Bloodroot
Scientific Name(s): Sanguinaria canadensis L. Family: Papaveraceae (poppies)
Common Name(s): Bloodroot , red pucoon , red root , coon root , paucon , sweet slumber , tetterwort , snakebite , Indian paint
Clinical Overview
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Uses of Bloodroot
Bloodroot was used historically as a treatment for skin cancers, polyps, and warts, although there are no clinical trials to support these uses. It was marketed in the early 1980s in toothpastes and mouthwashes for the prevention of gum disease and plaque; however, more recent studies have found it inferior to drugs such as doxycycline and chlorhexidine.
Bloodroot Dosing
Bloodroot is emetic at doses of 30 to 125 mg in humans. It was formerly an ingredient in toothpastes and mouthwashes, but its use has been discontinued because of toxicity concerns.
Contraindications
Contraindications have not yet been identified.
Pregnancy/Lactation
Documented adverse effects, including emmenogogue effect and uterine stimulant action. Avoid use.
Bloodroot Interactions
None well documented.
Bloodroot Adverse Reactions
Recent studies have found a strong correlation between the use of sanguinarine dental products and oral leukoplakia, a possible precursor to oral cancer. Bloodroot is contraindicated during pregnancy.
Toxicology
An expert panel reviewed the toxicological literature on bloodroot in 1990 and found no cause for concern. Concern since has been stimulated by reports of cytotoxicity of sanguinarine to cultured cells from oral tissue and inhibition of neutrophil function.
Botany
Bloodroot is an early spring wildflower that grows in woodlands of the eastern United States and Canada. Its single white flower emerges from the ground folded within a grey-green leaf and the delicate petals rapidly detach as the seed pod matures. The stout rhizome yields a bright red latex when cut, giving the plant its common name. The root and rhizome are collected in the fall for medicinal use.
History
Bloodroot was used by eastern Native American tribes as a red dye and in the treatment of ulcers, skin conditions, and as a blood purifier. All of these medicinal uses apparently derive from the appearance of the blood-red latex exuded from the fresh root. The juice was also used for coughs and sore throats, with the bitter taste masked by placing the juice on a lump of maple sugar that was then sucked. Higher oral doses were observed to have expectorant and emetic properties. The root entered 19th century medicine as a caustic topical treatment for skin cancers, polyps, and warts. In 1983 an extract of bloodroot was marketed in toothpaste and mouthwashes for prevention of gum disease and plaque (see Pharmacology).
Chemistry
Sanguinaria root is an abundant source of isoquinoline alkaloids, with the major quaternary alkaloids sanguinarine and chelerythrine having been isolated in the 19th century. A dimeric isoquinoline, sanguidimerine, was isolated as a major constituent more recently. 1 , 2 Protopine is also a major constituent. Other minor alkaloids 3 possess similar structures. The biosynthesis of sanguinarine and related alkaloids was studied in a related plant, Macleaya cordata (papaveraceae), which is an alternate commercial source. 4 It was demonstrated that alkaloid biosynthesis in bloodroot cell cultures was induced by the flavonoids quercitin or rutin but not by related compounds baicalein, naringin, naringenin, catechin, caffeic acid, and benzoic acid, 5 and that this process appeared to require both protein kinase C and G protein signal transduction. 6
The alkaloids have been characterized and quantified by a variety of methods. Detection in edible cooking oils (see Toxicology) was accomplished with thin-layer chromatography, 7 while saliva levels of sanguinarine have been determined by ion-pair HPLC. 8 More recently, FAB mass spectroscopy, 9 reversed-phase HPLC, 10 and capillary electrophoretic methods 11 have been reported.
Bloodroot Uses and Pharmacology
Bloodroot was used historically as a treatment for skin cancers, polyps, and warts, although there are no clinical trials to support these uses.
Mechanism of actionSanguinarine has been found to intercalate with DNA 12 , 13 , 14 favoring GC-rich sequences. 13 , 15 It has also been found to inhibit NaK-ATPase 16 , 17 , 18 in several systems, including human erythrocytes. 19 A431 cancer cells were found to undergo apoptosis at lower doses of sanguinarine than normal cells. 20 Other documented effects are inhibition of tubulin function by sanguinarine and chelerythrine, 21 and protein kinase C inhibition. 22 This latter effect has been shown to depend on reaction of the alkaloids with critical thiol groups. 22 Such a mechanism may also underlie some of these alkaloids' other diverse effects, including inhibition of liver aminotransferase, 23 inhibition of phosphorylation of a mitochondrial protein from rat heart, 24 inhibition of NFκB activation, 25 and induction of calcium release from sarcoplasmic reticulum. 26
Antimicrobial activitySanguinarine has long been known to have antibiotic activity in vitro. 27 An ecological role in chemical defense of the plant against microorganisms and herbivores has been postulated; 28 given the broad variety of bioactivity noted above and the high concentration of alkaloids, this hypothesis is quite reasonable. The cholera bacterium, for example, is sensitive to sanguinarine. 29
Animal dataResearch reveals no animal data regarding the use of bloodroot as an antimicrobial agent.
