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Andrographis (Andrographis paniculata)


Andrographis paniculata
Synonyms / Common Names / Related Terms
Andrographolide, Chuan Xin Lin, Green chiretta, Kalmegh leaf extract, Kan Jang®, King of Bitters, Kold Kare®, Remdex®.







Mechanism of Action

Pharmacology:

  • Constituents: Andrographolide, a diterpene lactone compound, is believed to be the principal active agent.20 Other possibly active constituents include neoandrographolide, andrographiside, 14-deoxy-11,12-didehydroandrographolide, deoxyandrographolide, and arabinoglycan proteins. 5-Hydroxy-7,8-dimethoxy (2R)-flavanone-5-O-beta-D-glucopyranoside, 5-hydroxy-7,8,2',5'-tetramethoxy-flavone-5-O-beta-D-glucopyranoside, andrographic acid, and andrographidine A have also been isolated from Andrographis paniculata.19
  • Anti-HIV effects (proposed): 14-dehydroandroandrographolide succinic acid monoester (DASM) may inhibit proteolytic cleavage of the HIV envelope glycoprotein, thus acting as a protease inhibitor for HIV (in vitro).21 In a Phase I dosing trial in HIV positive patients, investigators reported a significant rise in CD4 counts at a dose of 10mg/kg/day; however, this dose was not well-tolerated by most patients with adverse reactions that included multiple cases of allergic reactions, fatigue, headache, painful lymphadenopathy, nausea, and diarrhea.7
  • Anti-inflammatory: Andrographolide inhibits NK-kappaB binding to DNA in vitro, reducing expression of a variety of inflammatory proteins, including COX-2.15 In rat neutrophils, it also appears to exert anti-inflammatory action via a decrease in gene expression required for neutrophil adhesion and transmigration.16 In mice with experimental autoimmune encephalomyelitis, an inflammatory demyelinating disease that serves as an animal model for multiple sclerosis, andrographolide significantly inhibited T-cell and antibody responses to myelin antigens.9 Andrographolide also reduced immune-stimulated nitric oxide production in vitro, either through accelerated degradation of the iNOS nitric-oxide producing protein or by suppressing expression of this protein.11,14 Neoandrographolide has also been shown in vitro and ex vivo to suppress nitric oxide synthesis in mice.13 Other in vitro studies suggest that the anti-inflammatory/anti-apoptotic action may be mediated by a decrease in free radical production through inhibition of release of cytochrome C by mitochondria.2 Andrographolide may also have mast-cell stabilizing activity in rats.
  • Antineoplastic effects: Several in vitro studies have indicated that andographolide has anticancer effects.17,18,19 Specifically, andrographolide and isoandrographolide have ED50 values of 6.5 and 5.1mcg/mL, respectively, when added to KB cells.19 Based on their experience with andographolide and human cancer cells, Zhou et al. postulate that andrographolide may induce apoptosis in human cancer cells via activation of caspase 8 in the extrinsic death receptor pathway and subsequently with the participation of mitochondria.17
  • Cardiovascular effects: Studies in dogs have shown a decrease in myocardial reperfusion injury following ischemic events, possibly mediated by a decrease in the level of free radicals generated by ischemia.22 Studies in rabbits report that andrographolide may help reduce restenosis after angioplasty by reducing the secretion of endothelial growth factors that contribute to restenosis.10 Rat studies show a possible hypotensive effect as well.12
  • Genitourinary effects: Animal studies show possible decreased spermatogenesis by preventing cytokinesis of dividing spermatogenic cell lines.8
  • Hematologic effects: In vitro studies have demonstrated an antithrombotic effect via inhibition of PAF-induced platelet aggregation.1
  • Hepatoprotective effects: In mouse models of chemically-induced hepatotoxicity, andrographolide, neoandrographolide, and andrographiside all reduced levels of lipid peroxidation, glutathione depletion, and enzymatic leakage, possibly through antioxidant effects.6 A choleretic effect was seen in rats and guinea pigs with paracetamol-induced liver damage.5
  • Hypoglycemic effects: Studies in rabbits suggest that a water extract of andrographis can prevent hyperglycemia induced by oral glucose administration, probably through an effect on glucose absorption from the gut4; there is no effect on fasting blood sugar levels with chronic administration of the extract. A rat study showed increased digestion and absorption of carbohydrates in rats after the administration of andrographolide. This is believed to be mediated by activation of intestinal disaccharidases.23 Recent animal studies report that there may also be an increased glucose metabolism in rats treated with andrographolide.24
  • Immunomodulatory properties: Andrographolide alone and the standardized andrographis combination product Kan Jang® were found to increase the formation of TNF-alpha and Beta2MG in vitro; the fixed combination was more effective than the andrographolide alone.25 In vitro andrographolide also increased TNF-alpha production and cytotoxic activity of lymphocytes against certain cancer cell lines, as well as demonstrating potential direct anticancer activity by induction of cell-cycle inhibitory protein p27 and decreased expression of cyclin-dependent kinase.3

