Andrographis Paniculata: a Review of Pharmacological Activities and Clinical E!Ects Shahid Akbar, MD, Phd

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Andrographis paniculata: A Review of Pharmacological Activities and Clinical E!ects Shahid Akbar, MD, PhD

Introduction combination with other medicinal plants. In Andrographis paniculata is a plant that has been modern times, and in many controlled clinical effectively used in traditional Asian medicines for trials, commercial preparations have tended to be centuries. Its perceived “blood purifying” property standardized extracts of the whole plant. results in its use in diseases where blood “abnor- Since many disease conditions commonly treated malities” are considered causes of disease, such as with A. paniculata in traditional medical systems skin eruptions, boils, scabies, and chronic undeter- are considered self-limiting, its purported benefits mined fevers. "e aerial part of the plant, used need critical evaluation. "is review summarizes medicinally, contains a large number of chemical current scientific findings and suggests areas where constituents, mainly lactones, diterpenoids, further research is needed. diterpene glycosides, flavonoids, and flavonoid glycosides. Controlled clinical trials report its safe and effective use for reducing symptoms of uncomplicated upper respiratory tract infections. Since many of the disease conditions commonly treated with A. paniculata in traditional medical systems are considered self-limiting, its purported benefits need critical evaluation. "is review summarizes current scientific findings and suggests further research to verify the therapeutic Shahid Akbar, MD, PhD – efficacy of A. paniculata. Chairman and professor, A. paniculata, known on the Indian subconti- department of pharmacology, nent as Chirayetah and Kalmegh in Urdu and Qassim University, Saudi Ara- bia; former professor of phar- Hindi languages, respectively, is an annual plant, macology, Medical University 1-3 ft high, that is one of the most commonly of the Americas, Nevis, West used plants in the traditional systems of Unani Indies; Editor, International Journal of Health Sciences; and Ayurvedic medicines. It is called Creat in Uses in Traditional Medical Systems author of book Garlic – The English and is known as the “king of bitters.” It A. paniculata has been reported as having Stinking Magic Herb grows in hedge rows throughout the plains of India antibacterial, antifungal, antiviral, choleretic, Correspondence Address: 1,2 College of Pharmacy, and is also cultivated in gardens. It also grows in hypoglycemic, hypocholesterolemic, and adapto- 3 Qassim University, P.O. Box many other Asian countries and is used as a genic effects. In the Unani system of medicine, it 6800, Buraidah 51452, traditional herbal medicine in China, Hong Kong, is considered aperient, anti-inflammatory, emol- Kingdom of Saudi Arabia Email: the Philippines, Malaysia, Indonesia, and "ailand. lient, astringent, diuretic, emmenagogue, gastric [email protected] or "e aerial parts are most commonly used; and liver tonic, carminative, antihelmintic, and [email protected] however, the whole plant or roots are mentioned antipyretic. Due to its “blood purifying” activity it for certain limited purposes in some manuscripts. is recommended for use in cases of leprosy, gonor- Traditionally, the plant was used as an infusion, rhea, scabies, boils, skin eruptions, and chronic and decoction, or powder, either alone or in seasonal fevers.1 Juice or an infusion of fresh

