Andrographis paniculata (Burm.f.) Nees

Last update: 17 November 2014

Scientific Name

Andrographis paniculata (Burm.f.) Nees

Synonyms

Justicia paniculata Burm.f. [1]

Vernacular Name

Malaysia Hempedu bumi, akar cerita, empedu tanah [2], pokok cerita [3]
English Creat, green chireta, king of bitters [4],   Indian echinacea [5]
China Shuang xin Lian [4], chuan xin lian,Si fang lian [5]
India Bhunimba (Sanskrit); nilavembu, kirata [4], maha-tita,kalmegh [5]
Indonesia Ki oray (Sundanese); sambilata (Javanese); ampadu (Padang); sambiloto, bidara, ki peurat, papitan, sadilata, takila, takilo [4]
Philippines Aluy, likha (Tagalog); sinta (Bikol)[5]
Thailand Fa thalaai (Bangkok); khee-pang-hee (Chinese); yaa kannguu (Songkhla); fa thalai joan, fa thalai jone, nam laai pang phon [4]
Vietnam C[oo]ng c[ooj]ng, kh[oor] di[eej]p, xuy[ee]n t[aa]m li[ee]n [4]
Myanmar Hsay-Khar-gyi, nga-yoke-kar [6]
France Roi des amers [7].

Geographical Distributions

Andrographis paniculata is a tropical and sub-tropical herb widely found in Asia including India, Sri Langka, Bangladesh, Thailand, Peninsular Malaysia, Indonesia, the Philippines, China and Australia. It is now widely naturalized in most of these regions. It has also been introduced in the West Indies and Central America possibly for its ornamental value. [8]

This plant is locally common and often gregarious. It exhibits weedy characteristics and occurs from sea-level up to 1600 m altitude. The plants can be found in a wide variety of habitats such as hill slopes, wastelands, farms, dry or wet lands, sea shores, roadsides, village groves, open sandy locations and fields and even in monsoon and teak forest receiving only 10-20% of full light. [8][9]

Botanical Description

A. paniculata is a flowering herbaceous plant from the family of Acanthaceae. It is a perennial herb that can grow from 30-100 cm tall. [8]

The stem is woody with a diametre of 0.5-1.0 cm [10] [11]. It branches sharply, winged in the upper part [12]. The stem is distinctly 4-angular and smooth apart from a few hairs at the nodes [8].

The leaves are opposite, simple and narrowly ovate to lance-shaped measures 5-10 cm x 1.2-2.5 cm. Acuminate apex and have an attenuate base. The leaves are soft and hairless, entire margin and often gland-dotted. Short petiole up to 6 mm long, connected with the opposite petiole by transverse ridges [8]. The colour of the leave is pale beneath [12].

The flower is zygomorphic and bisexual. It is small in size, arranged in lax, axillary and terminal racemes or panicles combined into a pyramidal inflorescence. Thepedicelmeasures 1-7 mm long with 2 small bracteoles at the base. The sepal has 5 segments and are joined at the base, with glandular and aglandular hairs. The petal is bilabiate, white or rose colour with purple markings on the upper lip. The petal tube is between 5-6 mm long, slightly enlarged below the limb. The lower lip is 4-6 mm long, oblong and it is 2-toothed at the apex while the upper lip is deeply 3-lobed, also 4-6 mm in length. The stamens are 2 and are inserted at the petal tube apex and exserted. The filaments are hairy. The anther is inserted together, at the base they are united and bearded, deep purple to black in colour. The ovary is superior, 2-locular with 3-7 ovules in each cell, the style is curved upwards and the stigma is entire. [8]

The fruit is an erect, narrowly ellipsoidal, loculicidal and the capsule is glandular, 14-20 mm x 3 - 3.5 mm, many seeded. The seed is held up on a well-developed retinaculae hooks, almost rectangular, rugosely furrowed with 2 deep furrows. [8]

Cultivation

Soil Suitability and Climatic Requirement

This plant is suitable to be planted in moderate climatic condition, subtropical and tropical areas that receives about 1,500-2,000 mm rain per year. It can also survive in areas such as river bank, sandy soils and also hilly areas of up to 700 m above sea level. [10][11]

Field Preparation

Land Preparation

The planting area must be rotovated to improve the soil structure and to eliminate the weeds. The first rotavation is done to prepare the area for liming activity if the pH is low (acid soil). The second ploughing must be carried out after liming to ensure the lime is well incorporated into the soil to obtain the optimum effect. [10][11]

 

 agfig1
Figure 1: Land preparation to improve the soil structure. [11]

Production of Planting Materials

The seed is the best source of planting material for A. paniculata. It is advisable not to directly sow the seed into the soil due to its small size. The seed is recommended to be sown in styrofoam trays. The germinated seedlings, at the age of 2-3 weeks after sowing, are then transferred into the seedling trays. These seedlings are raised for another 3-4 weeks in the seedling trays (styrofoam or black plastic tray) before field planting. In normal situation, the 3 or 4-week-old seedlings can attain a height of up to 6-8 cm. The use of plastic trays makes the handling of the seedlings becomes more convenient during transplanting. [10][11]

 apnfig2
Figure 2: A. paniculata seedlings in seedling trays ready for field planting. [11]

Field Planting

Two plant rows per bed at a planting distance of 30 cm x 30 cm are recommended. This will give a population of 55 555 plants/ha. The use of optimum size seedlings produces new branches 2-3 weeks after transplanting. The flower will start to appear 6-8 weeks after transplanting followed by the formation of the seed pod 10 weeks after transplanting. [10] [11]

Field Maintenance

Fertilisation

For both bris and alluvial soils, chicken manure at 10 t/ha is recommended to be applied seven days  before transplanting by incorporating into the soil to a depth of 15 cm from the soil surface. This is followed with the application of semi-organic fertiliser using N:P:K (10:10:10) at 500 kg/ha at transplanting for bris soil. Only 250 kg/ha of semi-organic fertiliser is adequate for alluvial soil. [10][11][13]

Weed Control

Weed problem can be solved by using plastic mulch to cover the entire surface of the bed as soon as the fertiliser is applied and the drip tape is installed. Mulching will also help to ensure the harvested plants are not contaminated with sand, soil and organic materials such as weeds. [10][11]

Water Management

A. paniculata requires a sufficient amount of water for good growth. Water deficit at vegetative growth stage will hinder plant development and result in severe stunting of the plant. Insufficient water supply will also reduce nutrient uptake and promote premature flowering hence reduces the biomass yield. On the other hand, excess irrigation water will increase leaching of the nutrient resulting in the loss of fertiliser into the soil especially for the bris sandy soil. [10][11]

Pest and Disease Control

Currently, there are no serious pest and disease problems on the field planting of A. paniculata.  However, some problems related to viral infections do occur at the nursery stage. The problem can be solved by practicing good sanitary practices. [10]

Harvesting

A. paniculata can be harvested 8-10 weeks after field planting by cutting the stem at about 5 cm from the soil surface. At this growth stage, the flower buds start to develop. Harvesting at emergence of flower bud produces highest chemical content compared to early or late harvests. [10][11]

 

 apnfig3
Figure 3: Harvesting of A. paniculata by cutting the stem 5 cm from the soil surface [11].