Clinical dataMore relevant are studies of oral cavity microbes. Virtually all isolates from human dental plaque were growth-inhibited by sanguinarine at 16 mcg/ml; 30 consequently, shifts in the spectrum of species in the oral flora were not observed. 31 Clinical studies using bacterial counts of saliva did not show reductions in S. mutans or S. salivarius with sanguinarine, while chlorhexidine was effective using the same measures. 32 Another similar clinical study of sanguinarine with zinc chloride found reductions in plaque bacteria over a 6-month trial compared to placebo. 33 A transient overgrowth of sanguinarine-resistant bacteria, but not fungi, in the mouth was observed in a further clinical study. 34 Consistent with this result, 6 yeast species were not efficiently killed by sanguinarine, while other mouthwash ingredients were effective. 35
Antiplaque and gingivitis clinical studiesAnimal data
Research reveals no animal data regarding the use of bloodroot as an antiplaque agent.
Clinical dataEarly reports of small clinical studies indicated that sanguinarine might have use in plaque reduction. 36 , 37 , 38 , 39 Other studies using different methods questioned this efficacy, 40 while the addition of zinc was claimed to increase the efficacy of sanguinarine. 41 These studies were conducted over relatively short time periods. A 6-month, double-blind trial of sanguinarine toothpaste against plaque and gingivitis found no advantage over placebo. 42 When compared with a chlorhexidine mouthwash in a crossover trial, a sanguinarine-zinc mouthwash was less effective. 43 A direct comparison of sanguinarine with sodium fluoride toothpaste demonstrated equal activity against plaque and gingivitis. 44 A further 6-month trial showed moderate antiplaque and gingivitis activity for a sanguinarine mouthwash, but it was less effective than chlorhexidine. 45 A 6-month study of combined toothpaste and mouthwash in an orthodontic population showed benefit from sanguinarine by a variety of endpoints. 46 A review of studies from 1983 to 1990 suggested that the design of the clinical studies may have skewed results and proposed guidelines for improving further trials, including larger study populations, avoidance of crossover designs, and selection of appropriate controls. 47 Other studies have remained mixed. A small effect on plaque was seen for sanguinarine mouthwash compared with chlorhexidine 48 while safety and efficacy were reported in another study with combined sanguinarine toothpaste and mouthwash. 49 A further review concluded that sanguinarine was ineffective. 50 A comparison of sanguinarine-containing regimens with and without fluoride found a modest additional benefit for sanguinarine. 51 Attempts to market sanguinarine-containing products in the United Kingdom and Australia have met with skepticism. 52 , 53
The most recent extensive trials of sanguinarine-containing dental products have used new delivery systems. A biodegradable matrix was used to achieve modest plaque and gingivitis control with sanguinarine; however, it was not more effective than supragingival mechanical plaque control. 54 A 9-month study of subgingivally delivered sanguinarine versus doxycycline in periodontitis found doxycycline superior to sanguinarine, 55 , 56 as did another study. 57 A French clinical study suggested combined use of chlorhexidine and sanguinarine. 58 In summary, the current clinical status of sanguinarine in dental plaque and gingivitis prevention and treatment is that while modestly effective, it is inferior to chlorhexidine, doxycycline, and other newer agents under development.
Dosage
Bloodroot is emetic at doses of 30 to 125 mg in humans. It was formerly an ingredient in toothpastes and mouthwashes, but its use has been discontinued because of toxicity concerns. 59
Pregnancy/Lactation
Documented adverse effects, including emmenogogue effect and uterine stimulant action. 60 Avoid use.
Interactions
None well documented.
Adverse Reactions
Recent epidemiological work found a strong correlation of use of sanguinarine dental products with oral leukoplakia, a condition considered to be a possible precursor of oral cancer. 61 , 59 These concerns have been rendered somewhat moot by the removal of sanguinarine from the Viadent formulation, although some less widely promoted sanguinarine-containing products are still available in pharmacies.
