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Journal of Ethnopharmacology 115 (2008) 361–380

Review Dragon’s blood: Botany, chemistry and therapeutic uses Deepika Gupta a, Bruce Bleakley b, Rajinder K. Gupta a,∗ a University School of Biotechnology, GGS Indraprastha University, K. Gate, Delhi 110006, India b Department of Biology & Microbiology, South Dakota State University, Brookings, South Dakota 57007, USA Received 25 May 2007; received in revised form 10 October 2007; accepted 11 October 2007 Available online 22 October 2007

Abstract Dragon’s blood is one of the renowned traditional medicines used in different cultures of world. It has got several therapeutic uses: haemostatic, antidiarrhetic, antiulcer, antimicrobial, antiviral, wound healing, antitumor, anti-inflammatory, antioxidant, etc. Besides these medicinal applica- tions, it is used as a coloring material, varnish and also has got applications in folk magic. These red saps and resins are derived from a number of disparate taxa. Despite its wide uses, little research has been done to know about its true source, quality control and clinical applications. In this review, we have tried to overview different sources of Dragon’s blood, its source wise chemical constituents and therapeutic uses. As well as, a little attempt has been done to review the techniques used for its quality control and safety. © 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Dragon’s blood; Croton; Dracaena; Daemonorops; Pterocarpus; Therapeutic uses

Contents

1. Introduction ...... 362 1.1. Mythology ...... 362 1.2. Historical uses ...... 362 1.3. Ethnomedicinal uses ...... 363 2. Sources of Dragon’s blood ...... 363 2.1. Croton spp. (Euphorbiaceae) ...... 363 2.1.1. Chemical constituents ...... 363 2.1.2. Bioactivities and therapeutic uses ...... 363 2.2. Daemonorops spp...... 371 2.2.1. Chemical constituents ...... 371 2.2.2. Bioactivities and therapeutic uses ...... 371 2.3. Dracaena spp...... 371 2.3.1. Chemical constituents ...... 371 2.3.2. Bioactivities and therapeutic uses ...... 371 2.4. Pterocarpus spp...... 375 3. Quality control and safety ...... 375 4. Conservation needs ...... 376 5. Conclusion ...... 376 Acknowledgements ...... 376 References ...... 376

∗ Corresponding author. Mobile: +91 9871263252; fax: +91 11 23865941/2. E-mail address: [email protected] (R.K. Gupta).

0378-8741/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2007.10.018 362 D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380

1. Introduction as “Dragon Trees” (The Eleventh Labor of Hercules: The Apples of The Hesperides). Plants are used worldwide for the treatment of diseases and Dragon’s blood was also called “Indian cinnabar” by Greeks novel drugs continue to be developed through research from writers. The name “Dragon’s blood” dates back to the 1st cen- these plants. There are more than 20,000 species of higher plant, tury AD when a Greek sailor wrote, about an island called used in traditional medicines and are reservoirs of potential new Dioscorida where the trees yielded drops of cinnabar, in a ship- drugs. As the modern medicine and drug research advanced, ping manual “Periplus of the Erythrean Sea”. Plinius (1601) also chemically synthesized drugs replaced plants as the source of described that the resin got its name from an Indian legend based most medicinal agents in industrialized countries. Nevertheless on Brahma and Shiva. Emboden (1974) and Lyons (1974) had plants are an important source of lead compounds. However, in also summarized the history and mythology of Dragon’s blood. developing countries, the majority of the world’s population can- According to Lyons, the struggle between a dragon and an ele- not afford pharmaceutical drugs and use their own plant based phant that, at its climax, led to the mixing of the blood of the indigenous medicines. two creatures resulted in a magical substance, “Dragon’s blood” Dragon’s blood is a deep red resin, which has been used imbued with medicinal properties. as a famous traditional medicine since ancient times by many cultures. The term “Dragon’s blood” refers to reddish resinous 1.2. Historical uses products, usually encountered as granules, powder, lumps or sticks used in folk medicine. Dragon’s blood has been used for The crimson red resin was highly prized in the ancient world. diverse medical and artistic applications. It has astringent effect Dragon’s blood (Dracaena cinnabari) was used as a dye and and has been used as a hemostatic and antidiarrhetic drug. medicine in the Mediterranean basin. Miller and Morris (1988) The origin of Dragon’s blood is believed to be from Indian mention use of Dracaena resin as a coloring matter for varnishes, Ocean island of Socotra, now part of Yemen (Angiosperm tinctures, toothpastes, plaster, and for dying horn to make it look Phylogeny Group, 1974). However, there exists a great degree like tortoiseshell. Mabberley (1998) also notes that resinous sap of confusion regarding the source and identity of Dragon’s produced via incisions in the bark or stem of the Dracaena blood. Several alternative sources of Dragon’s blood from cinnabari was used by the Ancients to stain horn to resem- Canary Islands, Madeira, and South East Asia and also from ble tortoiseshell. People in Socotra used resin from Dracaena East and West Africa have been identified (Alexander and cinnabari for dying wool, glue pottery, breath freshener, to dec- Miller, 1995). Dragon’s blood was a name applied to many orate pottery and houses and even as lipstick (Alexander and red resins described in the medical literature, e.g. East Indian Miller, 1996). Due to the belief that it is the blood of the mythi- Dragon’s blood (from the fruit of Daemonorops draco (Willd.) cal animal, the dragon, it is also used in alchemy and for ritual Blume), Socotran or Zanzibar Dragon’s blood (exudates of magic. Dracaena cinnabari Balf. f.), Canary Dragon’s blood (exudates Dragon’s blood from both Dracaena and Daemonorops were formed from incisions of the trunk of Dracaena draco (L.) L.), also used for ceremonies in India. Sometimes Dracaena resin, West Indian Dragon’s blood (exudates of Pterocarpus draco but more often Daemonorops resin, was used in China as red L.), Mexican Dragon’s blood (resin of Croton lechleri Mull.¨ varnish for wooden furniture. These resins were used to color Arg.) and the Venezuelan Dragon’s blood (resin of Croton the surface of writing paper for banners and posters, used espe- gossypifolium Vahl) (Sollman, 1920). cially for weddings and for Chinese New Year. These red resins Mabberley (1998) suggests that Dragon’s blood was pro- were also used as pigment in paint, enhancing the color of duced originally from Dracaena cinnabari, later from Dracaena precious stones and staining glass, marble and the wood for draco and more recently from Daemonorops spp. Zheng et Italian violins. Fulling (1953) reported that Daemonorops resin al. (2004a,b,c) confirms this view and suggests Pterocar- was used in the preparation of drawings. Powdered forms of pus spp., Daemonorops draco and Croton spp. as substitutes Daemonorops resin were used extensively as an acid resist by for Dracaena spp. Thus, the term “Dragon’s blood” in gen- photoengravers during the 1930s (Pankow, 1988). In modern eral is used for all kinds of resins and saps obtained from times Daemonorops resin is still used as a varnish for violins, four distinct plant genera; Croton (Euphorbiaceae), Dracaena in photoengraving, as an incense resin, and as body oil. Dae- (Dracaenaceae), Daemonorops (Palmaceae), and Pterocarpus monorops resin is also added to red ink to make “Dragon’s (Fabaceae). Blood Ink,” which is used to inscribe magical seals and talismans. 1.1. Mythology Spanish naturalist and explorer P. Bernabe´ Cobo (1956) recorded for the first time that Croton’s sap was used widely According to a Greek myth, Landon, the hundred-headed throughout the indigenous tribes of Mexico, Peru, and Ecuador dragon, guardian of the Garden of the Hesperides (the nymph in 1600s. In African-American folk magic or voodoo this daughters of Atlas, the titan who holds up earth and heaven) resin is used in mojo hands for money-drawing or love- was killed by either Hercules (in his quest) or Atlas (as punish- drawing, and is used as incense to cleanse a space of negative ment) while bringing back three golden apples from the garden, entities or influences. In neopagan witchcraft, it is used to depending upon the version of the myth. Landon’s red blood increase the potency of spells for protection, love, banishing and flowed out upon the land and from it sprung up the trees known sexuality. D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380 363

