Introduction
Introduction
The Curcuma species (Zingiberaceae) are a family of herbaceous perennial plants, widely distributed
throughout Asia, where their rhizomes are extensively used in culinary and traditional
medicinal practices [1]. Their therapeutic properties have been attributed to the polyphenolic curcuminoid
compounds. The most abundant curcuminoid in the rhizome is 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-hepadiene-3,5-dione,
commonly known as curcumin (1) [2]. Its structure, elucidated at the beginning of the 20th century, includes two oxy-substituted
aryl moieties (polyphenols) linked together by two α,β-unsaturated carbonyl groups. The molecule exhibits keto-enol tautomerism ([Fig. 1]).
Fig. 1 Chemical structures of curcumin (1) and its derivatives 2–14.
The enol form is stable at high temperatures and in acids, but unstable in alkaline
media and under light conditions. Being hydrophobic in nature, the poor solubility
of curcumin in aqueous solutions and its instability under physiological conditions,
especially in the gut region, lead to a poor oral bioavailability [3]. Rapid metabolism and a high rate of systemic elimination result in low plasma and
tissue levels of curcumin. In order to maximize the potential clinical applications
of this compound, efforts have been made to circumvent these restrictive pharmacokinetic
characteristics [4], [5]. Furthermore, the use of this class of molecule as parasiticidal agents has been
extensively studied (see [6], [7], [8] for reviews).
Around the world, parasites plague human beings, affecting developing countries in
particular. In tropical regions, regardless of economic status, plant preparations
have been used to cure parasitic disease throughout the ages. Curcuma is one of the most commonly used plant genera for this purpose. Our intention is
to present a novel review focusing on the antiparasitic effects of Curcuma-derived compounds, including curcuminoids and synthetic derivatives, particularly
in cases of tropical parasitosis, commonly found in areas where Curcuma grows. Furthermore, as infections caused by cosmopolitan parasites are becoming increasingly
detrimental to public health in these regions, the effect of Curcuma on these parasites will also be reviewed here.
Tropical Parasitosis
Tropical Parasitosis
Malaria
Malaria is caused by protozoa of the genus Plasmodium, transmitted through the bite of mosquitoes of the Anopheles genus. It is considered to be the top parasite affecting human health, killing about
1 million people annually and affecting almost 250 million people around the world
[9]. Commonly, affected patients present with fever, headache, and vomiting about 10
to 15 days after being bitten. Untreated, some species of Plasmodium can become life-threatening due to a decrease in the blood supply to vital organs.
Plasmodium has developed resistance to most antimalarials worldwide. Among the 15 commercially
available antimalarials, 12 are derivatives of two natural compounds, quinine and
artemisinin, which are still extracted from plants that have been used for centuries
in the treatment of intermittent fevers.
Various studies have been undertaken in order to evaluate the antiplasmodial properties
of the Curcuma extracts, curcumin and its derivatives. Murnigsih et al. [10] showed that water extracts of rhizomes of C. xanthorrhiza Roxb. and C. aeruginosa Roxb. were able to inhibit 40 % and approximately 90 %, respectively, of the growth
of P. falciparum in vitro, but the dose used in their test (1 mg/mL) was relatively high. Rasmussen et al.
[11] isolated curcumin (1), demethoxycurcumin (2) and bis-demethoxycurcumin (3), from the rhizomes of C. longa. These molecules inhibited 50 % of parasite growth in vitro at 3–4.2 µg/mL (approximately 8 µM) concentrations, almost 300 times higher than
that required of the control drug, chloroquine. Mishra et al. [12] synthesized some curcumin derivatives and claimed that curcumin-pyrazole (4), N-(3-nitrophenylpyrazole)curcumin (5), and 4-(4-hydroxy-3-methoxybenzylidene)curcumin (6) were able to inhibit 50 % of P. falciparum growth in culture more potently than curcumin, at concentrations of less than 1 µM.
