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Part to be used
The red latex exuded by rasping the bark. The principal species is Croton lechleri Muell.-Arg.
Active components
The principal components isolated from the latex are:
1. Benzyl-isoquinolinic alkaloid: Taspine
2. Proanthocyanidins (monomers, dimers and trimers of flavan-3-oles)
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3. Lignanes (dihydrobenzofurans):
- Methyl-cedrusyn
- Dimethyl-cedrusyn
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Furthermore, there are beta-sitosterol and beta-sitosterol-3-O-beta-D-glucopyranosid,1,3,5-Trimetoxibencene, 2,4,6-trimetoxiphenol, 3,4-dimetoxiphenol, alcohol 3,4-dimetoxibencyhlic and alcohol 4-hydroxiphenetilic.
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Pharmacological Action:
1.- Healing and anti-ulcerous activity
Stimulates in vitro the contraction of wounds, helps the formation of scabs and regenerates quickly the skin and helps to form collagen.
Life experiments with mice have shown that the taspine has a healing effect depending on its dosage. The taspine promotes the early phases of healing of a wound and its action mechanism may be related with the stimulation of the chemotaxis of fibroblasts.
The taspine reduces the ulceration indices, increases the thickness and the consistence of the gastric mucous layer in gastric ulcer caused by indomethacin in rats.
Dimethylcedrucine also intervenes in the healing of wounds. Latex, however, is four times more effective. Dragon Blood facilitates the healing of gastric ulcers, reducing the mieloperoxydase activity and the size of the ulcer. The polyphenols play an important role in the healing action, probably due to their capitation of free radicals. The proanthocyanidines stimulate the contraction of the wound and the formation of a dark scab which covers the wound. In fact, samples of latex with no dimethylcedrucine and with a very low proportion of taspine have shown a healing activity.
2.- Antiviral and antibacterial activities
Numerous studies support the antiviral activity of Dragon Blood. Experiments in vitro show that its proanthocyanidines inhibit different viruses DNA and RNA, including the herpes virus (HSV, types 1 and 2), hepatitis virus (A and B), the influenza virus A and the parainfluenza virus (PIV). It is also effective against the syncital respiratory virus. The viral activity against the two types of simple herpes viruses is due to that is inhibits the penetration of cells by the virus. However, it is inactive in case of the human cytomegalovirus. The 1,3,5-trimetoxibencene and the 2,4,6-trimetoxiphenol are very active against B. subtilis, more powerful than penicillin and chloranphenichole.
3.- Immune-modulating activity
Dragon Blood has shown in vitro an immune-modulating activity. It has a strong inhibiting activity on classic and alternative ways of the complement system and inhibits the proliferation of stimulated T cells. It shows a dual activity (antioxidant and pro-oxidant) in the modulation of the production of reactive species of oxygen (antioxidant and pro-oxidant activity) in neutrophiles and monocytes of human blood and the phagocytosis (inhibition/stimulation), depending on the tested concentration. Furthermore, it shows a strong inhibiting activity on the classical and alternative ways of the complement system.
Dragon Blood stimulates or inhibits the phagocytosis, by tests in vitro, in human neutrophiles and monocytes, depending on the concentration.
The stimulation of the phagocytosis comes with an increase of the number of cells that phagocyte more than one particle (phagocyte index).
There is also shown an inhibition of the proliferation of stimulated splenocytes with concanavaline A and of murine leukemia cells.
4.- Anti-diarrheic activity
Dragon Blood inhibits, depending on the dosage, the intestinal hypersecretion produced by the choleric toxin in mice. Furthermore, it inhibits the secretion of chloruro induced by phorscholine in vitro.
5.- Anti-inflammatory activity
The taspine shows an anti-inflammatory activity. The taspine is not the only responsible of the anti-inflammatory activity. The latex has shown a strong anti-inflammatory activity by intraperitoneal way. |
Systemic Medicine and Croton lechleri
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| Indications:
Topical use: healing of wounds and burns. Current damages by genital herpes in AIDS patients.
Internal use: gastroduodenal ulcers, treatment of diarrhea produced by choleric toxin and in AIDS patients, viral infections of respiratory ways. Treatment of viral infections of the respiratory ways.
In popular medicine, Dragon Blood is used as a co-helper for the treatment of self-immune sicknesses. Even if there are no clinical tests, the experimental tests show the immune-modulating activity of latex.
Contraindications
There have been neither contraindications nor interactions.
Should not be taken during pregnancy and lactancy without medical supervision. |
| Secondary effects:
None
Presentation:
Amber drop bottle with 30 ml of alcoholic extract 1:10 .
Dosage
10 drops of TID, with the meals. |
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References
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1: J Ethnopharmacol. 2004 Aug;93(2-3):351-357. A novel extract SB-300 from the stem bark latex of Croton lechleri inhibits CFTR-mediated chloride secretion in human colonic epithelial cells. Fischer H, Machen TE, Widdicombe JH, Carlson TJ, King SR, Chow JW, Illek B. Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. |
| An oligomeric proanthocyanidin (SP-303) extracted from the bark latex of the tree Croton lechleri (family Euphorbiaceae) is a potent inhibitor of cholera toxin-induced fluid accumulation and chloride secretion. The manufacturing process for SP-303 was optimized and simplified to produce an increased yield of the herbal extract. The novel extract (named SB-300) contained on average [Formula: see text] SP-303 by weight ( [Formula: see text]; [Formula: see text] lots). Here, we describe the effectiveness of SB-300 on cAMP-regulated chloride secretion, which is mediated by the cystic fibrosis transmembrane conductance regulator Cl(-) channel (CFTR) in human colonic T84 cells. Exposure of the apical surface to SB-300 blocked forskolin-stimulated Cl(-) secretion by [Formula: see text] with a half-maximal inhibition constant (K(B)) of [Formula: see text] microM. For SP-303, stimulated Cl(-) currents were decreased by [Formula: see text] % and K(B) averaged [Formula: see text] microM. There was no significant difference between the blocking kinetics of SP-303 and SB-300. Forskolin-stimulated whole cell Cl(-) currents were effectively blocked by extracellular addition of SB-300 ( [Formula: see text]; [Formula: see text] ) and to a similar extent by SP-303 (83 +/- 0.6%; [Formula: see text]; at 50microM each). Both extracts inhibited a time- and voltage-independent Cl(-) conductance, which indicated the involvement of CFTR Cl(-) channels. We conclude that both SP-303 (used in Provir((R))) and SB-300 (used in NSF Normal Stool Formula trade mark ) are novel natural products that target the CFTR Cl(-) channel. SB-300 is a low cost herbal extract and may present a complementary and alternative medicine approach for the treatment of fluid loss in watery diarrhea. |
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2: J Altern Complement Med. 2003 Dec; 9(6): 877-896.
