Phytomedicine 9: 427–432, 2002

© Urban & Fischer Verlag

http://www.urbanfischer.de/journals/phytomed
Phytomedicine

Phytochemical analysis and analgesic properties

of Curcuma zedoaria grown in Brazil
D. de Fátima Navarro1,2, M. M. de Souza3, R. A. Neto3, V. Golin3, R. Niero3, R. A. Yunes2,
F. Delle Monache4, and V. Cechinel Filho3
1
Departamento de Farmácia, Universidade Estadual de Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil
2
Departamento de Química, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil
3
Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI)/CCS, Itajaí, SC, Brazil
4
Centro Chimica dei Recettori, CNR, Universita Cattolica del Sacro Cuore, Rome, Italy

Summary

The present study describes the phytochemical analysis and analgesic activity of Curcuma zedoaria
rhizomes grown in Brazil. The results showed that the hydroalcoholic extract, fractions, specially
dichloromethane, and a pure compound, denoted as curcumenol (1), exhibited potent and dose-relat-
ed analgesic activity when evaluated in several models of pain in mice, including writhing, formalin
and capsaicin. Compound (1), which seems to be the main active principle from this plant, presented
promising analgesic effects, being several times more potent than different reference drugs evaluated
in the same experimental models. The calculated ID50 values (µmol/kg, i.p) were 22 and 12 when eval-
uated in writhing and capsaicin tests, respectively, and 29 µmol/kg in relation to the second phase of
the formalin model. The lack of effect in the hot plate test suggests that (1) act by a mechanism which
do not involves the participation of the opioid system. The phytochemical analysis indicated that the
chemical composition of the plant grown in Brazil is similar to that grown in other countries. The re-
sults confirm and justify the popular use of this plant for the treatment of dolorous processes.

Key words: Curcuma zedoaria, medicinal plant, analgesia, curcumenol

 Introduction

Rhizomes of Curcuma zedoaria R. Br. (Zingiber-
aceae), known as “zedoaria” or “gajitsu”, are employed
in China and in many other countries, including Brazil,
for the treatment of several ailments, such as cervical
cancer (Ma et al., 1995; Syu et al., 1998), hepatitis, in-
flammations (Tang and Eisenbrand, 1992) and dolor-
ous processes (Ma et al., 1995), among others (Teske
and Trentini, 1995).
Several studies have confirmed and also extended
most of the mentioned popular uses of this plant. In this
context, it was demonstrated its antifungal (Gupta et
al., 1976), antiulcer (Sakai et al., 1989), antimutagenic
(Lee and Lin, 1988), hepatoprotective (Rana and Avad-
hoot, 1992) and cytotoxic (Syu et al., 1998) properties.
It is well-documented that its main active principles are
terpenoids, specially sesquiterpenoids (Hikino et al.,
1968; Shiobara et al., 1985; Ma et al., 1995; Syu et al.,
1998), which also are produced by cultured cells
(Sakui et al., 1992).
However, these studies were focused on C. zedoaria
produced in Asiatic countries and little is known con-
cerning the plant grown in Brazil. Previous study car-

