A Review on Phytochemistry and Recent Pharmacology of Dragonʼs Blood (Croton lechleri), a Multifunctional Ethnomedicinal Resource from the Amazon Forest

Keywords

Sangre de Drago - Croton lechleri - Euphorbiaceae - phytochemicals - biological activities - natural resources

Introduction

Croton lechleri Muell. Arg. (Euphorbiaceae), commonly referred to as “Sangre de Grado” or “Sangre de Drago” (Dragonʼs blood) in Latin America, is one of the most widely used ethnomedicinal resources among rural and urban populations of the Amazon region, particularly in Peru. This species is traditionally employed for a variety of ailments, including wound healing, ulcers, toothaches, skin fungal infections, and rheumatism, among others [1].

Currently, numerous products derived from C. lechleri are commercialized and exported from South American countries. These include patented formulations and derivatives of its resin, some of which have undergone clinical studies [1], [2], [3]. The species is native to the Western Amazonian Forest, thriving at elevations of 100 – 1800 meters, with temperature ranges between 18 °C and 30 °C and annual rainfall of 2000 – 4000 mm. The trees typically grow to heights of 3 – 25 meters with diameters of 15 – 55 cm and have an estimated lifespan of 5 – 20 years. They possess smooth, thick bark and simple, alternate, heart-shaped leaves measuring 2.5 – 5 cm in length and 3 – 19 cm in width [4].

The trunk of C. lechleri contains a reddish latex whose consistency varies with the treeʼs age. Younger trees produce a more fluid resin, while older individuals yield a more viscous form. This resin is the primary medicinal product utilized by local communities and industries as a base for herbal formulations. It contains a mixture of alkaloids, including taspine, and other resinous compounds, which are responsible for the speciesʼ pharmacological activities [5]. In recent years, the increasing commercialization of C. lechleri products has spurred the development of sustainable management techniques for its cultivation. Additionally, studies have explored its broader applications, such as using its extracts as green corrosion inhibitors for admiralty brass in hydrochloric acid [6], [7].

In this sense, this review aims to compile and analyze the key phytochemical and pharmacological information on C. lechleri, emphasizing its importance as a leading phytotherapeutic resource in modern medicine.

Search Strategy

The study employed the specific search terms “Croton lechleri” AND “chemical” OR “Croton lechleri” AND “activity” to identify relevant articles. For the pharmacological activity documents, it took into account all publications since 2003, whereas no beginning year was indicated for the chemical study documents. Duplicate articles or those only citing studies on the topic were eliminated. Following meticulous selection, the documents relating directly to the central theme were included and discussed in the main review section. Scopus (30 documents) and Google Scholar (33 documents) were utilized as research databases.

Phytochemical Profile of Croton Lechleri Muell. Arg.

Phytochemicals from resin

Proanthocyanidins

According to Cai et al. (1991) [8], the blood-red resin of Croton lechleri contains proanthocyanidins as major constituents, presenting up to 90% of the dried weight ([Table 1]). Among the identified compounds, it was found the monomers (+)-catechin, (−)-epicatechin, (+)-gallocatechin, (−)-epigallocatechin, as well as the dimeric procyanidins B-1 and B-4, and the following dimers and trimers: catechin-(4α→8)- epigallocatechin, gallocatechin-(4α→8)-epicatechin, gallocatechin-(4α→6)-epigallocatechin, catechin-(4α→8)-gallocatechin-(4α→8)-gallocatechin, and gallocatechin-(4α→8)-gallocatechin-(4α→8)-epigallocatechin. It also identified higher oligomers with mean degree of polymerization of 4,5 – 6 and 6 – 7, and M_r up to 1830 and 2130, respectively [8]. Among the main large oligomers, it identified SP-303, which possesses remarkable antiviral activity [9], as well as SB-300, with an antitumoral mechanism [10], and crofelemer, which presented antisecretory antidiarrheal activity [11].

Table 1 Phytochemicals identified from C. lechleri.

