Introduction

Croton lechleri is a medium-sized tree (10-20 meters or 30-60 feet) native to the Amazonian region of the South American countries of Bolivia, Brazil, Colombia, Ecuador, and Peru. It most commonly grows in the northwest lowland Amazonian forest area in disturbed soil and along rivers and streams.^1-4 Despite its height, the tree has a narrow trunk of approximately 1 foot (30 cm) in diameter.¹ The large leaves are heart-shaped and bright green. The plant’s greenish-white blooms and small 3-part capsule fruit are borne on a spike and are relatively inconspicuous.5 Both the bark and the red latex that seeps from wounds made in the trunk are used medicinally.^1,3,4

History and Cultural Significance

C. lechleri (synonyms: C. draconoides, Oxydectes lechleri) is commonly known as sangre de drago in Peru and sangre de grado in Ecuador, both meaning dragon’s blood.6-8 This refers to the characteristic red or orange-red latex the trunk produces when cut, hence its standardized common name, dragon’s blood croton, according to the American Herbal Products Association’s Herbs of Commerce, 2^nd edition.^1,9 Due to its wide distribution in South America and its concomitant widespread traditional medicinal use, C. lechleri has a plethora of vernacular names—including uruchnum (Untsuri Shuar), lan huiqui (Quichua), masujuain (Cofan), and conéwé (Waorani) used in Ecuador's indigenous languages.⁴

Approximately 750 species of Croton grow throughout tropical and subtropical areas of both hemispheres.10 Milky white sap that is often toxic, or at least irritating to the skin, is common to members of the spurge family, Euphorbiaceae, and some Croton species have no latex at all.^10-12 However, a handful of species found in Mexico and Central and South America produce a red latex that is used medicinally; they include C. lechleri, C. draco, C. palanostigma, C. sordidus, C. urucurana, and C. xalapensis.^3,8,10-12

A 1996 survey in markets in and around Iquitos, Peru, of the ethnomedical uses of dragon’s blood, revealed that 30 of 52 randomly selected people (57%) used the stembark of C. lechleri for diarrhea.¹³ Traditional indications of the latex in South America include treatment of diarrhea and dysentery; treatment of bone cancer and tuberculosis; as a vaginal bath before and following childbirth; in hot water to speed internal healing after an abortion; for treatment of intestinal and stomach ulcers; to treat inflamed or infected gums, fractures, hemorrhoids, and leucorrhea (vaginal discharge, usually non-pathological); and for staunching blood flow and healing wounds.^1,5,13,14 The latex is so often used to stop bleeding in rural Peru that its indigenous common name means “liquid bandage.”⁸ It is also used traditionally for respiratory illnesses such as influenza, lung infections, pharyngitis, pneumonia, respiratory syncytial virus (RSV), tuberculosis, and tonsillitis, as well as bacterial skin infections, cholera, gastritis, herpes simplex, and oral candidiasis.^4,13

Sangre de drago latex has been available in various products in the United States since before the passage of the Dietary Supplements Health and Education Act (DSHEA) in 1994, and it is listed on the old dietary ingredients list of plants submitted by the Utah Natural Products Alliance to the US Food and Drug Administration as part of the Administration’s premarket notification program for New Dietary Ingredients.^4,15

Modern Research

An abundance of chemical constituents have been isolated from sangre de drago including alkaloids, diterpenes, lignans, phenols, phytosterols, proanthocyanidins, steroids, and tannis.^1,8 In vitro studies have been performed on some of these chemicals and some studies have proposed that a complex molecular compound from the latex, a proanthocyanidin oligomer, isolated and named crofelemer (SP-303, NP-303), is the principal active ingredient in the stem bark latex.¹³ Pharmacokinetic studies determined that there is little or no absorption of crofelemer from the GI tract into the bloodstream. SP-303 was standardized by the former Shaman Pharmaceuticals and became the chemical marker for its product Normal Stool Formula (67% by weight of each 350 mg tablet).^4,13 The intellectual property rights for SP-303 transferred to Napo Pharmaceuticals, Inc., and it is currently called crofelemer, the official United States Adopted Name (USAN) for the chemical compound (NP-303).