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428 D. de Fátima Navarro et al.
ried out by one of us (DFN) showed that this plant was
effective as supplement to regular control dental plaque
and gingivitis in humans (Sandrini et al., 1997).
In this present series of experiments we have investi-
gated the chemical composition and determined the pos-
sible analgesic properties of the hydroalcoholic extract
and some fractions as well as a sesquiterpene obtained
from rhizomes of C. zedoaria using distincts pharmaco-
logical models in mice. We also have compared the re-
sults with some analgesic drugs used clinically.
Formula: Structure of Curcu-
menol (1).
 Material and methods
Plant material
Cultivated rhizomes of C. zedoaria were collected at In-
dustria Klabin (Telêmaco Borba, Paraná, Brazil) in Jan-
uary 1999. The plant material was authenticated by
Prof. Renê Ferreira (Curso de Farmácia, UNIVALI) and
a voucher specimen was deposited at the Barbosa Ro-
drigues Herbarium (Itajaí) under number VC Filho 023.
Phytochemical analysis
Air-dried rhizomes (3.0 kg) were powdered and extract-
ed twice with dichloromethane at room temperature for
approximately five days each, and after with ethyl ac-
etate and methanol, respectively. The extracts were then
concentrated under reduced pressure given the respec-
tive fractions. Dichloromethane fraction (55 g), which
demonstrated the most promising analgesic activity, was
studied in more detail. A part of this fraction (50 g) was
chromatographed using a silica gel column eluted with a
mixture of hexane:ethyl acetate with increasing polarity.
The similar fractions by TLC were combined given sev-
eral fractions, which were analyzed preliminarily as
analgesic in mice (results not shown). The most active
fraction, denoted as F1 (3.5 g), was rechromatographed
over a silica gel column eluted with benzene:acetone
9:1, given about 500 mg of curcumenol (1) and 150 mg
of a mixture of phytosterols (specially sitosterol and
stigmasterol 2:1). The spectroscopic data (IR and NMR)
of compound (1) are identical to those reported in the lit-
erature (Hikino et al., 1968; Firman et al., 1988). Phyto-
sterols were confirmed by TLC and HRGC with authen-
tic samples. Other terpenes were evidenced in DCM
fraction, but their structures remain undetermined.
Chromatographic Analysis/HRGC
HRGC separation was carried out using a Shimadzu
model B-14 equipped with a denoted DB-1 (Dimethyl-
polysiloxane), J&W Scientific column (30 m long,
0.25 mm id. with 0.33 µm liquid phase). The carrier
gas was hydrogen at a flow rate of 2 ml/min which was
kept constant by regulation. Samples (1 µl) were inject-
ed with a split mode (split ratio 1:30), with detection
using a flame ionization detector (FID) system. The
temperature programmation was increased from at
80 °C to 280 °C at 8 °C/min, with a final isothermal of
10 min. Peak areas were processed using Chromato-
graphia Microquímica for Windows soft-ware.
Animals
Swiss mice of both sexes (25–35 g) were housed in auto-
matically controlled temperature conditions (23 ± 2 °C
and 12 h light-dark cycles). The animals were given access
to water and Nuvital chow ad libitum unless otherwise in-
dicated. The animals remained in the appropriate laborato-
ry of UNIVALI until some hours before of the experiments.
Pharmacological analysis
• Abdominal constriction response caused by intra-
peritoneal injection of diluted acetic acid: The ab-
dominal constriction induced by intraperitoneal in-
jection of acetic acid (0.6%), was carried out accord-
ing to the procedures described previously (Collier et
al., 1968; Souza et al., 1998) with minor modifica-
tions. Animals were pretreated with hydroalcoholic,
fractions or curcumenol (1) from C. zedoaria (1–10
mg/kg) or standard drugs intraperitoneally 30 min.
before the acetic acid injection. Control animals re-
ceived a similar volume of 0.9% NaCl (10 ml/kg,
i.p.). After the challenge, each mouse was placed in a
separate glass funnel and the number of abdominal
contractions of the abdominal muscles together with
stretching, was cumulatively counted over a period of
20 mins. Antinociceptive or analgesic activity was
expressed as the reduction of the number of ab-
dominal contractions between control animals and
mice pretreated with hydroalcoholic extract, frac-
tions or compounds.
• Formalin-induced pain: The procedure used was
essentially similar to that described previously (Hun-
skaar and Hole, 1987; Hunskaar et al., 1985, 1986;
Souza et al., 1998). Animals from the same strain were
 Phytochemical analysis and analgesic properties of Curcuma zedoaria
slightly anaesthetized with ether, except when used to
analyse the first phase of formalin-induced pain, and
20 µl of 2.5% (0.92% formaldehyde) made up of PBS
(phosphate buffered solution containing: NaCl 137 mM;
KCl 2.7 mM and phosphate buffer 10 nM) was injected
under the plantar surface of the left hindpaw. Animals
were acclimatized to the laboratory for at least 24 hrs
before the experiments. Two mice (control and treated)
were observed simultaneously for 0 to 30 mins follow-
ing formalin injection. The initial nociceptive scores
normally peaked after 5 mins (first phase, representing
the neurogenic pain), and after 15–30 mins after forma-
lin injection (second phase, representing the inflamma-
tory pain) (Hunskaar and Hole, 1987). Animals were
treated with saline 0.9% (10 ml/kg, i.p.), dichloro-
methane fraction or curcumenol (1) (3–15 mg/kg by
i.p. route) or with standard drugs 60 min before forma-
lin injection. After intraplantar irritant application, the
animals were immediately placed in a glass cylinder
(20 cm diammeter). The time spent by animals licking
or biting the injected paw was timed with a chronome-
ter and was considered indicative of pain. At the end of
the experiments the animals were sacrificed with ether,
the paws cut at the tibio-tarsic joint and weighed on an
analytical balance to investigate the interference of
studied compound (1) on formalin-induced inflamma-
tory oedema.
• Capsaicin-induced pain: The procedure used was
similar to that described previously (Sakurada et al.,
1993). The animals were placed individually in trans-
parent glass cylinders. Following the adaptation peri-
od, 20 µl of capsaicin (1.6 µg/paw) was injected
under the skin of the plantar surface of the right hind-
paw, using a microsyringe. The animals were ob-
429
served individually for 5 minutes following capsaicin
injection. The amount of time spent licking the inject-
ed paw was timed with a chronometer and was con-
sidered as indicative of nociception. Animals were
treated with the compound (1) (1–10 mg/kg, i.p.) or
saline (10 ml/kg, i.p.) 1 hour before administration of
capsaicin. Control animals received a similar volume
of 0.9% NaCl (10 ml/kg, i.p.).
Hot-plate test
The hot-plate was used to stimate the latency of re-
sponses according to the method described by Eddy
and Leimback (1953) with minor modifications. The
temperature of the hot-plate was maintained at 56 ± 3 °C.
The animals (n = 10) were placed on glass funnels in
the heated surface and the time between placing the an-
imals and the beginning of licking paws or jumping
were recorded as latency of response, in non-treated
(saline 10 ml/kg, i.p) or curcumenol (1) at 5, 10 and 60
mg/kg, i.p.) animals.
Statistical analysis
The results are presented as mean ± s.e.m. and statisti-
cal significance between groups was analysed by
means of the t test or analysis of variance followed by
Dunnett’s multiple comparison test, when appropriate.
P values less than 0.05 were considered significant.
When appropriated, the ID50 (the dose of compound
that reduced formalin-, acetic acid or capsaicin-in-
duced pain by 50% relative to control values) which
were estimated as geometric means accompanied by
their respective 95% confidence limits.