1.3. Ethnomedicinal uses Kew. The Economic Botany Collections at the Royal Botanic Gardens Kew (curated by the Centre for Economic Botany) Dragon’s blood was used by early Greeks, Romans, and contains perhaps the largest (80 accessions comprising of 34 Arabs for its medicinal properties. Locals of Moomy city on Dracaena accessions, 40 Daemonorops and 6 Croton) and most Socotra island used the Dragon’s blood (Dracaena) as a sort reliably identified assembly of Dragon’s blood resins. of cure-all, using it for things such as general wound healing, In this review, we discuss chemistry and therapeutic uses of a coagulant, curing diarrhoea, lowering fevers, dysentery dis- varieties of Dragon’s blood differentiated according to the plant eases, internal ulcers of mouth, throat, intestines and stomach, taxa from which they are obtained. Structures of some of the as an antiviral for respiratory and stomach viruses and for skin compounds reported from these sources are given in Fig. 1. disorders such as eczema. Dioscorides and other early Greek writers described its medicinal uses. Dragon’s blood (Dracaena) 2.1. Croton spp. (Euphorbiaceae) is used for treating dysentery, diarrhoea, hemorrhage and exter- nal ulcers in Yemeni folk medicine (Milburn, 1984). Dracaena Croton lechleri Mull.¨ Arg., the tree growing in Mexico, resin has strong astringent properties and is used as a muscle Venezuela, Ecuador, Peru and Brazil, is possibly the best-known relaxant (Milner, 1992). Gerarde and Johnson (1633) stated that source for Dragon’s blood. Other species are Croton draconoides Dragon’s blood (Dracaena) was used for over flow of courses Mull.¨ Arg., Croton draco Schlect & Cham., Croton urucurana (menses), in fluxes, dysenteries, spitting of blood and fastening Baill., C. xalapensis Kunth, Croton gossypifolium Vahl, Cro- of loose teeth. It was also used to treat gonorrhea, stoppage of ton erythrochilus Mull.¨ Arg. and Croton palanostigma Klotzsch. urine, watery eyes and minor burns (Parkinson, 1640). In China, When the trunk of the tree is cut or wounded, dark red, sappy the red resin of Dracaena cochinchinensis was used by local resin oozes out, known as Sangre de Drago (Dragon’s blood). people for treatment of wounds, leucorrhea, fractures, diarrhoea and piles as well as for intestinal and stomach ulcers (Cai and 2.1.1. Chemical constituents Xu, 1979). Table 2 summarizes the compounds reported from Dragon’s Daemonorops resin is also used in traditional Chinese blood of Croton spp. medicine to stimulate circulation, promote tissue regeneration by aiding the healing of fractures, sprains and ulcers and to con- 2.1.2. Bioactivities and therapeutic uses trol bleeding and pain (Bensky and Gamble, 1993). The medical 2.1.2.1. Antimicrobial and antiviral activity. Sangre de Drago applications of Dragon’s blood resins, mainly the Daemonorops (Croton) has been evaluated as a source of potential chemother- resin have been attributed to the presence of benzoic acid, which apeutic agents based on its ethnomedicinal uses. Chen et al. show antiseptic properties (Piozzi et al., 1974; Badib, 1991). (1994) had studied the antibacterial properties of blood-red sap Croton’s sap is a common household remedy used in Peru, other of Croton lechleri from Ecuador and reported compounds 2, 4, 6- Latin American countries, and among the Latin American pop- trimethoxyphenol, 1, 3, 5-trimethoxybenzene, crolechinic acid ulation of the United States. Croton’s sap is taken orally to cure and korberins A and B present in the sap to exhibit antibacterial different types of diarrhoea and cholera by the indigenous people activity individually. of Amazon basin (Carlson and King, 2000). Other ethnomedi- The aqueous ethanol extract, some fractions of the methanol cal uses of the sap of Croton lechleri in Peru are found in the extract, catechin and acetyl aleuritolic acid of Sangre de Drago treatment of bone fractures, leucorrhea, piles and hemorrhoids obtained from Croton urucurana are reported to show inhibition (Soukup, 1970). Sap of Croton lechleri was also used to speed of Staphylococcus aureus and Salmonella typhimurium (Peres up internal healing after an abortion (Castner et al., 1998) and in et al., 1997). Later, Gurgel et al. (2005) reported in vitro antifun- vaginal baths taken before childbirth (Duke and Vasquez, 1994). gal activity of Sangre de Drago from Croton urucurana, which Croton’s sap has been reviewed by many researchers for its could be due to the presence of catechins like gallocatechin and therapeutic uses (Jones, 2003; Gonzales and Valerio, 2006). epigallocatechin. Antiviral properties of Croton’s sap have also Various therapeutic properties of Dragon’s blood (Croton been evaluated. Extracts of Sangre de Drago have been reported spp.) have been described such as wound and ulcer healing, to have antiviral activity against influenza, parainfluenza, Her- antidiarrhoeic, anticancer, anti-inflammatory and antirheumatic pes simplex viruses I and II, and Hepatitis A and B (Chen et properties (Bettolo and Scarpati, 1979; Perdue et al., 1979; Chen al., 1994; Ubillas et al., 1994; Sidwell et al., 1994; Meza, 1999). et al., 1994; Pieters et al., 1995; Phillipson, 1995; Gabriel et al., SP-303 from Croton’s sap is the most studied constituent for its 1999; Holodniy et al., 1999; Miller et al., 2000). antiviral activity (Wyde et al., 1991, 1993; Barnard et al., 1992; Soike et al., 1992; Gilbert et al., 1993). SP-303 has shown in 2. Sources of Dragon’s blood vitro activity against Herpes simplex viruses (HSV-1 and HSV- 2), inhibition of thymidine kinase mutants of the viruses, and Dragon’s blood is a bright red resin that is obtained from dif- pronounced activity against acyclovir-resistant strains (Barnard ferent species of four distinct plant genera; Croton, Dracaena, et al., 1993; Safrin et al., 1993; Ubillas et al., 1994). Clini- Daemonorops, and Pterocarpus. Table 1 summarizes the differ- cal studies of SP-303 have also been done on AIDS patients ent botanical sources and common names of Dragon’s blood. (Orozco-Topete et al., 1997). Sethi (1977) reported taspine to Pearson and Prendergast (2001) have reviewed Dragon’s blood inhibit reverse transcriptase enzyme in cultures of several tumor samples from different sources kept at Royal Botanic Gardens viruses. 364 D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380

Table 1 Botanical sources and common names of Dragon’s blood Species Plant family Geographical origin Vernacular names