Bloodroot is contraindicated during pregnancy and has uterine-stimulating action.
Toxicology
Short-term toxicity studies of sanguinarine and Sanguinaria extracts in rats found minimal oral toxicity (LD50 1200 to 1700 mg/kg), probably because of its very limited gastric absorption, while sanguinarine was considerably more toxic via acute intravenous administration (LD50 29 mg/kg). 62 A dermal LD50 of > 200 mg/kg in rabbits was estimated. 62 No reproductive or developmental effects in rats and rabbits were reported. 63 An expert panel reviewed the toxicological literature on bloodroot in 1990 and found no cause for concern. 64 Despite its DNA intercalating ability, sanguinarine was not mutagenic in the Ames test. 65 Phototoxic effects against mosquito larvae have been reported. 66
Other cause for concern stems partly from reports of “epidemic dropsy” in India, where contamination of edible cooking oils with sanguinarine-containing Argemone mexicana seeds has been responsible for toxicity. 67 , 68 , 69 , 70 Further concerns were stimulated by reports of cytotoxicity of sanguinarine to cultured cells from oral tissue 71 and inhibition of neutrophil function. 72
Bibliography
1. Tin-Wa M, et al. Biological and phytochemical evaluation of plants. 8. Isolation of a new alkaloid from Sanguinaria canadensis . Lloydia 1970;33:267-69.2. Tin-Wa M, et al. Structure of sanguidimerine, a new major alkaloid from Sanguinaria canadensis (Papaveraceae). J Pharm Sci 1972;61:1846.
3. Kim D, et al. Dihydrosanguilutine, a new alkaloid from Sanguinaria canadensis . Phytochemistry 1975;14:834.
4. Takao N, et al. Biosynthesis of benzo[ c ]phenanthridine alkaloids sanguinarine, chelirubine and macarpine. Helv Chim Acta 1983;66:473.
5. Mahady G, et al. Quercetin-induced benzophenanthridine alkaloid production in suspension cell cultures of Sanguinaria canadensis . Planta Med 1994;60:553-57.
6. Mahady G, et al. Involvement of protein kinase and G proteins in the signal transduction of benzophenanthridine alkaloid biosynthesis. Phytochemistry 1998;48:93-102.
7. Balderstone P, et al. Detection and quantitative analysis of sanguinarine in edible oils. J Chromatogr 1977;132:359-62.
8. Reinhart P, et al. Sanguinarine levels in biological samples by high-performance liquid chromatography. J Chromatogr 1991;570:425-34.
9. Bambagiotti-Alberti M, et al. Characterization of Sanguinaria canadensis L. fluid extract by FAB mass spectrometry. J Pharm Biomed Anal 1991;9:1083-87.
10. Husain S, et al. Separation, identification and determination of sanguinarine in argemone and other adulterated edible oils by reversed-phase high-performance liquid chromatography. J Chromatogr A 1999;863:123-26.
11. Sevcík J, et al. Capillary electrophoretic determination of sanguinarine and chelerythrine in plant extracts and pharmaceutical preparations. J Chromatogr A 2000;866:293-98.
12. Maiti M, et al. Sanguinarine: A monofunctional intercalating alkaloid. FEBS Lett 1982;142:280-84.
13. Nandi R, et al. Binding of sanguinarine to deoxyribonucleic acids of differing base composition. Biochem Pharmacol 1985;34:321-24.
14. Sen A, et al. Interaction of sanguinarine iminium and alkanolamine form with calf thymus DNA. Biochem Pharmacol 1994;48:2097-102.
15. Bajaj N, et al. Sequence-selective, pH-dependent binding to DNA of benzophenanthridine alkaloids. J Mol Recognit 1990;3:48-54.
16. Straub K, et al. Sanguinarine, inhibitor of Na-K dependent ATPase. Biochem Biophys Res Commun 1975;62:913-22.
17. Cohen H, et al. Structural specificity of the NaK-ATPase inhibition by sanguinarine, an isoquinoline benzophenanthridine alkaloid. Biochem Pharmacol 1978;27:2555-58.
18. Seifen E, et al. Sanguinarine: a positive inotropic alkaloid which inhibits cardiac Na + ,K + -ATPase. Eur J Pharmacol 1979;60:373-77.
19. Cala P, et al. Effects of the plant alkaloid sanguinarine on cation transport by human red blood cells and lipid bilayer membranes. J Membr Biol 1982;64:23-31.