Fig. 1. Effect of the dichloromethane fraction

obtained from C. zedoaria rizhomes, against
acetic acetic acid-induced abdominal con-
strictions in mice. Each column represents
mean ± s.e.m. of six experimental values. *
p < 0.05; ** p < 0.01; *** p < 0.005.
Fig. 2. Effect of the dichloromethane fraction obtained from C. zedoaria
rizhomes, against formalin-induced pain in mice. Each column represents
mean ± s.e.m. of six experimental values. * p < 0.05; ** p < 0.01.
430 D. de Fátima Navarro et al.
Table 1. Comparison of the antinociceptive effect of curcumenol (1) with non-steroidal antiinflammatory and analgesic drugs
given intraperitoneally in mice.

Compound Writhing test Formalin test Capsaicin test

ID50 (µmol/kg) ID 50 (µmol/kg)
First phase1 Second phase2
ID50 (µmol/kg) ID 50 (µmol/kg)

Curcumenol (1) 22 (18–27) > 64 * 29 (24–40) 12 (9.5–27)

Aspirin 133 (73–243) Inactive 123 (77–209) NT
Dipyrone 162 (88–296) 154.5 (100–239) 264 (234–297) 208 (180–240)
Diclofenac 38 (30–49) > 94 34.5 (25–47) 47 (35–65)

NT = not tested. Each group represents the mean ± s.e.m. of six esperiments. 1 0–5 min licking (s); 2 15–30 min licking (s).
* Inhibition of 42.2 % at 64 µmol/kg.

