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REVIEW ARTICLE
Year : 2013  |  Volume : 3  |  Issue : 1  |  Page : 3-10

Phytopharmacological review of Andrographis paniculata (Burm.f) Wall. ex Nees


1 Pharmaology section, National Research Institute for Ayurveda-Siddha Human Resource Development, Aamkho, Gwalior Madhya Pradesh, India
2 Central Council for Research in Ayurvedic Sciences, Janakpuri, New Delhi, India

Date of Submission26-Apr-2012
Date of Acceptance20-May-2012
Date of Web Publication6-Feb-2013

Correspondence Address:
Yadu Nandan Dey
National Research Institute for Ayurveda-Siddha Human Resource Development, Aamkho, Gwalior- 474 009, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.106973

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   Abstract 

Andrographis paniculata [Burm. F] Nees is a potent drug used in Ayurveda, Siddha and Homoeopathy in many formulations and is effective in the treatment of various diseases like malaria, diabetes, viral hepatitis, cirrhosis, liver cancer, etc. For the long-term use in these conditions, establishment of safety of any given intervention is crucial. Hence in the present review the various journals, e-books, monographs, books, data base on medicinal plant, etc. from 1986 to 2010 and Ayurvedic classical text/ earliest literature on Indian Medicine like Charaka Samhita (400-500 A.D.), Sushruta Samhita (400-500 A.D.), Nighantus (500-1600 A.D.), etc. were searched manually and electronically for extracting the complete information about the plant. The particulars of pharmacological activities, drug interactions and contraindications were extracted from the published preclinical and clinical study reports focusing on the keywords, i.e. reported adverse effects and safety profile of the plant. Finally, the therapeutic safety of the plant extracts was concluded. The literature showed that in some preclinical animal studies, due to the bitter taste when the herb was given in very high dose it caused gastric discomfort, vomiting, loss of appetite, etc. However there are no adverse effects reported clinically when the plant is administered in human beings.

Keywords: Adverse event reports, Andrographis paniculata, contraindications, drug interactions, pharmacology, safety profile


How to cite this article:
Dey YN, Kumari S, Ota S, Srikanth N. Phytopharmacological review of Andrographis paniculata (Burm.f) Wall. ex Nees. Int J Nutr Pharmacol Neurol Dis 2013;3:3-10

How to cite this URL:
Dey YN, Kumari S, Ota S, Srikanth N. Phytopharmacological review of Andrographis paniculata (Burm.f) Wall. ex Nees. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2019 Jun 26];3:3-10. Available from: http://www.ijnpnd.com/text.asp?2013/3/1/3/106973


   Introduction Top


Andrographis paniculata [Burm. F] Nees [Syn.: Justicia latebrosa Ross., J. paniculata Burm F., J. stoicatalam. Ex Stevd.] [1] of family acanthaceae is a bitter herb commonly used in Siddha, Ayurveda, and homoeopathy medicines as well as tribal medicines in India and some other countries like Java, Malaysia (including Penang, Malacca, Pangkor Island which is south of Penang, and parts of Borneo), Indonesia (including West Java, the Celebes, and parts of Borneo), West Indies (including Jamaica, Barbados and the Bahamas), and elsewhere in the United States. The plant is chiefly found in plains throughout India from Himachal Pradesh to Assam and Mizoram, West Bengal, and all over South India and the whole plant part is used. The plant has Ayurvedic properties like Rasa-Tikta, Guna-Laghu, Ruksha, Veerya-Ushna, Vipaka-Katu, Doshaghnata-Kaphapittashamaka. Traditionally it is used as carminative (Deepana), Liver stimulant (Yakriduttejaka), Pittasaraka, Laxative (Rechana), anthelmintic (Krimighna), blood purifier (Rakta shodhaka), anti-inflammatory (Shothahara), swedajanana, antileprotic (Kusthaghna), antipyretic (Jwaraghana) and preventive major for malaria (vishmajwara-pratibandhaka), etc. Some Ayurvedic formulations containing A. paniculata which are used for the treatment of various diseases are Devadarvyadi kwatha churna, Pathyadi kwatha churna, Nimbadi kwatha churna, Argvadhadi kwatha churna, Tiktaka ghrita, Bhunimbadi kwatha, Bhunimbadya ghrita, and Bhunimbadyashtadashanga kwatha. The major chemical constituents present in A. paniculata are andrographolide, andrographin, panicolin, andrographolide, deterpene glucoside-neoandrographolide, andrographidihnes, neoandrographolide, chlorogenic, myristic acide, homoandrographolide, andrographiside andropanoside, etc. The different dosage forms of the plant with therapeutic doses are as follows: powder (1-3 g), juice (5-10 ml), Decoction (20-40 ml), liquid extract (0.5-1 ml). [2] Some proprietary medicines of A. paniculata are also available in the market to cure various diseases. The plant posses antimalarial, [3] anti-inflammatory, antioxidant, [4] antihepatitic, [5] antihyperglycemic, [6] anthelmintic, [7] antibacterial, [8] antipyretic, [9] and anticancer activity. [10]