Croton spp. Euphorbiaceae Tropics and subtropics Sangre de draco (Venezuela), Dragon’s blood worldwide Croton, Arleiia, Ian huiqui (Ecuador), Yawar gradwascca (Peru), Sangre de Drago/Grado Croton draco Schltdl. & Cham. Croton lechleri Mull.¨ Arg. Croton draconoides Mull.¨ Arg. Croton urucurana Baill. C. xalapensis Kunth Croton gossypifolium Vahl Croton erythrochilus Mull.¨ Arg. Croton palanostigma Klotzsch Daemonorops spp. Palmaceae South East Asia Jerang or Djerang (Indonesia), Longxuejie (China), Draconis Resina and Sanguis draconis (Sumatra), Kirin-kakketsu (Japan) Daemonorops draco (Willd) Blume D. didymophylla Becc. D. micracantha (Griff.) Becc. D. motleyi Becc. D. rubra (Reinw. ex Blume) Blume D. propinqua Becc. Dracaena spp. Dracaenaceae Socotra, Canary Islands, Zanzibar drop Madeira, East Africa D. cinnabari Balf. f. D. cochinchinensis (Lour.) S.C. Chen Dracaena draco (L.) L. Pterocarpus spp. Fabaceae West Indies and South East India kino, Malabar kino, Kino gum, America Guadaloupe Dragon’s blood, Padauk P. officinalis Jacq.

2.1.2.2. Antitumor and cytotoxic activity. There are various ated the effects of Sangre de Drago (Croton palanostigma)on reports showing Sangre de Drago (Croton) to exhibit cytotox- human cancer cells, AGS (stomach), HT29 and T84 (colon) and icity. Guerrero and Guzman´ (2004) carried out brine shrimp reported induction of apoptosis, and microtubular damages in lethality test (BSLT) to check the cytotoxicity of Croton lechleri. these cell lines. Croton lechleri sap has been reported to be used for treatment of cancer by many researchers (Hartwell, 1969; Pieters et al., 1992; 2.1.2.3. Antihemorrhagic activity. Castro et al. (1999) investi- Cai et al., 1993a,b). Recently, Gonzales and Valerio (2006) have gated the activity of organic extracts of Croton draco against reviewed Croton lechleri for its anticancer activity. hemorrhagic activity induced by the venom of the snake Both- A number of compounds isolated from Sangre de Drago rops asper. Total inhibition of hemorrhage was observed, (Croton) are found to show cytotoxicity. Taspine from Croton probably owing to the chelation of zinc required for the catalytic lechleri sap has shown potent activity against KB and V-79 cells, activity of venom’s hemorrhagic metalloproteinases. Aqueous while flavan-3-ols and proanthocyanidins, which are the major extracts of Croton urucurana antagonized the hemorrhagic components of the sap, are not cytotoxic (Itokawa et al., 1991; activity of the venom of Bothrops jararaca and proantho- Chen et al., 1994). Compound 3,4-O-dirnethylcedrusin from cyanidins were involved in this activity (Esmeraldino et al., Croton spp. was found not to stimulate cell proliferation, but 2005). rather protected cells against degradation in a starvation medium (Pieters et al., 1993). Chen et al. (1994) proposed that antitu- 2.1.2.4. Immunomodulatory activity. The human immune mor activity of Croton’s sap might be because of mechanisms response is a highly complex system involving both innate and other than cytotoxicity such as immunostimulation. Antiprolif- adaptive mechanisms. A biological or pharmacological effect erative effect of latex of Croton lechleri was also determined of compounds on humoral or cellular aspects of the immune in vitro on the human myelogenous leukemia K562 cells line response is referred as immunomodulating activity. Risco et (Rossi et al., 2003). Peres et al. (1997) have reported use of al. (2003) determined immunomodulatory activity of Sangre de Croton urucurana against cancer. Croton draco is also used to Drago from Croton lechleri in vitro and found that it exhibited a treat cancer (Gupta et al., 1996). Latex of Croton draconoides potent inhibitory activity on classical (CP) and alternative (AP) and Croton erythrochilus are also reported to be used against pathways of complement system and inhibited the proliferation cancer (Piacente et al., 1998). Sandoval et al. (2002) evalu- of activated T-cells. D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380 365

Tsacheva et al. (2004) evaluated latex of Croton draco, its port across guinea pig ileum when added to the serosal bath extracts and several latex components (flavonoid myricitrin, the in Ussing chambers and thus may prove to be a cost-effective alkaloid taspine and the cyclopeptides P1 and P2) for their influ- treatment for gastrointestinal ulcers (Miller et al., 2000). Use of ence on both CP and AP activation pathways of the complement latex of Croton lechleri has also been reported in the treatment system using a hemolytic assay and the best inhibition was found of different types of diarrhoea (Ubillas et al., 1994; Carlson for the classical pathway. and King, 2000). SP-303, a heterogeneous proanthocyanidin oligomer of Croton lechleri was found to inhibit in vivo cholera − 2.1.2.5. Antiulcer and antidiarrhoeal activity. There are toxin-induced fluid secretion and in vitro cAMP-mediated Cl reports showing potent antiulcer and antidiarrhoeal activity of secretion and thus may provide a useful broad-spectrum antidiar- Sangre de Drago (Croton). The extracts from Croton species rhoeal agent (Gabriel et al., 1999). Evaluation of safety and have been shown to impair the capsaicin-stimulated ion trans- efficacy of orally administered SP-303 was done for the symp-

Fig. 1. Structure of some of the compounds reported from different sources of Dragon’s bloods. 366 D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380

Fig. 1. (Continued ) tomatic treatment of diarrhoea in travelers (DiCesare et al., 2.1.2.6. Analgesic activity. Peres et al. (1998a) isolated several 2002) and in AIDS patients (Holodniy et al., 1999; Koch et al., compounds showing analgesic activity, namely campesterol, 1999; Koch, 2000). Fischer et al. (2004) derived a novel extract sitosterol, stigmasterol, acetyl aleuritolic acid, catechin, gallo- SB-300 from Croton lechleri that inhibited cAMP-regulated catechin and sitosterol glucoside from Croton urucurana and chloride secretion, mediated by the cystic fibrosis transmem- suggested existence of more potent analgesic compounds or brane conductance regulator Cl− channel (CFTR) in human existence of a synergistic effect. colonic T84 cells and may prove to be a potent antidiarrhoeal agent. Rozhon et al. (1998) have a patent on the use of proan- 2.1.2.7. Antioxidative activity. Desmarchelier et al. (1997) sug- thocyanidin polymer from Croton species as an antidiarrhoeal, gested that Sangre de Drago (Croton lechleri) is highly effective which was issued to Shaman Pharmaceuticals, Inc. USA. The in scavenging peroxyl and hydroxyl radicals at high concen- company has products based on extract from Croton lech- trations. However, prooxidant activity was observed at lower leri sap in the market, named as NSF and NSF-1B, claiming concentrations. When administered to mice subcutaneously, “clinically demonstrated relief from diarrhoea that won’t cause latex of Peruvian Croton lechleri inhibited hepatic lipid peroxi- constipation.” dation but only at concentration of 200 mg/kg in the livers of the Gurgel et al. (2001) evaluated antidiarrhoeal activity of animals; higher concentrations showed toxicity (Desmarchelier red sap obtained from Croton urucurana on castor oil- and de Moraes Barros, 2003). induced diarrhoea in rats, cholera toxin-induced intestinal Later, Risco et al. (2003) reported that depending upon secretion in mice and on small intestinal transit in mice the concentration, latex of Croton lechleri showed antioxi- and suggested potential utility of the red sap from Cro- dant or prooxidant properties, and stimulated or inhibited the ton urucurana in controlling secretory diarrhoea associated phagocytosis. Lopes et al. (2004) also evaluated antioxidant diseases. activity of Croton lechleri sap against the yeast Saccha- D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380 367