leaves is given to infants to relieve griping, irregu- identified as 5,7,2’,3’-tetramethoxyflavanone and lar bowel habits, and loss of appetite.2,4,5 "e leaves 5-hydroxy-7,2’,3’-trimethoxyflavone were isolated and root are also used in general debility, during from the whole plant,16 while 12 new flavonoids Key Words: andrographis, convalescence after fevers, for dyspepsia associated and 14 diterpenoids have been reported from the andrographolides, hepatopro- with gaseous distension, and in advanced stages of aerial parts.17,18 Two new flavonoid glycosides and a tection, colds, respiratory, 4,5 URTI, liver, hepatic dysentery. new diterpenoid (andrographic acid) were recently In China, the herb derived from the leaves or reported,19 and two new ent-labdane diterpenoid aerial parts of A. paniculata is known as glycosides were isolated from the aerial parts.20 Chuanxinlian, Yijianxi or Lanhelian. It is described as bitter and cold, is considered to be antipyretic, Mechanisms of Action detoxicant, anti-inflammatory, and detumescent, Hepatoprotective E!ects and is thought to remove “pathogenic heat” from A. paniculata is extensively used as a hepatostim- the blood. A. paniculata is used for the treatment of ulant and hepatoprotective agent in Indian systems pharyngolaryngitis, diarrhea, dysentery, cough of medicine.21 A. paniculata is also an ingredient in with thick sputum, carbuncle, sores, and snake several polyherbal preparations used as hepatopro- bites.6 Various preparations and compound tectants in India,22 one of which has been reported formulas of the herb have been used to treat as efficacious in chronic hepatitis B virus infec- infectious and non-infectious diseases, with tion.23 Very few studies on the effects of crude significant effective rates reported for conditions extracts of A. paniculata on liver function are such as epidemic encephalitis B, suppurative otitis available. Most studies for hepatic effects have media, neonatal subcutaneous annular ulcer, been conducted on either andrographolide or other vaginitis, cervical erosion, pelvic inflammation, purportedly active principles. herpes zoster, chicken pox, mumps, neurodermati- Shukla et al reported significant choleretic tis, eczema, and burns.6 effects of andrographolide in conscious rats and anesthetized guinea pigs. "e protection of Modern Uses andrographolide against acetaminophen-induced A primary modern use of A. paniculata is for the reduction in volume and contents of bile was better prevention and treatment of the common cold. It than that produced by silymarin.24 Multiple-dose appears to have antithrombotic actions, suggesting pretreatment with arabinogalactan proteins and a possible benefit in cardiovascular disease.7 andrographolide was protective against ethanol- Pharmacological and clinical studies suggest the induced hepatotoxicity in mice and was deemed potential for beneficial effects in diseases like comparable to the efficacy of silymarin.25 cancer8-12 and HIV infections.13 Choudhury and Poddar reported that oral pre- and post-treatment of adult rats with an extract of A. Phytoconstituents paniculata was protective against ethanol-induced A. paniculata contains diterpenes, lactones, and increase in serum transaminases. Administration flavonoids. Flavonoids mainly exist in the root, but of the extract to normal adult rats in single and have also been isolated from the leaves. "e aerial multiple doses for seven and 15 consecutive days parts contain alkanes, ketones, and aldehydes. did not significantly affect serum transaminases.26 Although it was initially thought that the bitter A comparative study on the effect of leaf extract substance in the leaves was the lactone androgra- or andrographolide on carbon tetrachloride

pholide, later investigations showed that the leaves (CCl4)-induced hepatic microsomal lipid peroxida- contained two bitter principles – andrographolide tion revealed a protective eﬀect of a single oral and a compound named kalmeghin. Four lactones dose of the extract and of andrographolide.

– chuanxinlian A (deoxyandrographolide), B However, high concentration CCl4-induced micro- (andrographolide), C (neoandrographolide) and D somal lipid peroxidation in vitro was completely (14-deoxy-11, 12-didehydroandrographolide) protected by the extract but not by androgra- – were isolated from the aerial parts in China.6 A pholide, indicating that the hepatoprotective effect diterpene glucoside (deoxyandrographolide- is not solely due to the presence of androgra- 19beta-D-glucoside) has been detected in the pholide.27 Hepatoprotective effects of the crude 14 leaves and six diterpenoids of the ent-labdane alcohol extract of leaves against CCl4-induced liver type, two diterpene glucosides and four diterpene damage have also been reported by Rana and dimers (bis-andrographolides A, B, C, and D) have Avadhoot.28 been isolated from aerial parts.15 Two flavonoids

Handa and Sharma compared andrographolide, hepatoprotection. Large, multicenter, clinical methanol extract of the whole plant containing studies are warranted to determine whether A. equivalent amounts of andrographolide, and an paniculata is eﬃcacious in patients with liver andrographolide-free methanol extract against diseases of various origins.