During the past decade, the indigenous or traditional system of medicine has gained importance in the field of medicine. In most of the developing countries, a large number of people depend on traditional practitioners, who in turn are dependent on medicinal plants, to meet their primary healthcare needs. [11] Plant-based medicines still play an important role in the primary healthcare of 80% of the world's population in both underdeveloped and developed countries. [12] The amount and type of food consumed are a fundamental determinant of human health. [13] Worldwide revolution for the improvement of patient safety is gaining momentum; hence the drug safety for the subject becomes even more prominent in the present day scenario. Cultivation of medicinal plants with laboratory-generated species is being attempted on the basis of chemical composition and is likely to be used in increased manner for commercial purpose. These changes may have profound impact on the safety and efficacy of the Ayurveda drugs in the market. Hence, a mechanism is required to be put in place to address the safety issues. [14]

Charaka Samhita, which is a classic textbook of Ayurveda, describes all the adverse reactions to medicines when they are prepared or used inappropriately. Charaka also describes, elegantly, several host-related factors as to be considered while selecting medicines in order to minimize adverse reactions like the constitution of the patient 0 (Prakriti), age (Vayam), disease (Vikruti), tolerance (previous exposure) (Satmya), psychological state (Satwa), digestive capacity (Ahara-shakti), etc. [15] A possible adverse drug reaction due to Vatsanabha (Aconite) resulting through an overdosing of Ayurvedic drugs was reported. [16] Adverse drug reaction is rarely reported from Ayurvedic drugs and hence this is difficult to find these reports through electronic retrieval system. The basic reason is unawareness of Ayurvedic physicians about collective use to this information resulting in their poor documentation and reporting. [17]

As A. paniculata is used for long period in various chronic diseases, it should be therapeutically safe for clinical purpose. So, the aim of the current review is to search the literature for the adverse events, safety/toxicity studies, and its interactions in combination with other drugs.

In this review, the literature was searched for the pharmacological effects of A. paniculata. The complete information about the plant has been collected from various books, journals, and Ayurvedic classical text/literature like Charaka Samhita, Susruta Samhita, Astanga Hridaya, Dhanwantari Nighantu, Bhavaprakash Nighantu, Raja Nighantu, Nighantu Ratnakar, Nighantu Adarsha, Dravyaguna Hastamalak, Chakra Dutta, Yogaratnakar, Sahasra Yoga, Bhaisajya Ratnavali, Dravyaguna Vigyana, Indian material Medica, Wealth of India, Data Base on Medicinal plants, etc. The journals were searched for the time period of 1986--2010. The particulars of pharmacological activities, drug interactions, and contraindications were extracted from the published preclinical and clinical study reports focusing on the adverse events and safety profile of the plant. Finally the therapeutic safety of the whole plant extracts was concluded.