Fig. 1. (Continued ) romyces cerevisiae and against maize plantlets treated with 2.1.2.8. Anti-inflammatory activity. In a study on edema in rats, the oxidative agents, apomorphine and hydrogen peroxide and Perdue et al. (1979) reported, for the first time, anti-inflammatory found that sap inhibited the cytotoxic effect of the alkaloid activity of alkaloid taspine isolated from Croton latex. Later, apomorphine in haploid yeast cultures as well as in maize Miller et al. (2001) concluded from a series of studies that the plantlets. Croton sap inhibits neurogenic inflammation by directly block- 368 D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380

Fig. 1. (Continued ) D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380 369

Fig. 1. (Continued ). ing sensory afferent nerve activation at both the prejunctional (2004) reported mutagenic activity of Croton lechieri sap for and postjunctional level. The latex from Croton lechleri has strain TA1535 of Salmonella typhimurium in the presence of strong anti-inflammatory activity when administered i.p. (Risco metabolic activation, a weak mutagenic activity for strain TA98 et al., 2003). and in a haploid Saccharomyces cerevisiae strain XV185-14c for the lys1-1, his1-7 locus-specific reversion and hom3-10 2.1.2.9. Mutagenic and antimutagenic activity. The mutagenic frameshift mutations. and antimutagenic activity of Croton lechieri sap was exam- ined through the Ames/Salmonella test and no mutagenicity of 2.1.2.10. Wound healing activity. Sangre de Drago (Croton)is 2-aminoanthracene was found in the Salmonella typhimurium commonly used as liquid bandage in the Amazon (Jones, 1995, strains T98 and T100 (Rossi et al., 2003). Later, Lopes et al. 2003). Vaisberg et al. (1989) reported a significant increase 370 D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380

Table 2 Chemical constituents reported from Croton spp. Compound name Bioactivity References

Croton draco Schltdl. & Cham. 1-Hydroxyjunenol; 2,3-dihydrovomifoliol; 3,4,5-tri Murillo et al. (2001) methoxycinnamyl alcohol; 9(11)-dehydrokaurenic acid; 9-dehydrovomifoliol; hardwikiic acid; p-hydroxybenzal-dehyde; p-methoxybenzoic acid; scopoletin; taspine (1) Croton urucurana Baill. Sonderianin (2) Antibacterial activity Craveiro and Silveira (1982), Peres et al. (1997, 1998b) Acetyl aleuritolic acid Antibacterial activity, Analgesic Peres et al. (1997, 1998a) activity ␤-Sitosterol; ␤-sitosterol-O-glucoside; campesterol; Analgesic activity catechin; gallocatechin; stigmasterol 12-Epi-methyl-barabascoate (3); Peres et al. (1998b) 15,16-epoxy-3,13(16)-clerodatriene-2-one (4) Fucoarabinogalactan (CU-1) Milo et al. (2002) Croton lechleri Mull.¨ Arg. Taspine (1) Anti-inflammatory activity, wound Perdue et al. (1979), Vaisberg et al. (1989), healing activity, cytotoxic activity Itokawa et al. (1991), Pieters et al. (1993), Porras-Reyes et al. (1993), Chen et al. (1994), Milanowski et al. (2002) 3,4-O-Dimethylcedrusin (7) Wound healing activity, inhibition of Pieters et al. (1990, 1992, 1993, 1995) cell proliferation Procyanidin B-1 and B-4 (27) Cai et al. (1991) Catechin; epigallocatechin; epicatechin; gallocatechin Cai et al. (1991), Chen et al. (1994) Catechin (4-␣-8)-gallocatechin (4-␣-6) gallocatechin; Cai et al. (1991), Phillipson (1995) catechin (4-␣-8)-gallocatechin (4-␣-8)-gallocatechin; gallocatechin (4-␣-6)-epigallocatechin; gallocatechin (4-␣-8)-epi-catechin; gallocatechin (4-␣-8)-gallocatechin (4-␣-8)-epi-gallocatechin Benzofuran-5-yl,2-3-dihydro:2-(3-dimethoxy-phenyl) Pieters et al. (1992) 7-methoxy-3-methoxy-carbonyl-propan-1-oic acid methyl ester; benzofuran-5-yl,2-3-dihydro:2-(4- hydroxy-3-methoxyphenyl)-7-methoxy-3-methoxy- carbonyl-propen-1-oic acid methyl ester ␤-Sitosterol; bincatriol; crolechinol (10); crolechinic acid Cai et al. (1993a), Chen et al. (1994) (11); daucosterol; hardwickiic acid 1,3,5-Trimethoxybenzene Cytotoxic activity, antibacterial activity 2,4,6-Trimethoxyphenol Antibacterial activity 3,4-Dimethoxybenzyl alcohol; 3,4-dimethoxy phenol; Cai et al. (1993a) 4-hydroxyphenethyl alcohol and its acetate; ␤-sitostenone; sitosterol-␤-d-glucopyranoside Korberin A (5); korberin B (6) Antibacterial activity Cai et al. (1993b), Chen et al. (1994) 4-O-Methylcedrusin (8) Pieters et al. (1993) SP-303 (MW = 2200 Da) Antiviral activity Ubillas et al. (1994), Sidwell et al. (1994) Catechin-(4-␣-8)-epigallocatechin Phillipson (1995) Ethyl acetate; ethyl propionate; 2-methyl butanol; Bellesia et al. (1996) 2-methylbutyl acetate; propyl acetate; 3-methybutyl acetate; eucalyptol; 1-butyl acetate; 3-methyl-2-pentanol Isoboldine (13); norisoboldine (12); magnoflorine (14) Milanowski et al. (2002) SB-300 (MW = 3000 Da) Antidiarrhoeal activity Fischer et al. (2004) in the rate of wound repair on topical application of the Cro- vian Sangre de Drago (Croton sp.), a lignan known as 3, ton lechleri sap to skin wounds of mice and found taspine as 4-O-dimethylcedrusin was isolated which protected endothe- the cicatrizant (wound healing) principle. A significant increase lial cells from undergoing degradation in a starvation medium in numbers of migrating cells in an in vitro test for wound- and stimulated endothelial cells, however at high concentra- ing of human fibroblasts also suggested role of taspine for tions it inhibited the cell proliferation (Pieters et al., 1992, wound healing (Vaisberg et al., 1989). From the sap of Peru- 1993). Porras-Reyes et al. (1993) performed a number of tests D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380 371 to determine how taspine accelerated wound healing and found (2004), M.Y. Xia et al. (2004), also studied the mechanism that taspine enhanced wound healing via increased fibroblast of Dracorhodin perchlorate induced apoptosis and concluded migration. that Dracorhodin perchlorate induced cell death via alteration Chen et al. (1994) studied the wound healing activity of Cro- of Bax/Bcl-XL ratio and activation of caspases. ton lechieri sap and concluded that several factors—the ability to form a film that protects against microbial invasion of wounds; 2.2.2.3. Hemostatic and antithrombotic activity. Daemonorops free radical scavenging activity of procyanidins; the high content draco has been studied for its ‘hemostatic’ and ‘vasoactive– of polyphenolics capable of binding proteins and enzymes; and antithrombotic’ activity in Chinese medicinal system (Kiangsu the anti-inflammatory and strong antibacterial action of polyphe- Institute of Modern Medicine, 1977). Studies have provided nols, together facilitating improved healing of damaged tissue, evidences that (2S)-5-methoxy-6-methyl-flavan-7-ol (MMF) may contribute to the wound repairing properties of sap. They possess antiplatelet activity (Tsai et al., 1995). Later, under- tested individual constituents of the sap and found endothelial lying mechanism for antiplatelet activity of MMF was related cell proliferation was increased by Procyanidin B-4 and most to inhibition of thromboxane formation via the inhibition of 2+ 2+ potently by (−)-epigallocatechin and (+)-gallocatechin. Lewis cyclooxygenase and suppression of [Ca ]i (intraplatelet Ca ) et al. (1992) has patented for taspine in DMSO (solvent), which increase (Tsai et al., 1998). healed wounds faster than DMSO alone. 2.3. Dracaena spp. 2.2. Daemonorops spp. The name Dracaena is derived from the Greek word Dragon’s blood resin is also obtained as deep red teardrop- ‘drakainia’ meaning a female dragon (Stern, 1992). The most shaped lumps, separated physically from the immature fruit of striking source is the Dracaena cinnabari Balf. f. which is the South-East Asian rattan- or cane-palm, Daemonorops of endemic to the island of Socotra (Yemen) west of Somalia. Pal- the Indonesian islands. The botanical source was previously inurus, a survey ship of Leut. J.R. Wellsted of the East India identified as Calamus draco Willd. (Daemonorops draco Willd. Company gave first description of the Dragon’s blood tree, Dra- Blume) by Barry et al. (1926), who also described the resinous caena cinnabari, calling it Pterocarpus draco (http://www.rbg- layer as being isolated by placing the fruits in sacks and pounding web2.rbge.org.uk/soqotra/history/page07.html) while under- them and the pulp being treated with boiling water. Subsequently taking a survey of Socotra for the Indian Government in 1835. the resin was kneaded into balls or long sticks. Various grades However, the species was first named and described by the Scot- have been identified by Howes (1949). Other species as source of tish botanist Sir lsaac Bailey Balfour when he visited the island resin are D. didymophylla Becc., D. micracantha (Griff.) Becc., in 1880 (Balfour, 1888). Three grades of Dracaena resin were D. motleyi Becc., D. rubra (Reinw. ex Blume) Blume and D. identified by Balfour (1883), the most valuable being tear-like propinqua Becc. in appearance, followed by one made of small chips and frag- ments, and the cheapest being a molten mixture of fragments 2.2.1. Chemical constituents and refuse. Table 3 summarizes the compounds reported from resin of Voyagers to the Canary Islands in the 15th century obtained Daemonorops draco (Willd.) Blume. Dragon’s blood as dried garnet colored drops from another species Dracaena draco (L.) L., a native to the Canary Islands 2.2.2. Bioactivities and therapeutic uses and Morocco. The canarian dragon tree Dracaena draco was 2.2.2.1. Antimicrobial and antiviral activity. Previously, first described in 1402 (Boutier and Le Verrier, 1872). The resin Mitscher et al. (1972) reported in vitro activity of commercial is exuded from the wounded trunk or branches of the tree. Dra- resin obtained from Daemonorops draco against Staphylococ- caena cochinchinensis (Lour.) S.C. Chen is another species used cus aureus and Mycobacterium smegmatis. This led to further in China as source of Dragon’s blood. evaluation of resin’s components exhibiting antimicrobial activity. Rao et al. (1982) reported that the antimicrobial 2.3.1. Chemical constituents activity of the resin from Daemonorops draco was due to the Table 4 summarizes the compounds reported from Dracaena presence of compounds Dracorhodin and Dracorubin. These spp., used as source of Dragon’s blood. compounds were found to be active against Staphylococcus aureus (ATCC 13709), Klebsiella pneumoniae (ATCC 10031), 2.3.2. Bioactivities and therapeutic uses Mycobacterium smegmafis (ATCC 607) and Candida albicans 2.3.2.1. Antimicrobial and antiviral activity. Mothana and (ATCC 10231). Lindequist (2005) reported antimicrobial activity of chloro- form and methanol extract of Dracaena cinnabari resin from 2.2.2.2. Antitumor and cytotoxic activity. Dracorhodin per- island Soqotra against Staphylococcus aureus (ATCC 6538), chlorate, a synthetic analogue of Dracorhodin, red pigment Bacillus subtilis (ATCC 6059), Micrococcus flavus (SBUG isolated from exudates of the fruit of Daemonorops draco, 16) and Escherichia coli (ATCC 11229). Kumar et al. (2006) has been reported to induce human melanoma A375-S2 cell also reported antimicrobial activity of exudes of red resin and human premyelocytic leukemia HL-60 cell death through of Dracaena cinnabari collected from India against Bacil- the apoptotic pathway (Xia et al., 2005, 2006). M. Xia et al. lus cereus var mycoides (ATCC 11778), Bacillus pumilus 372 D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380