In a 1993 in vitro study, SP-303 was evaluated for antiviral activity against RSV.¹⁶ EC₅₀ (half maximal effective concentration) values for SP-303 were equal to or better than ribavirin (the only drug approved for treatment of RSV at the time) in the same assays.

A multicenter, double-blind, placebo-controlled, Phase II study performed in 1997 evaluated a topical antiviral agent, Virend^® (15% SP-303 w/w, Shaman Pharmaceuticals, South San Francisco, CA) on recurrent genital herpes lesions in patients with AIDS.¹⁷ Patients received Virend (n=24) or placebo (n=21) 3 times per day for 21 days. Nine Virend patients (41%) experienced complete healing of lesions compared to 3 (14%) in the placebo group. Additionally, 50% of the Virend group became culture negative during treatment as opposed to 19% in the placebo group.

In a 1999 randomized, double-blind, placebo-controlled study to assess the safety and efficacy of treating diarrhea in patients with AIDS, participants discontinued all antidiarrheal medications for more than 24 hours before treatment. Twenty-six subjects received 500 mg of SP-303 orally and 25 received a placebo every 6 hours for 4 days.¹⁸ The SP-303 group experienced a statistically significant reduction in stool weight and abnormal stool frequency.

In one randomized, placebo-controlled study, 98 adult Indian patients with acute watery diarrhea for less than 24 hours were given either 250 mg crofelemer every 6 hours for 2 days or placebo.¹⁹ No antibiotics were allowed in this study. The crofelemer was rated better than placebo at alleviating diarrhea and clinical success was achieved in approximately 75% of the crofelemer group compared to 37% in the placebo group. Additionally, 12 patients in the placebo group required antibiotic rescue compared to 4 patients in the crofelemer group.

In another study, 100 Bangladeshi patients with cholera and acute, severely dehydrating, watery diarrhea were given a placebo, or 125 mg or 250 mg crofelemer QID (4 times per day) as an oral dose.¹⁹ The crofelemer or placebo treatment followed a 4-hour rapid rehydration therapy and oral administration of 1 gm azithromycin by one hour. Both crofelemer doses reduced watery stool volumes by approximately 25-30% in the 0-6 and 0-12 hour periods following the treatment, with the 125 mg dose showing a stronger trend toward reduction of watery stool.

Another randomized, double-blind, placebo-controlled study (n=184, 169 evaluated) examined the effect of SP-303 (Provir™, [100% SP-303 ± 10%]) on traveler’s diarrhea.20 Participants received 125 mg, 250 mg, or 500 mg Provir or placebo 4 times per day for 2 days. The mean number of hours from beginning treatment to the passage of the last unformed stool was 8.1, 8.4, and 6.1 hours, respectively, for the 3 Provir groups, compared to 38.7 hours for the placebo group. Partial or complete improvement on day one per the subjects’ assessments occurred in 85.4%, 91.3%, and 68.3% of the 3 Provir groups compared to 65.9% in the placebo group. Optimal doses were determined to be 125 mg and 250 mg QID for 2 days, which produced an 85-91% partial or complete improvement according to the subjects, compared to 66% for the placebo group.

In a randomized, double-blind, placebo-controlled study, crofelemer was evaluated for the treatment of diarrhea-predominant irritable bowel disease.21 Participants (n=242 from 38 sites in the United States) were given 125 mg, 250 mg, or 500 mg crofelemer or placebo 2 times per day. Crofelemer treatment did not result in significant stool consistency improvement, stool frequency, urgency, or adequate relief in the combined male and female groups; but female patients experienced significant improvement in abdominal pain and increased discomfort-free days. The authors concluded that further studies are warranted to evaluate crofelemer’s analgesic effect.

