Croton lechleri

Health Care Professional Information

Scientific Name
Croton lechleri
Common Name

Sangre de Drago, Dragon’s Blood, Sangre de Grado, Sangre de Dragón, SP-303, crofelemer

Clinical Summary

Croton lechleri is a tree that is found in many regions of South America (1). The dark red viscous latex of this plant, also known as Sangre de Grado or Dragon's blood, has been used in traditional medicine for diarrhea and wound healing.

In vitro and animal studies show that it can promote the healing of gastric ulcers (8), and inhibit cutaneous neurogenic inflammation (15). A proanthocyanidin oligomer isolated from the latex of Croton lechleri has shown benefits in the treatment of traveler diarrhea, and diarrhea experienced by AIDS patients (2) (3). A similar product crofelemer is approved by the FDA as a prescription drug to relieve diarrhea associated with antiretroviral therapy in HIV/AIDS patients (17). However, in a study of AIDS patients with recurrent genital herpes, it was found no more effective than placebo (14).
Sangre de Grado demonstrated apoptotic effects in cancer cells in vitro (4). However, it also increased the viability of leukemic cells in vitro (5). Further research is needed to verify such effects.

Purported Uses
  • Diarrhea
  • Cancer
  • Antiviral agent
  • Gastric ulcers
  • Neurogenic inflammation
  • Wound repair
Constituents
  • Alkaloids: Taspine (present in the sap), Sinoacutine (present in the leaves), glaucine, isoboldine, thaliporphine.
  • Proanthocyanidin oligomers
  • Flavonols· Procyanidins B1 and B4·
  • Diterpenes: bincatriol, crolechinol, crolechinic acid, hardwickiic acid, and koberins A and B.
  • Steroids: beta-sitosterol and beta-sitostenine*

*A mixture of Proanthocyanidin oligomers has been isolated from the sap of C. lechleri and is known as SP-303. SP-303 is largely composed of (-)-galloepicatechin and (+)-gallocatechin,(-)-epicatechin and (+)-catechin.

Mechanism of Action

SP-303, a mixture of proanthocyanidin oligomers was shown to inhibit cAMP-mediated chloride secretion in two intestinal epithelial cell lines (Caco-2 and T84) (6) (7). The dual inhibitory action of crofelemer, a purified proanthocyanidin oligomer, on two structurally unrelated prosecretory intestinal Cl(-) channels may account for the intestinal antisecretory activity (16). The sap of Sangre de Grado decreased capsaicin mediated chloride secretion in vitro (8) by inhibiting activation of sensory afferent nerves. Sangre de Grado irreversibly altered the microtubule structure of cancer cells, resulting in an inability of the cells to adhere and in turn induced cell death via apoptosis (4). It also inhibited the mutagenicity of 2-Aminoanthracene, although the direct mechanism is unknown (10). Topical application of Taspine, an alkaloid from Sangre de Grado sap, to a wound site produced an increase in wound healing activity (11) and an increase in the wound tensile strength 5-7 days following injury (12). Taspine promotes wound healing via increase in migration of fibroblasts to the wound site (11) by acting as a chemotactic factor for fibroblasts (12).

Pharmacokinetics

Oral administration of SP-303 resulted in little or no gastrointestinal absorption of SP-303 (1).

Adverse Reactions

Localized burning sensation upon topical application.
Upper respiratory tract infection, bronchitis, cough, flatulence, and increased levels of the liver enzyme bilirubin have been reported in a clinical study of crofelemer (17).

Herb Lab Interactions

Increased bilirubin has reported in clinical study using crofelemer (17).