Table 3 Chemical constituents reported from Daemonorops draco (Willd.) Blume Compound name Bioactivity References

Dracorhodin (17) Apoptic activity Brockmann and Junge (1943), Robertson and Whalley (1950), Rao et al. (1982), Gao et al. (1989), Xia et al. (2005) 2,4-Dihydroxy-5-methyl-6-methoxychalcone; Cardillo et al. (1971) 2,4-dihydroxy-6-methoxychalcone; 5-methoxy-7-hydroxyflavan (15) Nordracorhodin (16); nordracorubin (18) Cardillo et al. (1971), Rao et al. (1982) (2S) 5-Methoxy-6-methylflavan-7-ol (21) Antiplatelet effects Cardillo et al. (1971), Tsai et al. (1995, 1998) (2S)-5-Methoxyflavan-7-ol (22); Cardillo et al. (1971), Arnone et al. (1997) 5,7-dimethoxy-6-methylflavan Abietic acid; dehydroabietic acid; isopimaric acid; pimaric Piozzi et al. (1974), Trease and Evans (1978) acid; sandaracopimaric acid Secobiflavanoid Merlini and Nasini (1976) Dracorubin (19) Rao et al. (1982) Polysaccharide (MW = 25,000) Anticoagulant activity Gibbs et al. (1983) Dracoalban; dracoresene; dracoresinotannol Hsu (1986) Dammaradienol Antiviral activity, Anti-inflammatory Poehland et al. (1987), Bianchini et al. (1988), activity, cytotoxic activity Akihisa et al. (1996), Shen et al. (2007) Dracooxepine Arnone and Nasini (1989) Dracoflavan A Arnone and Nasini (1990) 2,4-Dimethoxy-3-methylphenol; dracoflavan B1; B2; C1; Anti-inflammatory activity Arnone et al. (1997) C2; D1; D2 1,6-Germacradien-5-ol; benzoic acid; bicyclogermacrene; Ford et al. (2001) cis-9,10-dihydrocapsenone; germacrene-d; ␣-copaene; ␣-cubebene; ␣-humulene; ␤-caryophyllene; ␤-cubebene; ␤-elemene; ␦-cadinene 4,6-Dihydroxy-2-methoxy-3-methyldihydrochalcone Shen et al. (2007)

