Abstract
Andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (2) are active constituents of Andrographis paniculata (Burm. f.), family Acanthaceae. A. paniculata extracts are reported to have antiviral, antipyretic, immunostimulant and anticancer activities. In this study, 1 and its 14-acetyl- (4) and 3,19-isopropylidenyl- (3) derivatives, as well as 2 and its 3,19-dipalmitoyl-derivative (5), were intraperitoneally tested for their analgesic, antipyretic, anti-inflammatory and acute toxicity effects in animal models. Analgesic effects were tested in mice using hot plate and writhing tests to distinguish the central and peripheral effects, respectively. The results showed that, at 4 mg/kg, all tested substances have significant analgesic effects, and the highest potency was seen with 3, 4 and 5. Increasing the dose of 3 and 5 to 8 mg/kg did not increase the analgesic effect. In the writhing test, 3 and 5, but not 1, showed significant results. In a baker’s yeast-induced fever model, 3 and 5 significantly reduced rats’ rectal temperature (p < 0.05). In a carrageenan-induced inflammation model, 1, 3 and 5 significantly reduced rats’ paw volume. Doses of 3 and 5 up to 100 mg/kg did not show any serious toxic effects. From this study, 3 and 5 are the most interesting derivatives, showing much greater potency than their parent compounds. These could be further developed as analgesic, antipyretic and anti-inflammatory agents, without any serious toxicity.
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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 ofAndrographis paniculata and their succinoyl esters. Biochem. J. 338, 107–113 (1999).
Brochet, D., Micó, J. A., Martin, P., and Simon, P., Antinociceptive activity of beta-adrenoceptor agonists in the hot plate test in mice. Psychopharmacology 88, 527–528 (1986).
Chang, R. S., Ding, L., Chen, G. Q., Pan, Q. C., Zhao, Z. L., and Smith, K. M., Dehydroandrographolide succinic acid monoester as an inhibitor against the human immunodeficiency virus. Proc. Soc. Exp. Biol. Med., 197, 59–66 (1991).
Cui, L., Qiu, F., and Yao, X., Isolation and identification of seven glucuronide conjugates of andrographolide in human urine. Drug Metab. Dispos., 33, 555–562 (2005).
Deng, W. L., Nie, R. J., and Liu, J. Y., Comparison of pharmacological effect of four andrographolides. Yaoxue Tongbao, 17, 195–198 (1982).
Fujita, T., Fujitani, R., Takeda, Y., Takaishi, Y., Yamada, T., Kido, M., and Miura, I., On the triterpenoids of Andrographis paniculata: X-ray crystallographic analysis of andrographolide and structure determination of new minor diterpenoids. Chem. Pharm. Bull., 32, 2117–2125 (1984).
Ganesh, T., Improved biochemical strategies for targeted delivery of taxoids. Bioorg. Med. Chem. Lett., 15, 3597–3623 (2007).
Goldstein, D., Gofrit, O., Nyska, A., and Benita, S., Anti-HER2 cationic immunoemulsion as a potential targeted drug delivery system for the treatment of prostate cancer. Cancer Res., 67, 269–275 (2007).
Han, G. Du, G.-J., and Xu, Q.-T., Yang, S.-S., Studies of andrographolide maleate monoester and its antipyretic and antiinflammatory activities. Zhongguo Yaoxue Zazhi, 40, 628–631(2005).
He, X., Li, J., Gao, H., Qiu, F., Hu, K. Cui, X., and Yao, X., Six new andrographolide metabolites in rats. Chem. Pharm. Bull., 15, 586–589 (2003).
Heiati, H., Tawashi, R., Shivers, R. R., and Phillips, N. C., Solid lipid nanoparticles as drug carriers. Incorporation and retention of the lipophilic prodrug 3-azido-3-deoxythymidine palmitate Int. J. Pharm., 146, 123–131 (1997).
Iruretagoyena, M. I., Tobar, J. A., Gonzalez, P.A., Sepulveda, S. E., Figueroa, C. A., Burgos, R. A. et al., Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in mouses. J. Pharmacol. Exp. Ther., 312, 366–372 (2005).
Jada, S. R., Subur G.S., Mathew, C., Hamzah, A. S., Lajis, N. H., Saad, M. S. et. al., Semisynthesis and in vitro anticancer activities and andrographolide analogues Phytochem., 68, 904–12 (2007).