Bentzen et al. [13] and Foller et al. [14] suggested that curcumin promotes erythrocyte cell death by enhancing cytosolic Ca2+ activity and ceramide formation, thus leading to red cell membrane structural alterations,
which trigger phagocytosis by macrophages. Interestingly, as this phenomenon is not
encoded by plasmodial protein machinery, it is thus not expected to generate resistance
by genetic mutation of the parasite. Ligeret et al. observed that fluorinated curcumin
derivatives, such as atovaquone [15], were able to affect the mitochondrial machinery of Plasmodium at concentrations of 5 µM [16], a concentration corresponding to the half maximal inhibition concentration (IC50) of curcumin against erythrocytic stages [17]. Reddy et al. [17] showed that curcumin had an IC50 of 5 µM against P. falciparum in vitro corroborating the results of Rasmussen et al. [11]. Interestingly they also showed that when administrated orally, at a concentration
of 100 mg/kg/5 days, it decreased the blood parasitemia of P. berghei-infected mice by 80–90 %. In the hands of Cui et al. [18], curcumin had an IC50 ranging from 20 to 30 µM against P. falciparum [both chloroquine-resistant (CQ‐R) and ‐sensitive (CQ‐S) strains]. They also showed
that curcumin increased the production of reactive oxygen species and inhibited the
activity of plasmodial histone acetyltransferase, an enzyme required for chromatin
remodeling and transcriptional activation. Singh and Mishra confirmed this observation
using bioinformatic techniques [19]. Furthermore, their findings showed that in silico, curcumin could bind to the active site of sarco-endoplasmic reticulum Ca2+ ATPase, an ATP coupled Ca2+ ion pump involved in metabolic arrest. Based on computational analysis, Ji and Shen
also suggested that curcumin could bind to the plasmodium Ca2+ ATPase, PfATP6, through hydrophobic interactions and hydrogen bonds and efficiently
inhibit this crucial plasmodial enzyme [20]. This finding supports the reported enhancement of antimalarial activity on combining
artemisinin with curcumin [21], which forms covalent adducts with the transmembrane proteins. Nandakumar et al.
also showed that curcumin and artemisinin were additive in vitro and that 3 oral doses (100 mg/kg each) of curcumin after a single administration
of the artemisinin derivative arteether (1.5 mg/mouse/IM) were sufficient to cure
P. berghei-infected mice, preventing further infection outbreaks [21]. However, Martinelli et al. [22] showed that, in combination with a subcurative dose of artemisinin (150 mg/kg/4
days), curcumin at 300 mg/kg/4 days was not able to affect the growth of P. chabaudi in vivo, a strain of murine Plasmodium, resistant to artemisinin. They also showed that, in combination with piperine (20 mg/kg/4
days), which is thought to increase curcumin bioavailability, curcumin alone, or the
combination of curcumin and artemisinin had no conclusive effect on the course of
plasmodial growth. To increase the bioavailability of both curcumin and artemisin,
Lapenna et al. proposed, the use of micelles of sodium dodecyl sulfate (SDS) [5] but this theory remains untested against parasites.
Mishra et al. showed synergism between Andrographis paniculata (Burm. f.) Nees and Hedyotis corymbosa (L.) Lam. methanolic extracts and curcumin against CQ‐S and CQ‐R strains of P. falciparum in vitro [23]. This was also observed in vivo against P. berghei murine malaria, by administrating mice every day with 7 mg/kg intraperitoneally,
until they died at day 13 for the control group, and day 22 for mice treated with
the most effective combination, A. paniculata and curcumin. Drug combination therapies are now routinely used in endemic areas
in an effort to combat antimalarial resistance. One of the most studied mechanisms
of chemo-resistance involves a membrane-associated “drug pump” which transports drugs
out of the cell against a concentration gradient. One of these, the P-glycoprotein
(P‐gp) pump, plays a key role in anticancer drug resistance. Interestingly, this protein
is also found in Plasmodium with a correlation between amplification of its expression and increased resistance
to antimalarials (see [24] for a review). Chearwae et al. showed that curcuminoids were able to increase the
sensitivity of cancer cells to etoposide by modulating the function of P‐gp [25]. Consequently, we can speculate that curcumin derivatives may also act on plasmodial
P‐gp and could be used in conjunction with antimalarials in areas where resistance
prevents their use; however, further experimental research is required to support
this theory.