CCl4-induced liver damage in rats. "e CCl4-induced increases in serum transaminases, serum alkaline E!ects on Hepatic Metabolizing Enzymes phosphatase, serum bilirubin, and hepatic triglyc- Drug-herb and drug-nutrient interactions can erides were inhibited by 48.6-, 32- and 15 percent, adversely influence the clinical response to for andrographolide, methanol extract, and treatment. "erefore, the effect of herbal and andrographolide-free methanol extract, respec- nutrient compounds on hepatic metabolic enzymes tively. Since all three treatments resulted in that influence drug pharmacokinetics is an area of improvement in liver histology,29 a hepatoprotec- interest in modern medicine. Singh et al reported tive role of A. paniculata constituents other than that an 80-percent hydroalcohol extract (50 and andrographolide is suggested and corroborates the 100 mg/kg/day for 14 days) of A. paniculata to mice observation made by Choudhury and Poddar.27 significantly increased the levels of acid-soluble

"e CCl4-induced increase in pentobarbitone- sulfhydryl content, cytochrome P450 (CYP450), induced sleep time in mice is also completely cytochrome P450 reductase, cytochrome b5 normalized by andrographolide. "e eﬀects of reductase, glutathione S-transferase, and superox- intraperitoneal (i.p.) pretreatment for three ide dismutase at both doses; while signiﬁcant

consecutive days with andrographolide on CCl4- or increases in the levels of catalase, glutathione tert-butyl hydroperoxide-induced hepatotoxicity in peroxidase, and glutathione reductase were mice were compared with two other diterpenes observed only at higher doses.34 Both aqueous and – andrographiside and neoandrographolide. Both alcoholic extracts of A. paniculata are reported to compounds showed a greater protective effect than significantly increase the activities of CYP1A1 and andrographolide. "e protection by andrographi- CYP2B without affecting the total hepatic CYP450 side and neoandrographolide was comparable to contents in ICR male mice.35 Andrographolide silymarin, and neoandrographolide normalized significantly induced CYP1A1 and CYP1A2 mRNA glutathione levels.30 expression in cultures of mouse hepatocytes and Trivedi et al observed protection by both the acted synergistically with CYP1A inducers.36 A. crude extract of A. paniculata and andrographolide paniculata extract has recently been reported to against reduced activities of hepatic antioxidant noncompetitively inhibit CYP1A2 and CYP2C in rat enzymes (superoxide dismutase, catalase, and and human liver microsomes and competitively glutathione peroxidase), depletion of hepatic inhibit CYP3A4 in human microsomes; whereas, glutathione, and increased activities of hepatic andrographolide was found to be a weak inhibitor γ-glutamyl transpeptidase, glutathione-S-transfer- of rat CYP2E1 only.37 Similar effects of the extract ase, and lipid peroxidase caused by hexachlorocy- and andrographolide on CYP2C and CYP3A in rat clohexane in mice.31 Oral or i.p. pretreatment with and human hepatocyte cultures have been andrographolide was also protective against observed.38 Existing evidence is not sufficient to galactosamine-induced liver damage in rats and draw any conclusions on drug-herb interactions. prevented changes in biochemical parameters and More extensive studies on hepatic metabolizing liver histology. Similar protection was observed enzymes should be conducted in healthy humans when rats were treated with andrographolide and in humans taking medications that are post-acetaminophen challenge,32 and on an ex vivo susceptible to pharmacokinetic alterations by these preparation of isolated rat hepatocytes.33 inducible hepatic enzymes. Various extracts and constituents of A. paniculata were used in the experiments mentioned in Antimicrobial and Antiparasitic E!ects this subsection. All showed hepatoprotective A. paniculata has been extensively used to treat a effects. A. paniculata also showed benefits against variety of conditions of infectious origin in liver damage caused by agents with different traditional systems of medicine. Modern research hepatotoxic mechanisms, suggesting A. paniculata has investigated it for activity against various and its constituents are not agent-specific and bacteria, viruses, and parasites. Crude powder might have broad-spectrum hepatoprotective suspended in water was reported to be devoid of in effects. More research is needed to establish the vitro antibacterial activity against Salmonella, identity of the most effective component(s) for Shigella, Escherichia coli, gram A Streptococci, and

