Scientific Name(s): Andrographis paniculata (Burm.f.) Wall. Nees. Family: Acanthaceae
Common Name(s): Kalmegh (Hindi), Kalmegha (Snaskrit), Chuanxinlian (Chinese), Kalupnath , Kirayat (Hindi), Mahatita (King of Bitters), Alui , Bhunimba , Bhui-neem , Yavatikta (Sanskrit), Sam biloto (Malay)
Uses of Andrographis
Kalmegh has been used for liver complaints and fever, and as an anti-inflammatory and immunostimulant. In clinical trials, Andrographis extract has been studied for use as an immunostimulant in upper respiratory tract infections and HIV infection. The potential of andrographolide as an anticancer agent is being investigated. However, clinical evidence to support the use of Kalmegh for any indication is lacking.
The usual daily dose of andrographolides for common cold, sinusitis, and tonsillitis is 60 mg. Doses of 10 mg/kg resulted in the discontinuation of a clinical trial because of adverse reactions. Clinical trials in children with upper respiratory tract infection reported the use of andrographolide 30 mg daily for 10 days.
Contraindications have not been identified.
Documented adverse reactions. Abortifacient. Avoid use.
None well documented.
Andrographis Adverse Reactions
Headache, fatigue, rash, bitter/metallic taste, diarrhea, pruritus, and decreased sex drive were reported in 1 clinical trial. One HIV-positive participant experienced an anaphylactic reaction. Doses used in this trial were 10 mg/kg body weight.
Data are limited. Male reproductive adverse reaction studies have been equivocal.
A. paniculata is an erect annual herb that grows 30 to 110 cm in height and is native to India, China, and Southeast Asia. It is widely cultivated in Asia. The square stem has wings on the angles of new growth and is enlarged at the nodes, while small white flowers with rose-purple spots are borne on a spreading panicle. The plant produces yellowish-brown seeds, and all parts have an extremely bitter taste. The portion of the plant appearing above ground are harvested in the fall. The genetic variability of the species has been examined. 1 , 2
A. paniculata has been used for centuries in India, China, Thailand, and other Asian countries and is present in 26 different polyherbal formulations in the Ayurvedic traditional health system. Kalmegh is listed in the 1992 Pharmacopoeia of the Peoples Republic of China as a cold property herb used to rid the body of fevers and dispel toxins. An immunostimulant preparation known as Kan Jang , which contains Kalmegh and eleutherococcushas, been used in Scandinavian countries for 20 years. Kalmegh is also manufactured and marketed in the United States. 3 , 4 , 5
The diterpene lactone andrographolide was first isolated as a major constituent 6 and later characterized as a lactone. 7 , 8 Its full structure was determined in the 1960s, 9 , 10 and x-ray crystallography later confirmed the structure. 11 A number of related minor diterpenes and their glycosides have since been identified. 5 , 12 , 13 , 14 , 15 , 16 , 17 , 18 Methods of analysis, including high-pressure liquid chromatography and nuclear magnetic resonance, 19 have been published. A method for rapid isolation of andrographolide is also available. 20 When callus cultures of the plant were investigated, andrographolide and the other diterpenes were not produced. Instead, the sesquiterpenes paniculides A-C were found. 21 Other constituents of the plant include various flavones. 18 , 22
Andrographis Uses and PharmacologyAntimicrobial
Extracts of Andrographis and andrographolide derivatives have shown modest activity in vitro against HIV 18 , 23 , 24 , 25 , 26 ; however, a phase 1 study of andrographolide showed no effect on viral replication after 6 weeks, despite increased CD4 counts. 27
The extract of A. paniculata blocked Escherichia coli enterotoxin-induced secretion in rabbit and guinea pig models of diarrhea. 31 Andrographolide and 3 other related diterpenes were responsible for this action. 32 Other in vitro experiments present conflicting results for the action of andrographolide and leaf extracts on E. coli . 33 , 34Cancer
Animal and in vitro experiments using human cancer cell lines to investigate the potential anticancer effects of A. paniculata have found andrographolide responsible for the observed effects rather than other diterpenes. 5 , 35 , 36 Various mechanisms of action have been proposed, including enhancement of chemokine activity, inhibition of tumor-specific angiogenesis affecting cell cycle progression, and induction of apoptosis. 35 , 36 , 37 , 38 Cancer cell lines investigated include prostate, breast, cervical, colon, hepatoma, melanoma, and lymphocytic leukemia. Researchers are now focusing on synthesizing compounds based on andrographolide to improve selectivity and potency. 35 , 39