Leishmaniasis
Leishmaniasis is a parasitic disease, caused by a protozoan of the genus Leishmania, and transmitted by phlebotomine sandflies. More than 350 million people live in
“at risk” areas and more than 12 million people are currently infected [26]. Clinically, cutaneous forms affect the skin and mucus membranes while visceral
leishmaniasis affects some internal organs, leading to potentially fatal complications.
Few effective drugs are available. Antimony-containing compounds, meglumine antimonate
and sodium stibogluconate are generally used as an initial treatment, followed by
amphotericin B, fluconazole and pentamidine if necessary. All of these drugs require
parenteral administration in equipped health centers. Miltefosine is the only agent
that has been shown to be effective by oral administration, but only against some
forms of leishmaniasis. Thus alternative treatments are urgently needed.
Koide et al. [27] showed that curcumin inhibited 50 % of L. major promastigote growth at 37.6 µM. Araujo et al. [28] had similar results with curcumin (IC50 of 24 µM) on promastigotes of L. amazonensis and also showed that methylcurcumin (7) was more active at lower concentrations (< 5 µg/mL). Methylcurcumin administered
to Balb/c mice (20 mg/kg) at the time of infection, resulted in a decrease in lesion
size of approximately 65 %, when measured 75 days after infection. Interestingly,
no inflammation was observed in the area where the drug was injected, which may be
due to the well-known anti-inflammatory properties of curcuminoids [28].
Rasmussen et al. [11] showed that curcumin (1), demethoxycurcumin (2) and bis-demethoxycurcumin (3), isolated from the rhizomes of C. longa, have some parasiticidal activities against L. major (IC50 ranging from 22 to 60 µM). Curcumin proved to be the most potent of the compounds.
Gomes et al. [29] synthesized curcuminoids by condensing 2,4-pentanedione with differently substituted
benzaldehydes and found that 1,7-bis-(2-hydroxy-4-methoxyphenyl)-1,6-heptadiene-3,5-dione)
(8) was the most effective against L. amazonensis promastigotes (IC50 24 µM).
Saleheen et al. determined the activity of curcumin against promastigote forms of
L. major, L. tropica and L. infantum and showed that it had an average IC50 of 5.3 µM [30]. Furthermore, against axenic amastigote cells of the L. major strain, curcumin was a more potent parasiticidal agent than pentamidine, the control
drug (10 and 13.5 µM, respectively). Alves et al. studied the impact of the synthetic
curcuminoids, diarylheptanoids and diarylpentanoids on the growth of promastigotes
of L. amazonensis, L. braziliensis and L. chagasi and against L. amazonensis axenic amastigotes. The tested compounds were shown to be most effective against
L. braziliensis promastigotes (IC50 ranged from 2 to 78 µM) [31]. For L. amazonensis the IC50 values ranged from 1 to 373 µM and 6 to 331 µM for L. chagasi promastigotes. In the case of L. amazonensis axenic amastigotes, the IC50 varied from 56 to 435 µM. Pentamidine isethionate, the reference drug, was as effective
as the most potent compound. The authors highlighted that lipophilic diarylheptanoids
were more efficient than diarylpentanoids, against the three species of Leishmania. Oxygenated functions in the aromatic ring governed the potency of the most active
compounds. Finally, p-methoxy substituents were also shown to be important for leishmanicidal activity.
The authors reported that 5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-4-methoxyphenyl)-1,4,6-heptatrien-3-one
(9), which contained an m-hydroxy moiety in the aromatic ring, was the most active compound against L. amazonensis promastigote growth. The curcumin derivative which proved most effective against
L. braziliensis (IC50 of 2 µM), had a p-methoxy substituent and a m-phenolic group protected by an acetylated function [5-hydroxy-7-(4-acetoxy-3-methoxyphenyl)-1-phenyl-1,4,6-heptatrien-3-one]
(10) [32]. Das et al. studied the impact of curcumin on L. donovani, responsible for visceral forms of the disease and showed that it induced cell cycle
arrest at the G2/M phase in promastigote forms [33]. They observed that phosphatidylserines were exposed to the outer leaflet of the
plasma membrane and that mitochondrial membrane depolarization followed the elevation
of cytosolic calcium concentration. Furthermore, they observed the release of cytochrome
c into the cytosol and nuclear alterations.