Literature Summary and Critique

Orozco-Topete R, et al. Safety and Efficacy of Virend for Topical Treatment of Genital and Anal Herpes Simplex Lesions in Patients with AIDS. Antiviral Research 1997; 35: 91-103.
A multicenter, double-blind, placebo-controlled study found that a topical preparation containing 15% SP-303 was no more effective than placebo in treating recurrent genital herpes lesions in AIDS patients. Of the 45 patients recruited for this study, 24 were randomly assigned to the treatment group and 21 to the placebo group. At the end of the study, there was a higher percentage of patients in the treatment group whose lesions had completely healed as compared to the placebo group. However, these results were not statistically significant (P = 0.079). Several patients withdrew from this study (for a variety of reasons that included experiencing a burning sensation at the site of application, advancing HIV disease, and death.)

Holodniy M, et al. 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 Gastroenterology 1999; 94 (11): 3267-3273.
A multicenter, phase II, double-blind, placebo-controlled study found that oral administration of SP-303 may be effective in the treatment of diarrhea in AIDS patients. Fifty-one patients were randomized to receive either a 500 mg oral tablet of SP-303 or placebo every 6 hours over the course of 4 days. Using a daily measures analysis over the four days of treatment, the authors demonstrated that patients who received SP-303 tablets had a significant reduction in stool weight (p = 0.008), as well as a reduction in abnormal stool frequency (p = 0.04) when compared to those who received placebo. The authors report that oral administration of SP-303 seems to be safe and well tolerated.

DiCesare D, et al. A Double Blind, Randomized, Placebo-Controlled Study of SP-303 (Provir) in the Symptomatic Treatment of Acute Diarrhea Among Travelers to Jamaica and Mexico. Am J Gastroenterology 2002; 97(10): 2585-2588.
A double blind, randomized, placebo-controlled study found that oral administration of SP-303 may be effective in the treatment of travelers' diarrhea. A total of 184 patients were recruited for this study who had all traveled to Mexico or Jamaica and presented with a clinical history of abrupt onset non bloody diarrhea of a duration of 48 hours or less. The participants were randomly assigned to 1 of 4 treatment groups that were given tablets containing either 125 mg SP-303, 250 mg SP-303, 500 mg SP-303, or placebo. Participants were instructed to take the tablets four times a day for a total of two days. The authors found that oral administration of SP-303 was effective in shortening the duration of travelers' diarrhea by 21%. In addition, the authors also reported a partial or complete improvement of symptoms on day 1 in the treatment group.

References
  1. Jones K. Review of sangre de drago (Croton lechleri)—a South American tree sap in the treatment of diarrhea, inflammation, insect bites, viral infections, and wounds: traditional uses to clinical research. J Altern Complement Med 2003;9(6):877-96.
  2. DiCesare D, DuPont HL, Mathewson JJ, et al. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol 2002;97(10):2585-8.
  3. Holodniy M, Koch J, Mistal M, et al. 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(11):3267-73.
  4. Sandoval M, Okuhama NN, Clark M, et al. Sangre de grado Croton palanostigma induces apoptosis in human gastrointestinal cancer cells. J Ethnopharmacol 2002;80(2-3):121-9.
  5. Styczynski J, Wysocki M. Alternative medicine remedies might stimulate viability of leukemic cells. Pediatr Blood Cancer 2006;46(1):94-8.
  6. Fischer H, Machen TE, Widdicombe JH, et al. A novel extract SB-300 from the stem bark latex of Croton lechleri inhibits CFTR-mediated chloride secretion in human colonic epithelial cells. J Ethnopharmacol 2004;93(2-3):351-7.
  7. Gabriel SE, Davenport SE, Steagall RJ, Vimal V, Carlson T, Rozhon EJ. A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion. Am J Physiol 1999;276(1 Pt 1):G58-63.
  8. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol 2000;279(1):G192-200.
  9. Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dermatol 2001;117(3):725-30.
  10. Rossi D, Bruni R, Bianchi N, et al. Evaluation of the mutagenic, antimutagenic and antiproliferative potential of Croton lechleri (Muell. Arg.) latex. Phytomedicine 2003;10(2-3):139-44.
  11. Vaisberg AJ, Milla M, Planas MC, et al. Taspine is the cicatrizant principle in Sangre de Grado extracted from Croton lechleri. Planta Med 1989;55(2):140-3.
  12. Porras-Reyes BH, Lewis WH, Roman J, Simchowitz L, Mustoe TA. Enhancement of wound healing by the alkaloid taspine defining mechanism of action. Proc Soc Exp Biol Med 1993;203(1):18-25.
  13. Chen ZP, Cai Y, Phillipson JD. Studies on the anti-tumour, anti-bacterial, and wound-healing properties of dragon's blood. Planta Med 1994;60(6):541-5.
  14. Orozco-Topete R, Sierra-Madero J, Cano-Dominguez C, et al. Safety and efficacy of Virend for topical treatment of genital and anal herpes simplex lesions in patients with AIDS. Antiviral Res 1997;35(2):91-103.
  15. Pereira U, Garcia-Le Gal C, Le Gal G, et al. Effects of sangre de drago in an in vitro model of cutaneous neurogenic inflammation. Exp Dermatol. 2010 Sep;19(9):796-9.
  16. Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels.Mol Pharmacol. 2010 Jan;77(1):69-78.
  17. FDA approves first anti-diarrheal drug for HIV/AIDS patients. FDA News Release. US Food and Drug Administration; December 31, 2012. Accessed January 14, 2013.