Staphylococcus aureus, even at a concentration of 25 Cardiovascular E!ects mg/mL crude powder. Administration of a single Aqueous extract of A. paniculata produced a oral dose of powder, up to 6 g, to healthy volun- dose-dependent fall in systolic blood pressure of teers in a randomized crossover manner or daily both spontaneously hypertensive rats (SHRs) and administration of 0.12-24 g/kg body weight to rats normotensive Wistar-Kyoto rats, with a corre- for six months also failed to show any ex vivo sponding significant decrease in plasma angioten- antibacterial activity.39 Singha et al reported sin converting enzyme (ACE) activity and lipid significant antibacterial activity of an aqueous peroxidation in kidneys in extract-treated SHRs. extract and attributed it to the combined effect of "e decreases in ACE activity and lipid peroxida- andrographolides and arabinogalactan proteins.40 A tion were not significantly altered in normotensive similar conclusion was reached by Zaidan et al who Wistar-Kyoto rats, an indication that suggests its found crude aqueous extract of leaves exhibit hypotensive effect in hypertensive and normoten- significant antimicrobial activity against gram- sive rats is not mediated through identical mecha- positive S. aureus, methicillin-resistant S. aureus nisms.50 "e hypotensive effect of n-butanol and (MRSA), and gram-negative Pseudomonas aerugi- aqueous fractions of the crude water extract is nosa, but had no activity against Escherichia coli or antagonized or attenuated by phentolamine, Klebsiella pneumoniae.41 "e ethanol extract was hexamethonium, pyrilamine, and cimetidine, but also devoid of significant activity against enterohe- not by propranolol, atropine, or captopril.51 morrhagic strains of E. coli.42 However, the fall in mean arterial pressure pro- Andrographolide, neoandrographolide, and duced by 14-deoxy-11, 12-didehydroandrogra- 14-deoxy-11,12-didehydroandrographolide are pholide (DDA), one of the three active diterpenoids, reported to be viricidal against herpes simplex in anesthetized Sprague-Dawley rats was attenu- virus 1 (HSV-1) without having any significant ated in the presence of propranolol, hexametho- cytotoxicity at viricidal concentrations.43 nium, and captopril. DDA also antagonized the "e alcohol extract of the rhizome was reported positive chronotropic effect of isoproterenol on the to possess significant in vitro activity against isolated rat right atria in a non-competitive and Ascaris lumbricoides.44 "e chloroform extract dose-dependent manner.52 Hypotensive and completely inhibited malarial parasitic growth negative chronotropic effects of DDA have been within 24 hours of incubation at a concentration of corroborated by a recent study that suggested that 0.05 mg/mL. "e same inhibition was achieved in vascular smooth muscle is the major site of 48 hours with methanol extract at a concentration hypotensive activity of DDA and high-DDA of 2.5 mg/mL.45 Mishra et al found that a methanol extracts.53 extract significantly inhibited Plasmodium falci- Several studies investigated the effect of water parum at a 50-percent inhibitory concentration extract and active constituents of A. paniculata, 46 (IC50) of 7.2 µg/mL. "e four xanthones – both pre- and post-experimental myocardial 1,8-dihydroxy-3,7-dimethoxyxanthone, 4,8-dihy- infarction (MI), in animals. A water extract was droxy-2,7-dimethoxyxanthone, 1,2-dihydroxy-6,8- administered intravenously one hour after MI in dimethoxyxanthone, and 3,7,8-trimethoxy-1- dogs. Treatment restricted the infarct size and hydroxy-xanthone – isolated from the roots of the produced a milder core ischemic area than in plant, also showed in vitro anti-malarial activity control dogs; similar results were also observed against Plasmodium falciparum and in vivo activity with flavones extracted from the root.54,55 in Swiss albino mice infected with Plasmodium Experimental myocardial ischemia-reperfusion berghei.47 "e same xanthones also exhibited injury in dogs results in ultrastructural changes in antiprotozoal activity against Trypanosoma brucei, the ischemic region with an increase in Ca2+ and Trypanosoma cruzi, and Leishmania infantum.48 reduced superoxide dismutase, Ca2+-ATPase, and Water decoction of the leaves exhibited filaricidal Na+-K+-ATPase activities. Treatment with an activity, both in vitro and in dogs.49 extract of A. paniculata prevented Ca2+ overloading Clinical relevance of these studies is inconclusive of the ischemic region and the fall in enzyme since results are predominantly in vitro or ex vivo. activities.56,57 A refined extract (API0134) adminis- Many of the in vitro results obtained were also tered intravenously 45 min post-ischemia induc- achieved at concentrations that may not be tion prevented increase in the left ventricle clinically feasible. end-diastolic pressure and preserved relatively normal cardiac output and rhythm in dogs with experimental ischemia-reperfusion myocardial