Metabolite class	Identified substances	References
Proanthocyanidins	(+)-catechin, (−)-epicatechin, (+)-gallocatechin, (−)-epigallocatechin, procyanidins B-1 and B-4, catechin-(4α→8)- epigallocatechin, gallocatechin-(4α→8)-epicatechin, gallocatechin-(4α→6)-epigallocatechin, catechin-(4α→8)- gallocatechin-(4α→8)-gallocatechin, gallocatechin-(4α→8)-gallocatechin-(4α→8)-epigallocatechin, higher oligomers with mean degree of polymerization of 4,5 – 6 and 6 – 7, and Mr up to 1830 and 2130, respectively.	[8]
	SP-303	[9]
	SB-300	[10]
	Crofelemer	[11]
Phenolic acids	Gallic acid and Syringic acid	[16]
Phenolics	1,3,5- trimethoxybenzene, 2,4,6-trimethoxyphenol, 3,4-dimethoxyphenol, 3,4-dimethoxybenzyl alcohol, 4-hydroxyphenethyl alcohol and its acetate	[12]
Phytosterols	β-sitosterol, β-sitostenone
Saponins	β-sitosterol-β-d-glucopyranoside
	floribundic acid glucoside (clerodane)	[5]
Terpenoids	crolechinol and crolechinic acid (clerodanes)	[12]
	hardwickric acid, bincatriol, korberin A and korberin B (clerodanes)	[13]
	blumenol B, blumenol C and 4,5-dihydroblumenol A (megastigmanes)	[5]
Phenylpropanoids	3-(3,4,5-trimethoxyphenyl)-1-propanol and 3-(3,4-dimethoxyphenyl)-1-propanol
Lignans	3′,4-O-dimethylcedrusin, erythro-guaiacyl-glycerol-β-O-4′-dihydroconiferyl ether and 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-propane-1,3-diol
	4-O-methylcedrusin	[16]
Protoalkaloid	taspine	[5]
Alkaloids	magnoflorine, isoboldine, norisoboldine (aporphine)	[17]
	glaucine, and thaliporphine (aporphine)	[20]
	sinoacutine (morphinane)	[18]
Flavonoids	rutin and vitexin	[14]
	Quercetin related-structure glycosides tentatively identified	[15]
Phenolic derivatives	Pyrogallol-O-methyl-Galloyl-Glucoside and 4-Ethyl-Galloyl-Glucoside
Bark essential oil	sesquicineole (17.29%), a-calacorene (11.29%), 1,10-di-epi-cubenol (4.75%), b-calacorene (4.34%), limonene (4.20%), epicedrol (4.09%), p-cymene (2.61%), a-pinene (2.01%), and borneol (2.67%)	[21]

Terpenoids, phytosterols, and saponins

The chemical analysis of the chloroform extract from C. lechleri resin showed the major presence of phytosterols and saponins, which included β-sitosterol, β-sitosterol-β-d-glucopyranoside, and β-sitostenone, as well as the clerodane diterpenoids named crolechinol and crolechinic acid as minor constituents [12]. One year later, Chen et al. (1994) identified other related compounds in C. lechleri, which included the diterpenoids hardwickric acid, bincatriol, korberin A, and korberin B [13].

Polyphenols, flavonoids, and other phenolic compounds

Polyphenols, including flavonoids, and other phenolic compounds are also prominent in C. lechleri resin, so that the phenolic derivatives 1,3,5-trimethoxybenzene, 2,4,6-trimethoxyphenol, 3,4-dimethoxyphenol, 3,4-dimethoxybenzyl alcohol, 4-hydroxyphenethyl alcohol, and its acetate also were among the main chemicals found in the chloroform extract resin [12]. Furthermore, another study on polyphenols reported the glycoside-quercetin flavonoids rutin and vitexin as the main compounds of this class in C. lechleri [14], then correlated to the most recent work on chemical constituents of this species, which present 22 polyphenols substances, mainly glycosides from quercetin, frequently connected to methyl or acetyl groups, followed by gallic acid derivatives [15]. Still regarding phenolic compounds, gallic acid and syringic acid are also present in the metabolism of C. lechleri and the best extraction conditions for this metabolite class is to use water as the solvent at 35 °C during 90 min of the extraction, so that the concentrations varied from 8.8 to 46.57 mg GAE/g (gallic acid equivalent) [16].

Alkaloids and protoalkaloids

The content of the protoalkaloid taspine, one of the genus chemical markers, varies widely in the resin, being included within the range from 1.3% to 20.4%, with an approximate mean level of 9% (dry weight), in mature trees. Also, it is suggested that there are three alkaloid chemotypes of C. lechleri, with chemotype 1 containing glaucine, isoboldine, and thaliporphine and chemotype 2 containing isoboldine and thaliporphine, while the chemotype 3 contains only isoboldine [17]. Finally, another relevant alkaloid isolated from C. lechleri resin was sinoacutine, included in the morphinane subclass [18].

Other relevant compounds

De Marino et al. (2008) [5] conducted a bio-guided fractionation of resin that led to the isolation of another compounds, among them three megastigmanes, two phenylpropanoids, three lignans, besides the clerodane saponin, and the protoalkaloid taspine. The three megastigmanes (nor-isoprenoid derivatives) identified were blumenol B, blumenol C, and 4,5-dihydroblumenol A, whereas 3′,4-O-dimethylcedrusin, erythro-guaiacyl-glycerol-β-O-4′-dihydroconiferyl ether, and 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-propane-1,3-diol were the lignans. Moreover, it identified the phenylpropanoids 3-(3,4,5-trimethoxyphenyl)-1-propanol and 3-(3,4-dimethoxyphenyl)-1-propanol and the clerodane saponin floribundic acid glucoside [5]. In that time, the identification of lignans in C. lechleri was not the first mention, once Pieters (1998) had previously identified another lignan named 4-O-methylcedrusin, besides 3′,4-O-dimethylcedrusin, which in turn are benzodihydrofuran lignans [19].