Changtam et al. showed that some curcuminoids (11–14) exhibited EC50 values of less than 5 mM against L. major promastigotes and L. mexicana amastigotes [34]. On the contrary, Chan et al. showed that the anti-nitric oxide properties of curcumin
protected promastigotes and amastigotes of the visceral species, L. donovani, and promastigotes of the cutaneous species, L. major, against the effects of pro-oxidant molecules S-nitroso-N-acetyl-D,L-penicillamine and DETANONOate [35]. Most of the published results on curcuminoids against Leishmania have been obtained against the promastigote, instead of the more relevant amastigote
stage inside macrophages. Consequently it is not clear if the activity described in
the literature reflects the real leishmanicidal properties of these molecules. Therefore,
the potency of these molecules should perhaps be re-examined in a more appropriate
model, such as infected macrophages.
Trypanosomiasis
Trypanosoma are flagellate protozoa belonging to the genus of kinetoplastids. They are transmitted
by blood-feeding invertebrates, infecting a variety of hosts and causing various diseases
in humans, including Chagas disease (T. cruzi) [36] in Central and South America and sleeping sickness (T. brucei) in Africa [37]. In mammals they circulate through the blood and tissue fluids and may also be localized
intracellularly (T. cruzi). Treatments are limited to benznidazol and nifurtimox for Chagas disease with low
curative rates if administrated in the chronic phase of the disease, and pentamidin,
suramin melarsoprol, and eflornithine against African trypanosoma with variable cure rates.
Nose et al. showed that curcumin inhibited African Trypanosoma in vitro [38] at around 5 µM for bloodstream forms and around ten times more for procyclic forms
of T. brucei brucei (the tsetse fly stage). Changtam et al. [34] reported that some curcumin derivatives have potent trypanocidal activity against
the T. brucei brucei bloodstream form. The most active compound 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one
(15) had an EC50 value of 0.007–0.053 µM, almost 2-fold more active than the standard veterinary drug
diminazene aceturate. The enone structure apparently contributed to the trypanocidal
activity [34]. The authors also showed that the curcuminoids had low toxicity to human embryonic
kidney cells. As few trypanocidal drugs are currently available, further study is
essential to fully exploit the potential role of curcuminoids in the treatment of
trypanosomiasis.
Schistosomiasis
Schistosoma spp. are responsible for the most widely distributed flat worm infections known to
human kind in developing countries, affecting 200 million people in 74 countries [39]. Their parasitic life cycle starts with the larvae penetrating through the skin
of their host. After a larval migration through the lungs, adults parasitize mesenteric
blood vessels and liberate embryonated eggs through urine or feces. In water the miracidial
stage hatch from the egg, actively looking for intermediate hosts (various genera
of snails) within which they transform into sporocysts. There, approximately 1 month
later, thousands of cercariae are produced by asexual multiplication, ready to penetrate
a new host. The migration of the eggs through the liver, intestine or bladder causes
inflammation and scarring. The few drugs available include oxamniquine for the treatment
of intestinal schistosomiasis, metrifonate for urinary schistosomiasis, and praziquantel
for all forms of schistosomiasis [40], [41].
El-Ansary et al. studied the impact of oil extracted from C. longa on Schistosoma mansoni-infected mice [42]. They showed that although the control drug praziquantel was more effective in lowering
worm burden, the C. longa extract was more potent in reducing the egg count. The latter was also able to normalize
some biochemical parameters (pyruvate kinase, glucose, AMP-deaminase and adenosine
deaminase). El-Banhawey et al. reported that an ethanolic extract of C. longa administered to S. mansoni infected mice, was able to reduce alkaline phosphatase levels and increase the glycogen
concentration, when compared to nontreated mice [43]. Interestingly in treated but not infected mice, they also observed higher glycogen
reserves. The extract also increased body weight while praziquantel treatment had
no effect. Both products were effective in reducing granuloma size in infected mice.