 Results presence of curcumenol at Rt = 13.8 min and several

non polar compounds. Since curcumin seems be one of
In order to determine the possible analgesic action of the main active compound present in plants of the
C. zedoaria, we have initially prepared a hydroalcoholic genus Curcuma (Masuda et al., 1992; Anto et al., 1998;
extract from rhizomes, because that this part is more uti- Rasmussen et al., 2000) and considering that some au-
lized in folk medicine. The crude extract caused pro- thors reported it from C. zedoaria (Syu et al., 1998), we
nounced effect when analyzed against writhing and for- have verified by TLC if it is produced in the plant
malin models in mice (results not shown). Thus, we grown in Brazil. The results indicated the absence of
have prepared three fractions with solvents of increas- this compound in detectable concentration.
ing polarity, such as dichloromethane (DCM), ethyl ac-
etate and methanol. All the fractions were pharmacolog-
ically analyzed, and DCM showed the better analgesic
potential, being studied in more details.
The results shown in Fig. 1 indicate that DCM caused
dose-dependent analgesic effect given by intraperitoneal
route, inhibiting acetic acid-induced writhing responses
in mice. It presented a calculated ID50 value (and 95%
confidence limit) of 3.6 (2.5–6.6) mg/kg, with maximum
inhibition of 69.5%, being several times more active
than some reference drugs. Two well-known analgesic
and antiinflammatory drugs, such as aspirin and dipy-
rone, presented ID50 of 25 and 57 mg/kg, respectively, in
the same experimental model.When analyzed in the for-
malin test, DCM significantly inhibited dose-dependent-
ly both the first and second phases by the systemic route
(Fig. 2). The calculated ID50’s values were 8.6 (6.2–15.8)
mg/kg and 9.4 (6.7–17.6) mg/kg, with maximum inhibi-
tion of 54.4 and 52.9% for 1th and 2th phases, respective-
ly. The reference drugs practically prevented only the in-
flammatory effects (second phase) (Table 1). Fig. 3. HRGC pro-
Phytochemical analysis (TLC) carried out with file of dichlromethane
DCM revealed the presence of several compounds, and fraction from C. zedo-
aria rizhomes. C shows
the strong positive reaction with anisaldehyde-sulfuric
the presence of curcu-
acid suggests the predominance of terpenoids. The menol (1). Chromato-
chromatographic profile by HRGC of dichlormethane graphic conditions: see
fraction from C. zedoaria rhizomes (Fig. 3) shows the experimental part.
 Phytochemical analysis and analgesic properties of Curcuma zedoaria
On the other hand, the use of chromatographic proce-
dures permited us to isolate a sesquiterpene from DCM,
which was identified as curcumenol (1), already isolated
previously from this plant (Hikino et al., 1968; Matsuda
et al., 1998). As can be observed in Table 1, compound
1 exerted potent analgesic effects in all the chemical
models of pain in mice. It was highly effective in in-
hibiting acetic acid-induced writhing responses, with
ID50 of 22 µmol/kg, being about 2 to 7-fold more potent
than reference drugs. In the formalin test, curcumenol
(1) inhibited dose-dependently both the first and second
phases, but the effect was more pronounced against the
late phase, with ID50 of 29 µmol/kg, being 9 and 4-fold
more active than dipyrone and aspirin, respectively, and
equipotent to the diclofenac. Curcumenol (1) was also
effective in antagonizing the formalin-induced hindpaw
oedema causing inhibition of about 40% at 64 µmol/kg.
In the capsaicin model, the curcumenol exerted a pro-
nounced activity, with ID50 of 12 µmol/kg, whereas
dipyrone and diclofenac presented ID50 of 208 and
47 µmol/kg, respectively (Table 1).
In the hot-plate test, curcumenol (1) (5–60 mg/kg,
i.p.) was not capable of increasing the latency period of
pain induced by heating of the plate. Phytosterols were
not analyzed in this study because we have previously
demonstrated that they exert analgesic activity in mice,
with potency similar to that of aspirin and ac-
etaminophen (Santos et al., 1995).
 Discussion
The results reported in the present investigation demon-