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.
Jones K. Armana Research, Inc., Halfmoon Bay , British Columbia , Canada . |
| OBJECTIVE: The objective of this review is to provide an overview of the pharmacologic evidence that may or may not support clinical and ethnomedical uses of the sap of sangre de drago (dragon's blood; Croton lechleri Mull . Arg. ). Data sources used were BIOSIS, EMBASE, PubMed, TOXLIT, International Pharmaceutical Abstracts, manual searches, papers on file from peer-reviewed journals, textbooks available at Armana Research, Inc., and researchers in the field of South American botanical medicine. CONCLUSIONS: The results of in vitro and in vivo studies largely support the majority of ethnomedical uses of sangre de drago including the treatment of diarrhea, wounds, tumors, stomach ulcers, herpes infection, the itching, pain and swelling of insect bites, and other conditions. Clinical studies of sangre de drago products have reported positive results in the treatment of traveler's and watery diarrhea and the symptoms of insect bites. Because the sap has shown low toxicity and preparations used in clinical studies were well tolerated, further clinical and pharmacologic studies are anticipated. Acknowledgment of the diversity in the chemical makeup of the sap from one geographic area to another and the recent characterization of alkaloid chemotypes of sangre de drago will require that materials developed for clinical use are standardized. |
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3: Planta Med. 2003 Sep; 69(9): 785-94.
Immunomodulatory activity and chemical characterisation of sangre de drago (dragon's blood) from Croton lechleri.
Risco E, Ghia F, Vila R, Iglesias J, Alvarez E, Canigueral S.
Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Universitat de Barcelona, Spain. |
The immunomodulatory activity of the latex from Croton lechleri (sangre de drago) was determined by in vitro assays. Classical (CP) and alternative (AP) complement pathways activities were determined in human serum. Intracellular generation of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) and monocytes, and phagocytosis of opsonised fluorescent microspheres were measured by flow cytometry. Free radical scavenging activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Activity on proliferation of murine lymphocytes was also investigated. In addition, anti-inflammatory activity was assayed in vivo by carrageenan-induced rat paw oedema test. Some of the activities were compared with those of the isolated alkaloid taspine. Sangre de drago from Croton lechleri showed immunomodulatory activity. It exhibited a potent inhibitory activity on CP and AP of complement system and inhibited the proliferation of activated T-cells. The latex showed free radical scavenging capacity. Depending on the concentration, it showed antioxidant or prooxidant properties, and stimulated or inhibited the phagocytosis. Moreover, the latex has strong anti-inflammatory activity when administered i. p. Taspine cannot be considered the main responsible for these activities, and other constituents, probably proanthocyanidins, should be also involved. |
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4: Phytomedicine. 2003 Mar; 10(2-3): 139-44.
Evaluation of the mutagenic, antimutagenic and antiproliferative potential of Croton lechleri (Muell. Arg.) latex.
Rossi D, Bruni R, Bianchi N, Chiarabelli C, Gambari R, Medici A, Lista A, Paganetto G. CATgroup--Centro Analisi Territoriali, Copparo, Ferrara, Italy. |
| Sangre de Drago is a red viscous latex extracted from Croton lechleri (Euphorbiaceae) cortex, renowned in South American popular medicine for its wound-healing properties. The in vitro antiproliferative effects were determined on the human myelogenous leukemia K562 cells line (IC50 = 2.5 +/- 0.3 microg ml(-1)). The mutagenic and antimutagenic activity of C. lechleri sap was examined by means of the Ames/Salmonella test. No mutagenic activity was found on the Salmonella typhimurium strains T98 and T100, either with or without S9 activation. On the other hand, the sap showed an inhibitory effect against the mutagenic activity of the indirectly acting mutagen 2-Aminoanthracene in presence of S9 and a moderate protective activity against directly acting mutagens Sodium Azide and 2-Nitrofluorene. Therefore we suggest that C. lechleri sap interacts with the enzymes of the S9 mix, thereby inhibiting the transformation of 2-Aminoantracene into its active forms. |
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5: J Nat Prod. 2002 Jun; 65(6): 814-9.
Geographic distribution of three alkaloid chemotypes of Croton lechleri.
Milanowski DJ, Winter RE, Elvin-Lewis MP, Lewis WH.
Department of Biology, Washington University , St. Louis , Missouri , USA . |
| Three known alkaloids, isoboldine (2), norisoboldine (1), and magnoflorine (8), have been isolated for the first time from Croton lechleri, a source of the wound healing latex "sangre de grado". An HPLC system was developed, and a large number of latex and leaf samples of C. lechleri from 22 sites in northern Peru and Ecuador were analyzed to gain an understanding of the natural variation in alkaloid content for the species. Up to six alkaloids were found to occur in the leaves including, in addition to those listed above, thaliporphine (3), glaucine (4), and taspine (9), whereas the latex contained only 9. Taspine (9) is the component that has been previously found to be responsible for the wound healing activity of C. lechleri latex, and its mean concentration throughout the range examined was found to be 9% of the latex by dry weight. In addition, three chemotypes are defined based on the alkaloid content of the leaves, and the geographic distribution of these chemotypes is discussed along with a quantitative analysis of the alkaloid content as a function of chemotype. |
6: Rev Biol Trop. 2001 Mar; 49(1): 259-64.