injury.58 Andrographolide pretreatment of rat mitochondrial electron chain complexes and the cardiomyocytes is reported to protect them against resultant increase in nitric oxide (NO) in different hypoxia/reoxygenation injury in a time-dependent parts of rats’ brains was prevented by simultane- manner. "is effect was associated with upregula- ous treatment with the water and ethanol extracts tion of cellular reduced glutathione (GSH) level and of A. paniculata or andrographolide; the water antioxidant enzyme activities.59 extract exhibited greater antioxidant activity than Wang and Zhao studied the effects of A. panicu- the ethanol extract.64 Phytochemical analysis lata on restenosis after experimental balloon showed higher flavonoid but lower phenol contents angioplasty. Pretreatment with A. paniculata in water extract than in ethanol extract.65 Verma extract prevented atherosclerotic iliac artery and Vinayak compared the antioxidant effects of stenosis in rabbits produced by de-endothelializa- the aqueous extract on liver defense systems in tion and high cholesterol diet. Restenosis after lymphoma-bearing AKR mice. "e aqueous extract experimental angioplasty in the stenosed arteries significantly increased the activities of catalase, was also significantly prevented. "e extract superoxide dismutase, and glutathione-S-transfer- inhibited cell growth and DNA synthesis in a ase enzymes and reduced lactate dehydrogenase dose-dependent manner. "is is similar to the activity.66 A methanol extract inhibited formation mechanism by which stents are coated with drugs of reactive oxygen species (ROS) in vitro and that inhibit cell division.60,61 completely inhibited carrageenan-induced inflam- Aqueous extract, andrographolide, and DDA mation.67 Andrographolide pretreatment signifi- inhibit thrombin-induced platelet aggregation in cantly attenuates accumulation of phorbol-12- time- and concentration-dependent manners. myristate-13-acetate (PMA)-induced formation of Extracts with a higher DDA concentration have less ROS and N-formyl-methionyl-leucyl-phenylalanine inhibitory activity than extracts with lower DDA (fMLP)-induced adhesion of rat neutrophils.68 concentration, indicating the presence of other However, PMA-induced formation of ROS and compounds in the water extract with antiplatelet fMLP-induced adhesion and transmigration of aggregation activity.62 Andrographolide inhibits peripheral human neutrophils was only partially platelet-activating factor (PAF)-induced platelet reversed by andrographolide. "is study suggests aggregation in a dose-dependent manner without that prevention of ROS production was partly affecting the biosynthesis of eicosanoids.7 mediated by the direct activation of protein kinase An extract of A. paniculata significantly inhibited C by PMA and partly mediated by down-regulation ex vivo ADP-induced platelet aggregation in 63 of surface Mac-1 expression, an essential integrin patients with cardiac and cerebral vascular diseases for neutrophil adhesion and transmigration, three hours after administration. "irty-three of respectively.69 these patients who were observed for platelet Excessive amounts of NO and prostaglandin E2 aggregation after one week experienced even more (PGE2), due to expression of inducible isoforms of significant effects. Serotonin release from platelets nitric oxide synthase (iNOS) and cyclooxygenase-2 was significantly reduced in 20 extract-treated (COX-2) from activated macrophages, play a volunteers, while the plasma serotonin levels significant role in inflammatory processes. remained unchanged.63 Lipopolysaccharide (LPS) stimulates and promotes Reports regarding hypotensive activity of secretion of pro-inflammatory cytokines from extracts and some constituents are consistent. macrophages and causes induction of iNOS, Further studies are needed to establish the resulting in increased production of NO. mechanisms of action, constituents with hypoten- Incubation of macrophages with methanol extract, sive actions, constituent interactions with blood andrographolide, and neoandrographolide inhibits pressure-lowering medications, and clinical efficacy LPS-stimulated NO production in a concentration- in hypertensive humans. "e results of cardiovas- dependent manner.70-73 Andrographolide-induced cular and platelet antiaggregation studies require reduction of iNOS activity may be due to reduced further exploration in clinical situations. expression of iNOS protein.71,72 Andrographolide also fully restores the maximal contractile response Antioxidant and Anti-in"ammatory Activities of thoracic aorta to phenylephrine after incubation Antioxidant and anti-inflammatory activities of with LPS, and attenuates the fall in mean arterial A. paniculata and its constituents have been blood pressure of anesthetized rats due to LPS.71 reported by various investigators. Das et al Unlike andrographolide, neoandrographolide was reported that nicotine-induced inhibition of also effective ex vivo in suppressing NO production