The need for caution has been raised by one group of researchers because andrographolide-enhanced SDF-1-chemokine activity might induce tumor cell metastasis. 38 A. paniculata extract has also induced cell differentiation in mouse myeloid leukemia cells. 40Immunostimulant
Both antigen-specific and antigen-nonspecific immune responses in mice were stimulated by andrographolide and an ethanolic extract; the extract was more potent than andrographolide, suggesting that other constituents also were immunostimulants. 41 Inhibition of passive cutaneous anaphylaxis and mast cell stabilization was observed in studies of the purified diterpenes in rats. 42Clinical data
A systematic review of 4 clinical trials found A. paniculata , either alone or in a fixed combination with A. senticosus ( Kan Jang ), significantly more effective than placebo ( P < 0.0001 and P = 0.0002, respectively) in reducing the severity of upper respiratory tract infections and related symptoms. The review found a lack of outcome consistency in the included studies. 43 Other clinical trials have demonstrated similar results for respiratory infections, but methodology in these trials is of poor quality. 3 , 44 , 45
A small study in patients with familial Mediterranean fever (Nߙ=ߙ24) found a decrease in frequency, duration, and severity of febrile attacks, compared with placebo. 46
Extracts of Andrographis have demonstrated hypoglycemic action in rats with streptozotocin- and alloxan-induced diabetes, supporting a traditional use of Kalmegh. 18 , 48 , 49 Clinical trials are lacking.
Animal experiments suggest that the extract of A. paniculata is hepatoprotective, 52 , 53 , 54 but clinical trials are lacking. Hepatic drug-metabolizing enzymes were elevated in 1 animal experiment, 54 however, in a clinical trial, elevated liver enzymes (AST and ALT) were reported. 27
Andrographolide has demonstrated anti-inflammatory effects in several cellular systems, including prevention of phorbol ester-induced reactive oxygen species and N-formyl-methionyl-leucyl-phenylalanine-induced adhesion in rat neutrophils, 55 , 56 inhibition of tumor necrosis factor-induced upregulation of intercellular adhesion molecule expression, and monocyte adhesion 57 and activation of protein kinase pathways. 58
Kalmegh dosage in clinical studies has ranged from 3 to 6 g of the crude plant.
The usual daily dose of andrographolides for common cold, sinusitis, and tonsillitis is 60 mg, 59 , 60 but doses up to 1,200 mg have been reported. 61 Andrographolide 48 mg daily was used in a trial of familial Mediterranean fever. 46 Doses of 5 to 10 mg/kg were used in a trial in HIV patients, but adverse reactions at this dosage stopped the trial. 27
Clinical trials in children with upper respiratory tract infection reported the use of andrographolide 30 mg daily for 10 days. 45
Documented adverse reactions. Abortifacient. Avoid use. 62
None well documented.
Research reveals few adverse reactions reported with the use of A. paniculata . However, adverse reactions (eg, headache, fatigue, rash, bitter/metallic taste, diarrhea, pruritus, decreased sex drive) during a phase 1 study of andrographolide in HIV required interruption of the trial. One HIV-positive participant experienced an anaphylactic reaction. Doses of andrographolide 10 mg/kg body weight were used when the adverse reactions became apparent. 27 In the same trial, elevated liver enzymes were experienced by many of the participants. Two cases of urticaria have been reported in other trials. 43
Toxicology studies are limited, but Kalmegh does not appear to be acutely toxic. Acute lethal doses (median lethal dose) in mice are reported to be more than 40 g/kg for andrographolide. 27
Male reproductive toxicology of Andrographis has been studied. A subchronic 60-day study in male rats showed no changes in testicular weight, histology, or testosterone levels. 63 However, detailed studies in rats given purified andrographolide for 48 days showed decreases in sperm counts and motility that were linked to disruption of spermatogenesis. 64
A small, short-duration, phase 1 clinical trial in healthy men found no negative effects at doses 3 times the usual daily dose of Kan Jang . Instead, a positive trend in the number of spermatozoids, percent active forms, and fertility indexes was found. Limitations of the study included the small number of participants (N = 14), the short duration of the study (10 days), and the low dose tested (3 times the normal dose versus 10-fold in animal studies). 59
Bibliography1. USDA, ARS, National Genetic Resources Program. Germplasm Resources Information Network - (GRIN) [Online Database]. National Germplasm Resources Laboratory, Beltsville, Maryland. Available from URL: http://www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?414228 (Accessed October 9, 2007).
