Plant remedies for peptic ulcers Licorice

Also known as glycyrrhiza, this herb consists of the dried rhizome (under- ground stem) and roots of Glycyrrhiza glabra L., known in commerce as Spanish licorice; of G. glabra L. var. glandulifera (Wald. & Kit.) Reg. & Herd., known in commerce as Russian licorice; or of other varieties of G. glabra L.

that yield a yellow and sweet wood (family Fabaceae). It is often referred to as licorice root.

52 Tyler's herbs of choice: The therapeutic use of phytomedicinals During World War II, a Dutch physician, F. E. Revers, noted that

peptic ulcer patients in the small city of Heerenveen in the northern part of the Netherlands improved markedly when treated with a paste containing 40 percent licorice extract prepared by a local pharmacist. 110

Revers used licorice paste to treat a number of ulcer patients success- fully, but in doing so he noted a serious side effect. About 20 percent of the patients developed edema, principally in the face and extremi- ties. However, those unpleasant effects disappeared promptly and com-

pletely when treatment was discontinued. During the intervening half century, a great many studies have been conducted on licorice, its constituents, and their effects. Much has been learned about the therapeutic usefulness and the side effects of the herb, but in essence, the findings remain the same. Licorice is useful in the treatment of peptic ulcers; depending on the dose, it may produce serious side effects. These undesirable effects are mineralocorticoid in nature. Specifically, they include headache, lethargy, sodium and water retention (the edema noted by Revers), excessive excretion of potassium, and high blood pressure. Eventually, heart failure or cardiac arrest may result. The medical literature is replete with references to cases of poisoning produced by overconsumption of licorice candy or licorice-containing tobacco. 111

Glycyrrhizin (glycyrrhizic or glycyrrhizinic acid), a triterpene glycoside with saponin-like properties, is contained in licorice in a range of 2–14 percent. Plant material of good quality contains at least 4 percent. It is responsible for the sweet taste of the herb; it is some fifty times sweeter than sugar. The glycoside has pronounced expectorant and antitussive properties. 112 On hydrolysis, glycyrrhizin loses its sweet taste and is con-

verted to glycyrrhetinic acid (glycyrrhetic acid) and two molecules of glucuronic acid. Both glycyrrhizin and its triterpene aglycone, glycyrrhetinic acid, possess distinct anti-inflammatory and antiallergic properties. These account for licorice’s effectiveness in treating ulcers. Both compounds also possess mineralocorticoid activity that accounts for the herb’s side effects.

Recent studies with glycyrrhetinic acid have revealed that the antiulcer effects of licorice are due to inhibition of 15-hydroxyprostaglandin dehydrogenase, an enzyme that metabolizes prostaglandins E 2 and F 2 α to the inactive 15-ketoprostaglandins (see Figure 3.2 ). By blocking prostaglandin metabolism, the biological half-life of the active compounds is extended and has the effect of raising the local concentration of prostaglandins in the stomach, which promotes protective mucous secretions and cell proliferation of the gastric mucosa, leading to the healing of ulcers. 113

15-hydroxyprostaglandin dehydrogenase belongs to a family of short- chain dehydrogenase reductase (SDR) enzymes that influence mamma- lian reproduction, hypertension, neoplasia, and digestion. Amino acid sequence analysis of enzymes in this family indicates that they have a

Chapter three: Digestive system problems

Increased levels in gastric mucosa promoting mucous secretion and cell proliferation

Prostaglandins E 2 and F 2α 15-hydroxyprostaglandin

dehydrogenase

15-ketoprostaglandins E 2 and F 2α (inactive)

Glycyrrhetinic acid (Licorice)

Cortisone (inactive mineralocorticoid)

11β-hydroxysteroid dehydrogenase type 2

Hydrocortisone

Increased activity at mineralocorticoid receptor resulting in Na + retention, K + excretion, and hypertension

Figure 3.2 Glycyrrhetinic acid inhibition of short-chain dehydrogenase reductase (SDR) enzymes.