Phytochemicals from leaves

According to the reports of two studies, the alkaloids magnoflorine, isoboldine, norisoboldine [17], glaucine, and thaliporphine are present in the C. lechleri leaf extracts [20].

Phytochemicals from essential oil

The work of Rossi et al. (2011) showed that the sesquiterpenes sesquicineole (17.29%), a-calacorene (11.29%), 1,10-di-epi-cubenol (4.75%), b-calacorene (4.34%), and epicedrol (4.09%) were the main constituents from the fresh stem bark essential oil collected in Ecuadorian Amazon and obtained by steam distillation. Also, the main monoterpenes were identified as a-pinene (2.01%), p-cymene (2.61%), limonene (4.20%), and borneol (2.67%). The yield was 0.061% and the density was equal to 1.01 g/mL [21].

Pharmacology of Croton Lechleri Muell. Arg.

Wound-healing activity

Wound-healing activity is one of the primary biological properties attributed to Croton lechleri resin ([Table 2]). Several studies have elucidated the key compounds responsible for this activity, as well as the potential mechanisms of action. Recently, a case study on wound treatment using C. lechleri reported that a cream containing 10% Sangre de Drago resin significantly accelerated the healing of ulcers in diabetic patients within a three-month period. In addition to the known mechanisms, the authors highlighted the potential contribution of the immunomodulatory activity associated with C. lechleri [22], [23]. In 2016, Namjoyan et al. demonstrated the wound-healing efficacy of a cream formulated with a 15% ethanolic extract of C. lechleri. Patients treated with this formulation were monitored until day 20, showing substantial improvement in wound healing. By day 3, the treated group achieved a 31.06% reduction in the affected area, compared to only 4.74% in the placebo group. By the final day, the treated group exhibited 95.73% healing, whereas the placebo group showed 78.10% [24]. Another case study reported the resolution of epithelial-origin disorders using C. lechleri resin. A patient with a gingival cleft experienced near-complete recovery after 12 months of treatment with a combination of C. lechleri resin and Myrciaria dubia pulp applied every 15 days using cotton wool. The patient showed wound contraction, collagen formation, and epithelial layer regeneration, likely resulting from a synergistic interaction between the two extracts. The high vitamin C content in M. dubia is known to enhance collagen synthesis, which may have contributed to the observed effects [25]. Finally, Wang et al. (2012) reported that C. lechleri resin stimulates osteoblast alkaline phosphatase activity and mineralization in MC3T3-E1 cells, thereby supporting bone-tissue repair [26].

Table 2 Recent described pharmacological activities of C. lechleri (since 2003).