Postharvest Handling

Drying of A. paniculata can be done by using commercial dryer or commercial drying barn. The product must be dried to reach a moisture content of 10-12 % to maintain the quality and to avoid fungus attack which is prevalent at higher moisture content. [10][11]

Estimated Cost of Production

Total cost of producing A. paniculata is about RM7700 (alluvial soil) to RM8300 (bris soil) per hectare. At the production level of 1,000-1,500 kg/ha on bris soil, the production cost of dried A. paniculata is RM5.50-RM8.30/kg. For alluvial soil, at yield of 500-800 kg/ha, the production cost of dried A. paniculata is RM9.60-RM15.30/kg. The production cost was estimated based on the cost of current inputs during writing of this article. [10][11]

Chemical Constituent

A. paniculata has been reported to contain diterpenes (e.g. andrograpanin, andrographolide, 14-deoxy-11,12-didehydroandrographolide, isoandrographolide, 14-deoxy-12-methoxyandrographolide, 14-deoxy-11,12-dihydoandrographolide, 12-epi-14-deoxy-12-methoxyandrographolide, 14-epi-andrographolide, 14-deoxyandrographolide, 14-deoxy-12-hydroxy-andrographolide, 14-deoxy-15-isopropylidene-11,12-didehydroandrographolide, 6’-acetylneoandrographolide, bisandrographolide A-D, andrographic acid, andrographiside and neoandrographolide), sesquiterpene (e.g. paniculides A-C), flavanone (e.g. andrographidin A-F and trimethoxyflavone), and flavonoid (e.g. andrographin, andropanoside, deoxyandrographiside, panicoline, 5-hydroxy-7,8-dimethoxy (2R)-flavanone-5-O-beta-D-glucopyranoside and 5-hydroxy-7,8,2',5'-tetramethoxy-flavone-5-O-beta-D-glucopyranoside, 5-hydroxy-7,8,2’,3’-tetramethoxyflavone, 5-hydroxy-7,8-dimethoxyflavone, 5-hydroxy-7,8-dimethoxy-flavanone, 5-hydroxy-7,2’,6’-trimethoxyflavone, 14-deoxy-11,12-dihydroandrographiside). [14][15][16][17][18][19][20][21][22][23][24][25][26]

Plant Part Used

Whole plant, leaves, aerial parts, roots.

Traditional Use

A. paniculata is traditionally used to support digestion and healthy cardiovascular and urinary systems [27]. It was reported to be used as anti-inflammatory, antibacterial, antivirus, fever and expectorant [9]. A. paniculata helps in treating constipation, induce blood clotting and controlling sugar content in the blood [28]. The plant was also reported to be able to increase body immunity system. It has potential to be used in commercial medicine for treating diabetes and high blood pressure [28] [29]. It is also used to treat chronic and intermittent fevers, mild malaria, curing snake-bites, insect’s stings, diabetes, hyperdipsia and burning sensation [30].

Much like western herbal medicine, Ayurveda medicine also values the use of A. paniculata in its relation to the liver and often used to treat jaundice. Additionally, it has been found useful in the treatment of dysentery, cholera, consumption, influenza, bronchitis, swelling and skin problems. During the influenza outbreaks in India, the tincture of the plant was used in arresting the progressing of the epidemic. [31]

The leaves considered to be an antihepatotoxic, an antihelmintic, an antipyretic, an antitumour and a contraceptive which rendered its advantageous in the treatment of coryza, cough, sore throat, tonsillitis, bronchitis, scrofula, enteritis, osteodynia, arthralgia, menstrual problems, postpartum haematometra, hypertension, diabetes, poisonous snake bites and insect bites. [32]

Preclinical Data

Pharmacology

Hepatoprotective activity

Alcohol extract of A. paniculata whole plant or leaves and its major constituent (andrographolide) exhibited protective effects against liver damage in rats induced by various hepatotoxic agents such as carbon tetrachloride, t-butylhydroperoxide, galactosamine and paracetamol. Hepatoprotective activity was monitored by estimating the serum transaminases (glutamic oxaloacetic transaminase (GOT) and glutamic pyruvate transaminase (GPT)), serum alkaline phosphatase, serum bilirubin and hepatic triglycerides in the experimental rats. The result showed the decrement in these biochemical parameters and significantly improved the toxin-induced histopathological changes in the liver comparable to hepatoprotective agent silymarin. [15] [33] [34] [35]

Alcohol extract of A. paniculata (25 mg/kg) and its diterpenes namelyandrographolide and neoandrographolide (6 mg/kg) administered orally to Plasmodium berghei K173-induced liver damage of Mastomys natalensis mice once daily for two weeks showed significant anti-hepatotoxic effect. The protective effect of andrographolide was comparable to those of neoandrographolide. [36]

In an ex vivo study, andrographolide isolated from A. paniculata whole plant (0.75-12 mg/kg) administered orally to rats was found to be able to reserving the toxic effects of paracetamol on certain liver enzymes, superior and more potent than silymarin (a clinically used hepatoprotective agent). It significantly increased the percent viability of the hepatocytes as tested by trypan blue exclusion and oxygen uptake tests [37]. Another study also concluded that the same compound from A. paniculata whole plant extract (1.5-12 mg/kg) showed choleretic activity by increasing bile volume as well as the amount of bile salts and bile acids in paracetamol-induced liver damage of rats and guinea pigs. The research also indicated that the compound was more potent than silymarin [38].