degree of sequence homology, and x-ray crystal structures of five members of the family demonstrate tertiary structure similarities. 114,115 Included in the SDR family is 11 β-hydroxysteroid dehydrogenase, which is also inhibited by glycyrrhetinic acid. 113

As illustrated in Figure 3.2, 11 β-hydroxysteroid dehydrogenase acts as a “gatekeeper” and controls hormone access to the mineralocorticoid receptor. There are at least two isoforms of the enzyme. In the kidney,

a high-affinity isoform designated type 2 converts the mineralocorticoid-active hydrocortisone to inactive cortisone, thereby protecting the mineralocorticoid receptor from hydrocortisone. Excessive licorice administration results in an inhibition of this conversion with a subse- quent increase in hydrocortisone levels and the undesirable effects of mineralocorticoid activity: namely, sodium retention, potassium excretion, and high blood pressure. 116

54 Tyler's herbs of choice: The therapeutic use of phytomedicinals In summary, by inhibiting SDR enzymes, glycyrrhetinic acid pro-

duces a therapeutic effect by increasing prostaglandin levels and produces adverse effects by increasing hydrocortisone levels.

Carbenoxolone, a semisynthetic derivative of glycyrrhetinic acid, is widely marketed outside the United States as an antiulcer drug. It is not yet available in the United States, so persons wishing to utilize licorice for treatment of this condition are restricted to the herb itself. Normally, it is consumed in the form of a beverage prepared by adding about ½ cup of boiling water to 1 teaspoonful (2–4 g) of the herb and simmering the mixture for five minutes. After cooling, strain and drink this quantity of beverage three times daily after meals. The German Commission E has approved the use of licorice in ulcer therapy but cautions that the treatment should not be continued longer than four to six weeks. 117 It recommends a dosage level of 200–600 mg of glycyrrhizin daily; with an herb of average quality, this regimen would provide an amount about midpoint in that range. Elderly persons or those suffering from cardiovascular disease, liver or kidney problems, or potassium deficiency should avoid consuming licorice unless they do so while under the care of a physician.

Licorice also has a considerable reputation as an expectorant and cough suppressant, and it is frequently utilized in the treatment of symp- toms associated with the common cold. Lozenges and candies containing licorice extract are especially suitable. However, particularly in the United States, one must make certain that they do contain real licorice. Most “licorice” candy manufactured in the United States is simply flavored with anise oil.

In addition to licorice’s antiulcer and expectorant/cough suppressant activities, a number of other potential uses have been studied in small animals and, in some cases, in human beings. 118 As a result, the herb is postulated to possess hypolipidemic (cholesterol and triglyceride lower- ing), anticariogenic (antiplaque and anti-tooth-decay features), antimicro- bial and antiviral, immunosuppressive, antianemia, and antihepatotoxic properties. Adequate evidence is not available to support the effectiveness of licorice in any of these conditions, but its local application as a hydrocortisone potentiator in preparations used to treat various skin conditions seems to hold considerable promise. 119

Ginger Investigations in small animals have shown that extracts of fresh ginger (see discussion in “ Nausea and Vomiting ”) inhibited gastric secretion and

the formation of stress-induced lesions. 119 The antiulcer activity of the herb requires confirmation but is certainly worthy of further study.

Chapter three: Digestive system problems

References

1. Tyler, V. E. The new honest herbal, 109–110. Philadelphia, PA: J. B. Lippincott. 2. Mowrey, D. B., and D. E. Clayson. 1982. Lancet I:655–657. 3. Stott, J. R. R., M. P. Hubble, and M. B. Spencer. 1985. Advisory Group for

Aerospace Research and Development. Conference Proceedings 372 39:1–6.