   Pharmacological Studies Top


Immuno-modulatory activity

A. paniculata has a wide range of medicinal and pharmacological applications. It was used in different traditional system of medicine and exhibits many activities. In 1993, Puri et al. reported that the ethanolic extract and purified diterpene andrographolides of A. paniculata (Acanthaceae) induced significant stimulation of antibody and delayed type hypersensitivity (DTH) response to sheep red blood cells (SRBC) in mice. [18] While in 2005, Reddy et al. isolated six known compounds andrographolide, 14-deoxy-11,12-didehydroandrographolide, andrograpanin, 14- deoxyandrographolide, (+/-)-5-hydroxy-7,8-dimethoxyflavanone, and 5-hydroxy- 7,8-dimethoxyflavone and one Novel bis-andrographolide from the aerial parts of A. paniculata and found positive results for the anti-HIV and cytotoxic activity. [19] The immunomodulatory properties of a diterpene lactone andrographolide and a standardized preparation (Coded name -Kan Jang) of A. paniculata were investigated. Proliferation of peripheral blood lymphocytes (PBL) induced by phytohemagglutinin (PHA) was enhanced by costimulation with Andrographolide and Kan Jang. At the same time Andrographolide and Kan Jang inhibit spontaneous proliferation of PBL in vitro. [20]

Antioxidant activity

Trivedi et al. studied the effect of the A. paniculata on antioxidant activity in mice by using the enzymes y-Glutamyl transpeptidase, glutathione-S-transferase, and lipid peroxidation compared to Benzenehexa Chloride (BHC). The activities of antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase, and the levels of glutathione were decreased following the BHC effect. [21]

Kamdem et al. in 2002 found the reaction mechanism of the superoxide scavenging activity of neoandrographolide isolated from A. paniculata. It was hypothesized that neoandrographolide might scavenge free radicals by donating the allylic hydrogen of the unsaturated lactone ring. It was found that the stoichiometry of the reaction between neoandrographolide and superoxide radical generated from KO 2 in DMSO was 2:1. One major reaction product was isolated and determined to be a diacid formed by the opening of the lactone ring. The antiradical activity of neoandrographolide proceeded by hydrogen abstraction from carbon C-15. A reaction mechanism was proposed. [22] After that in the year 2006, Sheeja et al. concluded that the methanolic extract of A. paniculata was found to inhibit the formation of oxygen derived free radicals such as superoxide (32%) hydroxyl radicals (80%), lipid peroxidation (80%), and nitric oxide (42.8%) in in vitro system. [23]

Anti-inflammatory activity

Immunological and biochemical studies were carried out in 2006 by Sheeja et al. to investigate protective effects of ethanolic extract of A. paniculata against cyclophosphamide (CTX)-induced toxicity in vivo. Histopathological analysis of small intestine also suggests that extract could reduce the CTX-induced intestinal damage. The level of proinflammatory cytokine TNF-alpha, which was elevated during CTX administration, was significantly reduced by the A paniculata extract administration. The lowered levels of other cytokines like IFN gamma, IL-2, GM-CSF, after CTX treatment, were also found to be increased by extract administration. [24]

It was reported by Liu et al. that oral administration of neoandrographolide (150 mg/kg) significantly suppressed ear edema induced by dimethyl benzene in mice. Oral administration of neoandrographolide (100--150 mg/kg) also reduced the increase in vascular permeability induced by acetic acid in mice. [25] A. paniculata can also inhibit the production of inflammatory mediators and alleviate acute hazards at its optimal dosages. [26] Shen et al. in 2002 observed that the andrographolide, an active component of A. paniculata, inhibits inflammatory responses by rat neutrophils. [27] It was also found to inhibit the tumor-specific angiogenesis by regulating the production of various pro and antiangiogenic factors by in vivo and in vitro studies. [28] In a study by Wang et al. (1994) A. paniculata was found to alleviate atherosclerotic artery stenosis induced by both deendothelialization and high cholesterol diet as well as lower restenosis rate after experimental angioplasty. [29] Further in a research by Coon et al. in 2004 it was also found to be safe and efficacious for the relief of symptoms of uncomplicated upper respiratory tract infection. [30] Poolsup et al. and Gabrielian et al. in their double-blind clinical study also proved that A. paniculata extract alone or in combination may be more effective than placebo and may be an appropriate alternative treatment of uncomplicated acute upper respiratory tract infection. [31],[32]