Kumar, V., Abbas, A. K., Fausto N. (Eds.), Robbins and Cotran Pathologic Basis of Disease, 7th ed. Elsevier Saunders: Philadelphia, (2005).
Lomlim, L., Jirayupong, N., and Plubrukarn, A., Heat-accelerated degradation of solid-state andrographolide. Chem. Pharm. Bull. 51, 24–26 (2003).
Madav, S., Tripathi, C., Tandan, S. K., and Mishra, S., Analgesic, antipyretic, and antiulcerogenic effects of andrographolide. Ind. J. Pharm. Sci. 57, 121–125 (1995).
Madav, S., Tandon, S. K., Lal, J., and Tripathi, C., Anti-inflammatory of andrographolide. Fitoterapia, 67, 452–458 (1996).
Marsh, D. J., Miura, G. I., Yagaloff, K. A., Schwartz, M. W., Barsh, G. S., and Palmiter, R., Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues. Brain Res., 848, 66–77 (1999).
Nakano, M., Denda, N., Matsumoto, M., Kawamura, M., Kawakubo, Y., Hatanaka, K. et al., Interaction between cyclooxygenase (COX)-1- and COX-2-products modulates COX-2 expression in the late phase of acute inflammation. Eur. J. Pharmacol., 559, 210–218 (2007).
Nanduri, S., Nyavanandi, V. K. Thunuguntla, S. S. R. et al., Synthesis and structure-activity relationships of andrographolide analogues as novel cytotoxicagents. Bioorg. Med. Chem. Lett., 14, 4711–4717 (2004).
Nasrallah H. A. et al, Efficacy and safety of three doses of paliperidone palmitate, an investigational long acting injectable antipsychotic, in schizophrenia. APA Meeting; Abstract NR4-036 (2008).
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, 7, 351–364 (2000).
Sheeja, K., Shihab, P. K., and Kuttan, G., Antioxidant and anti-Inflammatory activities of the plant Andrographis Paniculata Nees. Immunopharmacol. Immunotoxicol., 28, 129–140 (2006).
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., 135, 399–406 (2002).
Shen, Y-H., Li, R-T., Xiao, W-L., Xu, G., Lin, Z-W., Zhao, Q-S., and Sun, H-D., ent-Labdane diterpenoids from Andrographis paniculata. J. Nat. Prod., 69, 319–322 (2006).
Suo, X. B., Zhang, H., and Wang, Y-Q., HPLC determination of andrographolide in rat whole blood: study on the pharmacokinetics of andrographolide incorporated in liposomes and tablets. Biomed. Chromatogr., 21, 730–734 (2007).
Thamlikitkul, V. Dechatiwongse, T., Theerapong, S., Chantrakul, C., Boonroj, P., and Punkrut, W., Efficacy of Andrographis paniculata, Nees for pharyngotonsillitis. J. Med. Assoc. Thailand 74, 437–442 (1991).
Tomazetti, J., Avila, D. S., Ferreira, A. P., Martins, J. S. Souza, F. R., Royer, C., Rubin, M. A., Oliveira, M. R., Bonacorso, H. G., Martins, M. A., Zanatta, N., and Mello, C. F., Baker yeast-induced fever in young rats: Characterization and validation of an animal model for antipyretics screening. J. Neurosci. Methods, 147, 29–35 (2005).
Winter, C. A., Risley, G. A., and Nass, G. W., Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc. Soc. Exp. Biol. Med., 111, 544–547 (1962).
Xia, Y-F., Ye, B-Q., Li, Y-D., Wang, J.-G., He, X.-J., Lin, X., Yao, X., Ma, D., Slungaard, A., Hebbel, R. P., Key, N. S., and Geng, J.-G., Andrographolide attenuates inflammation by inhibition of NF-kB Activation through covalent modification of reduced cysteine 62 of p50. J. Immunol., 173, 4207–4217 (2004).
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Suebsasana, S., Pongnaratorn, P., Sattayasai, J. et al. Analgesic, antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals. Arch. Pharm. Res. 32, 1191–1200 (2009). https://doi.org/10.1007/s12272-009-1902-x
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DOI: https://doi.org/10.1007/s12272-009-1902-x