Revista Brasileira de Farmacognosia 27 (2017) 788–793

www.elsevier.com/locate/bjp

Review

Himatanthus drasticus: a chemical and pharmacological review of this

medicinal species, commonly found in the Brazilian Northeastern
region
Sheyla Cristina Xenofonte de Almeida a,b , Álefe Brito Monteiro a , Galberto Martins da Costa a ,
Glauce Socorro de Barros Viana b,c,∗
a
Universidade Regional do Cariri, Crato, CE, Brazil
b
Faculdade de Medicina Estácio de Juazeiro do Norte, Juazeiro do Norte, CE, Brazil
c
Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: In order to compile the empirical use, as well as the chemical, pharmacological and biological aspects
Received 21 November 2016 of Himatanthus drasticus (Mart.) Plumel, Apocynaceae, a review was carried out by searching PubMed,
Accepted 10 October 2017 Google Scholar, Scientific Electronic Online Library, Web of Science, Science Direct, Scopus and Cochrane.
Available online 3 November 2017
For that, works in English, Spanish and Portuguese, preclinical studies and revisions, addressing chemical,
pharmacological, biological properties and popular uses, from 1994 to 2017, were used. The therapeutic
Keywords: potential of the “milk-of-janaguba” (a mixture of the latex with water) became widely known for the
Antiulcer activity
treatment of neoplasias, mainly lung and lymphatic cancer types, in the 1970s. The available literature
Gastroprotective properties
Anti-inflammatory effects
presents works related to the anti-inflammatory, antinociceptive, antitumor and gastroprotective prop-
Laticifer plants erties of the latex from bark and leaves of H. drasticus. In addition, this review presents some of our own
results with the triterpene-rich fraction from H. drasticus, attempting to clarify its action mechanisms
at the molecular level. The antinociceptive and anti-inflammatory activities of H. drasticus are proba-
bly associated with inhibitions of inflammatory mediators, as TNF-alpha, iNOS, COX-2 and NF-kB. Most
importantly, a triterpene-rich fraction also inhibited HDAC activity, and compounds with this activity
have been considered as therapeutic agents with antitumor activity. In conclusion, although the litera-
ture shows several works on species of the Himatanthus genus, including H. drasticus, dealing with some
bioactive compounds as triterpenes, translational studies focusing upon the clinical uses of this medicinal
species are still in great need.
© 2017 Sociedade Brasileira de Farmacognosia. Published by Elsevier Editora Ltda. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction worldwide. In addition, the past decade has witnessed a huge global
interest in the use of medical plant products (Briskin, 2000).
Tropical forests are the major source of biodiversity. Brazil, that The Himathantus genus belongs to the Apocynaceae family
holds about a third of the world flora, has an undeniable wealth of which is one of the most important plant sources of pharmaco-
biologically active compounds. This wealth of the Brazilian biodi- logically active chemical compounds (DiStasi and Hiruma-Lima,
versity is reflected in the popular use of medicinal plants (Yunes 2002). The Apocynaceae family is composed of only fourteen
et al., 2001). Scientific advancements have validated the popu- species (Plumel, 1991). These species have been used in tradi-
lar use of medicinal plants as potential therapeutic alternatives tional medicine for treating bacterial, parasitic and inflammatory
(Arnous et al., 2005). Furthermore, natural bioactive compounds diseases, cancer, endocrine (diabetes), gastrointestinal and also
represent more than 50% of all drugs in therapeutics (Pan et al., central nervous system disorders and pain in general (Santos et al.,
2013) and, in this context, it is important to mention that the 2013). Some pharmacological properties were evaluated by in vitro
pharmaceutical industry is crucial for economic development and in vivo preclinical studies, as hypoglycemic (Tiong et al., 2015;
Kazeem and Ashafa, 2015; Pereira et al., 2015), analgesic and anti-
inflammatory (Sheu et al., 2009; Lucetti et al., 2010; Camargo et al.,
2013), anticonvulsant (Ya’u et al., 2008), antitumor (Almeida et al.,
∗ Corresponding author.
2004; Mousinho et al., 2011), antimicrobial (Kariba et al., 2001;
E-mail: glauce.viana@pq.cnpq.br (G.S. Viana).