Cytotoxic activity

Hydro-alcoholic extract of A. paniculata was examined by Singh RP et al. to indicate the chemopreventive potential of A. paniculata against chemotoxicity including carcinogenicity on drug metabolizing enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase (LDH), and lipid peroxidation in the liver of Swiss albino mice. In the lung, SOD, catalase and DTD, in the kidney catalase, DTD and GST, and in the fore stomach SOD and DTD showed a significant increase at both dose levels of treatment. [5] While the in vivo anticancer activity of the isolated compound Andrographolide is substantiated against B16F0 melanoma syngenic and HT-29 xenograft models, these results by Rajagopal et al. in 2003 suggest that andrographolide is an interesting pharmacophore with anticancer and immunomodulatory activities. [33] Further, in 2004, a positive anticancer and immunomodulatory activity of the methanolic extract were screened Kumar et al. for human cancer and immune cells. [10] In 2005 Cheung et al. carried out the in vitro cytotoxicities of the ethanolic extract of A. paniculata (APE) and its main diterpenoid components evaluated in various cancer cells. APE was found to be significantly growth inhibitory to human acute myeloid leukemic HL- 60 cells with an IC (50) value of 14.01 μg/ml after 24 hours of treatment. [34] In 2005, Wiart et al. found that some isolated compounds, i.e. Andrographolide, neoandrographolide, and 14-deoxy-11,12- didehydroandrographolide, ent-labdene diterpenes showed viricidal activity against herpes simplex virus 1 (HSV-1). None of these compounds exhibited significant cytotoxicity at viricidal concentrations. [35] Further, aqueous extracts of A. paniculata are expected to be scorpion venom antidotes with low cytotoxicity. [36] An early enhancement of antibody-dependent complement mediated cytotoxicity of A. paniculata was also observed by Sheeja et al. in 2007 in normal as well as tumor-bearing animals. APE and ANDLE administration could significantly enhance the mitogen-induced proliferation of splenocyte, thymocyte, and bone marrow cells. The production of interleukin-2 and interferon-gamma in normal and Ehrlich ascites carcinoma-bearing animals was elevated. [37] latest by 2006 in an experimental study by Zhou et al., it was shown that the key mediators in relaying the cell death signaling initiated by Andrographolide was found to be proapoptotic Bcl-2. [38]

Antidiabetic activity

Antidiabetic property of A paniculata was confirmed by Borhanuddin et al. and Husen et al. in aqueous extract [39],[40] and by Zhang et al. in ethanolic extract. [41] Along with antihyperglycaemic property, the ethanolic extract may also reduce oxidative stress in diabetic rats as studied by Zhang et al.[6] Further, It was concluded by Yu BC et al. in 2003 that the andrographolide was responsible for the antihyperglycemic activity. [42] Finally in 2006, the antidiabetic potential of A. paniculata was found to restore impaired estrous cycle in alloxan-induced diabetic rats. [43]

Hepatoprotective activity

In 1993, Shukla et al. found that andrographolide has a significant dose-dependent protective activity against paracetamol-induced toxicity on ex vivo preparation of isolated rat hepatocytes. [44] In the same year Kapil et al. proved the protective effects of A. paniculata on hepatotoxicity induced in mice by carbon tetrachloride. [45]

Other pharmacological activities

Instead of the activities reported earlier A. paniculata was also found to be possessing antimalarial, [46] antihypertensive, [47] antimicrobial, [48] and antifertility [49],[50] activities.