Unfortunately in the El-Banhawey study neither the dose nor the route of administration
were documented. Shoheib et al. studied the effect of turmeric extracts on freshly
shed cercariae from infected Biomphalaria alexandrina snails [44]. They observed a decrease in pathogenicity, mean number of deposited eggs, mean
diameter of liver granulomas and level of IL-10 gene expression at 10 ppm. In these
conditions, they also achieved complete reduction of infectivity of the studied cercariae.
Allam [45] infected mice with cercariae of S. mansoni and administrated curcumin at a dose of 400 mg/kg, intraperitoneally, to circumvent
the low rate of absorption via oral administration. At that dose, curcumin reduced
worm and egg tissue burden by 31–44 %, hepatic granuloma by 79 % and liver collagen
contents by approximately 40 %. Hepatic enzymatic activities, particularly that of
catalase, were also restored. Hepatospleenomegaly was improved and eosinophilia decreased.
Those improvements were associated with reduced levels of interleukin-12 and tumor
necrosis factor alpha. Nevertheless, the IL-10 concentration was not significantly
altered. At the immunological level, specific IgG and IgG1 responses against both
soluble worm and egg antigens were increased while IgM and IgG2a responses remained
unchanged. Magalhaes et al. investigated the activity of curcumin against S. mansoni adult worms in vitro and showed that their viability and their fecundity decreased at doses ranging from
5–20 µM while doses up to 100 µM were effective at killing worms [46].
Cosmopolitan Parasitosis
Cosmopolitan Parasitosis
Helminthiasis
Angiostrongylus cantonensis is a nematode (roundworm) commonly found in the pulmonary arteries of rats. Humans
are incidental hosts, infected through ingestion of larvae in undercooked snails (the
primary intermediate hosts, for developing larvae) or contaminated water and vegetables.
Ingested larvae migrate to the central nervous system through the blood stream. They
then cause eosinophilic meningoencephalitis, leading to permanent brain and nerve
damage or death. This is a serious public health issue in Southeast Asia and the Pacific
Basin. In serious cases, treatments are symptomatic and include classic anti-helminthics,
such as albendazole and corticoids. Shih et al. with an A. cantonensis-induced eosinophilic meningitis model in BALB/c mice, showed that the administration
of curcumin moderately reduced the eosinophil count without any larvicidal effect
[47]. They argued that the inactivity of curcumin could be due to inefficient passage
through the blood-brain barrier.
Toxocara canis is a cosmopolitan helminth parasite found in dogs and cats that can inadvertently
infect humans by the ingestion of eggs passed through animal feces. Infected patients
present “larva migrans” symptomatology. Albendazole combined with corticoids is the
first line treatment. Kiuchi et al. isolated cyclocurcumin from the rhizome of C. longa. Combined with other curcuminoids it presented some nematocidal activity against
the second stage larvae of T. canis [48].
It seems then, that against nematodes (at least Angiostrongylus and Toxocara) there is not enough experimental evidence to support the consideration that curcumin
derivatives act as potential nematicides.
Babesiosis
Babesiosis is an infection of red blood cells caused by a parasite of the genus Babesia (B.) that is transmitted through the bite of a tick [49]. It is very similar to malaria except that it does not colonize liver cells. Symptoms
include fever, fatigue and hemolytic anemia lasting from several days to several months.
Treatment commonly combines clindamycin and quinine or atovaquone and azithromycin.
