Scientific Name(s): Croton lechleri Muell. -Arg.
Common Name(s): Blood of the dragon, Crofelemer, Drago, Dragon's blood, Sangre de drago, Sangre de grado, SP-303
The genus Croton comprises approximately 750 species of trees and shrubs commonly found in tropical and subtropical regions. The C. lechleri tree stands 10 to 20 m high, and the trunk is covered with smooth, mottled bark. When the bark is cut or damaged, it oozes a red, sap-like resin, which makes the tree appear to be bleeding. The plant bears heart-shaped leaves 15 to 30 cm in size, as well as 3-celled fruits from small flowers borne on tall, thin spikes.1, 2
A number of other sources of "dragon's blood" are documented, including the genera Dracaena, Daemonorops, and Pterocarpus, as well as mercury sulfide.3 Synonyms include Oxydectes lechleri and Croton draco.
Dragon's blood is mentioned in early Greek, Roman, and Arabic records; however, the source of the preparation varies. As "sangre de grado" (blood of the dragon), its recorded use has been extensive among Latin American countries since the 1600s: both the bark and resin have been used internally and externally to stop bleeding, heal wounds, and treat GI problems (including piles and hemorrhoids).3, 4 The sap has also been used in childbirth and as a remedy for cancer.3, 5, 6, 7
Among other alkaloids, taspine has been isolated from C. lechleri sap, and sinoacutine has been isolated from the leaves.2, 8, 9 Proanthocyanidins (or oligomers) and flavonols are the major phenolic constituents of the sap of C. lechleri, including galloepicatechin, gallocatechin, epicatecin, and catechin.7, 10, 11, 12, 13 Diterpenes and steroidal compounds have also been described.2 The bark essential oil consists primarily of sequiterpenes and monoterpenes.14
Uses and Pharmacology
Antibacterial and Antiviral effects
Antiviral effects have also been seen with C. lechleri extracts and may be related to viral penetration of the cell membrane. Crofelemer demonstrates broad in vitro activity against DNA and RNA viruses, including respiratory syncytial virus, influenza A, parainfluenza virus, herpesvirus types 1 and 2, and hepatitis A and B.13, 16, 17 The constituent taspine inhibited RNA-directed DNA polymerase activity from certain virus types, including leukemia and sarcoma virus.3, 18
Limited clinical studies have been conducted to evaluate antiviral effects. In a 1997 phase 2 clinical study, a 15% crofelemer ointment was not superior to oral acyclovir therapy in the treatment of genital herpes simplex virus infections.2
C. lechleri extracts increased apoptosis in Helen Lake tumor cells and other human cancer cell lines, and they have inhibited tumor growth in mice.3, 6, 7, 19 Thaspine (taspine), a topoisomerase inhibitor, alone induced apoptosis in mouse models of colon cancer.9 An inhibitory effect against mutagens has been demonstrated in vitro.7
Conversely, leukemic cells from children were exposed to C. lechleri extracts and showed both resistance to the extract and increased survival times.20
Clinical studies evaluating the effect of C. lechleri in cancer are lacking.