Diterpenes and other constituents from Croton draco (Euphorbiaceae).
Murillo RM, Jakupovic J, Rivera J, Castro VH. Escuela de Quimica and CIPRONA (Centro de Investigacion de Productos Naturales), Universidad de Costa Rica, Costa Rica.
Croton draco (Euphorbiaceae) from Guadalupe, San Jose , Costa Rica was collected in July 1992 and phytochemically studied (leaves, seeds, wood, bark, sap and flowers separately). Commonly known compounds such as 1-hydroxyjunenol, p-hydroxybenzaldehyde, p-methoxybenzoic acid, 3,4,5-trimethoxycinnamyl alcohol, the coumarin scopoletin, the nor-terpenoids 9-dehydrovomifoliol and 2,3-dihydrovomifoliol were obtained. Taspine, two aporphinic alkaloids, the diterpenes 9(11)-dehydrokaurenic acid, hardwikiic acid, the corresponding new 12-oxo derivative as well as five clerodanes and a phorbol ester were also isolated. Three clerodanes were not previously described and their NMR spectroscopical data and MS fragmentation patterns are reported. |
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7: Altern Med Rev. 2001 Dec; 6(6): 567-79.
Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest with a particular emphasis on Una de Gato and Sangre de Grado.
Williams JE. California Acupuncture College , San Diego , CA , USA . |
Viral diseases, including emerging and chronic viruses, are an increasing worldwide health concern. As a consequence, the discovery of new antiviral agents from plants has assumed more urgency than in the past. A number of native Amazonian medicines of plant origin are known to have antimicrobial and anti-inflammatory activity, although only a few have been studied for their antiviral properties and immunomodulating effects. Those most studied include: Sangre de Grado (drago) (Croton lechleri) in the Euphorbiaceae family and Una de Gato (Uncaria tomentosa) in the Rubiaceae family. This article reviews the chemical composition, pharmacological properties, state of current research, clinical use, and potential antiviral and immunomodulating activity of these and other plants from the Peruvian Amazon.
Publication Types:
• Review
• Review, Tutorial |
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8: Phytochemistry. 2000 Apr; 53(8): 851-4.
Synthesis of methyl dihydrohardwickiate and its C-4 epimer. Structural amendment of natural crolechinic acid.
Costa M, Perles EC. Departamento de Quimica, UFMS, Mato Grosso do Sul, Brazil. |
| Reduction of the alpha, beta-unsaturated ester moiety of (+)-methyl hardwickiate with magnesium in methanol afforded methyl (4aS,6S,8aS,1R,5R)-5, 6,8a-trimethyl-5-[2'-(3"-oxoyl)-ethyl-perhydro-1-naphthalenyl]- carboxaylate, while reduction with sodium in n-propanol, followed by esterification with diazomethane, furnished its C-4 epimer. After comparison of the 1H- and 13C-NMR data of these compounds with those reported for crolechinic acid isolated from Croton lechleri, a stereochemical revision for the natural product is suggested. |
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9: J Nat Prod. 1999 Oct; 62(10): 1385-9.
Detecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo culture.
Kennelly EJ, Flynn TJ, Mazzola EP, Roach JA, McCloud TG, Danford DE, Betz JM. Center for Food Safety and Applied Nutrition , U.S. Food and Drug Administration, Washington , D.C. USA . |
| The novel alkaloid thalictroidine (1), as well as the known alkaloids taspine (2), magnoflorine (3), anagyrine (4), baptifoline (5), 5,6-dehydro-alpha-isolupanine (6), alpha-isolupanine (7), lupanine (8), N-methylcytisine (9), and sparteine (10), were identified from an extract of Caulophyllum thalictroides rhizomes. N-Methylcytisine exhibited teratogenic activity in the rat embryo culture (REC), an in vitro method to detect potential teratogens. The structure of 1 was elucidated using various spectroscopic methods, primarily by NMR techniques. Thalictroidine, anagyrine, and alpha-isolupanine were not teratogenic in the REC at tested concentrations. Taspine (2) showed high embryotoxicity, but no teratogenic activity, in the REC. |
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10: J Ethnopharmacol. 1997 Oct; 58(2): 103-8.
Effects of Sangre de Drago from Croton lechleri Muell.-Arg. on the production of active oxygen radicals.
Desmarchelier C. Catedra de Microbiologia Industrial y Biotecnologia: Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Argentina. |
The total reactive antioxidant potential (TRAP) of 'Sangre de Drago' from Croton lechleri (Euphorbiaceae) was determined by monitoring the intensity of luminol enhanced chemiluminescence enhanced by peroxyl radicals derived from thermolysis of 2,2'-azo-bis(2-amidinopropane). The TRAP index was calculated as 935.4 +/- 141 microM, measured as equivalents of Trolox concentration. On the other hand, the additive incorporation of lower concentrations yielded an instantaneous increase in chemiluminescence, suggesting a prooxidant activity at these levels. DNA sugar damage induced by Fe(II) salts was also used to determine the capacity of the latex to suppress hydroxyl radical-mediated degradation of DNA. As in the case of luminol enhanced chemiluminescence, Sangre de Drago was highly effective in reducing oxidation of DNA at higher concentrations, but showed an increase in the production of TBARS at lower doses, as compared to the control. Finally, antioxidant activity was tested using hydroperoxide-initiated chemiluminescence in rat liver homogenates, and the latex showed an increase in light emission, suggesting the presence of prooxidant compounds.
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11: Phytochemistry. 1995 Apr; 38(6): 1319-43.
A matter of some sensitivity.
Phillipson JD. Department of Pharmacognosy, School of Pharmacy , University of London , U.K.