Aqueous extract of A. paniculata leaves (12 mg/kg body weight) administered orally to benzene hexachloride (BHC)-induced liver damage in Swiss strain albino mice (20-30 g) showed hepatoprotective action compared to control group with standard diet. This extract showed protective effects by decreasing superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione levels and lipid peroxidase level [39]. In addition, andrographolide isolated from extract of A. paniculata also was capable to reverse the liver tumour in male mice using the BHC experimental model [40]

Antioxidant activity

Andrographolide isolated from extract of A. paniculata and hexachlorocyclohexane (BHC) given orally to mice significantly (p ≤ 0.05) increased the levels of glutathione, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase compared to BHC control group. The levels of gamma-glutamyl transpeptidase and glutathione-s-transferase significantly decreased (p ≤ 0.05) compared to control group. [41]

Aqueous extract of A. paniculata leaves (400 mg/kg) administered orally to streptozotocin -induced diabetic (intraperitoneally 45 mg/kg) male Wistar rats for 45 days significantly (p < 0.01) decreased the blood glucose level and increased the activity of superoxide dismutase and catalase. [42]

Aqueous extract of A. paniculata in different doses administered orally to lymphoma bearing AKR mice showed an increase in catalase, superoxide dismutase and glutathione S-transferase levels which leading to a decrease in oxidative stress. [43]

Renoprotective activity

Aqueous extract of A. paniculata whole plant (200 mg/kg) administered orally to gentamicin-induced nephrotoxicity in male Wistar albino rats for 10 days decreased the levels of serum creatinine, serum urea and blood urea nitrogen by 176.92%, 106.27% and 202.90%, respectively. [44]

Antidiabetic activity

Ethanol extract of A. paniculata  aerial part at different doses (0.1, 0.2, and 0.4 g/body weight) were administered orally to streptozotocin-induced diabetic Sprague Dawley rats (200-250 g) for a duration of 2 weeks significantly (p < 0.001) reduced the fasting serum glucose levels of diabetic rats compared to metformin control. [45]

Extract of A. paniculata leaves (0.5 g/kg and 1.0 g/kg) and its andrographolide (5 mg/kg and 10 mg/kg) administered orally to adult male albino rats (100-120 g body weight) accelerated intestinal digestion and absorption of carbohydrates by activating the brush border membrane bound hydrolases (lactase, maltase and sucrose) of the small intestine in dose- and time-dependent manner. The maximum stimulation was obtained at 6 hour after administration. [46]

Aqueous extract of A. paniculata leaves (0.625 - 2.5 mg/mL) showed a very strong insulin in vitro secreting effect towards a glucose-responsive clonal insulin-secreting cell line (BRIN-BD11). BRIN-BD11 incubated in the Modified Kreb-Ringer media solution containing glucose and A. paniculata extract was compared to glucose only control and standard glibenclamide (100 mM). Studies on the insulin stimulatory effect have reported that A. paniculata is a strong, dose dependent insulinotropic agent, glucose dependent and independent insulin secreting agent, stimulated the first phase of insulin secretion, and mostly affected ATP-dependent potassium channels (K+ ATP) comparable to the standard. [47]

Cardiovascular activity

Crude aqueous extract of A. paniculata (WE) and its semi-purified fractions (n-butanol (FB) and aqueous (FC)) significantly decreased the mean arterial blood pressure (MAP) of anaesthetized Sprague-Dawley rats in a dose-dependent manner.  The ED50 values for WE, FB and FC were 11.4, 5.0 and 8.6 mg/kg respectively [48]. In another study, an isolated diterpenoid from A. paniculata namely 14-deoxy-11,12-didehydroandrographolide (DDA) was also found to reduce MAP and heart rate of anaesthetized rats in a dose-dependent manner with the maximum decrease were 37.6 ± 2.6% and 18.1 ±4.8%, respectively. [49]

Antihypertensive activity

Aqueous extract of A. paniculata exhibited a dose-dependent hypotensive effect on the systolic blood pressure by reducing circulating angiotensin-converting enzyme in the plasma along with reducing free radical levels in the kidney of spontaneously hypertensive rats (SHR) compared to their normotensive controls Wistar-Kyoto (WKY) rats. [50]

Nitric oxide activity

Two diterpene lactones isolated from A. paniculata, namely 14-deoxyandrographolide (DA) and 14-deoxy-(11,12)-didehydroandrographolide (DDA) stimulated the release of nitric oxide from human endothelial cells with DDA caused a greater production compared to DA. [51]

Anti-inflammatory activity

Andrographolide of A. paniculata leaves inhibited the platelet-activating factor -induced human blood platelet aggregation in a dose-dependent manner (IC50 = 5 µM). [52]

Andrographolide (30-300 mg/kg) administered orally to rat significantly inhibited carrageenin-, kaolin- and nystatin-induced paw oedema as well as the weight of granuloma induced by cotton pellet and decreased oedema in adjuvant-induced arthritis [53]. Another study showed andrographolide (0.1 to 10 µM) was able to prevent phorbol-12-myristate-13-acetate (PMA)-induced reactive oxygen species (ROS) production and N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophils adhesion to rat, suggested its ability as an anti-inflammatory drug. [54]

Andrographolide isolated from Andrographis paniculata leaves was found useful in the treatment of inflammatory conditions such as asthma by inhibiting the NF-kappaB pathway at the level of inhibitory kappaB kinase-beta activation in BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. [55][56]  

Neoandrographolide isolated from A. paniculata extract inhibited nitric oxide production by 35 and 40% both in vitro and ex vivo in orally administered (5 and 25 mg/kg/d) mouse peritoneal macrophages elicited by Bacillus Calmette-Guéin and stimulated by lipopolysaccharide. [57]

Analgesic and antipyretic activity

Andrographolide from A. paniculata (300 mg/ kg bodyweight) administered orally to mice significantly (p< 0.05) showed analgesic activity using acetic acid-induced writhing and Randall Selitto’s tests. Andrographolide (100 and 300 mg/kg, oral) also significantly (P < 0.05) showed antipyretic effect after 3h of administration in Brewer’s yeast-induced pyrexia in rats and significantly (p < 0.05) possed anti-ulcerogenic activity at 100 and 300 mg/kg doses in aspirin induced ulceration in rats [58]. In another study, ethanol extract of A. paniculata was found to produce results comparable to 200 mg of aspirin [59].

Antidiarrhoeal activity

Andrographolide and neoandrographolide, diterpene compounds isolated from alcohol extract of A. paniculata showed antidiarrhoeal activity against E. coli LT and LT/ST enterotoxins, similar effect as loperamide, a common antidiarrhoeal drug. However, andrographolide was found to be superior against ST enterotoxin, which is the most common cause of epidemics of neonatal diarrhoea. [60]

Immunostimulant activity

Ethanol extract of A. paniculata as well as its purified andrographolides induced significant stimulation of antibody and delayed type hypersensitivity (DTH) response to sheep red blood cells (SRBC); and stimulated nonspecific immune response of the animals measured in terms of macrophage migration index (MMI) phagocytosis of 14C-leucine labelled E. coli and proliferation of splenic lymphocytes in mice in vivo. However, the stimulation for both antigen specific and non-specific immune responses was superior in the ethanol extract than andrographolide. [61]

Antitumour activity

Andrographolide of the A. paniculata whole plant extract has been reported to induce the apoptosis of cancer cell by increasing the lymphocytes proliferation and production of interleukin-2. It also was reported to increase tumour necrosis factor-alpha (TNF-alpha) production and CD marker expression in vivo, resulting in increased cytotoxic activity of lymphocytes against cancer cells. [62]

