IngredientsCroton lechleri is a species of flowering plant in the spurge family, Euphorbiaceae, that is native to northwestern South America. A medium-sized tree, it is a medicinal plant species used widely by multiple ethnolinguistic groups in the western Amazon basin to treat a variety of ailments. The tree grows from 10–20 m high in the upper Amazon region of Peru, Ecuador, and Colombia; although tall, the trunk is usually less than 30 cm in diameter and is covered by smooth, mottled bark. It has large, heart-shaped, bright-green leaves and unique, greenish-white flowers on long stalks.
The genus Croton is a large one, with 750 species of trees and shrubs distributed across the tropical and subtropical regions of both hemispheres. Crotons are rich in active alkaloids, and several species are well-known medicinal plants used as purgatives and tonics.
It is commonly known as sangre de grado (Peruvian Spanish), sangre de drago (Ecuadorian Spanish), or sangre de grada (Bolivian Spanish), all names referring to this tree's — and several related species' — thick red latex. Other indigenous names include conéwé (Waorani in Ecuador), lan huiqui (Quichua in Ecuador), uruchnum (Untsuri Shuar in Ecuador), and masujuain (Cofan in Ecuador/Colombia).
The Peruvian name sangre de grado means "blood of the dragon" in Spanish. In Ecuador it is named sangre de drago, also meaning "dragon's blood." When the trunk of the tree is cut or wounded, a dark red, sappy resin oozes out as if the tree is bleeding — earning this local name.
The name Sangre de Grado / Sangre de Drago is applied to the viscous latex sap derived from the bark of several Croton species — including C. dracanoides, C. erythrochilus, C. gossypifilius, C. lechleri, C. palanostigma, C. sakutaris, and C. urucurana — indigenous to the South American rainforests. C. lechleri is the most extensively studied species and the one from which the FDA-approved pharmaceutical derivative crofelemer is extracted.
The latex has medicinal properties and is used by local peoples as a liquid bandage, applied to seal wounds, as it dries quickly to form a protective skin-like barrier. The sap is a popular and effective herbal treatment, and so it is commonly harvested from the wild for both local use and for trade. It is also an ingredient of commercial cosmetic preparations. In commerce, the raw sap/latex is the primary preparation; it is also available as liquid extracts, encapsulated powdered extracts, topical preparations, and — in its purified pharmaceutical form (crofelemer) — as 125 mg delayed-release tablets.
The red sap or latex (and also its bark) has a long history of indigenous use in the rainforest and in South America. An early reference dating back to the 1600s notes that Spanish explorer P. Bernabé Cobo found the sap was being used by indigenous tribes throughout Peru and Ecuador. Multiple ethnolinguistic groups in the western Amazon basin have used it to treat a variety of ailments.
The red bark latex of this tree is used in South America to treat a variety of diseases, including topical administration to treat herpes simplex lesions, cuts, and for wound healing. Ethnomedically, the latex is topically applied for the treatment of pain and itching associated with insect bites and stings, as well as plant reactions. It is applied to the gums of patients after tooth extractions, is utilized as a vaginal wash in cases of excessive bleeding, and in the treatment of herpes where it is applied topically.
For centuries, the sap has been used to cover abrasions, cuts, scratches, blisters, bites, and stings to seal wounds and injuries to protect from infection. The sap dries quickly, forming a barrier similar in thickness to the top layer of skin and is considered by some as a "second skin."
Oral administration in traditional practice has been used for diarrhea, stomach ulcers, hepatitis, lung problems, flu, cough, and diabetes. Sangre de Drago is most often utilized by mixed-descent and native people of the Peruvian Amazon for flu and diarrhea. It is taken internally for tonsillitis, throat infections, tuberculosis, peptic ulcers, intestinal disorders, rheumatism, and to enhance fertility and is used by both adults and children. It is also used extensively to stop bleeding, for herpes virus lesions, and for wound healing.
In Peruvian herbal medicine it is recommended for hemorrhaging, as an antiseptic vaginal douche, and topically for healing wounds. It is also used internally for ulcers in the mouth, throat, intestines, and stomach; as an antiviral for upper respiratory viruses, stomach viruses, and HIV; internally and externally for cancer; and topically for skin disorders, insect bites, and stings. In Brazilian traditional medicine the sap is currently used for wounds, hemorrhaging, diarrhea, mouth ulcers, and as a general tonic.
The latex has a deep red or burgundy color that is attributed to its substantial proanthocyanidin content, estimated to be approximately 90% of the solid constituents of the sap. Crofelemer — the most-studied purified fraction — is an oligomeric proanthocyanidin mixture primarily composed of (+)-catechin, (–)-epicatechin, (+)-gallocatechin, and (–)-epigallocatechin monomer units linked in random sequence. The average degree of polymerization for the oligomers ranges between 5 and 7.5, as determined by phloroglucinol degradation. The molecular weight of this compound is 2100.
