中 西醫 combined conference 2011.10.19

1. 報告者：fellow 1 陳筱惠 指導醫師：方基存教授 中西醫combined conference2011.10.19

2. Kidney Injury, Electrolyte and Acid-Base Abnormalities Associated With Use of Alternative Medicine Products April 2009 Dialysis & Transplantation

3. Anthraquinones: laxatives • Parsley (Petroselinum • crispum) and juniper (duniperus communis): diuretics • Licorice: sodium/water retention, potassium loss, hypertension • Alfalfa (Medicago sativa), dandelion (Taraxaturn o~cinale), horsetail (Equisetum arvense), and nettle (Urtica dioica): contain potassium Medicinal Herb Use and the Renal Patient Jourual of Renal Nutritwn, Vol 8, No 1 (January), 1998: pp 40-42

4. Licorice • Genus: Glycyrrhiza (Leguminosae) • About 30 species: G. glabra, G. uralensis, G. inflata, G. aspera, G. Korshinskyi and G. eurycarpa, G. glabra • Other common names: sweet root • Description: • Perennial herb with sweet tasting roots • Native to the Mediterranean, the Mideast, Russia, and Asia • Used as flavoring, sweetener, and medicinal herb Medicinal uses of licorice through the millennia: the good and plenty of it Molecular and Cellular Endocrinology, 78 (1991) 1-6

5. Used part: roots, rhizomes • Known active constituents: • Triterpenoid saponins: mostly glycyrrhizin, which is 50 times sweeter than sugar • Flavonoids • Isoflavones • Coumarin derivatives

6. Pharmacology • Glycyrrhizin is hydrolyzed to glycyrrhetinic acid in the intestine by intestional bacteria.

7. Pharmacokinetics • Glycyrrhizin: • Peak serum concentration: less 4 hours • Not detectable at 96 hours • Glycyrrhetinic acid: • Peak serum concentration: 24hour • Still detectable in 72 hour • Excretion: mostly by GI tract, 2% metabolite in urine

8. Uses Phytother. Res. 22, 709–724 (2008)

9. Activities – experimental and clinical studies • Anti-inflammatory activities: • Inhibit glucocorticoid metabolism and potentiates their effects • Inhibit classical complement pathway activation • Inhibit reactive oxygen species (ROS) generation by neutrophils • COX-2 inhibition??

10. Antimicrobial and antiviral activities: • Restore the effects of oxacillin and β- lactam antibiotic against MRSA • E. coli, E. aerogenes, K. pneumoniae • B. subtilis • Helicobacter pylori

12. Antioxidative activities: • Preventing microsomal lipid peroxidation induced by Fe (III)-ADP/NADPH and licochalcone B, D • Inhibited lipid peroxidation in rat liver • Antioxidant toward LDL oxidation

13. Hepatoprotective activities :

14. Gastrointestinal activities: • Antiulcer properties, as effectively as an H2 blocker • Raising the local concentration of prostaglandins that promote mucous secretion and cell proliferation in the stomach

15. Antitumor activities:

16. Central nervous system activities: • Inhibit serotonin reuptake, antidepressant activity in both the forced swim test (FST) and tail suspension test (TST) in mice • Anticonvulsant effect in PTZ and lithiumpilocarpine- induced convulsion models • Protective effects in cerebral ischemia-reperfusion injury in rats

17. Cardiovascular activities: • Antiplatelet aggregation effect • Vasorelaxant effect • Anti-angiogenic effect • Estrogen-like activities, modulate vascular injury and atherogenesis

18. Immunological activities: • Inducer of type 2 antagonistic CD41 T cells in in vivo and in vitro studies • Stimulate macrophage-derived NO production • Up-regulate iNOS expression through nuclear factor kB (NF- kB) transactivation in murine macrophages • Induce interferon activity and augment natural killer cell activity • Inhibitory effects on TNF-alpha-induced IL-8 production in intestinal epithelial cells • Anticomplementary activity and mitogenic activity

19. Adverse reactions

20. Licorice toxicity:unknown prevalence, but not common • In Denmark, average licorice consumption 2kg per person per year, no epidemics of licorice toxicity have been reported

21. Almost all reported cases of licorice-induced problems from licorice containing liqueurs, candies, gum, laxatives, or chewing tobacco rather than from the use of licorice as medicine. In chinese medicine licorice is always used as part of mixture, and the synergistic effects of mixtures, as well as perhaps dose differences, may prevent problems.

23. Licorice and pseudoaldosteronism • Licorice induced hypermineralocorticoidism NEJM Vol. 325 No.17 1223-1227 • How to Diagnose and Treat a Licorice-induced Syndrome with Findings Similar to that of Primary Hyperaldosteronism Internal Medicine Vol. 43, No. 1 (January 2004) • Pseudoaldosteronism due to the concurrent use of two herbal medicines containing glycyrrhizin: interaction of glycyrrhizin with angiotension-converting enzyme inhibitor Clin Exp Nephrol (2006) 10:131–135 • Pseudohyperaldosteronism, Liquorice,and HypertensionTHE Journal of Clinical Hypertension VOL. 10 NO. 2 February 2008

24. The previous theory: the binding of its active components, glycyrrhizic acid, to mineralocorticoid receptos • Argument: • The affinity of glycyrrhetinic acid for mineralocorticoid receptor is 0.01% of that of aldosterone. • Licorice or glycyrrhetinic acid dose not have mineralcorticoid effects in patients with Addison’s disease or adrenalectomized rats unless cortisone or hydrocortisone is administered concomitantly.

25. Accepted mechanism now: inhibit 11B-hydroxysteroid dehydrogenase

26. The clinical profile of liquorice-induced pseudohyperaldosteronism is similar to the syndrome of apparent mineralocorticoid excess.

27. Subjects with history of chronic licorice ingestion were found that renin-aldosterone axis was suppressed. Normal function resumed within 2~4 months after licorice was discontinued.

28. The daily dose of glycyrrhizin that induces pseudoaldosteronism ranges from 20mg to 586mg. • The reported durations of use have ranged from 6 days to 15 years. • Artificial liquorice flavoring agents not containing glycyrrhizin would not influence mineralocorticoid metabolism.

29. Disease development has sometimes been triggered by the concomitant use of glycyrrhizin with insulin, diuretics, or oral contraceptives. • The mineralocorticoid effects of glycyrrhizin had been hidden by the concurrent use of an ACE inhibitor.

30. Treatment of this syndrome: • Cessation of licorice • Potassium-sparing diuretic, such as spironolactone • Low salt diet

31. On encountering clinical manifestations suggesting mineralocorticoid excess  • Liddle syndrome • Cushing syndrome • Conn syndrome • Apparent mineralocorticoid excess (AME), Deoxycorticosterone (DOC)-producing tumor • Licorice-induced pseudoaldosteronism

32. Thanks for your listening