The benzylidene derivative of andrographolide was found as a potential antitumour agent to inhibit growth of breast (MCF-7) and colon (HCT-116) cancer cells by downregulating CDK4 to promote a G(1) phase cell cycle arrest, together with induction of apoptosis. Microculture tetrazolium, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and sulphorhodamine B (SRB) assays were utilized in assessing the in vitro growth inhibition and cytotoxicity of compounds while fluorescence microscopy and flow cytometry assay for apoptotic cell death. [63]

Andrographide from the extraction of A. paniculata whole plant was found to have cytotoxic activity towards prostate cancer (PC-3) cells in a dose-dependent manner (IC50 value = 23.3 mmol/L) compared with widely used anti-tumor, cisplatin in vitro. The nuclear morphology of PC-3 cells monitored after treated with andrographolide confirmed its ability to induce the apoptosis of the cells via the activation of caspase 3, up-regulation of bax and downregulation of bcl-2. [64]

Dichloromethane fraction of the methanol extract of A. paniculata showed antitumour and immunomodulatory activity in human cancer and immune cells significantly inhibited the proliferation of colon cancer HT-29 cells (GI50 = 10 μg/ml) and increased the proliferation human peripheral blood lymphocytes (HPBLs) by 52% at low concentrations in vitro. [65]

Andrographolide is reported to cause cell-cycle arrest at G0/G1 phase through induction of cell-cycle inhibitory protein p27 and decreased expression of cyclin-dependent kinase 4 (CDK4 [66]. The addition of andrographolide to 5-FU (5-fluorouricil), a commonly used chemotherapeutic agent, was found to produce synergistic apoptosis in cancer cells [67]. The compound increased caspase-8, p53 activity and significantly changed  Bax conformation in these cells, resulting in increased losses of mitochondrial membrane potential, increased release of cytochrome c, and activation of caspase-9 and caspase-3. The results suggested that andrographolide may be effective in combination with 5-FU for the treatment of human carcinoma cells SMMC-7721 [68].

Ethanol extract of A. paniculata and its andrographolide showed a cytotoxic T lymphocyte (CTL) activity and reduction of tumour growh in BALB/c mice in Winn's neutralization assay using CTL sensitive EL4 thymoma cells as target cell. The extract and compound increased the CTL production by enhancing the secretion of IL-2 and IFN-γ by T cells, thus inhibit the tumour growth. The survival time of EL4 alone (27.1 days) was increased to 51.1 and 44.5 days in the extract and andrographolide treated mice with 88.5 % and 64.2 % of life span increment, respectively. [69]

Andrographolide of A. paniculata showed antitumour activity through its anti-inflammatory properties with the inhibition of the upregulation of adhesion molecules expression and endothelial adhesiveness to leucocytes. The result of the incubation of andrographolide (0.16–16.7 µg /mL) with the tumour necrosis factor-α (TNF)-induced upregulation of ICAM-1expression and endothelial-monocyte adhesion showed a concentration-dependent reduction of the TNF-induced enhancement of endothelial monocyte adhesion. Andrographolide also showed that at a concentration 150 µg/mL, it was overtly cytotoxic to endothelial cell monolayers and showed significant inhibition of DNA synthesis at a concentration of 50 mg/mL. [70]

Hydroalcohol extract of A. paniculata (50 and 100 mg/kg body weight/day) given orally to Swiss Albino rats (6-8 weeks) significantly increased the levels of acid soluble sulphydryl (-SH) content, cytochrome P450, cytochrome P450 reductase, cytochrome b5 reductase, GST, DTD and SOD at both doses while at dose 100 mg/kg, the levels of catalase, glutathione peroxidase and glutathione reductase were increased. Both the dosages of A. paniculata showed a significant decrease in activity of lactate dehydrogenase and malondialdehyde (MDA) formation. [71]

Andrograpanin, an isolate active compound of A. paniculata enhanced the chemokine stromal cell-derived factor-1alpha (SDF-1alpha)-induced leukocytes chemotaxis in Jurkat and THP-1 cells. The effect was recognised as CXC chemokine receptor-4 (CXCR4) specific because the andrograpanin could not enhance other chemokines. [20]

Antimicrobial activity

Antimalarial

Chloroform extract of A. paniculata whole plant demonstrated high anti-malarial effects against Plasmodium falcifarum with complete inhibition after 24 hours at a concentration of 0.05 mg/mL and complete inhibition after after 48 hours at concentration of 0.025 mg/mL. This extract also showed higher antimalarial activity against Plasmodium berghei compared to Piper sarmentosum and Tinospora crispa. [72]

A compound of 1,2-dihydroxy-6,8-dimethoxy xanthone isolated from A. paniculata  roots (30 mg/kg intraperitoneally once daily for four days) showed antimalarial effect without cytotoxicity (IC50 > 16 µg/mL) on pre-infected P. berghei Swiss Albino mice with 62.1 % reduction of parasitaemia. [73]

A similar study has shown that compound 1,2-dihydroxy-6,8-dimethoxy xanthone isolated from A. paniculata roots (30 mg/kg) administered intraperitoneally to P. berghei-infected Swiss albino mice possessed antimalarial activity without cytotoxicity by inhibiting the P. berghei multiplication and showed about 62%parasitaemia reduction using the 4-day suppressive test. [74] 

Antiviral

Ethanol extract of A. paniculata aerial parts (25 µg/mL) and its andrographolide (5 µg/mL) significantly (p < 0.05) inhibited the expression of Epstein-Barr virus (EBV) lytic proteins, Rta, Zta and EA-D during the viral lytic cycle in P3HR1 cells by inhibiting the transcription of two EBV immediate-early genes (BRLF1 and BZLF1) that encode Rta and Zta, respectively. [75]

Andrographolide and 14-Deoxy-11,12-didehydroandrographolide isolated from n-hexane extract of A. paniculata aerial part showed anti-human immunodeficiency virus (HIV) activity with EC50 49.0 µg/mL and 56.8 µg/mL respectively after 7 days incubation with HIV-1MN cells. [76]

Another compound of A. paniculata, namely dehydroandrographolide succinic acid monoester (DASM) has been found to be an inhibitor against some strains of human immunodeficiency virus (HIV)in vitro.The compound (50-200 (average, 108) µg/mL) showed no toxicity to the H9 cell but inhibited the HIV-1 (IIIB) at the minimal concentration of 1.6-3.1 (average 2.0) µg/mL and inhibited two other strains of HIV-1 and a strain of HIV-2. [77]

Anti-allergic activity

Andrographolide and neoandrographolide given orally to rats showed antiallergic activity by significantly possessed anti-passive cutaneous anaphylaxis (PAC) and mast cell stabilizing activity against compound 48/80 and in sensitized mast cells against egg albumin induced degranulation compared to disodium cromoglycate. [78]

Psychopharmacological activity

Methanol extract of A. paniculata powdered herbs (100, 200, 300 mg/kg) given orally to Swiss albino mice (18-22 g) and Charles-Foster rats (18-22 g) significantly (p < 0.05) altered their behaviour patterns (pentobarbitone-induced sleeping time) and reduced their spontaneous motility (acetic acid-induced writhing, pentylene tetrazole-induced convulsion and strychnine-induced convulsion) compared to saline control and 10 mg/kg standard drug diazepam. [79]

Toxicity

No documentation.