SP-303, a large proanthocyanidin oligomer isolated from the latex, has demonstrated broad activity against a variety of DNA and RNA viruses. SP-303 and crofelemer are terms often used interchangeably in the literature to denote this purified proanthocyanidin fraction, though crofelemer refers specifically to the pharmaceutical preparation approved by the U.S. FDA.
The remaining approximately 10% of the sap is largely the alkaloid taspine, as well as catechin, epigallocatechin, epicatechin, and low amounts of terpene compounds. It has been shown that Sangre de Drago from Croton draconoides and Croton lechleri contains an alkaloid identified as taspine, which exhibits anti-inflammatory activity.
The wound healing activity of dragon's blood has been evaluated including the alkaloid taspine, the dihydrobenzofuran lignan 3',4-O-dimethylcedrusin, and proanthocyanidins as key constituents. 3',4-O-Dimethylcedrusin improved wound healing in vivo by stimulating the formation of fibroblasts and collagen.
Crofelemer is a botanical drug substance (oligomeric proanthocyanidin) extracted from the stem bark latex of the Croton lechleri tree. It undergoes minimal systemic absorption following oral administration and acts locally within the gastrointestinal (GI) tract by inhibiting the two principal chloride ion channels in the luminal membrane of enterocytes.
Using cell lines and measurement procedures to isolate the effects on individual membrane transport proteins, crofelemer at 50 µM had little or no effect on the activity of epithelial Na⁺ or K⁺ channels or on cAMP or calcium signaling. Crofelemer inhibited the cystic fibrosis transmembrane regulator (CFTR) Cl⁻ channel with maximum inhibition of ~60% and an IC₅₀ ~7 µM. Crofelemer was also found to strongly inhibit the intestinal calcium-activated Cl⁻ channel TMEM16A by a voltage-independent inhibition mechanism with maximum inhibition >90% and IC₅₀ ~6.5 µM. The dual inhibitory action of crofelemer on two structurally unrelated prosecretory intestinal Cl⁻ channels may account for its intestinal antisecretory activity.
Crofelemer has a unique mechanism leading to inhibition of chloride ion secretion by blocking chloride channels in the gastrointestinal lumen. This reduces efflux of sodium and water, which in turn reduces the frequency and consistency of diarrhea.
Taspine was found to be the principal cicatrizant agent in murine models and is able to increase the chemotaxis of human fibroblast cells, which is the most likely mechanism by which the resin and taspine accelerate the wound healing process. The chemotaxis of fibroblasts aids the reformation of the matrix following re-epithelialization, allowing for the regeneration of damaged skin. Topical application of taspine to a wound site produced an increase in wound healing activity and an increase in wound tensile strength 5–7 days following injury. Taspine promotes wound healing via increased migration of fibroblasts to the wound site by acting as a chemotactic factor for fibroblasts.
The beneficial effect of dragon's blood on wound healing was confirmed in vivo. Dragon's blood stimulated contraction of the wound, formation of a crust, formation of new collagen, and regeneration of the epithelial layer. This was in part due to the proanthocyanidins present in dragon's blood, which stimulate contraction of the wound and precipitate with proteins, forming a dark crust covering the wound.
The antiviral mechanism of SP-303 seems to derive from its direct binding to components of the viral envelope, resulting in inhibition of viral attachment and penetration of the plasma membrane.
The sap of C. lechleri decreased capsaicin-mediated chloride secretion by inhibiting activation of sensory afferent nerves. The plant's capacity to inhibit neurogenic inflammation has been noted in experimental models, though human evidence for this specific mechanism is currently lacking.
In one study, it irreversibly altered the microtubule structure of cancer cells, preventing adhesion and inducing apoptosis. These findings are from in vitro studies and have not yet been confirmed in human clinical trials.
DiCesare, DuPont, Mathewson, et al. conducted a double-blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico, published in the American Journal of Gastroenterology (2002; 97:2585–8). A total of 184 persons (>17 years) were selected and doses of 125 mg, 250 mg, or 500 mg of SP-303 or a matching placebo were administered four times a day for 2 days. Enterotoxigenic E. coli was found to be the etiologic agent in 19% of cases. Duration of diarrhea was markedly shortened (21%) during 48 hours of therapy. SP-303 at doses of 125 mg and 250 mg was found to be most effective, resulting in 85–91% partial or complete improvement.