   Adverse Events Top


Animal studies consistently showed that A. paniculata has very little toxicity. However large oral doses of A. paniculata may cause gastric discomfort, vomiting, loss of appetite. These side effects appear to be due to the bitter taste of andrographilide. Anaphylactic reactions may occur if the crude drug extract is injected. [51]

In a clinical study by Thamlikitkul et al. in 1991, 152 adult patients with pharyngotonsillitis were randomized to receive either paracetamol or 3 g/ day of A. paniculata or 6 g/day of A. paniculata for 7 days. The efficacy of paracetamol or high dose

A. paniculata was significantly more than that of low dose A. paniculata at day 3 in terms of the relief of fever and sore throat. Minimal and self-limiting side effects were found in about 20% in each group. [52] In a review on adverse events of A. paniculata by Joanna et al. it was concluded that it may be somehow safe and efficacious treatment for the relief of symptoms of uncomplicated upper respiratory tract infection and few adverse events were also reported. [53] But in a clinical study of andrographolide from A. paniculata for anti-HIV activity was conducted by Calabrese et al. in 2000. The trial was interrupted at 6 weeks due to adverse events including an anaphylactic reaction in one patient. All adverse events were resolved by the end of observation. [54] After that in 2005, adverse effects and tolerance were studied in type 2 diabetes mellitus for a period of 12 weeks. Parameters monitored included body weight, blood pressure, liver function tests, renal function tests, cardiac enzymes, hemogram, serum electrolytes, fasting blood glucose, HbA1c, blood cholesterol, serum triglycerides, and blood hormone levels (triiodotyronine, thyroxine, thyrotropin, insulin, fasting cortisol). A. paniculata did not induce significant adverse events based on parameters observed in the study but significantly lowered HbA1c and fasting serum insulin in patients with type 2 diabetes. [55] In a three-arm study comparing the efficacy of Kan Jang, a fixed herbal combination containing standardized A. paniculata, it was well tolerated and no side effects or adverse reactions were reported. [56]

Drug interactions

Chao-Feng Chien et al. studied the pharmacokinetic drug interaction and found that the clearance of theophylline was significantly increased and the area under concentration-time curve (AUC) was reduced in both andrographolide and A. paniculata extract pretreated groups at low-dose theophylline administration (1 mg/kg). The elimination half-life (t 1/2β) and mean residence time (MRT) of theophylline were shortened by 14% and 17%, respectively, in the AG pretreated group when high-dose theophylline (5 mg/ kg) was given. Some herbal components contained in APE may interact with theophylline and retard its elimination when theophylline was administered at a high dose. [57] In conjunction with other classes of drugs, there may be significant beneficial or harmful interactions of Andrographis. When being administered with anticoagulants, there may be increased risk of bruising and bleeding since Andrographis itself inhibits the platelet aggregation and prevents blood clots. Reduced drug activity in the case of immune-suppressants might be possible since A. paniculata is shown to be immunostimulatory. Andrographis is also known to terminate pregnancies. [18],[58],[59] However in a study by Pannosian et al. it was observed that per oral administration of APE during the first 19 days of pregnancy in doses of 200, 600, and 2000 mg/kg (i.e. doses 30, 90, and 300 fold higher than its daily therapeutic dose in humans) does not exhibit any effect on the elevated level of progesterone in the blood plasma of rats.

Hovhannisyan et al. in 2005 studied significant pharmacokinetic/pharmacodynamic interactions between the herbal products Kan Jang and Warfarin. The concomitant application of Kan Jang and Warfarin did not produce significant effects on the pharmacokinetics of Warfarin, and practically no effect on its pharmacodynamics. [60]