(ATCC14884), Bacillus subtilis (ATCC6633), Bordetella bron- 3-O-{O-␣-l-rhamnopyranosyl-(1 → 2)-␤-d-glucopyranoside} chiseptica (ATCC 4617), Micrococcus luteus (ATCC 9341), and (23S,24S)-spirosta-5,25(27)-diene-1␤,3␤,23,24-tetrol Staphylococcus aureus (ATCC 29737), Staphylococcus epider- 1-O-{O-2,3,4-tri-O-acetyl-␣-l-rhamnopyranosyl-(1 → 2)-␣- midis (ATCC 12228), Klebsiella pneumoniae (ATCC 10031), l-arabinopyranosyl}24-O-␤-d-fucopyranoside, isolated from Pseudomonas aeruginosa (ATCC 9027), Streptococcus faecalis the aerial parts of Dracaena draco are reported to show potent (MTCC 8043), and Aspergillus niger (MTCC 1344). Recently, cytostatic activity against HL-60 cells with IC50 value being Mothana et al. (2006) also reported antiviral activity of methanol 1.3 and 2.6 ␮g/ml, respectively compared with etoposide (IC50 extract of resin of Dracaena cinnabari against Herpes simplex 0.3 ␮g/ml) used as a positive control (Mimaki et al., 1999). virus and Human influenza virus. Gonzalez´ et al. (2003) also reported new steroidal saponins, Thus, Dracaena resin could be a rich source of antimicrobial Draconin A and Draconin B with cytotoxic activities against agents with possibly novel mechanisms of action. Interestingly, HL-60 cells from bark of Dracaena draco. The mechanism of resin from Dracaena cochinchinensis has been produced by these compounds’ cytotoxicity was also evaluated and found infection with Fusarium and Cladosporium spp. (Wang et al., to be via activation of apoptotic process. Recently a new 1999). In another study done by Jiang et al. (2003), inoculation cytotoxic steroidal saponin, Icogenin, has been isolated from of fungi Fusarium 9568D in abiotic branch and wood of Dra- Dracaena draco. Icogenin also inhibited growth of HL-60 cells caena cochinchinensis resulted in emergence of red resin from by induction of apoptosis (Hernandez´ et al., 2004). Dioscin, the inoculation points after 4–5 months incubation. The emerged from Dracaena draco also displayed cytotoxic activity similar resin was found to resemble the natural resin by UV-IR spectra to Icogenin. analysis. 2.3.2.3. Analgesic activity. Liu et al. (2004) observed that both 2.3.2.2. Antitumor and cytotoxic activity. Vachalkova et al. Dragon’s blood resin (D. cochichinensis) and loureirin B could (1995) studied carcinogenicity of three homoisoflavanoids and suppress TTX-S voltage-gated sodium currents depending upon four flavanoids isolated from the resin of Dracaena cinnabari. dose, which could be reason for its analgesic effect. Later, Al-Fatimi et al. (2005) reported cytotoxic activity of resin of Liu et al. (2005) studied the effects of Dragon’s blood and Dracaena cinnabari from Yemen against human ECV-304 its component loureirin B on tetrodotoxin-sensitive (TTX-S) cells. Dracaena draco has been found to be a rich source of and tetrodotoxin-resistant (TTX-R) sodium currents in trigem- cytotoxic steroidal saponins. Darias et al. (1989) reported, inal ganglion (TG) neurons using the whole-cell patch-clamp for the first time, the use of sap of Dracaena draco as an technique and found that both Dragon’s blood and loureirin anticarcinogen. Steroidal saponins, (25R)-spirost-5-en-3␤-ol B suppressed two types of peak sodium currents depending D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380 373

Table 4 Chemical constituents reported from Dracaena spp. Compound name Bioactivity References

Dracaena cinnabari Balf. f. (±)-7,4-Dihydroxy-3-methoxyflavan Braz et al. (1980), Achenbach et al. (1988), Masaoud et al. (1995c) 4,4-Dihydroxy-2-methoxychalcone (9) Meksuriyen and Cordell (1988), Masaoud et al. (1995c) 7,4-Dihydroxyflavone (23) Meksuriyen and Cordell (1988), Maxwel1 et al. (1989), Masaoud et al. (1995c) (2S)-7-Hydroxyflavan; (2S)-7-hydroxyflavan-4-one (20); Suchy´ et al. (1991), Masaoud et al. (1995c) 7-hydroxy-3-(4-hydroxybenzyl)-8-methoxychroman; 7-hydroxy-3-(4-hydroxy benzyl) chroman; loureirin C (24) 3-(4-Hydroxybenzyl)-7,8-methylendioxychroman Antioxidant activity Suchy´ et al. (1991), Masaoud et al. (1995c), Machala et al. (2001), Deepika and Gupta (2007) 2-Methoxysocotrin-5-ol, socotrin-4-ol; Masaoud et al. (1995a) homoisosocotrin-4-ol Cinnabarone (29) Masaoud et al. (1995b), Deepika and Gupta (2007) (2S)-7,3-Dihydroxy-4-methoxyflavan; Masaoud et al. (1995c) 4-hydroxy-2-methoxydihydrochalcone; 7-hydroxy-3-(3-hydroxy-4-methoxybenzyl)chroman 24-Methylenecycloartanol; 31-norcycloartanol; 4␣, Masaoud et al. (1995d) 14␣-dimethylcholest-8-en-3␤-ol; 4␣-methylcholest-7-en-3␤-ol; betulin; campesterol; cholest-4-en-3-one; cholesterol; cycloartanol; lanost-7-en-3␤-ol; lupeol; sitosterol; stigmast-22-en-3␤-ol; stigmastanol; stigmasterol Damalachawin (30) Himmelreich et al. (1995) 2,4,4-Trihydroxydihydrochalcone Antitumor activity, chemoprotective Gonzalez´ et al. (2000), Forejtn´ıkova´ et al. (2005) effects Dracophane (27) Vesela´ et al. (2002) 2,4-Dihydroxy-4,6-dimethoxydihydrochalcone; 3-(4- Deepika and Gupta (2007) (unpublished report) hydroxy-2-methoxyphenyl)-1-phenyl-1-propanone; 3,7-dihydroxy-4-methoxyflavan; 3,7-dihydroxy-4-methoxy homoisoflavan; 4,6-dihydroxy-7-methoxyhomoisoflavan; 4,6-dihydroxy-7-methoxyhomoisoflavan; 4,7-dihydroxy-5-methoxyhomoisoflavan; 4,7-dihydroxy-3-methoxy flavan; 4,7-dihydroxyhomoisoflavan; 4,7-dihydroxy-8-methylflavan; 4,7,8-trihydroxyhomoisoflavan; 7-hydroxy-5-methoxy-6-methylflavan; 7-hydroxy-3-(4-hydroxy benzyl)-4-chromanone; 7,10-dihydroxy-11-methoxydracae none; 10-hydroxy-11-methoxydracaenone; loureirin A Dracaena cochinchinensis (Lour.) S.C. Chen Loureirin A; loureirin c (24); loureirin B Analgesic activity Meksuriyen and Cordell (1988), Lu et al. (1998), Zhou et al. (2001a,b), Liu et al. (2004, 2005, 2006), Chen and Liu (2006), Zheng et al. (2006a,b) 7,4-Dihydroxyflavane Antifungal activity Wang et al. (1995), Zhou et al. (2001a,b), Zheng et al. (2006a,b) 7-Hydroxy-4-methoxyflavan; Lu et al. (1998) 6-hydroxy-7-methoxy-3-(4-hydroxybenzyl)chromane; 2,3,5,6-tetrachloro-1,4-dimethoxybenzene; 4-hydroxy-3,5-dimethoxystilbene 2, 4, 4-Trihydroxydihydrochalcone; 2, 4, Lu et al. (1998), Zhou et al. (2001a,b) 4-trihydroxy-6-methoxydihydrochalcone 2-Methoxysocotrin-5-ol; socotrin-4-ol; 2,4, Analgesic activity Zhou et al. (2001a,b), Liu et al. (2006) 4-trihydroxychalcone; 2-methoxy-4, 4-dihydroxychalcone; cochinchinenins 2-Methoxy-4,4-dihydroxychalcone (9) Zhou et al. (2001a,b), Zheng et al. (2006a,b) Dracaenoside A; B; C; D Zheng and Yang (2003a,b) 374 D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380