Holodniy, Koch, Mistal, et al. conducted a double-blind, randomized, placebo-controlled Phase II study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS (Am J Gastroenterol, 1999; 94:3267–73). Among 51 adults with AIDS and non-infectious diarrhea treated with SP-303 (crofelemer) or placebo every 6 hours for 4 days, reduction in stool weight was greater with crofelemer (–451 vs. –150 g daily by day 4) and there were no serious adverse events or changes in laboratory values.
In a randomized controlled study in HIV/AIDS patients with a history of diarrhea for at least 1 month while on antiretroviral therapy, 180 patients were randomized to crofelemer 125 mg orally twice a day versus placebo for 4 weeks. The primary endpoint was the percentage of patients who had two or fewer watery stools per week during at least two out of the four weeks of treatment. Patients who received crofelemer had a significant improvement in their daily stool consistency and number of daily watery bowel movements. Patients tolerated the drug well with minimal side effects. Based on this trial, on December 31, 2012, the FDA approved the use of crofelemer in HIV patients on antiretroviral therapy.
The trial was designed to measure clinical response, defined as the number of patients who had 2 or fewer watery bowel movements weekly. Results showed that 17.6% of patients taking crofelemer experienced clinical response compared with 8% taking placebo. In some patients, a persistent anti-diarrheal effect was seen for 20 weeks.
Crofelemer is the first (and so far only) agent to be approved by the US FDA specifically for the symptomatic relief of non-infectious (secretory) diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy (ART). Derived from the red sap of the Croton lechleri plant, crofelemer is the second botanical prescription drug approved by the FDA.
In multiple clinical trials in humans, oral SP-303 was shown to be not absorbed but was effective in improving traveler's and endemic watery diarrhea as well as HIV-associated non-infectious watery diarrhea; in all studies it was described as well tolerated with no differences in adverse events from what occurred with placebo.
Crofelemer has been shown to improve pain in women with irritable bowel syndrome–diarrhea (IBS-D). A trial evaluated the effect of crofelemer on abdominal pain in women with IBS-D, randomized to crofelemer (125 mg) or placebo twice daily for 12 weeks; 240 women were enrolled. There was no significant difference in overall percentage of pain/discomfort-free days between the groups. Supplementary analysis suggests it may help reduce abdominal pain in women with irritable bowel syndrome with diarrhea. Overall the evidence for IBS-D remains preliminary and inconclusive.
The evidence for crofelemer (purified from Sangre de Grado sap) in HIV/AIDS-associated non-infectious diarrhea and travelers' diarrhea is strong, supported by multiple randomized, double-blind, placebo-controlled trials and regulatory approval. Evidence for other diarrheal conditions is preliminary.
The wound healing activity of dragon's blood and some of its constituents — including the alkaloid taspine, the dihydrobenzofuran lignan 3',4-O-dimethylcedrusin, and proanthocyanidins — was evaluated in vivo on rats and compared with the wound healing activity of synthetic proanthocyanidins. The beneficial effect of dragon's blood on wound healing was confirmed. Dragon's blood stimulated contraction of the wound, formation of a crust, formation of new collagen, and regeneration of the epithelial layer.
For wound healing, there are no studies in humans that support this use, but animal studies suggest C. lechleri can decrease the time required for wound healing. The evidence base for wound healing thus remains preclinical (animal and in vitro studies only) and cannot yet be considered established in humans.
SP-303 has demonstrated broad activity against a variety of DNA and RNA viruses. In cell culture, SP-303 exhibits potent activity against isolates and laboratory strains of respiratory syncytial virus (RSV), influenza A virus, and parainfluenza virus. SP-303 also exhibits significant inhibitory activity against herpesvirus (HSV) types 1 and 2, including herpesviruses resistant to acyclovir and foscarnet. Inhibition was also observed against hepatitis A and B viruses.
SP-303 exhibited activity in RSV-infected cotton rats and African green monkeys, PIV-3-infected cotton rats, HSV-2-infected mice and guinea pigs, and influenza A-infected mice. The most successful routes of SP-303 administration for producing efficacy were: topical application to HSV-2 genital lesions in mice and guinea pigs, aerosol inhalation to influenza A-infected mice and PIV-3-infected cotton rats, and oral dosage to RSV-infected cotton rats.
The purified oligomeric proanthocyanidin fraction was first described in 1994 under the name SP-303 as an antiviral drug, but a study testing it for the treatment of herpes simplex did not show any benefit. The antiviral evidence thus remains largely preclinical (cell culture and animal models); clinical evidence for antiviral indications other than the diarrheal context is weak or negative.
In vitro and animal studies suggest C. lechleri can promote the healing of gastric ulcers. Studies done in animals showed that C. lechleri reduced the size of gastric ulcers, but human data are lacking. The evidence for gastric ulcer healing is preclinical only.