when macrophages were collected after oral to vehicle-treated diabetic controls.81 Extended administration of neoandrographolide and mean estrous cycles (eight days) was reduced to subjected to LPS stimulation.69 Andrographolide five days in treated diabetic rats.82 inhibited LPS-induced increase in tumor necrosis Andrographolide appears to dose-dependently factor-alpha (TNF-α) and granulocyte-macrophage reduce plasma glucose concentration in strepto- colony stimulating factor.74 Neoandrographolide zotocin-induced diabetic rats and normal rats, with 73 also inhibits PGE2 synthesis and TNF-α in a more marked effect in normal rats than in LPS-stimulated macrophages, and its oral adminis- diabetic rats.83 "is is a significant difference from tration to mice significantly suppresses dimethyl- the water extract, which did not show a glucose- benzene-induced ear edema and acetic acid-induced lowering effect in one study of normoglycemic vascular permeability.75 API0134, a refined extract rats.81 Andrographolide also attenuates the of A. paniculata, also significantly reduces activities increase in plasma glucose in response to an of lipid peroxide and endothelin, while the activi- intravenous glucose challenge in normal rats and ties of NO, cGMP, and superoxide dismutase are enhances the uptake of radioactive glucose by significantly enhanced in experimental atheroscle- isolated soleus muscle of streptozotocin-diabetic rotic rabbits.76 rats in a concentration-dependent manner. Repeated intravenous administration of androgra- Antihyperglycemic and Hypoglycemic E!ects pholide in diabetic rats for three days resulted in an Water extract of A. paniculata significantly increase in mRNA and protein levels of glucose prevents orally administered glucose-induced transporter (GLUT4) in the soleus muscle, an hyperglycemia in nondiabetic rabbits without indication that the glucose-lowering effect of affecting epinephrine-induced hyperglycemia. andrographolide could be due to better glucose Chronic administration of the extract for six weeks utilization by skeletal muscle.83 However, after in also showed no effect on fasting blood glucose vitro experiments, Wibudi et al concluded that the level.77 However, ethanol extract, administered hypoglycemic effect of A. paniculata is due to orally twice daily for 14 days to streptozotocin- insulin release from pancreatic β-cells through induced diabetic rats significantly reduced fasting ATP-sensitive potassium channels, similar to other serum glucose and increased body weight in a insulinotropic antidiabetic agents.84 In vitro dose-dependent manner. "e extract also signifi- experiments conducted by Subramanian et al cantly lowered levels of thiobarbituric acid-reactive suggested that inhibition of alpha-glucosidase and substances in liver and kidney compared to alpha-amylase enzyme could be the mechanism by vehicle-treated rats, while significantly increasing which the ethanol extract of A. paniculata and the activity of superoxide dismutase and catalase andrographolide produce hypoglycemic effect.85 enzymes and hepatic glutathione concentrations in Available evidence suggests that the hypoglyce- diabetic rats.78 An ethanol extract at a dose of 400 mic and antihyperglycemic activities of the extract mg/kg body weight twice daily for two weeks to and andrographolide may involve different mecha- diabetic rats produced a 49.8-percent reduction in nisms in normal and diabetic conditions. Water fasting serum triglyceride levels. "is was greater extract seems to be a more suitable candidate for than the 27.7-percent decline achieved with 500 further studies as it does not affect fasting blood mg/kg body weight metformin twice daily for 14 glucose levels of nondiabetic animals. days.79 An aqueous extract (50 mg/kg body weight) Identification of blood glucose-lowering constitu- given to streptozotocin-diabetic rats resulted in a ents in both water and ethanol extracts may be of 52.9-percent decrease in blood glucose levels. value. Freeze-dried material decreased blood glucose by 61.8 percent at a lower dose of 6.25 mg/kg body E!ects on Reproductive Systems weight.80 Similar results were obtained by Dandu A number of animal studies report an effect of A. and Inamdar with oral administration of an paniculata on male and female reproduction. Early aqueous extract of A. paniculata leaves. A dose of reports of oral administration of powdered stem 400 mg/kg lowered blood glucose level of strepto- indicated an antifertility effect in male Wistar mice, zotocin-induced animals and increased activity of but no impact on fertility in female mice.86,87 In has superoxide dismutase and catalase. Oral adminis- also been reported that administration of A. tration of the decoction also significantly reduced paniculata resulted in abortion in pregnant blood glucose levels in alloxan-induced diabetic rabbits.6 Intraperitoneal injection of the decoction rats, and reduced food and water intake compared of aerial parts to female albino mice was reported