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The development of sensitive chromatographic and spectroscopic techniques for the isolation and structure determination of natural products has greatly facilitated phytochemical investigations. Chemical investigations of herbarium material have resulted in the isolation of indole, quinoline and isoquinoline alkaloids from a wide number of plants. Examples of novel natural products from higher plants are given and include alkaloids, terpenoids, phenolics and quinones. Some plants investigated have not yielded the types of constituents which would have been predicted from them. Plant tissue cultures provide alternative sources of biologically active compounds and examples investigated include Cinchona, Ailanthus, Brucea and Artemisia for antiprotozoal compounds and Datura for tropane alkaloids. Biological tests are useful for bioassay-guided fractionation of plant extracts and examples of the isolation of a series of natural products with antiprotozoal and cytotoxic activities are given. Chemical and biological investigations into the traditional medicine Dragon's blood (Croton lechleri) from S. America and a Chinese prescription for the treatment of atopic eczema are described. The use of radio-ligand binding assays for the detection of a wide range of biological activities is discussed. Sensitivity of chemical and biological techniques has greatly improved prospects for finding new drug entities from plants and for investigating traditional medicines. Basic phytochemical investigations should continue to be encouraged especially in view of the rapid loss of plant species.
Publication Types:
• Review
• Review, Academic |
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12: Planta Med. 1994 Dec; 60(6): 541-5.
Studies on the anti-tumour, anti-bacterial, and wound-healing properties of dragon's blood.
Chen ZP. Department of Pharmacognosy, School of Pharmacy , University of London , U.K. |
| Three in-vitro assays have been adopted to examine the cytotoxicity and anti-bacterial activity of the blood-red sap of Croton lechleri from Ecuador , and to examine its effect upon the proliferation of endothelial cells. The sap was found not to be cytotoxic. Several simple phenolic compounds and diterpenes showed a potent anti-bacterial activity. The sap has little effect upon the proliferation of endothelial cells, and no single active ingredient was identified. A mechanism for the wound-healing property of the sap has been proposed. |
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13: J Nat Prod. 1993 Jun; 56(6): 899-906.
Isolation of a dihydrobenzofuran lignan from South American dragon's blood (Croton spp.) as an inhibitor of cell proliferation.
Pieters L, de Bruyne T, Claeys M, Vlietinck A, Calomme M, vanden Berghe D. University of Antwerp, Belgium. |
Dragon's blood is a red viscous latex extracted from the cortex of various Croton spp. (Euphorbiaceae), most commonly Croton lechleri, Croton draconoides (or Croton palanostigma), and Croton erythrochilus. It is used in South American popular medicine for several purposes, including wound healing. Bioassay-guided fractionation of dragon's blood, using an in vitro test system for the stimulation of human umbilical vein endothelial cells, has resulted in the isolation of a dihydrobenzofuran lignan, 3',4-O-dimethylcedrusin or 4-O-methyldihydrodehydrodiconiferyl alcohol [2-(3',4'-dimethoxyphenyl)-3-hydroxymethyl-2,3-dihydro-7-methoxybenzo furan-5- propan-1-ol] [1] as the biologically active principle. A related compound, 4-O-methylcedrusin [2-(3',4'-dimethoxyphenyl)-3-hydroxymethyl-2,3-dihydro-7-hydroxybenzo furan-5- propan-1-ol] [2], and the alkaloid taspine [3], also isolated from dragon's blood, were not active in the same assay. A cell proliferation assay, measuring the incorporation of tritiated thymidine in endothelial cells, showed that compound 1 did not stimulate cell proliferation, but rather inhibited thymidine incorporation, while protecting cells against degradation in a starvation medium.
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14: Proc Soc Exp Biol Med. 1993 May; 203(1): 18-25.
Enhancement of wound healing by the alkaloid taspine defining mechanism of action.
Porras-Reyes BH. Division of Plastic Surgery, Washington University School of Medicine, Saint Louis , Missouri .
Taspine (mol wt 369,000) is an alkaloid extracted from trees of Croton (family Euphorbiaceae) of the western Amazon region that has been used by natives and others as a vulnerary agent. Taspine was purified from tree sap to test its healing properties using different topical concentrations in the paired rat surgical incision model. Wound tensile strength and histology were evaluated. Samples treated with 250 micrograms, but not those treated with 50 micrograms or 10 micrograms, had significant higher values for MBS than paired controls (26%, P < 0.005, and 30%, P < 0.001, by Days 5 and 7, respectively). Taspine did not modify MBS at Day 12. Sample treated with 250 micrograms had significantly greater mononuclear cellular infiltration at Days 5 and 7 but not at Day 12. To better understand the effect of taspine as an enhancer of wound healing, we conducted in vitro studies in cell cultures. Taspine stimulated chemotaxis for fibroblasts. Taspine did not have an effect on specific assays for macrophage chemotaxis, neutrophil activation, fibroblast proliferation, or matrix assembly. Taken together, the data suggest that taspine promotes early phases of wound healing in a dose-dependent manner with no substantial modification thereafter. Its mechanism of action is probably related to its chemotactic properties on fibroblasts and is not mediated by changes in extracellular matrix.
15: Chem Pharm Bull ( Tokyo ). 1991 Apr; 39(4): 1041-2.
A cytotoxic substance from Sangre de Grado.
Itokawa H, Ichihara Y, Mochizuki M, Enomori T, Morita H, Shirota O, Inamatsu M, Takeya Tokyo College of Pharmacy, Japan.
Taspine has been isolated as a cytotoxic substance from Sangre de Grado, sap of Croton palanostigma (Euphorbiaceae), by bioassay guided fractionation. The cytotoxicity (IC50) of taspine was found to be 0.39 microgram/ml against KB cells and 0.17 microgram/ml against V-79 cells.
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17: Planta Med. 1989 Apr; 55(2): 140-3.
Taspine is the cicatrizant principle in Sangre de Grado extracted from Croton lechleri.