Pharmacodynamics/Kinetics:

  • Time to peak: In humans, maximum plasma levels of andrographolide after a typical therapeutic dose of 20mg (four tablets of Kan Jang® preparation) are reached after 1.5-2 hours.26
  • Metabolism: Andrographolide appears to be intensively metabolized in a dose-dependent fashion. Renal excretion does not play a significant role in its elimination. The half-life of andrographolide is approximately 6.6 hours.26
  • EC50 and IC50: In an in vitro study using mouse cells, bisandrographolide A extracted from Andrographis paniculata potently activated transient receptor potential 4 (TRPV4) channels with an EC50 of 790-950nm.27
  • The ethanol extract of Andrographis paniculata significantly inhibited growth of human acute myeloid leukemic HL-60 cells with an IC50 value of 14.01mcg/mL after 24 hours of treatment. 18

References
  1. Amroyan, E., Gabrielian, E., Panossian, A., Wikman, G., and Wagner, H. Inhibitory effect of andrographolide from Andrographis paniculata on PAF-induced platelet aggregation. Phytomedicine  1999;6(1):27-31. 10228608
  2. Chen, J. H., Hsiao, G., Lee, A. R., Wu, C. C., and Yen, M. H. Andrographolide suppresses endothelial cell apoptosis via activation of phosphatidyl inositol-3-kinase/Akt pathway. Biochem Pharmacol 4-1-2004;67(7):1337-1345. 15013849
  3. Rajagopal, S., Kumar, R. A., Deevi, D. S., Satyanarayana, C., and Rajagopalan, R. Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. J Exp Ther Oncol  2003;3(3):147-158. 14641821
  4. Borhanuddin, M., Shamsuzzoha, M., and Hussain, A. H. Hypoglycaemic effects of Andrographis paniculata Nees on non-diabetic rabbits. Bangladesh Med Res Counc Bull  1994;20(1):24-26. 7880153
  5. Shukla, B., Visen, P. K., Patnaik, G. K., and Dhawan, B. N. Choleretic effect of andrographolide in rats and guinea pigs. Planta Med  1992;58(2):146-149. 1529026
  6. Kapil, A., Koul, I. B., Banerjee, S. K., and Gupta, B. D. Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata. Biochem Pharmacol  7-6-1993;46(1):182-185. 8347130
  7. Calabrese, C., Berman, S. H., Babish, J. G., Ma, X., Shinto, L., Dorr, M., Wells, K., Wenner, C. A., and Standish, L. J. A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytother Res  2000;14(5):333-338. 10925397
  8. Akbarsha, M. A. and Murugaian, P. Aspects of the male reproductive toxicity/male antifertility property of andrographolide in albino rats: effect on the testis and the cauda epididymidal spermatozoa. Phytother Res  2000;14(6):432-435. 10960897
  9. Iruretagoyena, M. I., Tobar, J. A., Gonzalez, P. A., Sepulveda, S. E., Figueroa, C. A., Burgos, R. A., Hancke, J. L., and Kalergis, A. M. Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse. J Pharmacol Exp Ther  2005;312(1):366-372. 15331658
  10. Wang, D. W. and Zhao, H. Y. Prevention of atherosclerotic arterial stenosis and restenosis after angioplasty with Andrographis paniculata nees and fish oil. Experimental studies of effects and mechanisms. Chin Med J(Engl) 1994;107(6):464-470. 7956489
  11. Chiou, W. F., Lin, J. J., and Chen, C. F. Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipopolysaccharide. Br J Pharmacol  1998;125(2):327-334. 9786505
  12. Zhang, C. Y. and Tan, B. K. Hypotensive activity of aqueous extract of Andrographis paniculata in rats. Clin Exp Pharmacol Physiol 1996;23(8):675-678. 8886488