2. Padmesh P , Sabu KK , Seeni S , Pushpangadan P , et al. The use of RAPD in assessing genetic variability in Andrographis paniculata Nees, a hepatoprotective drug. Curr Sci . 1999;76:833-835.
3. Gabrielian ES , Shukarian AK , Goukasova GI , et al. A double blind, placebo-controlled study of Andrographis paniculata fixed combination Kan Jang in the treatment of acute upper respiratory tract infections including sinusitis. Phytomedicine . 2002;9(7):589-597.
4. Panossian A , Davtyan T , Gukassyan N , et al. 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.
5. Kumar RA , Sridevi K , Kumar NV , Nanduri S , Rajagopal S . Anticancer and immunostimulatory compounds from Andrographis paniculata . J Ethnopharmacol . 2004;92(2-3):291-295.
6. Boorsma W . Meds Lands Plant . 1996;18:63-66.
7. Gorter M . The bitter constituent of Andrographis paniculata . Rec Tray Chim . 1914;33:239-243.
8. Schwyzer R , et al. Uber andrographolid. Helv Chim Acta . 1951;34:652-677.
9. Cava MP , et al. The structure of Andrographolide. Tetrahedron . 1962;18:397-403.
10. Chan W , et al. The stereochemistry of andrographolide. Chem Ind . 1963;495.
11. Smith A , et al. Andrographolide: an x-ray crystallographic analysis. J Crystallogr Spectrosc Res . 1982;12:309-319.
12. Kleipool R . Constituents of Andrographis paniculata Nees. Nature . 1952;169:33-34.
13. Fujita T , et al. On the diterpenoids of Andrographis paniculata : x-ray crystallographic analysis of andrographolide and structure determination of new minor diterpenoids. Chem Pharm Bull . 1984;32:2117-2125.
14. Balmain A , et al. Minor diterpenoid constituents of Andrographis paniculata Nees. J Chem Soc Perkin . 1973;1247-1251.
15. Chen W , et al. Deoxyandrographolide-19-13-D-glucoside from the leaves of Andrographis paniculata . Planta Med . 1982;45:245-246.
16. Jantan I , et al. ent-14-13-Hydroxy-8(17),12-labdadien-16,15-olide-313,19-oxide: a diterpene from the aerial parts of Andrographis paniculata . Phytochemistry . 1994;37:1477-1479.
17. Smith PL , Maloney KN , Pothen RG , Clardy J , Clapham DE . Bisandrographolide from Andrographis paniculata activates TRPV4 channels. J Biol Chem . 2006;281(40):29897-29904.
18. Reddy VL , Reddy SM , Ravikanth V , et al. A new bis-andrographolide ether from Andrographis paniculata nees and evaluation of anti-HIV activity. Nat Prod Res . 2005;19(3):223-230.
19. Medforth C , et al. A conformational study of diterpenoid lactones isolated from the Chinese medicinal herb Andrographis paniculata . J Chem Soc Perkin . 1990;1011-1016.
20. Rajani M , et al. A rapid method for isolation of andrographolide from Andrographis paniculata Nees (Kalmegh). Pharm Biol . 2000;38:204-209.
21. Allison A , et al. Paniculides A, B, and C, bisabolenoid lactones from tissue cultures of Andrographis paniculata . Chem Commun . 1968;1493.
22. Kuroyanagi M , et al. Flavonoids from Andrographis paniculata . Chem Pharm Bull . 1987;35:4429-4435.
23. Otake T , et al. Screening of Indonesian plant extracts for anti-human immunodeficiency virus-type I (HIV-1) activity. Phytother Res . 1995;9:6-10.
24. Chang R , et al. Inhibition of growth of human immunodeficiency virus in vitro by crude extracts of Chinese medicinal herbs. Antiviral Res . 1988;3:163-176.
25. Yao XJ , Wainberg MA , Parniak MA . Mechanism of inhibition of HIV-1 infection in vitro by purified extract of Prunella vulgaris . Virology . 1992;187(1):56-62.