Pharmacological activity	Main description	References
Wound-healing activity	A 10% cream-based C. lechleri resin promoted the fast improvement of ulcers in diabetic patients, within a 3-month period.	[22]
	A 15% ethanolic-extract-based cream caused a fast wound-healing resolution, with 31.06% and 95.73% of healed area after the 3rd and 20th days, respectively.	[24]
	A treatment with the C. lechleri resin and Myrciaria dubia pulp, each soaked in a cotton wool, for 15 days led to wound contraction, new collagen formation, and the epithelial layer regeneration on gingival cleft.	[25]
	C. lechleri resin stimulated osteoblast alkaline phosphatase activity and mineralization in MC3T3-E1 cells, promoting bone tissue repair.	[26]
Cytotoxic and antitumoral activity	Leaf methanolic extract displayed in vitro and in vivo activity against HeLa by oral and intraperitoneal routes.	[14]
	C. lechleri resin presented antiproliferative effect on the human myelogenous leukemia K562 cell line (IC50 = 2.5 ± 0.3 µg/mL).	[27]
	C. lechleri resin inhibited SK23 cell proliferation starting from 1 mg/mL, while starting after 10 mg/mL it inhibited the HT-29 and LoVo cell lines. Also, taspine (0.1 mg/mL) inhibited SK23 and HT29 cell proliferation.	[28]
	A xamanic preparation of C. lechleri resin and its 1 : 1 dilution were toxic to prostate cancer cells PC3, by promotion of caspase cascade.	[29]
	The twig extracts from C. lechleri showed dose-dependent cytotoxicity, with Soxhlet ethanol extract demonstrating the highest selectivity toward A375 melanoma cells over HaCat skin cells.	[15]
Antimicrobial activity	Pure C. lechleri resin showed 90% bactericidal effect on Helicobacter pylori.	[31]
	The resin ethanolic extract 50% inhibited 100% of the ulcer patientsʼ isolated bacteria, including Staphylococcus aureus, Streptococcus sanguis, S. aglactiae, S. uberis, Stenotrophomonas maltophilia, Burkholderia cepacia, Pseudomonas aeruginosa, and Escherichia coli.	[32]
	The crude resin displayed moderate antimicrobial activity for Staphylococcus epidermidis (1000 ppm) and Bacillus subtilis (125 ppm), whereas the bark tincture exhibited moderate antimicrobial activity only on Bacillus subtilis (125 ppm).	[33]
Antileishmanial activity	The resin of C. lechleri exhibited an IC50 of 5.04 µg/mL against L. amazonensis and an IC50 of 9.05 µg/mL against L. guyanensis.	[34]
Antidiarrheal activity	The exposure of the apical surface to bark extract blocked forskolin-stimulated · Cl− secretion by 92.2 ± 3.0% with a half-maximal inhibition constant (KB) of 4.8 ± 0.8 M. For SP-303, stimulated Cl− currents were decreased by 98.0 ± 7.2% and KB averaged 4.1 ± 1.3 M.	[10]
	Crofelemer inhibited (CFTR) Cl− channel with maximum inhibition of ~ 60% and an IC50 ~ 7 µM and strongly inhibited the intestinal calcium-activated · Cl− channel TMEM16A by a voltage-independent inhibition mechanism with maximum inhibition > 90% and IC50 ~ 6.5 µM.	[11]
Anti-inflammatory activity	The resin exhibited immunomodulatory properties, through the classical (CP) and alternative (AP) pathways of the complement system and suppressing the proliferation of activated T-cells, as well as presented higher free radical scavenging activity.	[23]
Dermocosmetical application	A cream containing C. lechleri resin 3% and P. granatum seed oil 4% caused significant skin modifications at the level of the dermis thickness (14.85% increase), hydration (30.32%), and elasticity of stratum corneum (9.75%), after 6 weeks of treatment.	[35]
Smooth muscles contraction and cardiovascular activity	The resin (10 to 1000 µg/mL) induced concentration-dependent vasoconstriction in rat caudal arteries, which occurred independently of the endothelium. Pre-treatment with resin (100 µg/mL) enhanced the contraction induced by carbachol (1 µM), while contractions induced by KCl (60 mM) or capsaicin (100 nM) remained unaffected.	[38]
	The resin of C. lechleri inhibited BSA glycation and demonstrated a protective effect against LDL oxidation, extending the Lag phase by nearly 60% at a concentration of 0.8 mg/mL.	[39]

Cytotoxic activity

The cytotoxic activity of Croton lechleri extracts is well documented. The methanolic extract from its leaves demonstrated low IC₅₀ values in HeLa cells (17 µg/mL); however, it did not exhibit toxic effects against normal human cells. The induction of cell death in HeLa cells was confirmed by a 30% increase in apoptosis (Annexin/PI) compared to untreated controls [14]. Additionally, C. lechleri resin exhibited antiproliferative effects on the human myelogenous leukemia K562 cell line (IC₅₀ = 2.5 ± 0.3 µg/mL) [27] and inhibited SK23 cell proliferation at concentrations starting from 1 mg/mL, whereas concentrations 10 times higher were required to inhibit growth in HT-29 and LoVo cell lines. Furthermore, taspine (0.1 mg/mL) inhibited the proliferation of both SK23 and HT-29 cells. Both C. lechleri resin and taspine inhibited cancer cell proliferation, with taspine showing greater activity against SK23 cells, particularly after 48 hours of treatment. It was observed that C. lechleri resin (1 mg/mL) caused a disruption of microtubule structure, while taspine (0.5 mg/mL) led to an increase in acetylated alpha-tubulin and altered cellular morphology, primarily in SK23 cells. Moreover, treatment with C. lechleri resin at concentrations of 10 and 50 mg/mL influenced the cell cycle. At 50 mg/mL, a dramatic reduction in the number of cells in the G1/G0 and S phases was observed, accompanied by a significant increase in sub-G0 cells [28]. In 2018, Hess evaluated the effects of a shamanic preparation of C. lechleri resin on prostate cancer PC3 cells, both as a whole extract and in a 1 : 1 resin/water ratio. The study found that the positive effect was mediated through the promotion of the caspase cascade [29]. Additionally, twig extracts of C. lechleri exhibited dose-dependent cytotoxicity, with the Soxhlet ethanol extract showing the highest selectivity for A375 melanoma cells over HaCat skin cells. All extracts induced apoptosis and necrosis, triggering programmed cell death in cancer cells. Both the Soxhlet ethanol and pressurized ethanol extracts selectively inhibited cell cycle progression in A375 cells compared to HaCat cells, leading to cell cycle arrest primarily in the G1 and G2/M phases and a reduction in DNA synthesis, as evidenced by a decrease in the S-phase population [15]. Thus, the antitumoral activity of C. lechleri appears to result from a synergistic effect involving specific mechanisms, such as its high antioxidant capacity and antimutagenic activity. These effects were observed in various studies using Salmonella species treated with carcinogenic compounds such as 2-aminoanthracene, nitrofluorene, 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ), and 2-amino-3,4-dimethylimidazo-[4,5-f]quinoline (MeIQ) [21], [30]. These findings support the promising potential of C. lechleri resin or essential oil as an adjuvant in anticancer therapies.