20. Ahmad N, et al. Differential antiproliferative and apoptotic response of sanguinarine for cancer cells versus normal cells. Clin Cancer Res 2000;6:1524.
21. Wolff J, et al. Antimicrotubule properties of benzophenanthridine alkaloids. Biochemistry 1993;32:13334-39.
22. Gopalakrishna R, et al. Modifications of cysteine-rich regions in protein kinase C induced by oxidant tumor promoters and enzyme-specific inhibitors. Methods Enzymol 1995;252:132-46.
23. Walterová D, et al. Inhibition of liver alanine aminotransferase activity by some benzophenanthridine alkaloids. J Med Chem 1981;24:1100-03.
24. Lombardini J, et al. Effects of benzophenanthridine alkaloids on the phosphorylation of an approximately 44 kDa protein present in a mitochondrial fraction of the rat heart. Biochem Pharmacol 1996;51:151-57.
25. Chaturvedi M, et al. Sanguinarine (pseudochelerythrine) is a potent inhibitor of NF-kB activation, IkBa phosphorylation, and degradation. J Biol Chem 1997;272:30129-34.
26. Hu C, et al. Induction of skeletal muscle contracture and calcium release from isolated sarcoplasmic reticulum vesicles by sanguinarine. Br J Pharmacol 2000;130:299-306.
27. Mitscher L, et al. Antimicrobial agents from higher plants. An investigation of Hunnemannia fumariaefolia pseudoalcoholates of sanguinarine and chelerythrine. Lloydia 1978;41:145-50.
28. Schmeller T, et al. Biochemical activities of berberine, palmatine and sanguinarine mediating chemical defence against microorganisms and herbivores. Phytochemistry 1997;44:257-66.
29. Nandi R, et al. Sensitivity of vibrios to sanguinarine. Experientia 1983;39:524-25.
30. Dzink J, et al. Comparative in vitro activity of sanguinarine against oral microbial isolates. Antimicrob Agents Chemother 1985;27:663-65.
31. Godowski K. Antimicrobial action of sanguinarine. J Clin Dent 1989;1:96-101.
32. Hoover J, et al. Efficacy of chlorhexidine and sanguinarine mouthrinses on selected salivary microflora. J Can Dent Assoc 1990;56:325-27.
33. Harper D, et al. Effect of six months use of a dentifrice and oral rinse containing sanguinaria extract and zinc chloride upon the microflora of the dental plaque and oral soft tissues. J Periodontol 1990;61:359-63.
34. Godowski K, et al. Whole mouth microbiota effects following subgingival delivery of sanguinarium. J Periodontol 1995;66:870-77.
35. Giuliana G, et al. In vitro antifungal properties of mouthrinses containing antimicrobial agents. J Periodontol 1997;68:729-33.
36. Southard G, et al. Sanguinarine, a new antiplaque agent: Retention and plaque specificity. J Am Dent Assoc 1984;108:338-41.
37. Wennstrom J, et al. Some effects of a sanguinarine-containing mouthrinse on developing plaque and gingivitis. J Clin Periodontol 1985;12:867-72.
38. Wennstrom J, et al. The effect of mouthrinses on parameters characterizing human periodontal disease. J Clin Periodontol 1986;13:86-93.
39. Parsons L, et al. Effect of sanguinaria extract on established plaque and gingivitis when supragingivally delivered as a manual rinse or under pressure in an oral irrigator. J Clin Periodontol 1987;14:381-85.
40. Etemadzadeh H, et al. Lacking anti-plaque efficacy of 2 sanguinarine mouth rinses. J Clin Periodontol 1987;14:176-80.
41. Southard G, et al. The relationship of sanguinaria extract concentration and zinc ion to plaque and gingivitis. J Clin Periodontol 1987;14:315-19.
42. Mauriello S, et al. Six-month effects of a sanguinarine dentifrice on plaque and gingivitis. J Periodontol 1988;59:238-43.
43. Moran J, et al. A clinical trial to assess the efficacy of sanguinarine-zinc mouthrinse ( Veadent ) compared with chlorhexidine mouthrinse ( Corsodyl ). J Clin Periodontol 1988;15:612-16.
44. Mallatt M, et al. Clinical effect of a sanguinaria dentifrice on plaque and gingivitis in adults. J Periodontol 1989;60:91-95.