https://doi.org/10.1016/j.bjp.2017.10.002
0102-695X/© 2017 Sociedade Brasileira de Farmacognosia. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
 S.C. Almeida et al. / Revista Brasileira de Farmacognosia 27 (2017) 788–793 789

Suffredini et al., 2002; Vital and Rivera, 2011; Camargo et al., 2013), anti-inflammatory, antinociceptive, antitumor and gastroprotec-
antidepressant (Camargo et al., 2013) and antiprotozoal activities tive properties of its latex, bark and leaves, but with a deficiency
(Reina et al., 2012). in relation to the central nervous system and also microbiological
The distribution of the genus is restricted to Panama and studies (Box 1).
South America and, among other species, it comprises Himatanthus Colares et al. (2008a) described cytotoxic and antinociceptive
articulatus (Vahl) Woodson (heterotypic synonym of H. sucuuba); activities for the ethanol extract of the stem bark, in classic research
Himatanthus attenuatus (Benth.) Woodson; Himatanthus bracteatus models. The cytotoxic activity was tested with an in vitro method
(A. DC.) Woodson; Himatanthus drasticus (Mart.) Plumel; Himatan- against Artemia salina, showing that the 50% lethal dose equals
thus obovatus (Müll Arg.) Woodson; Himatanthus phagedaenicus to 257 ppm. The antinociceptive effect was evaluated through the
(Mart.) Woodson; Himatanthus semilunatus Markgr; Himatanthus writhing test, induced by acetic acid and the hot plate test that
tarapotensis (Schum ex Markgr.) Plumel; Himatanthus revolutus showed an effect only in the writhing test, in a dose-dependent
(Huber) Spina & Kinoshita (Spruce) Woodson (Spina, 2016). manner (200 mg/kg and 400 mg/kg, p.o.). Additionally to this study,
Furthermore, the species H. drasticus (Mart.) Plumel is geograph- a phytochemical investigation was performed by 1 H and 13 C NMR
ically distributed in French Guiana, Suriname, Guyana and in the mass and infrared spectrometry, characterizing the presence of the
North, Midwest, Southeast and Northeast Brazil. In this last area, esterified triterpene lupeol cinnamate.
it is mainly found in the Araripe plateau (Cariri region, South of The lupeol and esters have been identified in other parts
Ceará State; Lorenzi and Matos, 2008). In Brazil, it inhabits the areas of H. drasticus. From its latex, lupeol acetate was isolated and
of Cerrado, Caatinga and the Amazon, occurring in the States of tested in models of nociception and inflammation by Lucetti et al.
Minas Gerais, Bahia, Sergipe, Alagoas, Pernambuco, Rio Grande do (2010), showing a pronounced analgesic activity in the model of
Norte, Ceará, Paraíba, Piauí, Maranhão, Pará and Roraima. In Ceará, writhings induced by acetic acid. In the formalin test, it inhibited
it is known as “janaguba”; in Minas Gerais and Bahia, as “tiborna”, the pain in both the initial (neurogenic) and the late (inflam-
“jasmim-manga” and “raivosa”; in Piaui, as “pau-de-leite”; in Rio matory) phases, possibly via the opioid system, and showed an
Grande do Norte, “joanaguba” and in the Amazon, as “sucuuba” effective antiedematogenic activity, in the model of paw edema
(Plumel, 1991; Spina, 2004). induced by carrageenan and dextran. Although the Lucetti et al.
(2010) study assigned the anti-inflammatory and antinocicep-
tive effects of the triterpene lupeol acetate isolated from the
Ethnopharmacological aspects
latex, Matos et al. (2013) attributed these effects to the protein
fraction obtained from the latex with water (“janaguba milk”),
The latex of Himatanthus drasticus is widely used in eth-
however devoid of lupeol. The protein fraction tested by the meth-
nomedicine for the prophylaxis, cure and relief of various diseases.
ods of neutrophil migration induced by carrageenan, administered
The therapeutic potential of the “milk-of-janaguba”, as the mixture
orally, showed a better effect at the lowest dose (1 mg/kg). How-
of the latex with water is commonly called, became widely known
ever, intravenously administered, the protein fraction exhibited a
for its use in the treatment of neoplasia, after medical reports of