Clinical Data

Clinical findings

Uncomplicated upper respiratory tract infections

A study conducted with 95 people in treatment (verum) group versus 90 people in placebo group to investigate the efficacy and tolerability of Kan Jang supplement which contains A. paniculata fixed combination in individuals with upper respiratory tract infection including sinusitis. This supplementation significantly improved the body temperature, headache, muscle aches, throat symptoms, cough, nasal symptoms, general malaise and eye symptoms of the verum group, indicated the positive effect for acute upper respiratory tract infections treatment and to relieve the inflammatory symptoms of sinusitis. [80]

A randomized trial for the effectiveness of the A. paniculata  with Eleutherococcus extracts preparation (Kan-Yang or Kan Jang tablets Sweden) involved 53 children with acute respiratory viral infection (ARVI) versus 40 ARVI children given conventional treatment was conducted. The treatment with Kan-Yang showed tolerance in promoting the cure of early acute uncomplicated respiratory disease. [81]

A review of the literature and meta-analysis of randomized controlled trials to assess the efficacy of A. paniculata leaves extract and commercial preparation of Kan jang tablets (combination of A. paniculata with Acanthopanax senticosus (Eleutherococus senticosus)) in the symptomatic treatment of uncomplicated upper respiratory tract infection was performed.  A total of 433 patients reported in three trials were included in the statistical analysis. Both extract showed promising effect for the treatment more effective than placebo. [82]

Two randomized double blind, placebo-controlled studies were performed in Sweden where subjects were consumed orally standardized A. paniculata extract (Kan Jang) tablets for uncomplicated upper-respiratory tract infections. Both the total symptom and total diagnostic scores showed improvement in the treated group when compared with the placebo. This extract also has been reported to give improvements in muscle pain, cough, throat symptoms, headache, nasal symptoms, eye symptoms and body temperature. [83]

Uncomplicated common cold

Clinical studies conducted on 107 healthy volunteers students (both genders) in a Public School, Metropolitan Region of Santiago, Chile given Kan Jang tablets (commercial preparation of A. paniculata dried extract) as oral consumption significantly reduced the symptoms and duration of the common cold compared to placebo. [84]

A group of 158 adult patients of both genders recruited for a randomized double blind study in Valdivia, Chile were given A. paniculata SHA-10 dried extract (1200 mg/day) to be consumed orally. It showed that this plant reduced the prevalence and intensity of the symptoms in uncomplicated common cold beginning at second day of treatment. No adverse effects were observed or reported. [85]

Pharyngotonsilitis

A Thai research team has shown that a high dose (orally 2 g per time for thrice daily) of A. paniculata extract significantly relieved fever and sore throat compared to low dose (1 g per time for thrice daily). [86]

Atheroschelorotic arterial stenosis

The comparative effects of oral consumption of andrographolide and fish oils in a group of patients following angioplasty compared to control were investigated.  An angiographic follow-up on four weeks later showed 57% of control group had severe restenosis compared to the andrographolide-treated group which only minor incidences of restenosis was reported. The fish oil treated group had restenosis as severe as the control group. [87]

Anti-HIV activity

A dose-escalating clinical trial on 13 HIV positive patients and five HIV uninfected, healthy volunteers showed that andrographolide (10 mg/kg bodyweight) may inhibit HIV-induced cell cycle dysregulation, leading to a rise in CD4+ lymphocyte levels in HIV-1 infected patients. However, dosages used in this study caused side effects, including headache, fatigue, bitter/metallic taste in the mouth and elevated liver enzymes (which returned to normal after the treatment was stopped). [88]

Rheumatoid arthritis relief

A clinical study involved 60 patients with rheumatoid arthritis found that Paractin tablets made of A. paniculata extract (standardized to 30% andrographolide) administered three times a day for 14 weeks decreased the intensity of joint pain while also reduced rheumatoid factor, IgA and C4 compare to placebo group. [89]

Antiplatelet aggregation

A. paniculata extract significantly (p < 0.001) inhibited adenosine diphosphate (ADP)-induced platelet aggregation in 63 patients of cardiac and cerebral vascular diseases. Moreover the serotonin (5-HT) release reaction study observed in 20 volunteers taking A. paniculata showed that it significantly (p < 0.01) decreased, but plasma 5-HT level remained unchanged. The results showed that the extract could inhibit the release of dense and alpha granules from platelets and dilating of canalicular system and suggested that a raise of platelet cAMP level might be the mechanism of antiplatelet effect. [90]

Precautions

Side effects

A. paniculata was reported safe in recommended doses [91]. Large doses of A. paniculata may cause gastric discomfort, vomiting and loss of appetite [92].

High doses (5-10 mg/kg body weight) may lead to side effects such as nausea, diarrhoea and bitter/metallic taste in the mouth. Other infrequent side effects include headache, dizziness, drowsiness, fatigue, chest discomfort, increased nasal discharge, stuffy nose and lymph node pain. Use with caution in pre-existing low blood pressure, diabetes and bleeding disorder conditions. [93]

Pregnancy/Breast Feeding

A. paniculata showed contraceptive effects in mice and abortifacient effects in pregnant rabbits when fed this herb. Although a similar effect has not been observed in humans, A. paniculata should not be taken during pregnancy or by women trying to conceive. [92] [94] [95]

Age limitation

No documentation.

Adverse reaction

No documentation.

Interaction & Depletion

Interaction with drug

Based on pharmacology, use with caution in individuals taking anticoagulant medications, such as aspirin or warfarin (Coumadin) [52].

Animal study has indicated that A. paniculata may has antithrombic properties. This could lead to potential/theoretical interactions with anticoagulants and other antithrombic medications including other botanicals and dietary supplements having similar properties. [96]

Interaction with other herbs

No documentation.

Contraindications

No documentation.

Case report

No documentation.

Uses supported by clinical data

No documentation.

Dosage

Dosage Range

An amount of 1.5 to 5 g of dried herbs [86].

Doses as high as 1000 to 2000 mg, 3 times daily have been used in some studies as cited by Thamlikitkul et. al. [86]

1-4 mL of A. paniculata juice, 14-28 mL of infusion, 2.5-5 mL of extracts has been reported. [97]

Most Common Dosage

Doses of 500-3,000 mg of A. paniculata leaves have been taken by mouth three times daily. [93]

A tea made with one teaspoon of herb per one cup of water, steeped for 5-10 minutes, has been taken during meals for digestive problems. [93]

For respiratory infections, preparations have been taken by three or four times daily that contain total daily dosage of 48-60 mg of andrographolide. A 300 mg Kan Jang® tablet (contain 4 % andrographolides) has been taken four times daily for cold treatment with a total daily dosage of 48 mg andrographolides. [93]

Standardisation

A. paniculata is usually standardised to its andrographolide content of 4 to 6%. Other standard profiles were documented in the Malaysian Herbal Monograph. [98]

Poisonous

No documentation.