Vaisberg AJ, Milla M, Planas MC, Cordova JL, de Agusti ER, Ferreyra R, Mustiga MC, Carlin L, Hammond GB. |
| Sangre de Grado extract used by Peruvian natives as a cicatrizant agent, was collected from trees of the species Croton lechleri growing in the Peruvian jungle. The Sangre de Grado was found to contain one alkaloid identified as taspine and which was shown to be the active cicatrizant principle by an in vivo test in mice. This alkaloid exhibited a dose-related cicatrizant effect and an ED50 of 0.375 mg/kg. Experiments with taspine hydrochloride in order to study its mechanism of action in cell culture systems showed that the alkaloid was non-toxic to human foreskin fibroblasts at concentrations below 150 ng/ml and that it had no effect on cell proliferation. On the other hand, taspine hydrochloride was found to increase the migration of human foreskin fibroblasts. This effect on the migration of fibroblasts is probably the mechanism by which Sangre de Grado and taspine hydrochloride accelerate the wound healing process. Using the two-stage mouse skin carcinogenesis system, we have been able to show that neither Sangre de Grado nor taspine hydrochloride had carcinogenic or tumour promoter activity after 17 months of treatment. |
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18: J Pharm Sci. 1979 Jan; 68(1): 124-6.
South American plants II: taspine isolation and anti-inflammatory activity.
Perdue GP, Blomster RN, Blake DA, Farnsworth NR.
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Croton lechleri L. (Euphorbiaceae), a plant from the Upper Amazon Valley of Peru, yielded the alkaloid taspine. The anti-inflammatory activity of taspine hydrochloride was studied using the carrageenan-induced pedal edema method, the cotton pellet-induced granuloma method, and the adjuvant polyarthritis model. |
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19: Am J Gastroenterol. 2002 Oct;97(10):2585-8. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico . DiCesare D, DuPont HL, Mathewson JJ, Ashley D, Martinez-Sandoval F, Pennington JE, Porter SB. The University of Texas-Houston School of Public Health , USA . |
| OBJECTIVE: The study was designed to evaluate the effectiveness of SP-303 (Provir), a plant-derived product with novel antisecretory properties, in the treatment of travelers' diarrhea. METHODS: A total of 184 persons from the United States who acquired diarrhea in Jamaica or Mexico were enrolled in a double-blind, placebo-controlled study examining the effectiveness of three doses of SP- 303 in reducing illness. Subjects were treated with 125 mg, 250 mg, or 500 mg SP-303 or a matching placebo four times a day for 2 days. Subjects kept daily diaries of symptoms and were seen each day for 3 days. Of the subjects, 169 (92%) were included in the efficacy analysis. RESULTS: The most common etiological agent identified was enterotoxigenic Escherichia coli, found in 19% of subjects. The mean time interval from taking the first dose of medication until passage of the last unformed stool during 48 h therapy (TLUS48) was 38.7 h for the placebo group. TLUS48 was shortened by SP-303: 30.6 h for the 125-mg dose group (p = 0.005); 30.3 h for the 250-mg group; and 32.6 h for the 500-mg group (p = 0.01). Treatment failures were seen in 29.3% in the placebo group compared with 7.3% (p = 0.01), 4.3 (p = 0.002), and 9.8 (p = 0.026) in the three treatment groups. SP-303 was well tolerated at all doses. CONCLUSIONS: SP-303 was effective in shortening the duration of travelers' diarrhea by 21%. This antisecretory approach works directly against the pathophysiology of travelers' diarrhea and is not likely to potentiate invasive forms of diarrhea or to produce posttreatment constipation. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial |
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20: Aids Alert. 1998 Sep;13(9):101. Metabolic consequences present new challenge. [No authors listed] |
| AIDS: The 12th World AIDS Conference in Geneva reported disturbing metabolic side effects from potent new therapies, particularly those therapies that use protease inhibitors. Cases of lipodystrophy, hypercholesterole anemia, and coronary artery disease have been reported. Conference attendees also discussed a need for a new definition of AIDS-related wasting. One proposed definition was the involuntary loss of 3 percent body weight in 1 month, 5 percent in 6 months, or 10 percent and greater in 12 months. Diarrhea is a major consequence of wasting and antiretroviral therapies, however, it seems more controllable because of a new drug called Provir (SP-303). Publication Types: Congresses Newspaper Article |
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21: AIDS Treat News. 1998 Jul 17;(No 299):8.
AIDS diarrhea: phase III trial recruiting in over 30 U.S. sites.
[No authors listed]
AIDS: Shaman Pharmaceuticals is recruiting volunteers for a study of Provir (SP-303), an experimental drug being used to treat diarrhea. The drug has been used in South America to treat diarrhea, and works by directly reducing the abnormal flow of water into the intestines. The study involves 6 days of inpatient treatment, and 21 days of outpatient treatment. Volunteers will receive either varying dosages of the drug or a placebo. Enrollment criteria, contact information, and a list of study locations are included. Publication Types: Newspaper Article
22: Treat Rev. 1997 Aug;(No 25):5.
Herpes study and resources.