Antitumoral activity

An in vivo assay performed by Alonso-Castro et al. (2012) showed that the leaf methanolic extract of C. lechleri presented a LD₅₀ equal to 356 mg/kg by intraperitoneal route (i. p.) and 500 mg/kg by oral route, so that, when administrated at 1, 10, and 50 mg/kg i. p., the extract inhibited the tumor growth by 38%, 48%, and 59%, respectively, in mice bearing HeLa tumors [14].

Antimicrobial activity

The antibacterial activity of C. lechleri resin against Helicobacter pylori was observed only with the pure product, producing a 90% bactericidal effect [31]. The loss of antibacterial activity following dilution seems to be typical for this species, since a similar effect was observed in the study of Corralez-Ramírez (2013), in which the resin ethanolic extract 50% inhibited 100% of the ulcer patientsʼ isolated bacteria in an agar diffusion test, including Staphylococcus aureus, Streptococcus sanguis, S. aglactiae, S. uberis, Stenotrophomonas maltophilia, Burkholderia cepacia, Pseudomonas aeruginosa, and Escherichia coli. However, the 33% and 25% dilutions presented effect of 88.88% and 66.66%, respectively, only in some of the aforementioned bacteria species. Conversely, the petroleum ether extract 50% inhibited only 55.55% of S. agalactiae, S. uberis, S. aureus, and E. coli, with the 33% and 25% dilutions presenting no effect on all bacteria species [32]. Also, it was found that the crude resin indicates moderate antimicrobial activity for Staphylococcus epidermidis using a 1000 ppm concentration and for Bacillus subtilis (125 ppm), whereas the bark tincture displayed moderate antimicrobial activity only on Bacillus subtilis, at the dosage of 125 ppm. In this study, no antimicrobial activity was verified for E. coli, S. aureus, and Streptococcus sp. [33].

Antileishmanial activity

The resin of C. lechleri exhibited an IC₅₀ of 5.04 µg/mL against L. amazonensis and an IC₅₀ of 9.05 µg/mL against L. guyanensis. Cytotoxic evaluation was conducted in J774 cells at the same concentrations used in the leishmanicidal assay, but a concentration of 25 µg/mL showed approximately 50% toxicity to the host cell. The tests conducted were promising, as the tested extract was also able to inhibit the growth of L. amazonensis promastigotes after an infection assay with J774 cells [34].

Antidiarrheal activity

The activity of the bark extract (SB-300) and an isolated proanthocyanidin SP-303 on colon cancer cells was evaluated by Fischer et al. (2004) [10]. They described the effectiveness of these active principles on cAMP-regulated chloride secretion, which is mediated by the cystic fibrosis transmembrane time and voltage-independent conductance regulator Cl⁻ channel (CFTR) in human colonic T84 cells. In this assay, the exposure of the apical surface to SB-300 blocked forskolin-stimulated Cl⁻ secretion by 92.2 ± 3.0% with a half-maximal inhibition constant (K_B) of 4.8 ± 0.8 M. For SP-303, stimulated Cl⁻ currents were decreased by 98.0 ± 7.2% and K_B averaged 4.1 ± 1.3 M. Also, forskolin-stimulated whole-cell Cl⁻ currents were effectively blocked by extracellular addition of SB-300 (63 ± 8.5%; 50 M) and to a similar extent by SP-303 (83 ± 0.6%; 50 M) [10]. In a similar study, crofelemer, another proanthocyanidin isolated from C. lechleri, had little or no effect on the activity of epithelial Na⁺ or K⁺ channels or on cAMP or calcium signaling, in a concentration of 50 µM. Crofelemer inhibited (CFTR) Cl⁻ channel with maximum inhibition of ~ 60% and an IC₅₀ ~ 7 µM, so that its action at an extracellular site on CFTR produced a voltage-independent block with stabilization of the channel closed state. Moreover, crofelemer did not affect the potency of thiazolidinone or glycine hydrazide CFTR inhibitors, whereas it resisted washout, with < 50% reversal of CFTR inhibition after 4 h. Crofelemer also strongly inhibited the intestinal calcium-activated · Cl⁻ channel TMEM16A by a voltage-independent inhibition mechanism with maximum inhibition > 90% and IC₅₀ ~ 6.5 µM, so that the dual inhibitory effect of crofelemer on two structurally unrelated prosecretory intestinal Cl⁻ channels is related to its intestinal antisecretory activity [11].

