Croton lechleri

• How It Works

  Croton lechleri has not been shown to treat cancer in humans.

  The dark red sap of C. lechleri, a tree found in many regions of South America, has been used in traditional medicine for wound healing and gastric ulcers. SP-303, a mixture of proanthocyanidin oligomers derived from the plant, was found effective in the treatment of traveler’s diarrhea and diarrhea experienced by AIDS patients. Now known as crofelemer, it is has been approved by the FDA to treat AIDS-associated diarrhea.

  Studies done in animals showed that C.lechleri reduced the size of gastric ulcers and also decreased the time required for wound healing but human data are 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 have shown that C. lechleri is effective in the treatment of traveler’s diarrhea and the diarrhea experienced by AIDS patients
  • To treat cancer
    Laboratory studies showed that C. lechleri can kill cancer cells but human data are lacking
  • To treat viral infections
    One clinical trial found that C. lechleri, 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 C. lechleri 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 C. lechleri can decrease the time required for wound healing
• Do Not Take If

  If you are taking Dacomitinib: Crofelemer was reported to worsen dacomitinib-induced diarrhea in mice. Clinical relevance is not known.

• Scientific Name

  Croton lechleri

• Clinical Summary

  Croton lechleri is a tree that is found in many regions of South America ⁽¹⁾. Its dark red viscous latex, 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 mixture of proanthocyanidin oligomers isolated from the latex of C. lechleri has shown benefits for the treatment of travelers’ diarrhea ⁽²⁾, and diarrhea experienced by AIDS patients ^(3) (18). Named crofelemer, it has been approved by the FDA as a prescription drug to relieve diarrhea associated with antiretroviral therapy in AIDS patients ⁽¹⁷⁾. A clinical trial is underway to determine feasibility and tolerability of crofelemer for preventing diarrhea in breast cancer patients receiving trastuzumab, pertuzumab, and docetaxel or paclitaxel (THP), or trastuzumab, pertuzumab, docetaxel, and carboplatin (TCHP) ⁽¹⁹⁾.

  In other studies, crofelemer was reported to be no more effective than placebo in AIDS patients with recurrent genital herpes ⁽¹⁴⁾, while topical use of a cream containing C. lechleri resin and pomegranate seed oil was found useful in preventing and improving skin changes associated with striae distensae (dermal scarring) ⁽²⁰⁾.

  C. lechleri demonstrated apoptotic effects in cancer cells ⁽⁴⁾. However, it also increased the viability of leukemic cells ⁽⁵⁾. Further research is needed to determine the anticancer potential.

• Purported Uses
  • Diarrhea
  • Cancer
  • Antiviral agent
  • Gastric ulcers
  • Neurogenic inflammation
  • Wound repair
• 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 C. lechleri  also decreased capsaicin mediated chloride secretion ⁽⁸⁾ by inhibiting activation of sensory afferent nerves. In another study, it irreversibly altered the microtubule structure of cancer cells, rendering them incapable of adhering and in turn inducing cell death via apoptosis ⁽⁴⁾. It also inhibited the mutagenicity of 2-Aminoanthracene, although the mechanism is unknown ⁽¹⁰⁾. Topical application of Taspine, an alkaloid derived from C. lechleri 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⁾.

• Contraindications
  • Dacomitinib: Crofelemer was reported to worsen dacomitinib-induced diarrhea in a murine model. Clinical relevance is not known ⁽²¹⁾.
• 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. US Food and Drug Administration; August 14, 2017. Accessed March 27, 2019.

  18. Macarthur RD, Hawkins TN, Brown SJ, et al. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV Clin Trials. 2013 Nov-Dec;14(6):261-73.

  19. Gao JJ, Tan M, Pohlmann PR, Swain SM. HALT-D: A Phase II Evaluation of Crofelemer for the Prevention and Prophylaxis of Diarrhea in Patients With Breast Cancer on Pertuzumab-Based Regimens. Clin Breast Cancer. 2017 Feb;17(1):76-78.

  20. Bogdan C, Iurian S, Tomuta I, Moldovan M. Improvement of skin condition in striae distensae: development, characterization and clinical efficacy of a cosmetic product containing Punica granatum seed oil and Croton lechleri resin extract. Drug Des Devel Ther. 2017 Feb 24;11:521-531.

  21. Van Sebille YZA, Gibson RJ, Wardill HR, Ball IA, Keefe DMK, Bowen JM. Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer. Int J Cancer. 2018 Jan 15;142(2):369-380.