[No authors listed]
AIDS: Herpes is caused by a virus that causes recurring bouts of cold sores or genital lesions. The differences between herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) are explained. Herpes outbreaks can become harder to treat when the immune system is damaged by HIV. Acyclovir and famciclovir are safe and effective treatments, but preventing infection is especially important in HIV-infected individuals, as the amount of HIV in the blood increases during a herpes outbreak. World Wide Web addresses are provided for alternative herpes treatment information. A current trial is studying the effectiveness of acyclovir used with an antiviral gel, SP-303. Participants will be treated with acyclovir alone or with acyclovir and SP-303 gel. Call the Network for referral information. Publication Types: Newspaper Article |
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23: Clin Infect Dis. 2000 Jun;30(6):908-14. Epub 2000 Jun 14. Management of protease inhibitor-associated diarrhea. Sherman DS, Fish DN. University of Colorado Health Sciences Center, Denver, CO 80262, USA. |
| Diarrhea is a common and often inadequately treated complication in patients with human immunodeficiency virus infection. Diarrhea has a significant impact on quality of life (QOL) and can contribute to malnutrition, weight loss, immunosuppression, and mortality. In addition, diarrhea may have a significant impact on compliance with antiretroviral therapy; however, this impact has not been adequately assessed. Medications, including protease inhibitors (PIs), are recognized as a common cause of diarrhea. Treatment of PI-associated diarrhea is largely nonspecific; most of the available literature is published only in abstract form and is based primarily on retrospective and survey data. Agents for which some efficacy has been shown for treatment of PI-associated diarrhea include oat bran, psyllium, loperamide, calcium carbonate, SP-303, and pancrelipase. Practitioners and patients need to work together to determine which treatment modality is appropriate based on efficacy, cost, and lifestyle. Management of diarrhea is crucial to improving QOL, controlling weight loss, and enhancing overall efficacy of antiretroviral therapy. Publication Types: Review Review, Tutorial |
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24: Am J Gastroenterol. 1999 Nov;94(11):3267-73. 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. Holodniy M, Koch J, Mistal M, Schmidt JM, Khandwala A, Pennington JE, Porter SB. AIDS Research Center, VA Palo Alto Health Care System and Stanford University, California 94304, USA. |
| OBJECTIVE: The aim of this study was to investigate the safety and effectiveness of orally administered SP- 303 in patients with AIDS and diarrhea. METHODS: This is a multicenter, phase II, randomized, double blind, placebo-controlled study. HIV-positive subjects with a history of a CD4 count <200 or an AIDS-defining illness were admitted to an inpatient study unit and screened for diarrhea defined as at least three abnormal (i.e., soft or watery) stools and > 200 g of abnormal stool weight over a 24-h period. Subjects discontinued all antidiarrheal agents >24 h before enrollment. Stool samples were studied for routine pathogens. Subjects received 500 mg p.o. of SP-303 or placebo every 6 h for 96 h (4 days). Stool frequency and weights were recorded. Subjects were monitored for symptoms and side effects and were seen 1 wk later in follow-up. RESULTS: A total of 26 subjects received SP-303, and 25 received placebo. There were no significant demographic differences between treatment arms. A total of 41 subjects (80%) were receiving antiretroviral therapy and 39 subjects (77%) were receiving at least one protease inhibitor. Stool studies revealed no pathogens in 48 of 51 patients (94%). There were no serious adverse events or laboratory abnormalities. The SP-303 treatment group demonstrated a mean reduction from baseline stool weight of 451 g/24 h versus 150 g/24 h with placebo on day 4 of treatment (p = 0.14), and a mean reduction in abnormal stool frequency of three abnormal stools in 24 h versus two in 24 h in the placebo group (p = 0.30). Daily measures analysis over 4 days of treatment demonstrated that SP-303 subjects had a significant reduction in stool weight (p = 0.008) and abnormal stool frequency (p = 0.04) when compared to placebo-treated subjects. CONCLUSIONS: SP-303 is safe and well tolerated. These results suggest that SP-303 may be effective in reducing stool weight and frequency in patients with AIDS and diarrhea. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial |
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25: Am J Physiol. 1999 Jan;276(1 Pt 1):G58-63. A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion. Gabriel SE, Davenport SE, Steagall RJ, Vimal V, Carlson T, Rozhon EJ. Department of Pediatric Gastroenterology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. |
| We have identified an agent (SP-303) that shows efficacy against in vivo cholera toxin-induced fluid secretion and in vitro cAMP-mediated Cl- secretion. Administration of cholera toxin to adult mice results in an increase in fluid accumulation (FA) in the small intestine (FA ratio = 0.63 vs. 1.86 in control vs. cholera toxin-treated animals, respectively). This elevation in FA induced by cholera toxin was significantly reduced (FA ratio = 0.70) in animals treated with a 100 mg/kg dose of SP-303 at the same time as the cholera treatment. Moreover, when SP-303 was administered 3 h after cholera toxin, a dose-dependent inhibition of FA levels was observed with a half-maximal inhibitory dose of 10 mg/kg. In Ussing chamber studies of Caco-2 or T84 monolayer preparations, SP-303 had a significant effect on both basal current and forskolin-stimulated Cl- current. SP-303 also induced an increase in resistance that paralleled the observed decrease in current. These data suggest that SP-303 has an inhibitory effect on cAMP-mediated Cl- and fluid secretion. Thus SP-303 may prove to be a useful broad-spectrum antidiarrheal agent. |
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26: Antiviral Res. 1997 Jul;35(2):91-103. Safety and efficacy of Virend for topical treatment of genital and anal herpes simplex lesions in patients with AIDS. Orozco-Topete R, Sierra-Madero J, Cano-Dominguez C, Kershenovich J, Ortiz-Pedroza G, Vazquez-Valls E, Garcia-Cosio C, Soria-Cordoba A, Armendáriz AM, Teran-Toledo X, Romo-Garcia J, Fernandez H, Rozhon EJ. Instituto Nacional de la Nutricion , Delegacion Tlalpan, Mexico, D.F. |