Line drawing

 apnfig4

 

 

Figure 4: The line drawing of A. paniculata [8].

References

  1. The Plant List. Ver 1.1. Andrographis paniculata (Burm.f) Ness. [homepage on the internet]. c2013. [updated 2012 March 23; cited 2014 Oct 3] Available from: http://www.theplantlist.org/tpl1.1/record/kew-296861
  2. Zainon AS, Rasadah MA, Nik Musa’adah M. Tumbuhan ubatan untuk rawatan penyakit radang (Siri alam dan rimba: No.8) Kuala Lumpur: Institut Penyelidikan Perhutanan Malaysia; 2004. p 70.
  3. FRIM. Andrographis paniculata (Burm.f) Ness. [homepage on the Internet]. c2013 [updated 2013; cited 2014 Oct 1]. Available from :www.forestry.gov.my/herba/hempedubumi_en.pdf
  4. Quattrocchi U. CRC World dictionary of medicinal and poisonous plants: common names, scientific names, eponyms, synonyms and etymology. Boca Raton, Florida: CRC Press; 2012. p. 283.
  5. Philipine medicinal plants. Sinta. Andrographis paniculata (Burm. f.) Wall. ex Nees [homepage on the Internet]. [updated 2015 Apr; cited 2014 Oct 1]. Available from: http://www.stuartxchange.org/Sinta.html
  6. Kyaw S, Myo NT. Medicinal plants of Myanmar: Identification and uses of some 100 commonly used species series (1). Forest Resource Environment Development & Conservation Association; 2004. p. 30.
  7. Nguyẽ̂n VD, Nguyẽ̂n GC. Selected medicinal plants in Vietnam. Volume 1. Science and Technology Publishing House; 1999. p.70.
  8. Sugati SS, Wiryowidagdo S, Sasanti R, et al. Andrographis paniculata (Burm.f.). In: de Padua LS, Bunyapraphatsara N, Lemmens RHMJ editors. Plant Resources of South-East Asia No. 12(1): Medicinal and poisonous plants 1. Leiden, Netherlands: Backhuys Publisher, 1999; p.119-123.
  9. Yaacob M, Kadir AA, Hasan Z. Hempedu Bumi (Andrographis paniculata): Tumbuhan ubatan popular. Selangor: MARDI; 2009. p. 45.
  10. Yaacob M, Maarof MG, Puteh M. Hempedu Bumi (Andrographis paniculata). In: Penanaman tumbuhan ubatan dan beraroma. Selangor: Institut Penyelidikan dan Kemajuan Pertanian Malaysia (MARDI), 2005; p.36-42.
  11. Yaacob M, Mamat W Z W, Hussain Y, Ariffin Z. Manual Teknologi Penanaman Hempedu Bumi. Selangor: Institut Penyelidikan dan Kemajuan Pertanian Malaysia (MARDI); 2005.
  12. Oudhia P. Purdue Horticulture Aromatic and Medicinal Plant Database; Bhuinimb or Kalmegh (Andrographis paniculata Nees.) [homepage on the Internet]. c2002 [updated 2014 September 30; cited 2014 September 30]. Available from: http://www.hort.purdue.edu/newcrop/CropFactSheets/andrographis.html
  13. Ariffin Z, Sharizan A, Hussin S. Effect of organic fertiliser (Kokei) and population density on the yield and Andrographolide content of hempedu bumi (Andrographis paniculata) grown on bris and alluvial soils. Proceedings of the Malaysian Society of Soil Science Conference; 2003 April 15-16; Kota Bharu, Kelantan. Kuala Lumpur: Malaysian Society of Soil Science, MARDI, UiTM; 2003.
  14. Duke JA. Handbook of phytochemical constituents of GRAS herbs and other economic plants. Boca Raton, Florida: CRC Press; 2000. p. 43.
  15. Kapil A, Koul IB, Banerjee SK, Gupta BD. Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata. Biochem Pharmacol. 1993;46(1):182-185.
  16. Suebsasana S, Pongnaratorn P, Sattayasai J, et al. Analgesic, antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals. Arch Pharm Res. 2009;32(9):1191-1200.
  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. Kleipool RJC. Constituents of Andrographis paniculata Nees. Nature. 1952;169:33-34.
  19. Singha PK, Roy S, Dey S. Protective activity of andrographolide and arabinogalactan proteins from Andrographis paniculata Nees. against ethanol-induced toxicity in mice. J Ethnopharmacol. 2007;111(1):13-21.
  20. 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-1alpha-induced leukocytes chemotaxis. J Cell Biochem. 2005;95(5):970-978.
  21. Li W, Xu X, Zhang H, Ma C, Fong H, van Breemen R, Fitzloff J. Secondary metabolites from Andrographis paniculata. Chem Pharm Bull(Tokyo). 2007;55(3):455-458.
  22. Fujita T, Fujitani R, Takeda Y, et al. On the diterpenoids of Andrographis paniculata: X-ray crystallography analysis of andrographolide and structure determination of new minor diterpenoids. Chem Pharm Bull. 1984;32(6):2117-2125.
  23. Gupta KK, Taneja SC, Dhar KL, Atal CK. Flavonoids of Andrographis paniculata. Phytochemistry. 1983;22(1):314-315.
  24. Kuroyanagi M, Sato M, Ueno A, Nishi K. Flavonoids from Andrographis paniculata. Chem Pharm Bull. 1987;35:4429-4435.
  25. Matsuda T, Kuroyanagi M, Sugiyama S, Umehara K, Ueno A, Nishi K. Cell-differentiation-inducing diterpenes from Andrographis paniculata. Chem Pharm Bull. 1994;42(6):1216-1225.
  26. Muntha KR, Mopuru VB, Duvvuru G, Madugala MM, Christelle C, Bernard B. A flavone and an unusual 23-carbon terpenoid from Andrographis paniculata. Phytochemistry. 2003;62(8):1271-1275.
  27. Wan Zaki WM, Zaharah A, Musa Y. Penanaman tumbuhan ubatan & beraroma. In: Musa Y, Muhammad Ghawas M. Mansor P, editors.  Hempedu bumi (Andrographis paniculata). Serdang: MARDI, 2005; p. 36-42.
  28. Kamarudin MS, Latiff A. Tumbuhan ubatan Malaysia. Kuala Lumpur: Pearson Malaysia Sdn. Bhd; 2002. p. 564.
  29. Zaharah A, Wan Zaki WM, Yahaya H, Musa Y. Manual teknologi penananaman Hempedu Bumi. Serdang: MARDI; 2005.
  30. Burkill IH. A dictionary of the economic products of the Malay Peninsula. Volume 1. London: Published on behalf of the governments of the Straits settlements and Federated Malay states by the Crown agents for the colonies; 1935. p. 156-157.
  31. Premila MS. Ayurvedic Herbs: A clinical guide to the healing plants of traditional Indian medicine. Binghamton, NY: The Hayworth Press; 2012. p.111.