  13. Batkhuu, J., Hattori, K., Takano, F., Fushiya, S., Oshiman, K., and Fujimiya, Y. Suppression of NO production in activated macrophages in vitro and ex vivo by neoandrographolide isolated from Andrographis paniculata. Biol Pharm Bull  2002;25(9):1169-1174. 12230111
  14. Chiou, W. F., Chen, C. F., and Lin, J. J. Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide. Br J Pharmacol  2000;129(8):1553-1560. 10780958
  15. Hidalgo, M. A., Romero, A., Figueroa, J., Cortes, P., Concha, I. I., Hancke, J. L., and Burgos, R. A. Andrographolide interferes with binding of nuclear factor-kappaB to DNA in HL-60-derived neutrophilic cells. Br J Pharmacol  2005;144(5):680-686. 15678086
  16. Shen, Y. C., Chen, C. F., and Chiou, W. F. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol  2002;135(2):399-406. 11815375
  17. Zhou, J., Zhang, S., Ong, C. N., and Shen, H. M. Critical role of pro-apoptotic Bcl-2 family members in andrographolide-induced apoptosis in human cancer cells. Biochem Pharmacol 7-14-2006;72(2):132-144. 16740251
  18. Cheung, H. Y., Cheung, S. H., Li, J., Cheung, C. S., Lai, W. P., Fong, W. F., and Leung, F. M. Andrographolide isolated from Andrographis paniculata induces cell cycle arrest and mitochondrial-mediated apoptosis in human leukemic HL-60 cells. Planta Med 2005;71(12):1106-1111. 16395645
  19. Li, W., Xu, X., Zhang, H., Ma, C., Fong, H., van Breemen, R., and Fitzloff, J. Secondary metabolites from Andrographis paniculata. Chem Pharm Bull (Tokyo) 2007;55(3):455-458. 17329890
  20. Jada, S. R., Hamzah, A. S., Lajis, N. H., Saad, M. S., Stevens, M. F., and Stanslas, J. Semisynthesis and cytotoxic activities of andrographolide analogues. J Enzyme Inhib Med Chem 2006;21(2):145-155. 16789428
  21. Basak, A., Cooper, S., Roberge, A. G., Banik, U. K., Chretien, M., and Seidah, N. G. Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters. Biochem J  2-15-1999;338 ( Pt 1):107-113. 9931305
  22. Guo, Z. L., Zhao, H. Y., and Zheng, X. H. An experimental study of the mechanism of andrographis paniculata nees (APN) in alleviating the Ca(2+)-overloading in the process of myocardial ischemic reperfusion. J Tongji Med Univ 1995;15(4):205-208. 8731924
  23. Choudhury, B. R. and Poddar, M. K. Andrographolide and kalmegh (Andrographis paniculata) extract: effect on intestinal brush-border membrane-bound hydrolases. Methods Find Exp Clin Pharmacol  1985;7(12):617-621. 3938507
  24. Yu, B. C., Hung, C. R., Chen, W. C., and Cheng, J. T. Antihyperglycemic effect of andrographolide in streptozotocin-induced diabetic rats. Planta Med  2003;69(12):1075-1079. 14750020
  25. Panossian, A., Davtyan, T., Gukassyan, N., Gukasova, G., Mamikonyan, G., Gabrielian, E., and Wikman, G. Effect of andrographolide and Kan Jang--fixed combination of extract SHA-10 and extract SHE-3--on proliferation of human lymphocytes, production of cytokines and immune activation markers in the whole blood cells culture. Phytomedicine  2002;9(7):598-605. 12487323
  26. Panossian, A., Hovhannisyan, A., Mamikonyan, G., Abrahamian, H., Hambardzumyan, E., Gabrielian, E., Goukasova, G., Wikman, G., and Wagner, H. Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine  2000;7(5):351-364. 11081986
  27. Smith, P. L., Maloney, K. N., Pothen, R. G., Clardy, J., and Clapham, D. E. Bisandrographolide from Andrographis paniculata activates TRPV4 channels. J Biol Chem 10-6-2006;281(40):29897-29904. 16899456




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