Consumer Information

How It Works

Bottom line: Sangra de Grado has not been shown to treat cancer in humans. An extract of the plant, crofelemer, is effective in treating certain forms of diarrhea

Sangre de Grado is derived from the dark red viscous sap (latex) of Croton lechleri, a tree that is found in many regions of South America. SP-303, an active ingredient of Sangre de Grado was found effective in the treatment of traveler's diarrhea and diarrhea experienced by AIDS patients. Studies done in animals showed that Sangre de Grado reduced the size of gastric ulcers and also decreased the time required for wound healing but human data is lacking. Laboratory studies indicate that it can kill cancer cells, but no studies have been done in humans.

Purported Uses
  • To treat diarrhea
    Clinical trials showed that Sangre de Grado is effective in the treatment of traveler's diarrhea and the diarrhea experienced by AIDS patients
  • To treat cancer
    Laboratory studies showed that Sangre de Grado can kill cancer cells but human data is lacking
  • To treat viral infections
    One clinical trial found that Sangre de Grado when used topically was no more effective than placebo in treating recurrent genital herpes lesions in AIDS patients
  • To treat gastric ulcers
    Animal studies have shown that Sangre de Grado can reduce the size of gastric ulcers, but there are no human studies
  • For wound healing
    There are no studies in humans that support this use, but animal studies have shown that Sangre de Grado can decrease the time required for wound healing
Research Evidence

Genital herpes associated with AIDS
In a multicenter clinical trial of AIDS patients with recurrent genital herpes lesions, 45 patients received either a topical preparation of 15% SP-303 or placebo. At the end of the study, patients in the SP-303 group reported complete healing of their lesions compared to those in the placebo group. However, authors of the study report that these results were not statistically significant. More studies are needed.

Diarrhea
In this study of 51 AIDS patients with diarrhea, 26 received a 500mg tablet of oral SP-303 whereas 25 patients received a placebo every 6 hours for 4 days. The authors demonstrated that patients in the SP-303 group had a significant reduction in stool weight and abnormal stool frequency compared to those in the placebo group.

Traveler's diarrhea
A total of 184 patients who reported symptoms of diarrhea following travel to Mexico or Jamaica received oral tablets of 125mg SP-303, 250mg SP-303, 500mg SP-303 or placebo. Patients who took SP-303 tablets reported shortening of the duration of diarrhea.

Side Effects
  • May cause skin irritation.
  • Upper respiratory tract infection, cough, gas, and increase in bilirubin levels reported in clinical study using crofelemer
Special Point

Crofelemer, derived from the Croton lechleri plant, is a botanical prescription drug approved by the FDA to treat HIV-associated diarrhea.

E-mail your questions and comments to aboutherbs@mskcc.org.