  32. Herbal Medicine Research Centre, Institute for Medical Research. Compendium of Medicinal Plants Used in Malaysia. Volume 1. Kuala Lumpur: HMRC IMR; 2002. p.47.
  33. Handa SS, Sharma A. Hepatoprotective activity of andrographolide from Andrographis paniculata against carbon tetrachloride. Indian J Med Res. 1990;92:276-283.
  34. Handa SS, Sharma A. Hepatoprotective activity of andrographolide against galactosamine and paracetamol intoxication in rats. Indian J Med Res. 1990;92:284-292.
  35. Rana AC, Avadhoot Y. Hepatoprotective effects of Andrographis paniculata against carbon tetrachloride-induced liver damage. Arch Pharm Res. 1991;14(1):93-95.
  36. Chander R, Srivastava V, Tandon JS, Kapoor NK. Antihepatotoxic activity of diterpenes of Andrographis paniculata (Kal-Megh) against Plasmodium berghei-induced hepatic damage in Mastomys natalensis. Int J Pharmacogn. 1995;33(2):135-138.
  37. Visen PKS, Shukla B, Patnaik GK, Dhawan BN. Andrographolide protects rat hepatocytes against paracetamol-induced damage. J Ethnopharmacol. 1993;40:131-136.
  38. Shukla B, Visen PK, Patnaik GK, Dhawan BN. Choloretic effect of andrographolide in rats and guinea pigs. Planta Med. 1992;58(2):146-149.
  39. Trivedi NP, Rawal UM. Hepatoprotective and antioxidant property of Andrographis paniculata (Nees) in BHC induced liver damage in mice. Indian J Exp Biol. 2001;39:41-46.
  40. Trivedi NP, Rawal UM, Patel BP. Potency of andrographolide as an antitumor compound in BHC-induced liver damage. Integr Cancer Ther. 2009;8(2):177-189.
  41. Trivedi NP, Rawal UM, Patel BP. Hepatoprotective effect of andrographolide against hexachlorocyclohexane-induced oxidative injury. Integr Cancer Ther. 2007; 6(3):271-280.
  42. Dandu AM, Inamdar NM. Evaluation of beneficial effects of antioxidant properties of aqueous leaf extract of Andrographis paniculata in STZ-induced diabetes. Pak J Pharm Sci. 2009;22(1):49-52.
  43. Verma N, Vinayak M. Antioxidant action of Andrographis paniculata on lymphoma. Mol Biol Rep. 2008;35(4):535-540.
  44. Singh P, Srivastava MM, Khemani LD. Renoprotective effects of Andrographis paniculata (Burm. f.) Nees in rats. Ups J Med Sci. 2009;114(3):136-139.
  45. Zhang CY, Tan BKH. Anti-diabetic property of ethanolic extract of Andrographis paniculata in streptozotocin-diabetic rats. Acta Pharmacol Sin. 2000;21(12):1157-1164.
  46. Choudary BR, Poddar MK. Andrographolide and kalmegh (Andrographis paniculata) extract: effect on intestinal brush-border membrane-bound hydrolases. Methods Find Exp Clin Pharmacol. 1985;7:617-621.
  47. Wibudi A, Kiranadi B, Manalu W, Winarto A, Suyono S. The traditional plant, Andrographis paniculata (Sambiloto), exhibits insulin-releasing actions in vitro. Acta Med Indones. 2008;40(2):63-68.
  48. Zhang CY, Tan BK. Mechanisms of cardiovascular activity of Andrographis paniculata in the anaesthetized rat. J Ethnopharmacol. 1997;56:97-101.
  49. Zhang CY, Tan BK. Cardiovascular activity of 14-deoxy-11,12-didehydroandrographolide in the anesthetized rat and isolated right atria. Pharmacol Res. 1998;38:413-441.
  50. Zhang CY, Tan BK. Hypotensive activity of aqueous extract of Andrographis paniculata in rats. Clin Exp Pharmacol Physiol. 1996;23:675-678.
  51. Zhang CY, Tan BKH. Effects of 14-deoxyandrographolide and 14-deoxy-11,12-didehydroandrographolide on nitric oxide production in cultured human endothelial cells. Phytother Res. 1999;13:157-159.
  52. Amroyan E, Gabrielian E, Panossian A, Wikman G, Wagner H. Inhibitory effect of andrographolide from Andrographis paniculata on PAF-induced platelet aggregation. Phytomedicine. 1999;6(1):27-31.
  53. Madav HC, Tripathi P, Mishra SK. Anti-inflammatory activity of andrographolide. Fitoterapia. 1996;67:452-458.
  54. Shen YC, Chen CF, Chiou WF. Suppression of rat neutrophil reactive oxygen species production and adhesion by the diterpenoid lactones andrographolide. Planta Med. 2000;6:314-317.
  55. Bao Z, Guan S, Cheng C, Wu S, et al. A novel antiinflammatory role for andrographolide in asthma via inhibition of the nuclear factor-kappaB pathway. Am J Respir Crit Care Med. 2009;179(8):657-665.
  56. Xia YF, Ye BQ, Li YD, et al. Andrographolide attenuates inflammation by inhibition of NF-kappa B activation through covalent modification of reduced cysteine 62 of p50. J Immunol. 2004;173(6):4207-4217.
  57. Bahtaku J, Hattori K, Takano F, Fushiya S, Oshiman K, Fujimiya Y. Suppression of NO production in activated macrophages in vitro and ex vivo by neoandrographolide isolated from Andrographis paniculata. Biol Pharm Bulletin. 2002;9:1169-1174.
  58. Madav HC, Tripathi P, Mishra SK. Analgesic, antipyretic and anti-ulcerogenic effects of andrographolide. Indian J Pharm Sci. 1995;57(3):121-126.
  59. Vedavathy S, Rao KN. Antipyretic activity of six indigenous medicinal plants of Tirumala Hills, Andra Pradesh, India. J Ethnopharmacol. 1991;33:193-196.
  60. Gupta S, Choudry MA, Yadava JNS, Srivastava V, Tandon JS. Antidiarrheal activity of diterpenes of Andrographis paniculata (Kal-Megh) against Escherichia coli enterotoxin in in vivo models. Int J Crude Drug Res. 1990;28(4):273-283.
  61. Puri A, Saxena R, Saxena RP, Saxena KC, Srivastava V, Tandon JS. Immunostimulant agents from Andrographis paniculata. J Nat Prod. 1993;56:995-999.
  62. Rajagopal S, Kumar RA, Deevi DS, Satyanarayana C, Rajagopalan R. Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. J Exp Ther Oncol. 2003;3(3):147-158.
  63. Jada SR, Matthews C, Saad MS, et al. Benzylidene derivatives of andrographolide inhibit growth of breast and colon cancer cells in vitro by inducing G(1) arrest and apoptosis. Br J Pharmacol. 2008;155(5):641-654.