potent and dose-dependent anti-inflammatory effect (10 mg/kg).
its effectiveness in the healing of lung and lymphatic cancers, in
The antinociceptive effect was demonstrated by inhibition of
the 1970s. Since that time, there has been a significant increase
writhings, induced by acetic acid, where the dose of 10 mg/kg
in latex extraction with therapeutic and scientific goals. In this
inhibited them by 60%, whereas in the formalin test this same
context, the city of Crato (Ceará State) has become a major extrac-
dose inhibited by 88% the paw licking, being more effective than
tion center, reaching exports of about 5000 l of “milk-of-janaguba”,
morphine (85%), in the second phase (inflammatory). These results
coordinated by the Roman Catholic Diocese of Crato and the Brazil-
suggest peripheral and central analgesic actions in the latex protein
ian Institute for the Environment and Renewable Natural Resources
fraction.
(IBAMA), for specific purposes of anticancer research (unpublished
The anti-inflammatory and antinociceptive actions of the latex
data) (Lorenzi and Matos, 2008).
protein fraction is reflected in the effects observed in experimental
In addition to the treatment of cancer, the “milk-of-janaguba”
models of arthritis, where the dose of 50 mg/kg, i.v., reduced the
has been consumed for a long time for other pathological condi-
cell influx, myeloperoxidase activity, nitric oxide levels, inflamma-
tions. Various ethnopharmacological studies register its oral use
tory cytokines (IL-1␤, IL-6) and edema caused by zymosan-induced
for the treatment of gastritis, ulcer, diabetes, worms, inflamma-
arthritis (Carmo, 2015). The protein fraction extracted from the
tion, heart disease, arthritis and as a laxative or, externally, for skin
latex showed an activity against the cell lines of Sarcoma 180 and
disorders and wound healing (Awaad et al., 2013; Ribeiro et al.,
Walker carcinoma 256, by the intraperitoneal route, not presenting
2014; Souza et al., 2014; Bitu et al., 2015; Saraiva et al., 2015;
orally the same effect, according to description studies of antitumor
Soares et al., 2015). The latex extraction process and preparation
and immunomodulatory activities associated with immunostimu-
of the “milk-of-janaguba” is made in a traditional manner, start-
lating properties (Mousinho et al., 2011).
ing with a longitudinal incision for the partial removal of the bark,
Furthermore, a pioneer preclinical study on antitumor activ-
employing for that a 10 × 30 cm knife. The latex exudes from the
ity of the crude methanol extract of H. drasticus leaves showed
bark and is stored with water. Subsequently, the mixture is filtered
low toxicity orally, at doses of 50, 300 and 2000 mg/kg, with
and placed into a one-liter bottle for settling and formation of a
significant tumor inhibition compared with Sarcoma 180, in a dose-
biphasic system, containing an off-white precipitate (1/4 to 1/3 of
dependent manner, compared to the control group (68% at the
the full bottle) and a slightly pink supernatant. The mixture should
dose of 400 mg/kg and 67.7% at the dose of 300 mg/kg). It also
be kept in a cold environment and is indicated for ingestion of a
presented an antitumor activity, relatively to the control animals
dose corresponding to an average cup, three times a day (Lorenzi
bearing Ehrlich carcinoma, in all doses tested. The preliminary
and Matos, 2008; Linhares and Pinheiro, 2013).
phytochemical investigations of this extract revealed the pres-
ence at a high concentration of the quercetin and rutin flavonoids,
Pharmacological properties and also found the presence of ␤-amyrin triterpene, condensed
proanthocyanidins and leucocyanidins (Sousa, 2009; Sousa et al.,
The pharmacological potential of the H. drasticus species has 2010).
been proven in various in vivo and in vitro preclinical stud- These authors also conducted studies on the toxicity and anti-
ies, that indicate a high concentration of works related to tumor activity after the oral administration of the H. drasticus latex.
790 S.C. Almeida et al. / Revista Brasileira de Farmacognosia 27 (2017) 788–793

