment of various ailments. The phytochemical
analysis revealed that a large number of active compounds
have been isolated from different species of Caralluma. The
pharmacological data summarized in this review reveal that
no work has been conducted on the isolated compounds for
anti-obesity and appetite-inhibitory activities. Only one
drug from C. fimbriata has been released under the trade
name Genaslim for body weight control, but the clinical
trials on the product does not support appetite-suppressant
activity in the extract even though GRAS status has been
given to the extract of C. fimbriata (Slimaluna). Because
only the extract of C. fimbriata is believed to be an antiobesity agent and appetite suppressor and no significant
scientific evidence supports such uses, therefore more research on the active biomolecules within the extract and
other species of this genus is required. Other biological
activities suggest possible leads for researchers to discover
herbal or galenic remedies with bona fide effects, but most
of the evidence remains suggestive but not conclusive so
further phytochemical and pharmacological research is
needed. Additional interventions are needed to address the
most serious public health concerns (i.e., obesity and diabetes) prevailing in developed and developing countries;
therefore plants in the genus Caralluma should be further
evaluated for their safety and efficacy. Several other
115
0.0500.71 lM
0.060.95 lM
0.0920.2 lM
J774 AI
HEK-293
WEHI-164 cell lines
NA
NA
NA
0.8
5.0
ND
ND
ND
5.0
ND
ND
ND
22.28
17.75
64.11
19.20
> 100
45.1
18.5
62.6
> 1.56
7.94
6.2
7.0
> 12.5
> 12.5
3.0
5.0
11.0
4.8
7.0
6.2
> 12.5
10.8
6.6
0.005
0.17
0.8
62.6
> 100
ND
> 100
0.25
0.34
< 0.1
57.65
22.28
17.75
64.11
19.20
> 100
ND
ND
ND
> 100
1.4
5.7
> 100
> 100
0.5
3.5
7.07
> 12.5
8.44
9.51
1.01 (1.83)a
6.04 (9.09)a
5.23 (9.03)a
1.85 (3.4)a
5.80
7.19
6.14
6.38
> 12.5
> 12.5
> 12.5
7.03
11 106
11 104
1.58
2.27
Chloroquine-resistant Plasmodium falciparum strain (K1)
and sensitive strain (FCR3) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-sensitive strain of P. falciparum (FCR3) (in vitro)
Drug-sensitive strain of P. falciparum (FCR3) (in vitro)
Drug-sensitive strain of P. falciparum (FCR3) (in vitro)
Drug-sensitive strain of P. falciparum (FCR3) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
Drug-resistant strain of P. falciparum (K1) (in vitro)
62.6
3.5
Cytotoxicity on
MRC5 IC50 (lg/mL)
62.6
Model/mode of
administration
0.5
IC50
(lg/mL)
Antitrypanosomal
Petroleum ether-soluble fraction of methanol
extract of C. tuberculata
Chloroform-soluble fraction of methanol extract
of C. tuberculata
Petroleum ethersoluble fraction of C. tuberculata
CHCl3 extract of C. tuberculata
Penicilloside A
Penicilloside B
Penicilloside C
Penicilloside D
Penicilloside E
Penicilloside F
Penicilloside G
Caratuberside C
Caratuberside D
Caratuberside E
Caratuberside F
Caratuberside G
Russelioside B
Russelioside C
Russelioside D
Russelioside E
Melarsoprol (control)
Pentamidine (control)
Suramine (control)
Effornithine (control)
Antiplasmodial (antimalarial)
Petroleum ether-soluble fraction of methanol
extract of C. tuberculata
Petroleum ether extract of C. tuberculata
Fraction C-2
Fraction C-3
Fraction C-4
Fraction C-5
Fraction C-2
Fraction C-3
Fraction C-4
Fraction C-5
Caratuberside C
Caratuberside D
Caratuberside E
Caratuberside F
Caratuberside G
Artemisinin (control)
Chloroquine (control)
Antiproliferative
Pregnane glycosidesb
Activity, extract/pure
compound
Table 2. Compounds/Extract of Caralluma Showing the Bioactivities (In Vitro), Dose, Model, and Toxicity
36
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
94
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
93,94,100
93,94,100
References
116
27
REFERENCES
27
No toxic effects23,24
NA
C. quadrangula (shole plant)
Anti-inflammatory
Anti-obesity (clinical trial)
Antioxidant (chemical
method; cell-free system)
Antigastric
Antinociceptive
NA
NA
NA
Humans
DPPH assay; phosphomolybdate
assay
DPPH assay; phosphomolybdate
assay
28
DISCLOSURE STATEMENT
NA
LD50 = 5 g/kg
31.5 1.0; 335 0.5
Rats
Mice/rats
Mice
NA
NA
NA
200400 mg/kg
200400 mg/kg
250, 500, 1000 mg/kg
100 mg/kg
NA
Rats
NA
No toxic effects99
91
20
90
92
No toxic effects74
Rats
250 mg/kg
NA
objectives such as genetic engineering for improved synthesis of desired metabolites in the species should be also be
included in future research.
Model
Effective dose
Dose range
Extract/pure compounds
Biological activity
Table 3. Compounds/Extract of Caralluma Showing Bioactivities, Dose Range, Dose, Model, and Toxicity
Toxicity/references
DUTT ET AL.
117
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