Table 4 (Continued ) Compound name Bioactivity References

25(R,S)-Dracaenosides E–H; M; O–Q; dracaenosides Zheng et al. (2004a,b,c) I–L; R; 25(S)-dracaenoside N; 25(R,S)-spirost-5-en-3-ol 3-O-␣-l-rhamnopyranosyl-(1,2)-[␣-l-rhamno pyranosyl-(1,4)]-␤-d-glucopyranoside; 25(R,S)-spirost-5-en-3-ol 3-O-␣-l-rhamnopyranosyl- (1,2)-␤-l-glucopyranosyl-(1,3)]-␤-d-glucopyranoside; 26-O-␤-d-glucopyranosyl 25(R,S)-furost-5-en-3,22␰,26-triol 3-O-␣-l-rhamnopyranosyl-(1,2)-[␤-d-glucopyranosyl (1,3)]-␤-d-glucopyranoside; 26-O-␤-d-glucopyranosyl 25(R,S)-spirost-5-en-3,22␰,26-triol 3-O-␣-l-rhamnopyranosyl-(1,2)-[␣-l- rhamnopyranosyl-(1,4)]-␤-d-glucopyranoside 7,4-Dihydroxyflavone (23); Zheng et al. (2006a,b) 7,4-dihydrohomoisoflavanone (26); 7,4-homoisoflavane (25); 10,11-dihydroxydracaenone C; dracaenogenin A and B 1-(4-O-␤-d-Glucopyranosyl)benzyl-ethan-2-ol; Zheng et al. (2006a,b) 3,4-dihydoxy-1-allylbenezene-4-O-␣-l- rhamnopyranosyl-(1 → 6)-O-␤-d-glucopyranoside; 1-hydroxy-3,4,5-trimethoxy benzene-1-O-␣-l- apiopyranosyl-(1 → 6)-O-␤-d-glucopyranoside; lophenol; ␤-sitosterol; stigma-5, 22-diene-3-ol; tachioside Dracaena draco (L.) L. 7,4-Dihydrohomoisoflavanone (26); Camarda et al. (1983) 7,4-homoisoflavane (25) 7-Hydroxy-3-(4-hydroxybenzyl)chroman-4-one Camarda et al. (1983), Gonzalez´ et al. (2000) 7-Hydroxy-3-(4-hydroxybenzyl)chroman Camarda et al. (1983), Gonzalez´ et al. (2000, 2003) (2S)-4,7-Dihydroxy-3-methoxy-8-methylflavan; Camarda et al. (1983), Gonzalez´ et al. (2000, 2004) (2S)-4,5-dihydroxy-7-methoxy-8-methylflavan 10-Hydroxy-11-methoxydracaenone Meksuriyen et al. (1987), Gonzalez´ et al. (2000) 3,4,5-Trimethoxycinnamyl alcohol Ponpipom et al. (1987), Gonzalez´ et al. (2000) 4,4-Dihydroxy-2-methoxychalcone (9) Achenbach et al. (1988), Gonzalez´ et al. (2000) (23S)-Spirost-5,25(27)-diene-1␤,3␤,23-triol Cytostatic activity Mimaki et al. (1999) 1-O-{4-O-acetyl-␣-l-rhamnopyranosyl-(1 → 2)-␣-l- arabinopyranoside}(45); (23S)-spirost-5,25(27)-diene-1␤,3␤,23-triol 1-O-{O-␣-l-rhamnopyranosyl-(1 → 2)-␣-l- arabinopyranoside} (46);(23S,24S)-spirosta-5,25(27)-diene-1␤,3␤,23,24- tetrol 1-O-{O-(4-O-acetyl-␣-l-rhamnopyranosyl)-(1 → 2)- ␣-l-arabinopyranoside} (47); (23S,24S)-spirosta-5,25(27)-diene-1␤,3␤,23,24-tetrol 1-O-{O-2,3,4-tri-O-acetyl-␣-l-rhamnopyranosyl- (1 → 2)-␣-l-arabinopyranosyl}24-O-␤-d- fucopyranoside (48); (25R)-spirost-5-en-3␤-ol 3-O-{O-␣-l-rhamnopyranosyl-(1 → 2)-␤-d- glucopyranoside} (33); spirost-5,25(27)-diene-1␤,3␤-diol 1-O-{O-␣-l-rhamnopyranosyl-(1 → 2)-␣-l- arabinopyranoside}(34); (23S)-spirost-5,25(27)-diene-1␤,3␤,23-triol 1-O-{O-␣-l-rhamnopyranosyl-(1 → 2)-O-[␤-d- xylopyranosyl-(l → 3)]-␣-l-arabinopyranoside}(35); 26-O-␤-d-glucopyranosyl-22-O-methylfurosta- 5,25(27)-diene-l␤,3␤,22␰,26-tetrol 1-O-{O-␣-l-rhamnopyranosyl-(l → 2)-O-␣-l- arabinopyranoside}(36) (23S,24S)-Spirosta-5,25(27)-diene-1␤,3␤,23,24-tetrol Mimaki et al. (1999), Hernandez´ et al. (2004) 1-O-{O-␣-l-rhamnopyranosyl}-(1 → 2)-␣-l- arabinopyranoside} (43) D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380 375

Table 4 (Continued ) Compound name Bioactivity References

(2S)-4,7-Dihydroxy-8-methylflavan; 3-(4-hydroxy Gonzalez´ et al. (2000) benzyl)-5,7-dimethoxychroman; 5,7-dihydroxy-3-(4-hydroxybenzyl)-chromone; 5,7-dihydroxy-3-(4-hydroxy benzyl)-chroman-4-one; 7-hydroxy-3-(4-hydroxybenzyl) chromone; isoliquiritigenin; liquiritigenin; xenognosin Loureirin C (24) Gonzalez´ et al. (2000, 2003) (2S)-3,7-Dihydroxy-4-methoxy-8-methylflavan Gonzalez´ et al. (2000, 2004) 7-Hydroxy-3-(4-hydroxybenzyl)-8-methoxychroman; Gonzalez´ et al. (2000), Hernandez´ et al. (2004) 3-(4-hydroxybenzyl)-7,8-methylendioxychroman (±)-7,4-Dihydroxy-3-methoxyflavan Gonzalez´ et al. (2000, 2003, 2004) 2,4,4-Trihydroxydihydrochalcone Chemoprotective effects Gonzalez´ et al. (2000), Forejtn´ıkova´ et al. (2005) Methyl protodioscin (39); draconin C (42); draconin A Apoptic activity Gonzalez´ et al. (2003) (40); draconin B (41) (−)-3-Hydroxy-4-methoxy-7-hydroxy-8-methylflavan; Cytotoxic activity Gonzalez´ et al. (2003), Hernandez´ et al. (2004) 3-O-[␣-l-rhamnopyranosyl(1 → 4)-␤- dglucopyranosyl] diosgenin (38); 4-allylcatecol; ␤-sitosterol; diosgenin (31); isoliquiritigenin; sitoindoside i; trans-␤-apo-8-carotenal; dioscin (37) (2S)-4,7-Dihydroxy-3-methoxyflavan; Cytotoxic activity Hernandez´ et al. (2004) (2S)-4,7-dihydroxy-3-methoxyflavan; diosgenone (32); shonanin; syringaresinol; icogenin (44) Dracoflavylium Melo et al. (2006) Dracol; icodeside Cytotoxic activity Hernandez´ et al. (2006)