The toxicity studies showed stimulant, followed by depressant

Box 1: Part of the plant, use in folk medicine, phar- reactions, on the central nervous system, demonstrating morpho-
macological and biological properties and chemical logical changes of liver, kidneys, lung and spleen. Moreover, the
constituents of Himatantus drasticus. analysis showed significant tumor inhibition, compared to the con-
Part of Use in folk Pharmacological Chemical References
trol, only for the Ehrlich carcinoma, at the highest dose tested
the medicine and constituents
plant biological (14 ml/kg). The phytochemical investigation identified the pres-
proper- ence of ␤-amyrin triterpene and ␤-sitosterol steroid, confirmed
ties by chromatographic methods. However, the study of França et al.
Latex Antitumoral, Gastroprotector, Lupeol acetate, Awaad et al. (2011) demonstrated that the latex mixture with water, at the doses
gastrointestinal immuno- ␣-amyrin, (2013); Bitu of 0.04 ml (the dose used for humans) and 0.06 ml, showed no anti-
disorders, heart modulator, ␤-amyrin, et al. (2015); tumoral effect in the model of lung cancer progression, induced by
diseases, antitu- ␤-sitosterol and Carmo (2015);
urethane in mice.
worms, mor, proteíns Colares et al.
inflammation healing, (2008a, 2008b); The H. drasticus latex was evaluated for its cytoprotective activ-
of the bowel analgesic Leite et al. ity in the formation of ethanol-induced ulcers in rats showing
and colon, and anti- (2009); Lorenzi a significant gastroprotective activity, probably attributed to the
prostate cancer, inflammatory. and Matos presence of tannins and terpenes presented by phytochemical
fibroids, (2008); Lucetti
hemorrhoids, et al. (2010); Luz
screening (Leite et al., 2009). A similar effect was observed in the
anemia, et al. (2014); work of Colares et al. (2008b) where the latex, at doses of 0.4
arthritis, fever, Marques and 0.2 ml/10 g, significantly suppressed hemorrhagic erosions in
irregular (2012); Matos the gastric mucosa, induced by ethanol and indomethacin, respec-
menstruation, et al. (2013);
tively. The authors justify the cytoprotective effect by the presence
female Moraga (2006);
infertility and Mousinho et al. of a triterpenoid mixture. More recently, Fiigueiredo et al. (2017)
rheumatism. (2011); Ribeiro observed that H. drasticus leaves possess antimicrobial activity
et al. (2014); against Klebsiela pneumoniae and display low cytotoxicity and anti-
Santos (2004); proliferative action on human peripheral blood mononuclear cells,
Saraiva et al.
stimulated by LPS. The authors associated these effects to the pres-
(2015); Soares
et al. (2015); ence of compounds such as plumieride, plumericin/isoplumericin,
Sousa et al. rutin, quercetin and derivatives, as well as chrogenic acid, in H.
(2010); Souza drasticus leaves.
et al. (2014);
Others (Marques, 2012) demonstrated that the protein frac-
Sousa (2009);
Souza (2015). tion (0.5 mg/kg) isolated from the latex of H. drasticus protects
Bark Antitumoral, Citotoxi- Tannins, the gastric mucosa, through antioxidant actions, with recovery of
influenza, can- flavonoids, the reduced glutathione levels, after gastric damage induced by
gastrointestinal dantinoci- phenols, ethanol. These data provide subsidy for a potential antiulcero-
diseases, ceptive. saponins,
genic effect of the protein fraction. An ointment produced from
vermifuge and steroids,
arthritis. coumarins, the protein fraction of H. drasticus latex (2%) had healing activity,
lupeolcinna- by encouraging reepithelization and the appearance of scar tis-
mate, lupeol sue excisional wounds, observed by macroscopic, histological and
acetate, ␣-
inflammatory mediators (Souza, 2015). The gastroprotective effect
amyrinacetate,
␣-
of proteins isolated from the latex of H. drasticus was also confirmed
amyrincinnamate, by Pinheiro et al. (2013), indicating that this protection appears to
␤-amyrin, be mediated, at least partly, by modulation of the NO/cGMP/KATP
plumieride, pathway, related to mucosal defense and maintenance of the stom-
isoplumieride,
ach blood flow.
proto-
plumericin A, Interestingly, the gastroprotective properties of H. lancifolius,
caffeoylp- a medicinal species of the Himatanthus genus, included in the
lumieride, 1st edition of the Brazilian Pharmacopeia (Baratto et al., 2009),
3-methoxy-3,4-
were also demonstrated with a fraction rich in indole alkaloids
dihydroplumieride
acid.
(Baggio et al., 2005). These authors observed that the protective
Leaves – Antitumoral. Quercetin, effects of this fraction included increased GSH levels of gastric
rutin, mucosa, indicating activation of GSH-dependent cytoprotective
condensed mechanisms, as well as an increased antioxidant capacity. In addi-
proanthocyani-
tion, some of these indole alkaloids were able to alter non-vascular
dins,
leucoantho- and vascular smooth muscle responsiveness, probably by the block-
cyanidins, fatty ade of the calcium entry or changes in the intracellular calcium
acids, utilization or mobilization (Rattmann et al., 2005). The effects
␤-amyrin,
of the alkaloid-rich fraction of H. lancifolius were also demon-
lupeol, mixture
of␤-sitosterol
strated on normal marrow cells and leukemic cell lines, and the
and data revealed a cytostatic activity for tumor cells (Lima et al.,
stigmasterol. 2010).
We recently investigated (Almeida, 2017) the latex fraction of H.
drasticus (Hd latex) and its triterpene-rich fraction (FJNB), on acute
models of nociception and inflammation, attempting to clarify
their molecular action mechanisms. We showed that FJNB presents
inhibitory effects on iNOS, COX-2, TNF-alpha, HDAC and NF-kB, and
these actions could be involved with the drug anti-inflammatory
 S.C. Almeida et al. / Revista Brasileira de Farmacognosia 27 (2017) 788–793 791