4. Grøntved, A., and E. Hentzer. 1986. ORL: Journal of Oto–Rhino–Laryngology and Its Related Specialties 48:282–286. 5. Wood, C. D., J. E. Manno, M. J. Wood, B. R. Manno, and M. E. Mims. 1988. Clinical Research Practices and Drug Regulatory Affairs 6:129–136. 6. Grøntved, A., T. Brask, J. Kambskard, and E. Hentzer. 1988. Acta Oto– Laryngologica (Stockholm) 105:45–49. 7. Schmid, R., T. Schick, R. Steffen, A. Tschopp, and T. Wilk. 1994. Journal of Travel Medicine 1 (4): 203–206. 8. Riebenfeld, D., and L. Borzone. 1999. Health Notes Review of Complementary and Integrative Medicine 6:98–101. 9. Holtmann, S., A. H. Clarke, H. Scherer, and M. Höhn. 1989. Acta Oto– Laryngologica (Stockholm) 108:168–174. 10. Stewart, J. J., M. J. Wood, C. D. Wood, and M. M. Mims. 1991. Pharmacology 42:111–120. 11. Ernst, E., and M. H. Pittler. 2000. British Journal of Anaesthesia 84:367–371. 12. Arfeen, Z., H. Owen, J. L. Plummer, A. H. Ilsley, R. A. C. Sorby-Adams, and

C. J. Doecke. 1995. Anaesthesia and Intensive Care 23:449–452. 13. Betz, O., P. Kranke, G. Geldner, H. Wulf, and L. H. J. Eberhart. 2005. Forsch. Komplemetarmed. Klass. Naturheilkd. 12 (1): 14–23. 14. Bundesanzeiger (Cologne, Germany): May 5, 1988. 15. Awang, D. V. C. 1992. Canadian Pharmaceutical Journal 125:309–311. 16. Kawai, T., K. Kinoshita, K. Koyama, and K. Takahashi. 1994. Planta Medica

60:17–20. 17. Phillips, S., R. Ruggier, and S. E. Hutchinson. 1993. Anaesthesia 48:715–717. 18. Visalyaputra, S., N. Petchpaisit, K. Sancharun, and R. Chouvaratna. 1998.

Anaesthesia 53:506–510. 19. Bone, M. E., D. J. Wilkonson, J. R. Young, J. McNeil, and S. Charlont. 1990. Anaesthesia 45:669–671. 20. Fischer-Rasmussen, W., S. K. Kjaer, C. Dahl, and U. Asping. 1990. European Journal of Obstetrics and Gynecological Reproductive Biology 38:19–24. 21. Vutyavanich, T., T. Kraisarin, and R. A. Ruangsi. 2001. Obstetrics and Gynecology 97:577–582. 22. Backon, J. Anaesthesia 46:705–706. 23. Awang, D. V. C., and A. Fugh-Berman. 2002. Alternative Therapies in Women’s

Health 4 (8): 57–60. 24. Haas,

H. Arzneipflanzenkunde, 78. Mannheim, Germany: B. I. Wissenschaftsverlag. 25. Hänsel, H. 1991. Phytopharmaka, 2nd ed., 121–123. Berlin: Springer–Verlag. 26. List, P. H., and L. Hörhammer, eds. 1973. Hagers Handbuch der Pharmazeutischen

Praxis, 4th ed., vol. 4, 1115. Berlin: Springer–Verlag. 27. Bundesanzeiger (Cologne, Germany): November 30, 1985; March 6, 1990. 28. Tanaka, S., T. Furukawa, K. Adachi, and M. Ishimoto, M. 1988. Iryo

56 Tyler's herbs of choice: The therapeutic use of phytomedicinals 29. Pahlow, M. 1985. Das Grosse Buch der Heilpflanzen, 330–331. Munich: Gräfe

und Unzer. 30. Bundesanzeiger (Cologne, Germany): July 6, 1988; March 6, 1990. 31. Bisset, N. G., ed. 1994. Herbal drugs and phytopharmaceuticals, English ed.