Subeki et al. showed that water extracts of C. zedoaria inhibited 50 % of parasite growth in vitro at approximately 42 µg/mL [50]. Murnigsih et al. also showed that water extracts from the rhizomes of C. xanthorrhiza and C. aeruginosa Roxb. inhibited more than 60 % of the B. gibsoni growth at a very high final concentration of 1 mg/mL [10]. C. xanthorrhiza was found to be the most active among the extracts. This plant, which is traditionally
used in Indonesia in the treatment of malaria, dysentery and cancer, had low toxicity
in mice (0.7 g/kg) when administrated intraperitoneally. Kasahara et al. isolated
zedoalactone derivatives with antibabesial activity against B. gibsoni and compared them with the reference drug diminazene aceturate [51] the IC50 of which was 0.6 µg/mL, while the zedoalactones were between 3 and almost 30 times
less active. Matsuura et al. isolated xanthorrhizol derivatives from C. xanthorrhiza, with IC50 values ranging from 0.6 µg/mL to 11.6 µg/mL against Babesia in vitro [52]. Yamada et al. showed that the 3′-p-hydroxybenzaldehyde derivative, the most active compound isolated from the tuber
of C. xanthorriza had an activity of only one-twelfth of that of the control drug against B. gibsoni in vitro (IC50 of 50 µM) [53]. Although the in vitro activity of some Curcuma derivatives seems promising, in vivo evidence is lacking and further studies are needed to confirm those results.
Coccidiosis
Cryptosporidium parvum is one of the most common waterborne diseases caused by a coccidian protozoan of
the worldwide-distributed genus Cryptosporidium [54]. It is localized in the intestines of mammals, via the classical fecal-oral route,
through contaminated food or water. In immunocompetent patients, cryptosporidiosis
causes an acute self-limiting diarrheal illness during 2 weeks, while in immunocompromised
individuals, symptoms are particularly severe and often fatal. As no effective therapy
has been developed to date, treatment involves fluid intake for rehydration and pain
management.
Shahiduzzaman et al. found that curcumin inhibited more than 95 % of Cryptosporidium parvum growth at 50 µM in human ileocecal adenocarcinoma cell cultures. Furthermore, doses
of 200 µM inhibited the infection of cells by the sporozoite forms [55]. On the contrary, the viability of C. parvum oocysts was not impaired after incubation with curcumin.
Toxoplasma gondii is also a cosmopolitan parasite, particularly dangerous to pregnant women and immunocompromised
patients, especially those with AIDS. Upon habitation of the Felidae species, sexual reproduction takes place, producing oocysts. These oocysts, when
ingested by other mammals, including humans that consume unwashed vegetables or improperly
cooked infected meat, transform into tachyzoites which are the motile, asexually reproducing
form of the parasite that colonize macrophages. They also transform into cysts, which
multiply into bradyzoites. In a letter to the editor of the Journal of the Egyptian Society of Parasitology, Abdel-Hady et al. claimed that a methanolic extract of C. longa had antitoxoplasma activity (EC50 of 0.18 mg/mL) but the authors did not provide any methodological information [56]. In the same journal Al-Zanbagi and Zelai showed that an ethanolic extract of the
same plant, previously incubated with tachyzoites of T. gondii, and then administered (400 mg/kg) to mice, inhibited parasite growth [57].
Giardiasis
Giardia lamblia (also known as G. duodenalis and G. intestinalis), is responsible for the most common cosmopolitan, waterborne intestinal infection
[54]. Its life cycle has two stages: flagellated trophozoites attach by their suckers
to the surface of the duodenal or jejunal mucosa. Upon passage through the bowel,
they transform into ovoid cysts. Those cysts are then excreted with bowel movements
and are found in feces. Infection of a new host occurs via contact with cysts in contaminated
food or water, or via direct contact with an infected person. Symptoms such as diarrhea,
abdominal cramps, flatulence and bloating may lead to malnutrition in chronic disease
states. Classic treatments include imidazole derivatives with sufficient water intake
for rehydration. Curcumin was tested on the Portland I strain of G. lamblia trophozoites [58]. The authors showed that 72 hours post-seeding, 30 µM of curcumin inhibited around
95 % of parasite growth. At that dose the adhesion capacity was affected and morphological
alterations were similar to those reported for metronidazol. These alterations were
characterized by protrusions formed under the cytoplasmic membrane and cellular swelling.
The authors concluded that curcumin induced apoptosis-like nuclear staining in a dose-
and time-dependent manner. Interestingly the bioavailability of curcumin is advantageous
to treat parasites of the digestive tract as most of the ingested curcumin does not
diffuse through the digestive barrier [59]. Nevertheless, to the best of our knowledge, no data have been reported on the in vivo activity of Curcuma derivatives against giardiasis.