activity. Furthermore, FJNB inhibitions of NF-kB and HDACs (shown

by us for the first time) may justify the popular use of H. drasticus
latex in the cancer treatment. The enzyme histone deacetylase is
considered an important target for cancer therapeutics (Qian et al.,
2007; Chen et al., 2017), and its inhibition was demonstrated in
ginsenosides (triterpenes saponins), the bioactive principle of Gin-
seng (Liu et al., 2015). An anticancer activity has also been shown in
triterpenoid isolated from wild bitter gourd (Bai et al., 2016), as well
as in other natural and synthetic triterpenoids (Save et al., 2012;
Lee et al., 2012; Tran et al., 2013), pointing out to the importance
of these bioactive compounds as potential candidates for cancer
treatment.

Chemical composition

Among other bioactive compounds present in the genus

Himatanthus, the most important are iridoids, a large group
of monoterpenoids widespread in nature, in many plant fam-
ilies, including the Apocynaceae family (Tundis et al., 2008).
Since these compounds are known to present several properties,
as neuroprotective, anti-inflammatory and immunomodulator,
hepatoprotective, cardioprotective, anticancer, hypoglycemic and
hypolipidemic, among other activities, they are probably involved
with the biological effects of the plant latex.
Interestingly, a recent ethnopharmacological survey, carried out
in three cities of the Ceará State, observed that the great majority
of healers reported to apply the latex from H. drasticus for the treat-
ment of ulcers, inflammation and cancer (Soares et al., 2015). These
same authors related that triterpenes and iridoids were shown to
be the main chemical compounds present in the genus Himatan-
thus. Other studies (Moraga, 2006) were carried out with ethanol
extracts from bark and fresh leaves of H. drasticus, that under-
went successive partitions with hexane, methylene chloride and Final considerations
ethyl acetate. Partitions in hexane of H. drasticus bark and leaves
were subjected to analysis by gas chromatography, coupled with Among the fourteen species of Himatanthus, only six were chem-
mass spectrometry (GC/MS). The analysis of extracts of H. drasticus ically and biologically evaluated, and the most studied species
leaves showed three main chemical constituents: lupeol acetate, was H. sucuuba. Extracts of leaves, barks and latex of three
lupeol cinnamate and ␤-amyrin, and the analysis of bark extracts species, including H. sucuuba, showed the presence of iridoids, as
showed only lupeol and ␤-amyrin, all belonging to the class of plumieride (major component in the aqueous extract from leaves
pentacyclic triterpenes. The mass spectra obtained allowed to con- and latex of H. sucuuba and H. bracteatus) and isoplumieride, a
firm the presence of the characteristic ions of these triterpenoids, minor component in these species, as well as in the third one, H.
which belong to the series of lupane and ursane or oleanane skele- stenophyllus (Ferreira et al., 2009). According to the present sur-
tons. From barks of H. drasticus, iridoids known as plumieride (1), vey, there are only studies in relation to the latex, bark and leaves
isoplumieride, protoplumericin A (2), coffee oil plumieride and of H. drasticus. The latex is the mostly used part in traditional
the 3-methoxy-3,4-dihidroplumieride acid, a novel iridoid, were therapy, however the literature registers few pharmacological and