(Teedrogen, M. Wichtl, ed.), 45–48. Boca Raton, FL: CRC Press. 32. Brunton, L. L. 1996. Agents affecting gastrointestinal water influx and motil- ity. In Goodman and Gilman’s the pharmacological basis of therapeutics, 9th ed., ed. J. G. Hardman, L. E. Limbird, P. B. Molinoff, and R. W. Ruddon, 917–936. New York: McGraw–Hill. 33. Robbers, J. E., M. K. Speedie, and V. E. Tyler. 1996. Pharmacognosy and pharma- cobiotechnology, 45–46. Baltimore, MD: Williams & Wilkins. 34. Ashraf, W., F. Park, J. Lof, and M. M. Quigley. 1995. Alimentary Pharmacology and Therapeutics 9:639–647. 35. Chesken, L. J., N. Kamal, M. D. Crowell, M. M. Schuster, and W. E. Whitehead. 1995. Journal of the American Geriatrics Society 43:666–669. 36. Anderson, J. W., N. Zettwoch, T. Feldman, J. Tietyen-Clark, P. Oeltgen, and C. W. Bishop. 1988. Archives of Internal Medicine 148:292–296. 37. Davidson, M. H., L. D. Dugan, J. H. Burns, D. Sugimoto, K. Story, and K. Drennan. 1996. American Journal of Clinical Nutrition 63:96–102. 38. Turley, S. D., B. P. Daggy, and J. M. Dietschy. 1996. Journal of Cardiovascular Pharmacology 27:71–79. 39. Alabaster O., Z. Tang, and N. Shivapurkar. 1996. Mutation Research 350:185–197. 40. Leng-Peschlow, E. 1993. Pharmacology 47 (suppl. 1): 14–21. 41. Robbers, J. E., M. K. Speedie, and V. E. Tyler. 1996. Pharmacognosy and pharma-

cobiotechnology, 50–52. Baltimore, MD: Williams & Wilkins.

42. Mereto, E., M. Ghia, and G. Brambilla. 1996. Cancer Letters 101:79–83. 43. Brusick, D., and U. Mengs. 1997. Environmental and Molecular Mutagenesis

29:1–9. 44. Robbers, J. E., M. K. Speedie, and V. E. Tyler. 1996. Pharmacognosy and pharma- cobiotechnology, 52–53. Baltimore, MD: Williams & Wilkins. 45. Bisset, N. G., ed. 1994. Herbal drugs and phytopharmaceuticals, English ed. (Teedrogen, M. Wichtl, ed.), 208–211. Boca Raton, FL: CRC Press. 46. Bundesanzeiger (Cologne, Germany): December 5, 1984. 47. Jekat, F. W., H. Winterhoff, and F. H. Kemper. 1990. Zeitschrift für Phytotherapie

11:177–184. 48. Bisset, N. G., ed. 1994. Herbal drugs and phytopharmaceuticals, English ed. (Teedrogen, M. Wichtl, ed.), 463–466. Boca Raton, FL: CRC Press. 49. Beck, H., and K. Beck. 1982. Schaufenster (supplement to Deutsche Apotheker Zeitung) 31 (8/9): 33–34. 50. Hänsel, R., and T. Haas. 1984. Therapie mit Phytopharmaka, rev. ed., 137–140. Berlin: Springer–Verlag. 51. Bisset, N. G., ed. 1994. Herbal drugs and phytopharmaceuticals, English ed. (Teedrogen, M. Wichtl, ed.), 348–350. Boca Raton, FL: CRC Press. 52. Bisset, N. G., ed. 1994. Herbal drugs and phytopharmaceuticals, English ed. (Teedrogen, M. Wichtl, ed.), 431–433. Boca Raton, FL: CRC Press. 53. Reynolds, J. E. F., ed. 1996. Martindale: The extra pharmacopoeia, 31st ed., 1748. London: Royal Pharmaceutical Society of Great Britain. 54. Bundesanzeiger (Cologne, Germany): August 14, 1987. 55. Bundesanzeiger (Cologne, Germany): February 1, 1990.