Scabies
Scabies is a skin infection, transmitted from one person to another through direct
or indirect contact, caused by the arthropod Sarcoptes (S.) scabiei, which burrows into skin producing rashes, itching and pain. Classical first line
treatment includes permethrine, which may cause allergic reactions. In a clinical
trial, neem (Azadirachta indica) and turmeric were combined as a paste (4 : 1 neem to turmeric), and applied topically
for up to 15 days [60]. This treatment cured around 97 % of the people in a cohort of 814 people suffering
from scabies. Nevertheless, it remained unclear if turmeric was really active against
S. scabiei or if its beneficial activity relied on its anti-inflammatory properties.
Conclusion and Perspectives
Conclusion and Perspectives
Despite international efforts to control parasitic diseases, the reality for numerous
patients living in developing countries remains unchanged from decades ago: they still
suffer and sometimes die because they cannot afford antiparasitic medicines with their
incomes. Furthermore many drugs are no longer effective due to the emergence of parasite
resistance to the treatments. In this context, new, safe, affordable and efficient
drugs are needed. An ideal therapeutic candidate must be effective within a short
period of time, safe for administration to small children and pregnant women, easy
to package, cheap and have a low propensity to generate resistance. Curcuma extracts and derivatives could fit these criteria against some parasites, being effective
(at least in vitro), cheap and well tolerated at very high doses (8 g/day) [61].
Nevertheless, Curcuma derivatives are poorly absorbed and are quickly metabolized in rodents and humans
[62], [63]. This inconvenience could be circumvented by using synthetic related compounds with
better absorption, distribution, metabolism, excretion and toxicity properties. Alternatively,
the combination of curcumin with a product known to enhance curcuminoid uptake in
humans, for example, piperine [63], [64], may overcome absorption and metabolism issues, although this concept is controversial
[22].
Regarding efficacy, in the case of malaria, we showed that although Curcuma derivatives had some antiplasmodial activity in vitro, this is not correlated with in vivo activity. However, the combination of curcumin with conventional drugs may enhance
the effectiveness of curcumin, while simultaneously delaying the emergence of resistance
to antimalarial treatments. This strategy could also lower the cost of therapy.
In the case of Leishmania, most investigations were conducted on the promastigote forms, and some against amastigotes,
but only one study showed some activity in vivo. Moreover, sensitivity to curcumin could be demonstrated against the bloodstream
stage of Trypanosoma brucei only once. This must be confirmed and studies against intracellular life cycle stages
must be performed. Against helminths, many studies lack experimental evidence of antiparasitic
activity. Nevertheless, it seems that Curcuma derivatives are able to reduce symptom severity and egg tissue burden of Schistosoma. In the case of Babesia, in vitro activity must be supported by in vivo studies. This is also the case for Giardia. Further studies are required to determine if the use of Curcuma derivatives could be of some interest in the anti-coccidial treatment, alone or in
association with classical drugs. Finally, in the treatment of scabies in association
with neem, Curcuma probably acts more as an anti-inflammatory than an anti-sarcoptes.
Consequently, taking into account their low bioavailability and the very variable
antiparasitic activity of Curcuma and derivatives, it is not surprising that this “golden spice” [1] has not been commercialized as an anti-infectious medicine (alone or in combination)
at a large scale to date. Generally, pharmaceutical companies are devoted to producing
new patentable drugs, rather than unpatentable phytomedicines, although the production
of a new formulation could circumvent this problem. Moreover, due to their chemical
structures, with a small sized polyphenol and flexible aliphatic chain, curcumin compounds
bind, in a nonspecific and covalent way to the active sites of many proteins [65], leading to indiscriminate effects. Also as for many natural compounds, Curcuma and its derivatives are often claimed to have remarkable properties, while the related
experimental procedures often lack methodological accuracy [66], [67]. Only meticulous experiments, replicated in different laboratories, and strictly
controlled clinical studies will bring definitive evidence of the benefit of Curcuma and its derivatives in the therapeutic arsenal against parasites.
