by Gayle Engels
2011; American Botanical Council
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
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
and Cultural Significance
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
Due to its wide distribution in South America and its concomitant
widespread traditional medicinal use, C.
a plethora of vernacular names—including uruchnum
used in Ecuador's indigenous languages.4
750 species of Croton
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
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.
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.
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
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
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
abundance of chemical constituents have been isolated from sangre
de drago including
alkaloids, diterpenes, lignans, phenols, phytosterols,
proanthocyanidins, steroids, and tannis.1,8
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
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
a 1993 in
study, SP-303 was evaluated for antiviral activity against RSV.16
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.
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.
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.
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
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.
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.
a randomized, double-blind, placebo-controlled study, crofelemer was
evaluated for the treatment of diarrhea-predominant irritable bowel
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.
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
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.
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.
dragon’s blood thrives in disturbed soil and produces a large
number of seeds, it is a good agricultural crop choice for parts of
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
Musaceae), chocolate (Theobroma
Euphorbiaceae), oranges (Citrus
and shade-grown coffee (Coffea
Rubiaceae), among others.4
Engels and Josef Brinckmann
Healing Power of Rainforest Herbs. Garden
City Park, NY: Square One Publishers; 2005.
Arg. USDA Germplasm Resources Information Network (GRIN). Available
Accessed September 1, 2011.
R, Jolad SD, Bruening RC, Kernan MR, King SR, Sesin DF, et al.
SP-303, an antiviral oligomeric proanthocyanidin from the latex of
(Sangre de Drago). Phytomedicine.
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
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.
JL, Timme SL, Duke JA. A
Field Guide to Medicinal and Useful Plants of the Upper Amazon.
Gainesville, FL: Feline Press; 1998.
of Life: 26th
July 2011. ITIS Species 2000. Available at:
Accessed September 1, 2011.
Name Details. The International Plant Names Index. Available at:
Accessed September 1, 2011.
K. Review of Sangre
South American tree sap in the treatment of diarrhea, inflammation,
insect bites, viral infections, and wounds: tradition uses to
clinical research. J
Altern Complement Med. December
M, Kartesz JT, Leung AY, Tucker AO. American
Herbal Products Association’s Herbs of Commerce.
2nd ed. Silver Springs, MD: American Herbal Products Association;
Field Guide to the Families and Genera of Woody Plants of Northwest
South America (Columbia, Ecuador, Peru), with supplementary notes on
herbaceous taxa. Chicago:
University of Chicago Press; 1996.
FR, Williamson JS, Rodriguez SV, Angeles G, Portugal VO. Bark
anatomy in Croton
Journal of Botany. 2009;96(12):2155-2167.
KS. Blood of the dragon: the sustainable harvest and replanting of
TJS, King SR. Sangre de drago (Croton
phytomedicine for the treatment of diarrhea. Review
of Complementary and Integrative Medicine. 2000;7(4):315-320.
JA, Vasquez R. Amazonian
Boca Raton, FL: CRC Press; 1994.
of the Utah Natural Products Alliance on the Food and Drug
Administration’s Request for Comment on FDA’s Premarket
Notification Program for New Dietary Ingredients. February 1, 2005.
US Food and Drug Administration website. Available at:
Accessed September 8, 2011.
DL, Huffman JH, Meyerson LR, Sidwell RW. Mode of inhibition of
respiratory syncytial virus by a plant flavonoid, SP-303.
R, Sierra-Madero J, Cano-Dominguez C, et al. Safety and efficacy of
for topical treatment of genital and anal herpes lesions in patients
with AIDS. Antiviral
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.
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.
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.
J Gastroenterol. 2002;97(10):2585-2588.
AW, Chaturvedi P. Evaluation of crofelemer in the treatment of
diarrhea-predominant irritable bowel syndrome patients. Digestion.