26. Basak A , Cooper S , Roberge AG , Banik UK , Chrétien M , Seidah NG . Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters. Biochem J . 1999;338(pt 1):107-113.
27. Calabrese C , Berman SH , Babish JG , et al. A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytother Res . 2000;14(5):333-338.
28. Misra P , et al. Antimalarial activity of Andrographis paniculata (Kalmegh) against Plasmodium berghei NK 65 in Mastomys natalensis. Int J Pharmacog . 1992;30:263-274.
29. Najib Nik A Rahman N , Furuta T , Kojima S , Takane K , Ali Mohd M . Antimalarial activity of extracts of Malaysian medicinal plants. J Ethnopharmacol . 1999;64(3):249-254.
30. Siti Najila MJ , Noor Rain A , Mohamad Kamel AG , et al. The screening of extracts from Goniothalamus scortechinii , Aralidium pinnatifidum and Andrographis paniculata for anti-malarial activity using the lactate dehydrogenase assay. J Ethnopharmacol . 2002;82(2-3):239-242.
31. Gupta S , et al. Antisecretory (antidiarrheal) activity of Indian medicinal plants against Escherichia coli enterotoxin induced secretion in rabbit and guinea pig ileal loop models. Int J Pharmacognosy . 1993;31:198-204.
32. Gupta S , et al. Antidiarrhoeal activity of diterpenes of Andrographis paniculata (Kal-Megh) against Escherichia coli enterotoxin in in vivo models. J Crude Drug Res . 1990;28:273-283.
33. Voravuthikunchai SP , Limsuwan S . Medicinal plant extracts as anti- Escherichia coli O157:H7 agents and their effects on bacterial cell aggregation. J Food Prot . 2006;69(10):2336-2341.
34. Singha PK , Roy S , Dey S . Antimicrobial activity of Andrographis paniculata . Fitoterapia . 2003;74(7-8):692-694.
35. Nanduri S , Nyavanandi VK , Thunuguntla SS , et al. Synthesis and structure-activity relationships of andrographolide analogues as novel cytotoxic agents. Bioorg Med Chem Lett . 2004;14(18):4711-4717.
36. Zhou J , Zhang S , Ong CN , Shen HM . Critical role of pro-apoptotic Bcl-2 family members in andrographolide-induced apoptosis in human cancer cells. Biochem Pharmacol . 2006;72(2):132-144.
37. Sheeja K , Guruvayoorappan C , Kuttan G . Antiangiogenic activity of Andrographis paniculata extract and andrographide. Int Immunopharmacol . 2007;7(2):211-221.
38. Ji LL , Wang Z , Dong F , Zhang WB , Wang ZT . Andrograpanin, a compound isolated from anti-inflammatory traditional Chinese medicine Andrographis paniculata , enhances chemokine SDF-1 alpha-induced leukocytes chemotaxis. J Cell Biochem . 2005;95(5):970-978.
39. Jada SR , Hamzah AS , Lajis NH , Saad MS , Stevens MF , Stanslas J . Semisynthesis and cytotoxic activities of andrographolide analogues. J Enzyme Inhib Med Chem . 2006;21(2):145-155.
40. Matsuda T , Kuroyanagi M , Sugiyama S , Umehara K , Ueno A , Nishi K . Cell differentiation-inducing diterpenes from Andrographis paniculata Nees. Chem Pharm Bull . 1994;42(6):1216-1225.
41. Puri A , Saxena R , Saxena RP , Saxena KC , Srivastava V , Tandon JS . Immunostimulant agents from Andrographis paniculata . J Nat Prod . 1993;56(7):995-999.
42. Gupta P , et al. Antiallergic activity of andrographolides isolated from Andrographis paniculata (Burm. f.) Wall. Pharm Biol . 1998;36:72-74.
43. Poolsup N , Suthisisang C , Prathanturarug S , Asawamekin A , Chanchareon U . Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials. J Clin Pharm Ther . 2004;29(1):37-45.
44. Hancke J , et al. A double-blind study with a new monodrug Kan Jang: decrease of symptoms and improvement in the recovery from common colds. Phytother Res . 1995;9:559-562.