isolated. From the leaves of H. drasticus, the flavonoid rutin was biological studies, even with the absence of works related to the
isolated. central nervous system and also to the plant antiparasitic prop-
From another study carried out with the lipid fraction pre- erties. Chemical studies indicate terpenes, as iridoids, the main
pared from the ethanol extract of the leaves, Santos (2004) characterized chemical class in the species and probably respon-
identified the presence of methyl esters of the undecanoic, sible, in a great part, for the pharmacological properties already
hexadecanoic, 9,12-octadecenoic, 9-octadecenoic, octadecanoic, demonstrated in the species. In conclusion, although the number
eicosanoic and octanoic fatty acids, the triterpene lupeol and the of basic studies on botanical, chemical and ethnopharmacologi-
steroids ␤-sitosterol and stigmasterol. Luz et al. (2014), studying cal aspects of medicinal plants is huge, the same is not true on
the hydroalcoholic extract and fractions (hexane, ethyl acetate, n- the connection between clinical and preclinical studies, includ-
butanol and aqueous) of the barks, identified compounds belonging ing authentication, quality control, pharmacology and toxicology,
to the classes of flavonoid heterosides, triterpenes, steroids, alka- what has been a matter of concern (Jia et al., 2013). Furthermore,
loids and tannins, that are active in biological and pharmacological well designed and coordinated studies focusing on “bench to bed
models, and as coumarins with antimicrobial, anti-inflammatory, side” application and conducted with medicinal species are highly
antiviral and antioxidant potentials, and saponins with hypocholes- in need.
terolemic and antifungal actions.
Furthermore, the H. drasticus latex was shown to have gastro- Authors’ contributions
protective effects in models of acute gastric lesion (Pinheiro et al.,
2013). This protection appears to be mediated by modulation of the SCXA was responsible for the experiments carried out with the
NO/cGMP/KATP pathway related to mucosal defense and mainte- active fraction from the H. drasticus and included in the present
nance of the stomach blood flow. review. In addition, SCXA and ABM conducted all the literature
792 S.C. Almeida et al. / Revista Brasileira de Farmacognosia 27 (2017) 788–793

survey. GMC was responsible for the chemical study and GSBV Leite, G.O., Penha, A.R.S., Silva, G.Q., Colares, A.V., Rodrigues, F.F.G., Costa, J.G.M.,
was responsible for the pharmacological study and writing of the Cardoso, A.L.H., Campos, A.R., 2009. Gastroprotective effectof medicinal plants
from Chapada do Araripe. Brasil. J. Young Pharm. 1, 54–56.
manuscript. Lima, M.P., Hilst, L.F., Mattana, F.V.R., Santos, C.A.M., Weffort-Santos, A.M., 2010.
Alkaloid-rich fraction of Himatanthus lancifolius contains anti-tumor agents
against leukemic cells. Braz. J. Pharm. Sci. 46, 273–280.
Conflicts of interest Linhares, J.F.P., Pinheiro, C.U.B., 2013. Caracterização do sistema de extração de
látex de janaúba (Himatanthus Willd. ExSchult.-Apocynaceae), no Município de
Alcântara, Estado do Maranhão, Brasil. Rev. Pan-Amazônica de Saúde 4, 23–31.
The authors declare no conflicts of interest. Liu, Z.-H., Li, J., Xia, J., Jiang, R., Zuo, G.-W., Li, X.-P., Chen, Y., Xiong, W., Chen, D.-L.,
2015. Ginsenoside 20(s)-Rh2 as potent natural histone deacetylase inhibitors
suppressing the growth of human leukemia cells. Chemico-Biol. Int. 242,
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