Anti-inflammatory activity

The anti-inflammatory activity of C. lechleri resin was evaluated in vivo using the carrageenan-induced paw edema test in rats. Some of the effects were compared to those of the isolated alkaloid taspine. The resin exhibited immunomodulatory properties, demonstrating potent inhibitory effects on both the classical (CP) and alternative (AP) pathways of the complement system and suppressing the proliferation of activated T-cells. The resin also displayed free radical scavenging activity, showing antioxidant or prooxidant effects depending on the concentration, and either stimulating or inhibiting phagocytosis. Additionally, when administered intraperitoneally, the resin demonstrated significant anti-inflammatory effects. However, taspine alone cannot be considered the primary compound responsible for these activities, suggesting that other constituents, likely proanthocyanidins, also play a significant role [23].

Dermocosmetic application

A cream containing C. lechleri resin 3% and Punica granatum seed oil 4% was tested for antistriae activity through in vivo clinical evaluation. The results revealed significant skin modifications at the level of the dermis thickness (14.85% increase), hydration (30.32%), and elasticity of stratum corneum (9.75%). The subjective self-assessment of the volunteers indicated that, after 6 weeks of cream application, striae become less defined and less depressed. Since striae is a complex event caused by multi-origin factors, which involves inflammation, edema, reduction of dermis elastic fibers, fibronectin, and collagens, and depending of the striae type supermelanization or its absence, the improvement of this condition seems to be related to the variety of metabolites in both herbal actives. The high antioxidant capacity of C. lechleri is well known, which probably contributes to the inhibition of inflammation in the first stages of striae production [5], [35], [36], [37].

Activity on smooth muscles and cardiovascular system

Sangre de Drago resin (Croton lechleri) demonstrated concentration-dependent vasoconstriction in rat caudal arteries at concentrations ranging from 10 to 1000 µg/mL, an effect that occurred independently of the endothelium. In arterial preparations pre-constricted with phenylephrine (0.1 µM) or KCl (30 mM), similar concentration-dependent vasoconstrictive effects were observed. To investigate the underlying mechanisms, selective inhibitors, including prazosin, atropine, and ritanserin, were applied. However, none of these inhibitors affected the vasoconstrictive response induced by the resin. Additionally, nifedipine, an L-type calcium channel blocker, did not alter the vasoconstriction induced by the resin, nor did capsaicin, a vanilloid receptor agonist, have any impact on this response. Further investigation into the action of C. lechleri resin on the rat gastric fundus revealed a slight increase in contractile tension. Pre-treatment with resin (100 µg/mL) enhanced the contraction induced by carbachol (1 µM), while contractions induced by KCl (60 mM) or capsaicin (100 nM) remained unaffected. These findings suggest that C. lechleri resin induces concentration-dependent increases in contractile tension in both vascular and gastric smooth muscle tissues [38]. Moreover, C. lechleri resin was found to inhibit bovine serum albumin (BSA) glycation and exhibited a protective effect against LDL oxidation, extending the lag phase by nearly 60% at a concentration of 0.8 mg/mL. The resin was also assessed for its effects on cell viability and reactive oxygen species (ROS) production in human umbilical vein endothelial cells (HUVECs), where it demonstrated significant free radical scavenging activity. Specifically, the resin (at 1.0 and 10.0 µg/mL) significantly reduced both baseline and H2O2-induced ROS levels in HUVECs [39]. These studies underscore the potential therapeutic value of C. lechleri resin in the management of vascular disorders.

Other relevant considerations about previous studies

Chen et al. (1994) demonstrated that the acetone fraction of Croton lechleri resin was the most active in promoting endothelial cell proliferation. Monomers of procyanidins, procyanidin B4, 4-hydroxyphenethyl alcohol, and β-sitosterol were identified as the main compounds involved in this mechanism. The authors suggested a multifactorial contribution to the wound-healing activity of the resin, which includes its ability to form a protective film against microbial invasion, the free radical scavenging activity of procyanidins, the high polyphenol content that binds proteins and enzymes in the wound environment, and the anti-inflammatory and potent antibacterial actions of polyphenols, all of which facilitate tissue repair [13]. Earlier, Pieters et al. (1993) demonstrated that the lignan 39,4-O-dimethylcedrusin exhibited similar effects in endothelial cells, protecting them from degradation in a starvation medium and promoting their growth [19].

The protoalkaloid taspine also promoted wound healing through a distinct mechanism, exhibiting a dose-related cicatrizant effect with an ED₅₀ = 0.375 mg/kg, although it did not influence cell proliferation. However, taspine increased the migration of human foreskin fibroblasts without showing toxic effects [40]. In a similar context, Porras-Reyes (1993) proposed that taspine may enhance fibronectin expression, offering an additional mechanism for its action in wound healing [41].