45. Spasov AA , Ostrovskij OV , Chernikov MV , Wikman G . Comparative controlled study of Andrographis paniculata fixed combination, Kan Jang and an Echinacea preparation as adjuvant, in the treatment of uncomplicated respiratory disease in children. Phytother Res . 2004;18(1):47-53.
46. Amaryan G , Astvatsatryan V , Gabrielyan E , Panossian A , Panosyan V , Wikman G . Double-blind, placebo-controlled, randomized, pilot clinical trial of lmmunoGuarda —a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra L. extracts in patients with Familial Mediterranean Fever. Phytomedicine . 2003;10(4):271-285.
47. Ko HC , Wei BL , Chiou WF . The effect of medicinal plants used in Chinese folk medicine on RANTES secretion by virus-infected human epithelial cells. J Ethnopharmacol . 2006;107(2):205-210.
48. Zhang XF , Tan BK . Anti-diabetic property of ethanolic extract of Andrographis paniculata in streptozotocin-diabetic rats. Acta Pharmacol Sin . 2000;21(12):1157-1164.
49. Husen R , Pihie AH , Nallappan M . Screening for antihyperglycaemic activity in several local herbs of Malaysia. J Ethnopharmacol . 2004;95(2-3):205-208.
50. Reyes BA , Bautista ND , Tanquilut NC , et al. Anti-diabetic potentials of Momordica charantia and Andrographis paniculata and their effects on estrous cyclicity of alloxan-induced diabetic rats. J Ethnopharmacol . 2006;105(1-2):196-200.
51. Zhang CY , Tan BK . Effects of 14-deoxyandrographolide and 14-deoxy-11,12-didehydroandrographolide on nitric oxide production in cultured human endothelial cells. Phytother Res . 1999;13(2):157-159.
52. Kapil A , Koul IB , Banerjee SK , Gupta BD . Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata . Biochem Pharmacol . 1993;46(1):182-185.
53. Trivedi N , et al. Hepatoprotective and toxicological evaluation of Andrographis paniculata on severe liver damage. Indian J Pharmacol . 2000;32:288-293.
54. Visen PK , Shukla B , Patnaik GK , Dhawan BN . Andrographolide protects rat hepatocytes against paracetamol-induced damage. J Ethnopharmacol . 1993;40(2):131-136.
55. Shen YC , Chen CF , Chiou WF . Suppression of rat neutrophil reactive oxygen species production and adhesion by the diterpenoid lactone andrographolide. Planta Med . 2000;66(4):314-317.
56. Hidalgo MA , Romero A , Figueroa J , et al. Andrographolide interferes with binding of nuclear factor-kappa B to DNA in HL-60-derived neutrophilic cells. Br J Pharmacol . 2005;144(5):680-686.
57. Habtemariam S . Andrographolide inhibits the tumor necrosis factor-a-induced upregulation of ICAM-1 expression and endothelial-monocyte adhesion. Phytother Res . 1998;12:37-40.
58. Chen JH , Hsiao G , Lee AR , Wu CC , Yen MH . Andrographolide suppresses endothelial cell apoptosis via activation of phosphatidyl inositol-3-kinase/Akt pathway. Biochem Pharmacol . 2004;67(7):1337-1345.
59. Mkrtchyan A , Panosyan V , Panossian A , Wikman G , Wagner H . A phase I clinical study of Andrographis paniculata fixed combination Kan Jang versus ginseng and valerian on the semen quality of healthy male subjects. Phytomedicine . 2005;12(6-7):403-409.
60. Cáceres DD , Hancke JL , Burgos RA , Sandberg F , Wikman GK . Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-l0 in reducing the symptoms of common cold. A randomized double blind-placebo study. Phytomedicine . 1999;6(4):217-223.
61. Thamlikitkul V , Dechatiwongse T , Theerapong S , et al. Efficacy of Andrographis paniculata , Nees for pharyngotonsillitis in adults. J Med Assoc Thai . 1991;74(10):437-442.
62. McGuffin M , Hobbs C , Upton ft Goldberg A , eds. American Herbal Products Associations Botanical Safety Handbook . Boca Raton, FL: CRC Press; 1997 .
63. Burgos RA , Caballero EE , Sánchez NS , Schroeder RA , Wikman GK , Hancke JL . Testicular toxicity assessment of Andrographis paniculata dried extract in rats. J Ethnopharmacol . 1997;58(3):219-224.
64. Akbarsha MA , 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.