  64. Zhao F, He EQ, Wang L, Liu K. Anti-tumor activities of andrographolide, a diterpene from Andrographis paniculata, by inducing apoptosis and inhibiting VEGF level. J Asian Prod Res. 2008;10(5-6):467-473.
  65. 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.
  66. 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.
  67. Han Y, Bu LM, Ji X, Liu CY, Wang ZH. Modulation of multidrug resistance by andrographolid in a HCT-8/5-FU multidrug-resistant colorectal cancer cell line. Chin J Dig Dis. 2005;6(2):82-86.
  68. Yang L, Wu D, Luo K, Wu S, Wu P. Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrial pathway involving p53 participation in hepatocellular carcinoma (SMMC-7721) cells. Cancer Lett. 2009;276(2):180-188.
  69. Sheeja K, Kuttan G. Activation of cytotoxic T lymphocyte responses and attenuation of tumor growth in vivo by Andrographis paniculata extract and andrographolide. Immunopharmacol Immunotoxicol. 2007;29(1):81-93.
  70. Habtemariam S. Andrographolide inhibits the tumor necrosis factor-a-induced up regulation of ICAM-1 expression and endothelial-monocyte adhesion. Phytother Res. 1998;12:37-40.
  71. Singh RP, Banerjee S, Rao AR. Modulatory influence of Andrographis paniculata on mouse hepatic and extra hepatic carcinogen metabolizing enzyme and antioxidant status. Phytotherapy Res. 2001;15:382-390.
  72. Rahman NNNA, Furuta T, Kojima S, Takane K, Mohd MA. Antimalarial activity of extracts of Malaysian medicinal plants. J Ethnopharmacol. 1999;64(3):249-254.
  73. Misra P, Pal NL, Guru PY, Katiyar JC, Srivastava V, Tandon JS. Antimalarial activity of Andrographis paniculata (kalmegh) against Plasmodium berghei NK 65 in Mastomys natalensis. Int J Pharmacognosy. 1992;30(4):263-274.
  74. Dua VK, Ojha VP, Roy R, et al. Anti-malarial activity of some xanthones isolated from the roots of Andrographis paniculata. J Ethnopharmacol. 2004;95(2-3):247-251.
  75. Lin TP, Chen SY, Duh PD, Chang LK, Liu YN. Inhibition of the epstein-barr virus lytic cycle by andrographolide. Biol Pharm Bull. 2008;31(11):2018-2023.
  76. 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.
  77. Chan RS, Ding L, Chen GQ, et al. Dehydroandrographolide succinic acid monoester as an inhibitor against the human immunodeficiency virus. Proc Soc Exp Biol Med. 1991;197(1):59-66.
  78. Gupta PP, Tandon JS, Patnaik GK. Antiallergic activity of Andrographolides isolated from Andrographis paniculata (Burm F) Wall. Pharm Biol. 1998;36:72-74.
  79. Mandal SC, Dhara AK, Maiti BC. Studies on psychopharmacological activity of Andrographis paniculata extract. Phytotherapy Res. 2001;15:253-256.
  80. 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.
  81. Shakhova EG, Spasov AA, Ostrovskiĭ OV, et al. Effectiveness of using the drug Kan-Yang in children with acute respiratory viral infection (clinico-functional data). Vestn Otorinolaringol. 2003;(3):48-50.
  82. 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.
  83. Melchior J, Spasov AA, Ostrovskij OV, Bulanov AE, Wikman G. Double-blind, placebo-controlled pilot and phase III study of activity of standardized Andrographis paniculata Herba Nees extract fixed combination (Kan jang) in the treatment of uncomplicated upper-respiratory tract infection. Phytomedicine. 2000;7(5):341-350.
  84. Caceras DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK. Prevention of common colds with Andrographis paniculata dried extract. A pilot double blind trial. Phytomedicine. 1997;4:101-104.
  85. Cáceres DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK. Use of visual analogue scale measurements (VAS) to assess the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind-placebo study. Phytomedicine. 1999;6(4):217-223.
  86. 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.
  87. Wang DW, Zhao HY. 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. 1994;107(6):464-470.
  88. Calabrese C, Berman SH, Babish JG, et al. A phase I trial of Andrographolide in HIV positive patients and normal volunteers. Phytother Res. 2000;14:333-338.
  89. Burgos RA, Hancke JL, Bertoglio JC, et al. Efficacy of an Andrographis paniculata composition for the relief of rheumatoid arthritis symptoms: a prospective randomized placebo-controlled trial. Clin Rheumatol. 2009;28(8):931-946.
  90. Zhang YZ, Tang JZ, Zhang YJ. Study of Andrographis paniculata extracts on antiplatelet aggregation and release reaction and its mechanism. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1994;14(1):28-35.
  91. Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med. 2004;70(4):293-298.
  92. Chang HM, But PPH, editors. Pharmacology and Applications of Chinese Materia Medica Vol II. Singapore: World Scientific; 1987. p.913-926.
  93. Healthline. Andrographis paniculata Nees, Kan Jang®, SHA-10. California: Healthline Networks, Inc. [homepage on the Internet]. c2005-2014 [cited 2014 November 17]. Available from: http://www.healthline.com/natstandardcontent/andrographis-paniculata-nees-kan-jang-sha#2
  94. Burgos RA, Aguila MJ, Santiesteban ET, Sánchez NS, Hancke JL. Andrographis paniculata (Ness) induces relaxation of uterus by blocking voltage operated calcium channels and inhibits Ca2+ influx. Phytother Res. 2001;15(3):235-239.
  95. McGuffin M. Hobbs C. Upton R. Goldberg A. Botanical Safety Handbook. Boca Raton: CRC Press; 1997. p.165.
  96. Zhao HY, Fang WY. Antithrombotic effects of Andrographis paniculata Nees in preventing myocardial infarction. Chin Med J (Engl). 1991; 104(9):770-775.
  97. Kapoor, LD. CRC Handbook of Ayurvedic Medicinal Plants. Boca Raton, FL: CRC Press; 1990. p. 39.
  98. Zhari I, Norhayati I, Jaafar L. Malaysian Herbal Monograph Volume 1. Kuala Lumpur: Malaysian Monograph Committee; 1999. p. 1.