| Virend (SP-303), a new topical antiviral agent with activity against herpesvirus, was evaluated in a multicenter, double-blind, placebo-controlled Phase II study for safety and effectiveness against recurrent genital herpes lesions in patients with AIDS. The primary endpoints of this study were complete healing of lesions and time to healing. Patients had a history of recurrent genital or anogenital herpes with at least one lesion and positive HSV culture at enrollment. Participants received Virend (15% ointment; 24 patients) or matching placebo (21 patients) three times a day for 21 days. Excluding two patients in the Virend group who received an initial treatment but were lost to follow-up, 9 of 22 (41%) patients treated with Virend experienced complete healing of their lesions compared with three (14%) patients in the placebo group (P = 0.053). Viral culture revealed that 50% of Virend-treated patients and 19% of placebo-treated patients became culture-negative during treatment (P = 0.06). Based on these preliminary clinical findings, further evaluation of Virend for topical treatment of genital herpes in patients with AIDS is planned. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial |
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27: Antiviral Res. 1994 Dec;25(3-4):185-92. Treatment of acyclovir-unresponsive cutaneous herpes simplex virus infection with topically applied SP-303. Safrin S, McKinley G, McKeough M, Robinson D, Spruance SL. Department of Medicine, University of California San Francisco, USA. |
| The naturally occurring polyphenolic biopolymer SP-303 has in vitro activity against both HSV-1 and HSV-2, including strains that are resistant to acyclovir. Nine AIDS patients with acyclovir-unresponsive mucocutaneous herpes simplex virus infection were treated with thrice daily topical SP-303T ointment in an open-label pilot study. Although a transient decrease in lesion size was observed in 4 patients during study drug therapy, and 3 patients sustained a quantitative decrease in virus burden, neither complete healing nor cessation of virus shedding occurred in any patient. Seven patients complained of pain or burning upon application of the study ointment, causing 1 patient to terminate the study. In summary, application of SP-303T ointment effected no significant improvement in the clinical course of 9 AIDS patients with acyclovir-unresponsive HSV infection. |
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28: Chemotherapy. 1994 Jan-Feb;40(1):42-50. Influenza virus-inhibitory effects of intraperitoneally and aerosol-administered SP- 303, a plant flavonoid. Sidwell RW, Huffman JH, Moscon BJ, Warren RP. Institute for Antiviral Research, Utah State University , Logan 84322-5600. |
| The phenolic biopolymer SP-303 was evaluated against experimentally induced influenza A (H1N1) virus infections in mice in a series of experiments. When 30, 10 or 3 mg/kg/day of SP-303 were administered intraperitoneally once daily for 8 days beginning either 48 h before or 4 h after virus exposure, only lung consolidation was significantly reduced; extended (p < 0.01) mean day to death was also seen in the late-therapy groups. The high dosage was lethally toxic in this experiment. A small-particle aerosol (SPA) of 10, 5 and 2.5 mg/ml of SP-303, administered for 1 h three times daily for 5 days beginning 4 h after virus exposure, exerted a similar antiviral effect. Twice-daily 1-hour SPA treatments for 3 days beginning 24 h before virus exposure using 4.3 mg/ml of SP-303 resulted in significant increases in mean day to death and reductions of lung consolidation but no inhibition of lung virus titer. Declines in influenza-induced arterial oxygen saturation, as determined by pulse oximetry, were less in all animals treated with SP-303 by SPA, but this reduced decline was significant (p < 0.01) only in the last experiment. Mice receiving SP-303 by SPA exhibited consistent but reversible hypothermia immediately after termination of treatment. |
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29: Chemotherapy. 1993 May-Jun;39(3):212-7. Mode of inhibition of respiratory syncytial virus by a plant flavonoid, SP-303. Barnard DL, Huffman JH, Meyerson LR, Sidwell RW. Institute for Antiviral Research, Utah State University , Logan . |
| A natural-product polyphenolic polymer of molecular weight 2,100 daltons designated SP-303, was found to have antiviral activity against respiratory syncytial virus (RSV) in the 2-10 microM range in plaque reduction assays and cytopathic-effect-inhibition assays. The material was also virucidal. The 50% effective concentration (EC50) for virucidal activity was 28 microM. Experiments were done to determine the mode(s) of RSV inhibition by SP-303. Interferon was not induced. SP-303 did not inhibit attachment at antiviral concentrations. However, the EC50 for inhibition of virus penetration by SP-303 was 0.48 +/- 0.19 microM. These data suggest that abolition of RSV penetration into host cells is one mechanism whereby SP-303 inhibits RSV replication. |
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30: Antiviral Res. 1993 May;21(1):37-45. SP-303 small-particle aerosol treatment of influenza A virus infection in mice and respiratory syncytial virus infection in cotton rats. Gilbert BE, Wyde PR, Wilson SZ, Meyerson LR . Department of Microbiology and Immunology, Baylor College of Medicine , Houston , TX 77030 . |
| A natural plant product, SP-303, was administered by small-particle aerosol to influenza A/HK virus-infected mice and RSV-infected cotton rats. Aqueous SP-303 at 2 mg/ml in the Collison nebulizer reservoir generated an aerosol with an output of 26 micrograms/l and a particle size distribution of 1.4 microns +/- 4.6 (MMAD +/- GSD). SP-303 at a dosage of 0.5-9.4 mg/kg per day administered for 3-4 days significantly increased both the rate and duration of survival of mice lethally infected with influenza A/HK virus. SP-303 was toxic to mice at 16 mg/kg per day as indicated by weight loss and a decrease in the duration of survival compared to control animals. From these data, a maximum therapeutic index (T.I.) of 12 was calculated. SP-303 given 3-4 days at dosages of 1.3-9.8 mg/kg per day was effective in reducing the pulmonary titer of RSV in infected cotton rats. However, at the 18.7 mg/kg per day dose a significant weight loss compared to control animals was observed; a T.I. of < or = 14 was estimated. These experiments demonstrate that aerosol administration of SP-303 was effective in the treatment of influenza A-infected mice and of RSV-infected cotton rats. |
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31: Chemotherapy. 1993 May-Jun;39(3):203-11.
Antiherpesvirus activity and mode of action of SP- 303, a novel plant flavonoid. Barnard DL, Smee DF, Huffman JH, Meyerson LR, Sidwell RW.
Institute for Antiviral Research, Utah State University , Logan . |
| SP- 303, a natural plant flavonoid polymer of molecular weight 2,100 daltons, was found to have antiviral activity against two strains of type 1 herpes-type simplex virus, including a thymidine-kinase-deficient strain, and a strain of type 2 herpes simplex virus. The 50% effective concentrations (EC50s) were 1-2 microM. Acyclovir, which was run in parallel, had values of 4-28 microM. Surprisingly, the compound was inactive against human cytomegalovirus. SP-303 was also virucidal at 50 microM. Interferon was not induced. The mode of antiviral action of this biopolymer was through inhibition of virus penetration into cells (EC50 = 2.1 +/- 0.2 microM). SP-303 also significantly reduced lesion formation in a mouse vaginal model when applied topically at 5-10%. |
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32: Antiviral Res. 1993 Feb;20(2):145-54.