Chapter three: Digestive system problems

57 56. Murray, M. T. 1995. The healing power of herbs, 2nd ed., 50–59. Rocklin, CA:

Prima Publishing. 57. Schilcher, H. 1984. Deutsche Apotheker Zeitung 124:1433–1442. 58. Forster, H. B., H. Niklas, and S. Lutz. 1980. Planta Medica 40:309–319. 59. Hof-Mussler, S. 1990. Deutsche Apotheker Zeitung 130:2407–2410. 60. Robbers, J. E., M. K. Speedie, and V. E. Tyler. 1996. Pharmacognosy and pharma-

cobiotechnology, 87. Baltimore, MD: Williams & Wilkins. 61. Robbers, J. E., M. K. Speedie, and V. E. Tyler. 1996. Pharmacognosy and pharma- cobiotechnology, 98–99. Baltimore, MD: Williams & Wilkins. 62. Lawrence Review of Natural Products: July 1990. 63. Bundesanzeiger (Cologne, Germany): November 30, 1985; March 13, 1986. 64. Blumenthal, M. 1990. HerbalGram 23:32–33, 49. 65. May, B., H.-D. Kuntz, M. Kieser, and S. Köhler. 1996. Arzneimittel-Forschung

46 (II): 1149–1153. 66. Beesley, A., J. Hardcastle, P. T. Hardcastle, and C. J. Taylor. 1996. Gut 39:214–219. 67. Wichtl, M. 1983. Deutsche Apotheker Zeitung 123:2114. 68. Wilkinson, S. M., and M. H. Beck. 1994. Contact Dermatitis 30:42. 69. Morton, C. A., J. Garioch, P. Todd, P. J. Lamey, and A. Forsyth. 1995. Contact

Dermatitis 32:281–284. 70. Pahlow, M. 1985. Das Grosse Buch der Heilpflanzen, 258–260. Munich: Gräfe and Unzer. 71. Carle, R., and O. Isaac. 1987. Zeitschrift für Phytotherapie 8:67–77. 72. Schilcher, H. 1987. Die Kamille. Stuttgart: Wissenschaftliche Verlagsgesellschaft,

152 pp. 73. Mann, C., and J. Staba. 1986. The chemistry, pharmacology, and commer- cial formulations of chamomile. In Herbs, spices, and medicinal plants: Recent advances in botany, horticulture, and pharmacology, vol. 1, ed. L. E. Craker and J.

E. Simon, 233–280. Phoenix, AZ: Oryx Press. 74. Bauer, R. 1992. The American Herb Association Newsletter 9 (1): 4. 75. Della Loggia, R., R. Carle, S. Sosa, and A. Tubaro. 1990. Planta Medica 56:657. 76. Lewis, W. H. 1992. Economic Botany 46:426–430. 77. Hausen, B. M., E. Busker, and R. Carle. 1984. Planta Medica 50:229–234. 78. Hausen, B. M. 1996. American Journal of Contact Dermatitis 7:94–99. 79. Awang, D. V. C. 2003. Leung’s (Chinese) Herb News 40:2. 80. Bundesanzeiger (Cologne, Germany): December 5, 1984. 81. Carle, R., I. Fleischhauer, and D. Fehr. 1987. Deutsche Apotheker Zeitung

127:2451–2457. 82. Carle, R., I. Fleischauer, J. Beyer, and E. Reinhard. 1990. Planta Medica 56:456–460. 83. Bundesanzeiger (Cologne, Germany): July 6, 1988; February 1, 1990; November 30, 1985. 84. Lawrence Review of Natural Products: March 1996. 85. Hänsel, R. 1991. Phytopharmaka, 2nd ed., 186–191. Berlin: Springer–Verlag. 86. Ammon, H. P. T., and M. A. Wahl. 1991. Planta Medica 57:1–7. 87. Jaspersen-Schib, R. 1991. Schweize Apotheker-Zeitung 129:706–710. 88. Snow, J. M. 1995. The Protocol Journal of Botanical Medicine (Autumn): 43–46. 89. Soni, K. B., A. Rajan, and R. Kullan. 1992. Cancer Letters 66:115–121. 90. Soni, K. B., and R. Kuttan. 1992. Indian Journal of Physiology and Pharmacology