strate for the first time that C. zedoaria grown in Brazil ex-
erts analgesic effects in mice, which are related specially to
the presence of terpenoids. One of them, the sesquiterpene
curcumenol (1), isolated from the active fraction (di-
chloromethane), produces potent and dose-dependent
analgesic action on different animal models in vivo.
The high potencies observed in the writhing test and for-
malin-induced pain test led us to suggest that compound (1)
is acting by some peripheral mechanism. There are some
signs in common with inflammatory pain associated with
the profile of analgesic effects (De Jesus et al., 2000).
Our results suggest that curcumenol (1) is effective in
abolishing acetic acid-induced pain in a non-opiod way, be-
cause the lack of analgesic effects in the hot-plate test, a tech-
nique that has a selectivity for opioid-derived analgesics
(Abbott and Melzack, 1982; Abbott and Franklin, 1986).
It is interesting to note that curcumenol (1), on formalin-
induced pain, a test which defines two distinct periods of
431
response, i.e., “early response” and “late response” (Hun-
skaar et al., 1985), inhibited both phases of pain, suggest-
ing that other mechanisms could be involved. The effect
produced in the first phase may be due to immediate and
direct effects on sensory receptors, bradykinin receptors or
glutamatergic way whereas for the last phase the antinoci-
ceptive effect is related to the inflammatory responses in-
duced by arachidonic acid cascade (Dubuisson and Den-
nis, 1977; Hunskaar, et al., 1985; Souza et al., 1998).
Curcumenol (1) was also effective in antagonizing
the formalin-induced hindpaw oedema suggesting an
associated antiinflammatory effect. The factor by which
this compound inhibits such an inflammatory oedema
induced by irritant could be through modulating the lib-
eration or blocking B2 receptor and prostaglandin recep-
tors systems (Corrêa and Calixto, 1993).
Another interesting result consisted in the potent ac-
tion of compound (1) in the capsaicin test, which provid-
ed more direct evidence of the analgesic effect of curcu-
menol on neurogenic pain. It is important to mention that
some well-known nonsteroidal antiinflammatory drugs,
including aspirin and paracetamol, are ineffective or ex-
hibit weak activity in the first phase of the formalin test
and in the capsaicin model, but they significantly inhibit
the second phase of the formalin-induced licking
(Table 1). When compared with standard drugs, curcu-
menol (1) was more potent in all models used (Table 1).
Studies conducted by other group of research with
curcumenol (1) and other principal sesquiterpenes
from C. zedoaria indicated that they show potent pro-
tective effect on D-galactosamine/lipolysaccharide-in-
duced liver injury in mice (Matsuda et al., 1998)
In summary, our results demonstrate that C. zedoaria
cultivated in Brazil produces active compounds which
act as analgesic in different models of pain in mice.
One of the main active components seems to be the
sesquiterpene curcumenol (1), also present in plants of
the same species cultivated in other countries, which
was several times more active than the reference drugs
used for comparison. Its potent analgesic effect encour-
ages further investigations of strutuctural modifica-
tions in order to obtain new analgesic compounds. The
mechanism by which the plant or active principles
exert analgesic activity still remains undetermined, but
our results suggest that it does not involves the partici-
pation of the opioid system.
Finally, our results confirm and justify the popular
use of this plant in folk medicine to treat dolorous pro-
cesses. However, additional studies are required to cor-
relate better the traditional use (way of preparation, ad-
ministration and dose) of this plant with the our results.
432 D. de Fátima Navarro et al.
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 Address
Valdir Cechinel Filho, NIQFAR/CCS/UNIVALI, Rua
Uruguai, 458; CEP 88302-202, Itajaí, SC, Brazil
Tel: ++55-47 341 7664, Fax: ++ 55-47-341 7601;
e-mail: cechinel@univali.br