Number given in parentheses corresponds to the structure of that compound given in Fig. 1. upon dose. Further, Liu et al. (2006) explored the material the bark and gradually harden. No major studies have been done basis for efficacy of modulation of Dragon’s blood on the on this source of Dragon’s blood. Trimble (1895), studied resin tetrodotoxin-resistant (TTX-R) sodium currents in dorsal root from Pterocarpus draco L. and obtained 34.85% tannins from ganglion (DRG) neurons. They suggested that analgesic effect this resin. of Dragon’s blood may be explained on the basis of interfer- ence with pain messages caused by the modulation of Dragon’s blood on TTX-R sodium currents in DRG neurons and could be 3. Quality control and safety due to the synergistic effect of three components cochinchinenin A, cochinchinenin B, and loureirin B. Recently, Chen and Liu Since Dragon’s blood, as a name, has been applied to resins (2006) carried out a computer simulation research for the effects obtained from different species from different continents; there of Dragon’s blood and its component loureirin B on sodium is a great need to identify them apart. There are other substi- channel in dorsal root ganglion cells. tutes as well, which are available in the market for Dragon’s blood such as Eucalyptus resinifera Sm. (Edwards et al., 2001). A powdered dark red coral from the Indian Ocean is also sold in 2.3.2.4. Antioxidative activity. Juranek´ et al. (1993) have Yemeni markets as “Dragon’s blood”. Glasgow’s Professor of reported antioxidant activity of three homoisoflavans isolated Chemistry, J. Dobbie and G. Henderson first tackled the issue from resin of Dracaena cinnabari. Machala et al. (2001) studied of chemical identification of the various resins under the name homoisoflavonoids and chalcones, isolated from the Dracaena of Dragon’s blood in 1883, on request of Prof. Bayley Balfour cinnabari, for their potential to inhibit cytochrome P4501A (Pearson, 2002). They reported, “the resins known as Dragon’s (CYP1A) enzymes and Fe (II)/NADPH dependent in vitro blood differ widely from one another, not only in their degree of peroxidation of microsomal lipids isolated from C57B1/10 purity, but also in their appearance” and that “specimens labeled mouse liver and found chalcones were poor antioxidants as having come from the same locality must, in reality, in some while 7,8-methylenedioxy-3 (4-hydroxybenzyl) chromane, a cases, have been derived from very different sources” (Dobbie homoisoflavonoid, exhibited a strong antioxidant activity. and Henderson, 1883). Dobbie and Henderson (1884) arranged red resins in four distinct groups: 1. Those soluble in chloroform, 2.4. Pterocarpus spp. carbon disulphide, and benzene completely; 2. Those soluble in chloroform, but insoluble in carbon disulphide and benzene; Pterocarpus officinalis Jacq., previously known as Pterocar- 3. Those soluble in chloroform and benzene and partly in car- pus draco L., is the only species known as a source of Dragon’s bon disulphide; and 4. Those, which are insoluble in all three blood. According to a description in the Bulletin of the Botani- reagents. cal Department, Jamaica, No. 45, July, 1893, when an incision Edwards et al. (1997) described Dragon’s blood resin (Dra- is made in the bark, drops of red sap ooze out, flow slowly down caena spp.) found on Socotra Island as the probable genuine 376 D. Gupta et al. / Journal of Ethnopharmacology 115 (2008) 361–380 source in antiquity, on the basis of Fourier transform Raman 5. Conclusion spectroscopic studies of several resins generically known as Dragon’s blood from different botanical and geographical Although Dragon’s blood has proved to be popular alter- sources. They have since described a Raman spectroscopic native or complementary medicine used in the treatment method to identify fake and unknown Dragon’s blood resins of many diseases, clinical trial evaluation of these claims from different botanical origins (Edwards et al., 2001, 2004). using currently accepted protocols is needed. One such All Dracaena spectra show the strong bands in the wave num- potential new drug for AIDS-related diarrhoea is, “Cro- ber region 1605–1500 cm−1 and can be generally identified by felemer” developed originally by Shaman Pharmaceuticals the strongest band at 1605 cm−1, the shoulder at ca. 1560 cm−1. from Croton lechleri. Since 2001, “Crofelemer” has been However, specimen degradation can be recognized by the loss purchased by the American pharmaceutical company, Napo of this shoulder at 1560 cm−1. Also, vibrational bands near Pharmaceuticals and is currently undergoing clinical trials 1170 cm−1 seen in the Dracaena draco spectra could be used as (http://www.aumag.org/lifeguide/WWSeptember05.html, biomarkers for Dracaena species. The main feature distinguish- http://www.botanical.com/botanical/mgmh/d/dragon20.html, ing Daemonorops Dragon’s blood resins from those of Dracaena http://www.drugs.com/npp/dragon-s-blood.html#ref3). is the presence of the narrow and intense band at 1600 cm−1, the This resin offers huge potential and we need to investi- doublets at 1510–1540 cm−1 and 1420–1450 cm−1 region and gate whether purified compounds isolated from Dragon’s blood also the medium intensity band at 1001 cm−1. Croton speci- may have better therapeutic potential as compared to crude men is distinguished by a broad band at 1612 cm−1, and also by extract. Since there is considerable variation in the chemical the medium intensity band at 784 cm−1. Later, Edwards et al. composition among various samples of Dragon’s Blood, quality (2004) identified the key molecular biomarker bands of Dragon’s control/assurance needs to be established for the traditional med- blood in the region 1400–1700 cm−1, which could be adopted ical trade. This review is an effort to highlight the potential and as a protocol for the identification of the botanical and possible problems related to the sources and possibilities of isolating new geographical sources of modern Dragon’s blood resins. pharmaceutically active molecules, using traditional knowledge No major toxicity has been reported from Dragon’s blood. in our search, for new and effective dugs molecules. The American Herbal Products Association (1997) lists San- gre de Drago (Croton) as Class I, meaning it can be consumed Acknowledgements safely when used appropriately. There are some instances when Dragon’s blood has been misrepresented as ‘opium’ and dis- tributed for use as a ‘drug’. Ford et al. (2001) had identified a We are grateful to Prof. Ulrike Lindequist, Institute of red substance as Dragon’s blood incense from Daemonorops Pharmacy, Ernst-Moritz-Arndt-University, Germany for her draco that was being mixed with marijuana and smoked as thorough revision of this review and providing us with her invalu- an alternative to opium in Virginia. They also screened the able suggestions. We acknowledge the financial support from substance for toxicity in various in vitro tests and suggested AICTE (8023/RID/NPROJ/RPS-38/2004-05). that that the abuse potential for Dragon’s blood incenses is minimal. References

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