In 2010, a pivotal Phase 3a, 6-month, double-blind, placebo-controlled study in HIV patients with chronic diarrhea receiving antiretroviral therapy (ART) was completed using crofelemer (ADVENT trial). The results of the study have not been published yet, but topline data were released to the public in November 2010. Crofelemer at a twice daily oral dose of 125 mg was significantly better than placebo treatment in the reduction of watery stools in the HIV patients receiving ART. The p-value for this study was 0.0096 for the primary endpoint. The results from the ADVENT study confirm the previous results observed in acute (1-week) trials in HIV patients with diarrhea.¹⁸

Future Outlook

Tapping C. lechleri over time for large quantities of latex ordinarily kills the trees in a short period of time and yields less latex than felling the tree and tapping it. Counterintuitively, felling trees to extract the latex is more sustainable. Studies have determined that there are approximately 3-10 trees per hectare in rainforest areas of the Andean Amazon region.¹² Shaman Pharmaceuticals sponsored reforestation and agroforestry initiatives with C. lechleri in the 1990s and determined that a ratio of 3 trees planted for every tree harvested was a safe ratio, but that replanting 5 trees when situations are favorable is even better. Primarily due to Shaman’s efforts, more than 230,000 trees have been planted across appropriate habitat in South America. By the end of 2011, Napo will have planted an additional 700,000 trees.

Because dragon’s blood thrives in disturbed soil and produces a large number of seeds, it is a good agricultural crop choice for parts of South America.⁴ Additionally, because it is a very fast-growing pioneer tree (i.e., species that establish themselves quickly in areas disturbed by fire and logging), it improves soil conditions in clear-cut areas through aeration, addition of organic material and important nutrients, balancing soil pH, and catalyzing microbial activity. It also provides shade for understory plants and grows well in plantation crop combinations with banana (Musa spp., Musaceae), chocolate (Theobroma cacao, Sterculiaceae), manioc (Manihot esculenta, Euphorbiaceae), oranges (Citrus sinensis, Rutaceae), and shade-grown coffee (Coffea spp., Rubiaceae), among others.⁴

—Gayle Engels and Josef Brinckmann

References

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2. Taxon: Croton lechleri Müll. Arg. USDA Germplasm Resources Information Network (GRIN). Available at: www.ars-grin.gov/cgi-bin/npgs/html/tax_search.pl. Accessed September 1, 2011.
3. Ubillas R, Jolad SD, Bruening RC, Kernan MR, King SR, Sesin DF, et al. SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de Drago). Phytomedicine. 1994;1(2):77-106.
4. Borges JR, King SR, Hughes K, Meza E, Nelson S, Romero C. Conservation of biocultural diversity in the Amazon and benefit sharing mechanism in the Amazon: Croton lechleri, a traditional indigenous resource. Paper presented at the INPI/EC seminar Role of Intellectual Property Protection in the Field of Biodiversity and Traditional Knowledge. September 9-11, 2001. South San Francisco, CA.
5. Castner JL, Timme SL, Duke JA. A Field Guide to Medicinal and Useful Plants of the Upper Amazon. Gainesville, FL: Feline Press; 1998.
6. Catalogue of Life: 26th July 2011. ITIS Species 2000. Available at: www.catalogueoflife.org/details/species/id/8164170. Accessed September 1, 2011.
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18. 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):3267-3273.
19. Bardhan PK, Sharma A, Bolmall C, et al. Safety and efficacy of a novel anti-secretory anti-diarrheal agent Crofelemer (NP-303), in the treatment of adult acute infectious diarrhea and cholera, with or without the use of antibiotics. U.S.-Japan Cooperative Medical Science Program (CMSP): 13th International Conference on Emerging Infectious Diseases (EID) in the Pacific Rim – Focused on Enteric Diseases. April 6-9, 2009. Kolkata, India.
20. 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):2585-2588.
21. Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel syndrome patients. Digestion. 2008;78(4):180-186.