Further, Pekthonga et al. carried out the inhibitory effect of A. paniculata extract (APE) and andrographolide (AND), on hepatic cytochrome P450s (CYPs) activities using rat and human liver microsomes. For this purpose, CYP1A2-dependent ethoxyresorufin-O-deethylation, CYP2B1-dependent benzyloxyresorufin-O-dealkylation, CYP2B6-dependent bupropion hydroxylation, CYP2C-dependent tolbutamide hydroxylation, CYP2E1-dependent p-nitrophenol hydroxylation, and CYP3A-dependent testosterone 6β-hydroxylation activities were determined in the presence and absence of APE or AND (0-200 μM). APE inhibited ethoxyresorufin-O-deethylation activity in rat and human liver microsomes, with apparent K i values of 8.85 and 24.46 μM, respectively. In each case, the mode of inhibition was noncompetitive. APE also inhibited tolbutamide hydroxylation both in rat and human microsomes with apparent K i values of 8.21 and 7.51 μM, respectively and the mode of inhibition was mixed type. In addition, APE showed a competitive inhibition only on CYP3A4 in human microsomes with K i of 25.43 μM. AND was found to be a weak inhibitor of rat CYP2E1 with a K i of 61.1 μM but did not affect human CYP2E1. So A. paniculata could cause drug--drug interactions in humans through CYP3A and 2C9 inhibition. [61] Validated analytical methods (HPLC, CE and GC-MS) for determining the amount of andrographolide (AND) in the blood plasma of rats and human volunteers following the oral administration of A. paniculata extract (APE) and A. paniculata fixed combination Kan Jang tablets were developed and used for the pharmacokinetic study. Andrographolide was quickly and almost completely absorbed into the blood following the oral administration of APE at a dose of 20 mg/kg body wt. in rats. Its bioavailability, however, decreased fourfold when a 10-times-higher dose was used. Since a large part (55%) of AND is bound to plasma proteins and only a limited amount can enter the cells, the pharmacokinetics of AND are described well by a one-compartment model. Renal excretion is not the main route for eliminating AND. It is most likely intensely and dose dependently metabolized. Following the oral administration of four Kan Jang tablets (a single therapeutic dose, equal to 20 mg of AND) to humans, maximum plasma levels of approximately 393 ng/ml (approx. 1.12 μM) were reached after 1.5-2 hours, as quantified using a UV diode-array detection method. Half-life and mean residence times were 6.6 and 10.0 hours, respectively. AND pharmacokinetics in humans are explained well by an open two-compartment model. The calculated steady state plasma concentration of AND for multiple doses of Kan Jang (after the normal therapeutic dose regimen, 3 × 4 tablets/day, about 1 mg AND/ kg body wt./day) was approximately 660 ng/ml (approx. 1.9 μM), enough to reveal any anti-PAF effect, particularly after drug uptake when the concentration of AND in blood is about 1342 ng/ml (approx. 3.8 μM, while for anti-PAF effect EC50 - 5 μM). [62]

Contraindications

In vivo studies in mice and rabbits suggest that Andrographis paniculata may have abortifacient activity. [63],[64] Conversely, no interruption of pregnancy, fetal resorption or decrease in the number of live offspring was observed in pregnant rats after intragastric administration of an extract of the aerial parts at 2 g/kg body weight during the first 9 days of gestation. [65] Andrographis paniculata may not be used during pregnancy or lactation in higher doses.

Toxicity studies

An acute toxicity study reported that the LD 50 of Andrographis paniculata is too high to be determined. A chronic toxicity study on dogs showed no pathological changes after administering 15 times the clinical dosage of Andrographolide. Andrographolide has not been associated with any side effects in human studies, although animal studies raise concerns about its effects on fertility. In one double-blind, placebo-controlled study, participants were monitored for changes in liver and kidney function, blood counts and any other laboratory measures. No problems were found in patients treated with 1200 mg/day of Andrographis paniculata. [66] Additionally in acute oral toxicity study, female rats were treated at 5000 mg/ kg of Formulation containing Andrograpolide and observed for signs of toxicity for 14 days. It did not produce any treatment-related toxic effects in rats. [67] Burgosa et al. in 1997 studied the possible testicular toxicity of Andrographis paniculata, Nees (Acanthaceae) standardized dried extract in male Sprague Dawley rats for 60 days and no testicular toxicity was found with the treatment of 20, 200, and 1000 mg/kg during 60 days as evaluated by reproductive organ weight, testicular histology, ultrastructural analysis of Leydig cells, and testosterone levels after 60 days of treatment. [68] In 2009, Allan et al. evaluated Wistar rats by orally administering 0, 20, 200, and 1000 mg/ kg of body weight per day, for 65 days prior to mating and 21 days during mating. The treated groups showed no signs of dose-dependent toxicity. The body weight gain and feed consumption were not affected at any of the dose levels. The testosterone levels and fertility indices in treatment groups were found to be comparable with those of the control indicating no effect on fertility. Total sperm count and sperm motility were not affected. The testes and epididymides did not show any gross and histopathological changes.