58 Tyler's herbs of choice: The therapeutic use of phytomedicinals 91. Selvam, R., L. Subramanian, R. Gayathri, and N. Angayarkanni. 1995. Journal

of Ethnopharmacology 47:59–67. 92. Bundesanzeiger (Cologne, Germany): November 30, 1985. 93. Bisset, N. G., ed. 1994. Herbal drugs and phytopharmaceuticals, English ed.

(Teedrogen, M. Wichtl, ed.), 173–175. Boca Raton, FL: CRC Press. 94. Lawrence Review of Natural Products: May 1991. 95. Bundesanzeiger (Cologne, Germany): April 23, 1987. 96. Bisset, N. G., ed. 1994. Herbal drugs and phytopharmaceuticals, English ed.

(Teedrogen, M. Wichtl, ed.), 486–489. Boca Raton, FL: CRC Press. 97. Bundesanzeiger (Cologne, Germany): December 5, 1984. 98. Lawrence Review of Natural Products: December 1987. 99. Dhiman, R. K., and Y. K. Chawla. 2005. Digestive Disease and Sciences 50 (10):

1807–1812. 100. Notka, F., G. Meier, and R. Wagner. 2004. Antiviral Research 64:93. 101. Huseini, H. F., S. M. Alavain, R. Heshmat, M. R. Heydari, and K. Abolmaali.

2005. Phytomedicine 12:619–624. 102. Wagner, H., and O. Seligmann. 1985. Liver therapeutic drugs from Silybum marianum. In Advances in Chinese medicinal materials research, ed. H. M. Chang, H. W. Yeung, W.-W. Tso, and A. Koo, 247–256. Singapore: World Scientific Publishing.

103. Review of Natural Products: January 1997. 104. Sonnenbichler, J., and I. Zetl. 1992. Planta Medica 58 (suppl.): A580. 105. Morazzoni, P., and E. Bombardelli. 1995. Fitoterapia 66:3–42. 106. Leng-Peschlow, E., and A. Strenge-Hesse. 1991. Zeitschrift für Phytotherapie

12:162–174. 107. Bundesanzeiger (Cologne, Germany): March 13, 1986. 108. Merfort, I., and G. Willuhn. 1985. Deutsche Apotheker Zeitung 125:695–696. 109. Lawrence Review of Natural Products: June 1988. 110. Nieman, C. 1962. Chemist and Druggist 177:741–745.

111. Tyler, V. E. 1987. The new honest herbal, 143–145. Philadelphia, PA: J. B. Lippincott. 112. Chandler, R. F. 1985. Canadian Pharmaceutical Journal 118:420–424. 113. Baker, M. E. 1994. Steroids 59:136–141. 114. Duax, W. L., J. F. Griffin, and D. Ghosh. 1996. Current Opinion in Structural

Biology 6:813–823. 115. Duax, W. L., and D. Ghosh. 1997. Steroids 623:95–100. 116. Walker, B. R., and R. Best. 1995. Endocrine Research 21:379–387. 117. Bundesanzeiger (Cologne, Germany): May 15, 1986. 118. Wren, R. C. 1988. Potter’s new cyclopaedia of botanical drugs and preparations,

173–175. Saffron Waldon, England: C. W. Daniel. 119. Teelucksingh, S., A. D. R. Mackie, D. Burt, M. A. McIntyre, L. Brett, and C. R. W. Edwards. 1990. Lancet 335:1060–1063.

chapter four

Kidney, urinary tract, and prostate problems

Plant remedies for peptic ulcers Licorice