45. Grossman E, et al. A clinical comparison of antibacterial mouthrinses: Effects of chlorhexidine, phenolics, and sanguinarine on dental plaque and gingivitis. J Periodontol 1989;60:435-40.
46. Hannah J, et al. Long-term clinical evaluation of toothpaste and oral rinse containing sanguinaria extract in controlling plaque, gingival inflammation, and sulcular bleeding during orthodontic treatment. Am J Orthod Dentofacial Orthop 1989;96:199-207.
47. Laster L, et al. New perspectives on Sanguinaria clinicals: Individual toothpaste and oral rinse testing. J Can Dent Assoc 1990;56:19-30.
48. Quirynen M, et al. Comparative antiplaque activity of sanguinarine and chlorhexidine in man. J Clin Periodontol 1990;17:223-27.
49. Harper D, et al. Clinical efficacy of a dentifrice and oral rinse containing sanguinaria extract and zinc chloride during 6 months of use. J Periodontol 1990;61:352-58.
50. Balanyk T. Sanguinarine: Comparisons of antiplaque/antigingivitis reports. Clin Prev Dent 1990;12:18-25.
51. Kopczyk R, et al. Clinical and microbiological effects of a sanguinaria-containing mouthrinse and dentifrice with and without fluoride during six months of use. J Periodontol 1991;62:617-22.
52. Grenby T. The use of sanguinarine in mouthwashes and toothpaste compared with some other antimicrobial agents. Br Dent J 1995;178:254-58.
53. Cullinan M, et al. Efficacy of a dentifrice and oral rinse containing sanguinaria extract in conjunction with initial periodontal therapy. Aust Dent J 1997;42:47-51.
54. Polson A, et al. 2 multi-center trials assessing the clinical efficacy of 5% sanguinarine in a biodegradable drug delivery system. J Clin Periodontol 1996;23:782-88.
55. Polson A, et al. Multi-center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. I. Study design, procedures, and management. J Periodontol 1997;68:110-18.
56. Polson A, et al. Multi-center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. II. Clinical results. J Periodontol 1997;68:119-26.
57. Drisko C, The use of locally delivered doxycycline in the treatment of periodontitis. Clinical results. J Clin Periodontol 1998;25:947-52, 978-79.
58. Tenenbaum H, et al. Effectiveness of a sanguinarine regimen after scaling and root planing. J Periodontol 1999;70:307-11.
59. Eversole LR, Eversole GM, Kopcik J. Sanguinaria-associated oral leukoplakia: Comparison with other benign and dysplastic leukoplakic lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2000;89:455-464.
60. Brinker FJ. Herb Contraindications and Drug Interactions . 2nd ed. Sandy, OR: Eclectic Medical Publications; 1998.
61. Damm D, et al. Leukoplakia of the maxillary vestibule — an association with Viadent ? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:61-66.
62. Becci P, et al. Short-term toxicity studies of sanguinarine and of two alkaloid extracts of Sanguinaria canadensis L. J Toxicol Environ Health 1987;20:199-208.
63. Keller K, et al. Reproductive and developmental toxicological evaluation of sanguinaria extract. J Clin Dent 1989;1:59-66.
64. Frankos V, et al. Safety of Sanguinaria extract as used in commercial toothpaste and oral rinse products. J Can Dent Assoc 1990;56:41-47.
65. Kevekordes S, et al. SOS induction of selected naturally occurring substances in Escherichia coli (SOS chromotest). Mutat Res 1999;445:81-91.
66. Arnason J, et al. Phototoxic and photochemical properties of sanguinarine. Photochem Photobiol 1992;55:35-38.
67. Shenolikar I, et al. Sanguinarine in the blood and urine of cases of epidemic dropsy. Food Cosmet Toxicol 1974;12:699-702.
68. Dalvi R. Sanguinarine: Its potential as a liver toxic alkaloid present in the seeds of Argemone mexicana . Experientia 1985;41:77-78.
69. Sachdev M, et al. Pathogenesis of epidemic dropsy glaucoma. Arch Ophthalmol 1988;106:1221-23.
70. Das M, et al. Clinicoepidemiological, toxicological, and safety evaluation studies on argemone oil. Crit Rev Toxicol 1997;27:273-97.
71. Babich H, et al. Cytotoxicity of sanguinarine chloride to cultured human cells from oral tissue. Pharmacol Toxicol 1996;78:397-98.
72. Agarwal S, et al. Effects of sanguinarium, chlorhexidine and tetracycline on neutrophil viability and functions in vitro. J Periodontal Res 1997;32:335-44.
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