In terms of antidiarrheal activity, SP-303 and pure resin were tested for antisecretory effects using various models. Gabriel et al. (1999) demonstrated that the half-maximal inhibitory dose of SP-303 against cholera-toxin-induced fluid accumulation was approximately 10 mg/kg. Additionally, pretreatment with C. lechleri resin (1 : 1000) in isolated guinea pig ileum inhibited chloride secretion induced by capsaicin by approximately 70% [42].

The anti-inflammatory properties of taspine were evaluated in an animal model of polyarthritis and compared to the effects of indomethacin (1 mg/kg/day, orally). Male rats receiving taspine (20 mg/kg/day, orally) for 3 days prior to adjuvant-induced arthritis and for 17 days post-induction exhibited a marked reduction in paw edema, with results comparable to or exceeding those of indomethacin. In a carrageenan-induced pedal edema study, oral administration of taspine (ED50 = 58 mg/kg) showed a 3- to 4-fold higher anti-inflammatory efficacy compared to phenylbutazone [43].

The antiviral activity of SP-303 has been more extensively studied than other resin constituents [9]. SP-303 demonstrated in vitro activity against herpes simplex viruses (HSV-1 and HSV-2), inhibiting thymidine kinase mutants, and exhibiting significant activity against acyclovir-resistant strains [44], [45]. SP-303 showed the strongest efficacy against various HSV-2 isolates, with an ED₅₀ ranging from 0.9 to 2.1 mg/mL. SP-303 did not induce interferon production, and its mechanism of action differs from that of ribavirin, which inhibits viruses during replication. SP-303 likely inhibits viral activity by interfering with plasma membrane penetration or adsorption at an early stage of the viral life cycle [9], [44]. In guinea pigs vaginally infected with HSV-2, the topical application of an ointment containing 10% SP-303 in dimethyl sulfoxide significantly reduced viral lesions 6 hours post-infection, with efficacy approximately half that of acyclovir 5% ointment. Similar results were observed in mice infected vaginally with HSV-2 after treatment with 10% SP-303 cream or oral administration of 90 mg/kg per day for 8 days. Mice treated topically with the SP-303 10% cream showed a significant reduction in mean lesion scores and 70% survival, compared to 100% survival in acyclovir-treated animals. Intraperitoneal (30 mg/kg per day) or oral SP-303 (270 mg/kg twice daily) administration did not show significantly different results compared to the 10% topical cream [9].

Regarding antiviral effects on other viral infections, SP-303 administered via small-particle aerosol at 9 mg/kg per day to mice infected with influenza A significantly improved survival, reduced pulmonary viral titers, minimized lung tissue damage, and decreased the occurrence of pneumonitis. However, oral or intraperitoneal administration did not yield statistically significant results [46]. Furthermore, SP-303 selectively inhibited several respiratory viruses in vitro [47] and prevented the respiratory syncytial virus (RSV) from penetrating cells [48]. In rats infected with RSV, single intraperitoneal doses of SP-303 (1 – 10 mg/kg per day) resulted in significant reductions in pulmonary viral titers (75% to 97%) compared to placebo, with the highest dose showing results comparable to ribavirin (90 mg/kg i. p., 99% viral titer reduction). Oral doses of 3 mg/kg twice daily significantly reduced viral titers (80% to 99% compared to placebo), but higher or lower doses failed to produce consistent results. Rats treated with 3 mg/kg and 10 mg/kg SP-303 intraperitoneally exhibited significant reductions in parainfluenza virus 3 (PIV3) viral titers (87% to 94%) [49]. In African green monkeys infected with RSV, oral doses of SP-303 (30, 90, or 270 mg twice daily for 7 days) significantly decreased RSV titers. No toxic effects or changes in clinical chemistry were noted in monkeys receiving oral doses of 100, 300, or 900 mg/kg per day for 5 days [50]. Additionally, taspine (70 – 98 mg/mL) inhibited reverse transcriptase by 50% in cell cultures of various tumor viruses, including simian sarcoma virus type I, Rauscher murine leukemia virus, and avian myeloblastosis virus [51].

Clinical trials with SP-303, particularly in HIV-related diarrhea, demonstrated promising results. In Phase III trials, affected patients experienced a 50% reduction in 24-hour stool weight by day 7 following treatment [52]. Furthermore, in AIDS patients, an ointment containing 15% SP-303 w/w showed positive outcomes in treating recurrent anogenital or genital herpes. After 21 days of treatment, 41% of the treated group showed total resolution, compared to only 14% in the placebo group [53].