Crofelemer is an antidiarrheal agent that inhibits both the cyclic adenosine monophosphate–stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (Cl–) channel and the calcium-activated Cl– channels (CaCC) at the luminal membrane of enterocytes. The CFTR Cl– channel and CaCC regulate Cl– and fluid secretion by intestinal epithelial cells. Crofelemer acts by blocking Cl– secretion and the accompanying high volume water loss in diarrhea, normalizing the flow of Cl– and water in the GI tract.13, 21, 22, 23 Experiments in mice have shown an action of C. lechleri sap on smooth muscle cells.24 In neonatal calves with experimentally induced enterotoxigenic Escherichia coli diarrhea, crofelemer increased fecal dry matter.25
A rat study of crofelemer for the severe diarrhea associated with dacomitinib, a tyrosine kinase inhibitor for cancer treatment, found no benefit for diarrhea and may have worsened GI toxicity.26
Crofelemer has been approved by the FDA for symptomatic relief of noninfectious diarrhea in patients with HIV/AIDS who are receiving antiretroviral therapy.23, 27 Clinical studies have been conducted in acute infectious diarrhea, diarrhea in patients with HIV, and diarrhea-predominant irritable bowel syndrome (IBS).13, 21, 23
In a phase 2 randomized, double blind, placebo-controlled study in patients with HIV-associated diarrhea (N = 51), administration of crofelemer 500 mg every 6 hours for 4 days resulted in a reduction in mean stool weight versus placebo (P = 0.14); however, reduction in stool frequency was insignificant.28
In a larger study (N = 374), crofelemer 125 mg twice daily for 4 weeks resulted in a reduction in daily watery stools (P = 0.04) and in daily stool consistency versus placebo (P = 0.02).29
In a trial evaluating crofelemer versus placebo in the treatment of travelers' diarrhea (N = 184), partial or complete resolution of symptoms occurred on day 1 among a significantly greater number of patients treated with crofelemer 125 and 250 mg 4 times daily than among the placebo group (P = 0.04 and 0.003 respectively); however, these results were not observed with crofelemer 500 mg.13, 16, 23, 30
Other, limited studies of infectious diarrhea suggest improvements in primary end points.13, 16 A multicenter, randomized, double-blind, placebo-controlled trial evaluated the efficacy of various doses of crofelemer in 241 adult men and women with diarrhea-predominant IBS. No improvement in stool consistency, frequency, or urgency was found over placebo at 12 weeks. However, improvements in pain-free days were observed in patients receiving crofelemer 500 mg twice daily (P = 0.03), particularly among female patients (P = 0.008).13, 16, 31
Reductions in the size of induced gastric ulcers in rats were achieved when sap from C. lechleri and Croton palanostigma was added to the rats' drinking water for 7 days. A decrease in bacterial counts of ulcers in the sap-drinking rats versus controls was also reported.2
Clinical data regarding the use of C. lechleri sap for gastric ulcers are lacking.
Anti-inflammatory actions of the taspine alkaloid from dragon's blood were first documented in 1979.32 Later studies confirmed these actions, leading to further studies in the area of wound healing. In one study, taspine was found to be the active cicatrizant principle by an in vivo test in mice; increased migration of human fibroblasts was suggested as the probable mechanism in this acceleration of the wound-healing process.33 Another report evaluating taspine's wound-healing properties demonstrated positive results (with higher dosing, these were seen earlier rather than later), using such parameters as wound tensile strength and histology; taspine also stimulated chemotaxis for fibroblasts. Data from the report suggest that taspine promotes early phases of wound healing in a dose-dependent manner.34 Another chemical constituent, a dihydrobenzofuran lignan also involved in wound healing actions, was isolated in 1993.35 Additionally, an in vitro study evaluating the effect of C. lechleri sap demonstrated inhibition of cutaneous neurogenic inflammation.36
Clinical data regarding the use of C. lechleri sap for wound healing are lacking.
The traditional oral dosage is 5 to 10 drops of the sap in water, once to twice per day for 5 days.2 For HIV/AIDS-related diarrhea, crofelemer 125 mg twice daily in adults. Safety and efficacy in children have not been established.38
Pregnancy / Lactation
Fetal Risk Recommendation: No Human Data—Probably Compatible. For more information on pregnancy and lactation, see the professional Crofelemer drug information monograph.
Category C. There are no adequate, well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.
Case reports for interactions with C. lechleri extracts are lacking.
In vitro studies have shown that crofelemer has the potential to inhibit cytochrome P450 isoenzyme 3A (CYP3A) and transporters MRP2 and OATP1A2 at expected concentrations in the gut. Because of the minimal absorption of crofelemer, the drug is unlikely to inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 systemically. Studies in healthy volunteers found no clinically relevant interactions of crofelemer with nelfinavir, zidovudine, or lamivudine.21, 38
No major toxic effects have been reported from consumption of C. lechleri extract, and studies evaluating crofelemer report low levels of GI-related adverse effects (eg, abdominal pain, flatulence, dyspepsia).13, 21 Combined data from HIV studies using crofelemer also report increased bilirubin; however, the clinical relevance of this finding is unclear because systemic absorption of crofelemer is minimal.39
Weak to no mutagenicity in Salmonella and yeast tests has been reported for the sap of C. lechleri,2, 37 and no mutagenicity of the plant essential oil was observed.14 Because the constituent taspine may be cytotoxic, it should not exceed 5,000 ppm.2, 33, 40 The acute oral median lethal dose of crofelemer in rats was determined to be greater than 300 mg/kg.2 Chronic mouse skin carcinogenesis models found no evidence of mutagenicity in topical sap applications.2
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