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Andrographis

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)

Clinical Overview

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.

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Andrographis Dosing

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

Contraindications have not been identified.

Pregnancy/Lactation

Documented adverse reactions. Abortifacient. Avoid use.

Andrographis Interactions

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.

Toxicology

Data are limited. Male reproductive adverse reaction studies have been equivocal.

Botany

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

History

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

Chemistry

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 Pharmacology

Antimicrobial

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

Activity in antimalarial screens has also been noted for Andrographis extracts, but clinical trials are lacking. 28 , 29 , 30

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 , 34

Cancer

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. 40

Immunostimulant
Animal data

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. 42

Clinical 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

Stimulation of the production of key cytokines and immune activation markers has been investigated as potential mechanisms of andrographolide immunomodulation. 4 , 38 , 47

Other uses

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.

Two older trials explored a possible hypotensive effect of andrographolide/Kalmegh, but further investigation has not been conducted. 50 , 51

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

Dosage

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

Pregnancy/Lactation

Documented adverse reactions. Abortifacient. Avoid use. 62

Interactions

None well documented.

Adverse Reactions

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

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

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