The antiviral activity of SP- 303, a natural polyphenolic polymer, against respiratory syncytial and parainfluenza type 3 viruses in cotton rats.
Wyde PR, Ambrose MW, Meyerson LR, Gilbert BE. Department of Microbiology and Immunology, Baylor College of Medicine , Houston , TX 77030. |
| SP- 303, a naturally occurring polyphenolic polymer (average M.W. = 2100 Da), was tested in cotton rats (Sigmoden hispidus) for antiviral activity against respiratory syncytial (RSV) and parainfluenza type 3 (PIV3) viruses, and for acute toxicity. Significant reductions in pulmonary RSV titers, compared to pulmonary RSV titers in comparably treated control animals, were seen in cotton rats given 1-10 mg SP-303/kg/day intraperitoneally (i.p.) on days 1 through to 3, after experimental inoculation with RSV. The minimum efficacious dose of SP-303 against PIV3, when given i.p. for 3 days, was 3 mg/kg/day. Higher doses of SP-303 could not be given i.p., as doses > or = 30 mg/kg/day given once daily by this route for 3 or more consecutive days caused both significant weight loss and death in infected or uninfected animals. Although no toxicity was observed following oral administration of up to 270 mg of SP-303 daily for 3 days, this compound had variable antiviral activity when given by this route. |
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33: American Journal of Physiology - Gastrointestinal and Liver Physiology 2000; 279: G192-G200.
Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado.
Miller M, Macnaughton W, Zhang XJ, Thompson JH, Charbonnet RM, Bobrowski P, Lao J, Trentacosti AM, Sandoval M. |
De partment of Pediatrics and Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208; 2 De partment of Pediatrics, Louisiana State University Medical Center, New Orleans, Louisiana 70112; 3 De partment of Physiology and Biophysics, Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1; 4 Universidad Nacional Agraria de la Selva , Tingo Maria, Peru; and 5 Rainforest Phytoceuticals, De lmar, New York 12054
Sangre de grado is an Amazonian herbal medicine used to facilitate the healing of gastric ulcers and to treat gastritis, diarrhea, skin lesions, and insect stings. This study was de signed to evaluate the gastrointestinal applications. Gastric ulcers were induced in rats by brief serosal exposure of the fundus to acetic acid (80%). Sangre de grado was administered in drinking water at 1:1,000 and 1:10,000 dilutions from the postoperative period to day 7 . Guinea pig ileum secretory responses to capsaicin, electrical field stimulation, and the neurokinin-1 (NK-1) agonist [Sar 9 ,Met(O 2 ) 11 ]substance P were examined in Ussing chambers. Sangre de grado facilitated the healing of experimental gastric ulcer, reducing myeloperoxidase activity, ulcer size, and bacterial content of the ulcer. The expression of proinflammatory genes tumor necrosis factor-  , inducible nitric oxi de synthase (iNOS), interleukin (IL)-1  , IL-6, and cyclooxygenase-2 was upregulated by ulcer induction but reduced by sangre de grado treatment, particularly iNOS and IL- 6. In Ussing chambers, sangre de grado impaired the secretory response to capsaicin but not to electrical field stimulation or the NK-1 agonist. We conclu de that sangre de grado is a potent, cost-effective treatment for gastrointestinal ulcers and distress via antimicrobial, anti-inflammatory, and sensory afferent- de pen de nt actions. |
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34. J. Invest. De rmatol., September 1, 2001; 117(3): 725 - 730.
Inhibition of Neurogenic Inflammation by the Amazonian Herbal Medicine Sangre de Grado.
M. J. S. Miller, N. Vergnolle, W. McKnight, R. A. Musah, C. A. Davison, A. M. Trentacosti, J. H. Thompson, M. Sandoval, and J. L. Wallace |
Department of Pediatrics, and Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, New York, U.S.A.; Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada; Department of Chemistry, State University of New York at Albany, and Rainforest Phytoceuticals, LLC, Delmar, New York, New York, U.S.A.
This study was designed to determine if the Amazonian medicinal sangre de grado, confers benefit by suppressing the activation of sensory afferent nerves. Methods: (i) vasorelaxation of rat mesenteric arteries in response to calcitonin gene-related peptide; (ii) rat paw edema in response to protease- activating peptide receptor 2-activating peptide; (iii) rat paw hyperalgesia in response to low-dose protease-activating peptide receptor 2-activating peptide or prostaglandin E 2 ; (iv) gastric hyperemia in response luminal capsaicin; (v) a clinical trial of a sangre de grado balm in pest control workers. The parent botanical was fractionated for evaluation of potential active components. In preconstricted rat mesenteric arteries, highly diluted sangre de grado (1:10,000) caused a shift to the right of the calcitonin gene-related peptide dose-response curve (p < 0.01). Paw edema in response to protease-activating peptide receptor 2-activating peptide (500 µg) was reduced by as single topical administration sangre de grado balm (1% concentration, p < 0.01) for at least 6 h. Hyperalgesia induced by either low-dose protease-activating peptide receptor 2-activating peptide (50 µg) or prostaglandin E 2 was prevented by sangre de grado balm. A fraction possessing analgesic and capsaicin antagonistic properties was isolated and high-performance liquid chromatography and gas chromatography-mass spectrometry analysis indicated that it was a proanthocyandin oligomer. In pest control workers, sangre de grado balm (Zangrado) was preferred over placebo, for the relief of itching, pain, discomfort, edema, and redness in response to wasps, fire ants, mosquitoes, bees, cuts, abrasions, and plant reactions. Subjects reported relief within minutes. We conclude that sangre de grado is a potent inhibitor of sensory afferent nerve mechanisms and supports its ethnomedical use for disorders characterized by neurogenic inflammation. |
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