The soothing effects of a 1% C. lechleri balm on itching and pain resulting from insect bites were evaluated in a group of 10 employees from a U. S. company. The bites caused immediate pain and severe itching, which persisted for weeks. Among the participants, 50% reported pain, 40% discomfort, 60% swelling, 60% redness, and 100% itching. A significant number of workers preferred the active balm over the placebo, with the average time to symptomatic relief being less than 2 minutes. These findings suggest that C. lechleri resin may suppress sensory nerve afferent activity, indicating its potential to alleviate various skin conditions associated with pain, edema, redness, discomfort, and itching [54].

Discussion

Phytochemistry from resin

The efficient wound-healing activity of Croton lechleri is likely attributed to the synergistic effects of various metabolite groups that contribute to tissue repair mechanisms. A major factor in this process is the high content of proanthocyanidins, which possess well-recognized antioxidant properties. These compounds help minimize the inflammatory phase of wound healing, thereby accelerating tissue repair and promoting a more organized restructuring of skin architecture [22]. Additionally, dimers and trimers, which are classified as condensed tannins, have the ability to reduce fluid loss through local vasoconstriction and bind to proteins at the skin edges, facilitating faster wound closure [55]. Furthermore, beta-sitosterol, lignans, and polyphenolic compounds possess significant antimicrobial and endothelial proliferation properties, contributing to the overall wound-healing efficacy of C. lechleri resin [13]. Lastly, the protoalkaloid taspine plays a critical role in fibroblast migration, an essential process in the central phase of wound healing, and contributes to the deposition of fibronectin networks, indicative of skin structural cohesion [40], [41].

Due to the commercialization of products marketed as “Dragonʼs Blood”, which are not related to C. lechleri or even the genus Croton, the identification of chemical markers is necessary for quality control. One solution is the simultaneous occurrence of the protoalkaloid taspine and the alkaloid isoboldine, the latter of which occurs in all chemical subtypes of C. lechleri [17], [56]. Additionally, the identification of specific proanthocyanidins, such as Crofelemer, SB-300, or SP-303, could be considered. Instruments like UV spectrophotometers or mass spectrometers would be sufficient for quality control and verification.

Pharmacological activities

Regarding cytotoxic and antitumoral effects, the antioxidant properties of proanthocyanidins and cell cycle interference by taspine are the primary mechanisms of action. These compounds demonstrate selectivity when tested on normal cells. The low IC₅₀ values and efficacy against various tumor cell lines further suggest that C. lechleri has potential as an antitumor agent. Clinical trials, both with and without combinations, should be conducted to verify the real effectiveness of C. lechleri resin in cancer treatment [27], [28].

In addition to their wound-healing and antitumor activities, C. lechleri resin and isolated proanthocyanidins have been shown to be effective in treating various diarrheal conditions, including those associated with HIV. Their anti-inflammatory properties contribute to improving this condition [3], [23]. The anti-inflammatory capacities of C. lechleri are linked to several ethnomedicinal uses and pharmacological observations, as the inflammatory mechanism is involved in processes such as healing, ulcers, and intestinal disorders [55], [57], [58]. C. lechleri may also improve the condition of topical leishmaniasis, acting directly on the etiological agent and preventing complications [34].

Moreover, the resinʼs antiviral activity, effects on smooth muscle contraction, inhibition of vascular oxidative events, and dermocosmetic applications have shown convincing results regarding its efficiency. These findings should encourage further stages of clinical trials and the exploration of their applicability in various therapeutic areas [3], [35], [38], [39].

Conclusion

In general, Croton lechleri, particularly its resin, has been shown to possess numerous health benefits, which align with its traditional ethnobotanical use in the Amazon region. As previously discussed, several of its products have undergone clinical testing and are currently commercially available for use in the health sector. While the species is primarily recognized for its wound-healing properties, it also demonstrates significant antitumor, antiviral, and anti-inflammatory effects, in addition to its beneficial effects on gastrointestinal function, among other actions. Furthermore, extensive research has been conducted to investigate the mechanisms underlying its therapeutic effects, as well as to elucidate its chemical components. These studies have significantly enhanced the understanding of the pharmacological and pharmacognostic properties of C. lechleri. In conclusion, the findings presented and discussed in this review highlight the need for continued research into the speciesʼ diverse biological activities. These further studies should focus on elucidating these activities in greater detail and facilitating the development of new products, including the chemical standardization of C. lechleri derivatives, ensuring that the full therapeutic potential of the species is realized in healthcare applications.

Contributorsʼ Statement

Data Collection: R. D. D. G. Albuquerque, D. Carrasco-Montañez, J. Carranza-González, Y. Ramos-Rivas; Design of the study: R. D. D. G. Albuquerque, F. R. León-Vargas; Analysis and Interpretation of the data: R. D. D. G. Albuquerque, F. R. León-Vargas; Drafting the manuscript: R. D. D. G. Albuquerque; Revision of the manuscript: F. León-Vargas, D. Carrasco-Montañez, J. Carranza-González, Y. Ramos-Rivas.

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