The possible effect of extract of A. paniculata Nees (A. paniculata) standardized to ≥10% andrographolide, the main bioactive component, on male fertility in albino Wistar rats was evaluated, by orally administering 0, 20, 200, and 1000 mg/kg of body weight per day, for 65 days prior to mating and 21 days during mating. The treated groups showed no signs of dose-dependent toxicity. The body weight gain and feed consumption were not affected at any of the dose levels. The testosterone levels and fertility indices in treatment groups were found to be comparable with those of the control indicating no effect on fertility. Total sperm count and sperm motility were not affected. The testes and epididymides did not show any gross and histopathological changes. No observed adverse effect level of extract of A. paniculata (≥10% andrographolide) was found to be more than 1000 mg/kg per day. [69]

A study was conducted to assess the genotoxicity of the standardized extract of A. paniculata (KalmCold™) through three different in vitro tests: Ames, chromosome aberration (CA), and micronucleus (MN). Ames test was performed at 5000 μg/ml, 1581 μg/ml, 500 μg/ml, 158 μg/ml, 50 μg/ml, 16 μg/ ml, while the clastogenicity tests were performed at 80 μg/ ml, 26.6 μg/ml, 8.8 μg/ ml for short-term treatment without S9; 345 μg/ml, 115 μg/ ml, 38.3 μg/ ml for short-term treatment with S9; and 46 μg/ ml, 15.3 μg/ ml, 5.1 μg/ml for long-term without S9 using DMSO as a vehicle control. Results of Ames test confirmed that KalmCold™ did not induce mutations both in the presence and absence of S9 in  Salmonella More Details typhimurium mutant strains TA98 and TAMix. In CA and MN, KalmCold™ did not induce clastogenicity in CHO-K1 cells in vitro. It is evident that KalmCold™ is genotoxically safe. Additionally in acute oral toxicity study, female rats were treated at 5000 mg/kg of KalmCold™ and observed for signs of toxicity for 14 days. KalmCold™ did not produce any treatment-related toxic effects in rats. [67]

The possible testicular toxicity of A. paniculata standardized dried extract was evaluated in male Sprague Dawley rats for 60 days. No testicular toxicity was found with the treatment of 20, 200, and 1000 mg/ kg during 60 days as evaluated by reproductive organ weight, testicular histology, ultrastructural analysis of Leydig cells, and testosterone levels after 60 days of treatment. The dried extract did not produce subchronic testicular toxicity effect in male rats. [68] A. paniculata is not having any toxicity and side effects. [70],[71]


   Conclusion Top


The above review reveals that the plant is safe at its therapeutic dose and is neither associated with any serious toxicity nor any side effects. However when administered at higher dose it may cause gastric discomfort, vomiting, loss of appetite, etc. due to bitter taste. In some conditions like pregnancy and lactation the high dose of the plant extracts should be contraindicated while it is safer to use the plant in its therapeutic dose. So it can been concluded from the above review that the whole plant extracts in their therapeutic doses are safe to be used without any adverse effects.


   Acknowledgment Top


We are grateful to Dr. Ramesh Babu Devalla, Director General, CCRAS and Dr. M.M Padhi, Deputy Director, CCRAS for their kind help and inspiration for doing this review.

 
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