The results of in vitro and in vivo studies largely support the majority of ethnomedical uses of sangre de drago including the treatment of diarrhea, wounds, tumors, stomach ulcers, herpes infection, the itching, pain and swelling of insect bites, and other conditions. Clinical studies of sangre de drago products have reported positive results in the treatment of travelers' and watery diarrhea and the symptoms of insect bites. The insect-bite evidence is based on clinical observations documented in the 2003 Jones review, not dedicated randomized controlled trials.
Its array of phytochemical action in preclinical studies includes anti-inflammatory, antioxidant, antimicrobial, antifungal, and antineoplastic properties. In one in vitro study, it irreversibly altered the microtubule structure of cancer cells, preventing adhesion and inducing apoptosis. It also inhibited mutagenicity of 2-Aminoanthracene, although the mechanism is unknown. All anticancer evidence is preclinical; no human clinical trials have evaluated Sangre de Grado or its constituents specifically for cancer treatment or prevention.
Its use by native people has led to scientific study and observation of its in vitro antioxidant activity as well as both mutagenic and antimutagenic behavior. Depending on the concentration, it showed antioxidant or prooxidant properties, and the stimulation or inhibition of phagocytosis. Antioxidant evidence is in vitro; clinical implications remain unstudied.
Crofelemer is FDA-approved for treatment of diarrhea in HIV/AIDS patients on antiretroviral therapy. It acts only luminally in the bowel owing to its size and polarity and is a dual inhibitor of the calcium-activated chloride channel and the cystic fibrosis transmembrane regulator, two of the three channels that control gastrointestinal chloride efflux. Given its mechanism of action, crofelemer may provide a targeted approach at preventing chemotherapy-induced diarrhea in patients with breast cancer receiving certain chemotherapy regimens. The primary aim of the HALT-D (NCT02910219) study is to compare the incidence of all-grade diarrhea for at least 2 consecutive days between patients who receive prophylaxis with crofelemer and those who do not. This application remains investigational.
A variety of traditional uses are associated with dragon's blood resin or sap, such as bleeding control, wound healing, and treatment of GI problems; however, clinical data are lacking to provide dosing recommendations for C. lechleri as a whole-plant preparation.
The following dosages have been reported specifically in published clinical studies of the purified SP-303/crofelemer fraction:
Crofelemer is not systemically absorbed, has relatively few side effects, and presents a targeted approach due to its large molecular size and polarity, which confine it to luminal activity within the gastrointestinal tract.
While its safety has not been evaluated in depth in large prospective studies in humans, dragon's blood is generally regarded as safe, and in several small clinical trials it has not been implicated in any severe adverse events. In small clinical trials for a variety of indications, dragon's blood has not been implicated in causing serum enzyme or bilirubin elevations during therapy.
A variety of toxicological evaluations demonstrated the safety of SP-303, particularly orally, which was predictable, since condensed tannins are a common dietary component.
In controlled trials of crofelemer, an extract of dragon's blood approved for use in non-infectious diarrhea, serum aminotransferase abnormalities arose in 1% to 2% of subjects, but the elevations were mild, transient, and asymptomatic, not requiring dose modification or discontinuation. Therapy with dragon's blood has not been linked to elevations in serum enzymes or to instances of clinically apparent liver injury. Serum enzyme elevations during crofelemer therapy are generally mild and self-limited, resolving even without drug interruption or dose reduction. Other causes of liver injury should be sought before assuming that the abnormalities are due to crofelemer.
Overall, oral crofelemer is a safe and tolerable drug as illustrated in clinical studies. In the Phase II clinical trial evaluating the use of crofelemer in HIV-infected patients, no serious adverse effects were reported by patients and the treatment was well tolerated.
There is not enough reliable information to know if sangre de grado is safe to use when pregnant or breast-feeding. Information regarding safety and efficacy in pregnancy and lactation is lacking.
No drug interactions are well documented for the whole sap or extracts. Animal studies suggest crofelemer may worsen dacomitinib-induced diarrhea; clinical relevance is not yet known. Because crofelemer is not systemically absorbed, the potential for pharmacokinetic drug interactions is considered low, though pharmacodynamic interactions in the GI tract cannot be excluded.
Its use by native people has led to scientific study and observation of its in vitro antioxidant activity as well as both mutagenic and antimutagenic behavior. Studies have noted concentration-dependent effects, with both mutagenic and antimutagenic properties observed in cell-based assays; the clinical significance of these in vitro findings for humans at typical doses remains uncertain.
Health conditions that Sangre de grado may help support.
Body systems that Sangre de grado may help support.
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