to prevent implantation and caused abortion at Clinical Studies different gestation periods. Early pregnancy was Dysentery/Gastroenteritis also terminated by intramuscular, subcutaneous, Studies conducted in China have reported and intravenous administration. Administration of therapeutic value in acute bacillary dysentery and progesterone or luteinizing hormone-releasing gastroenteritis. Ethanol extract tablets reportedly hormone completely or markedly antagonized the cured 88.3 percent of acute bacillary dysentery and abortifacient effects, indicating an interference 91.3 percent of acute gastroenteritis cases.6 with progesterone activity as a potential mecha- Andrographolide administration was reported to nism for this abortifacient effect. In addition, the cure 91 percent of acute bacillary dysentery cases.6 herb is reported to suppress growth of human "e same cure rate (91.1%) was achieved with a placental chorionic trophoblastic cells in vitro.6 compound tablet containing andrographolide and Zoha et al fed female mice sun-dried neoandrographolide (at a ratio of 7:3) in cases of Andrographis powder at a dose of 2 g/kg body bacillary dysentery. "is was reported to be higher weight/day for six weeks. When they were mated than cure rates obtained with furazolidine or with untreated males of proven fertility, pregnancy chloramphenicol.6 was inhibited in 100 percent of the animals. Conversely, more than 95 percent of untreated Infectious Diseases female mice in the control group became pregnant A. paniculata or its constituents have been used when mated with males in a similar fashion.88 to treat cases of leptospirosis, pulmonary tubercu- Akbarsha et al administered dry leaf powder to losis (especially the exudative type), tuberculous male albino rats (20 mg daily for 60 days). "ey meningitis, and acute pyelonephritis.6 In acute reported inhibition of spermatogenesis, degenera- pyelonephritis, the results were reported to be tive changes in the seminiferous tubules, regres- similar to those obtained with nitrofurantoin, but sion of Leydig cells, and regressive and/or degen- with fewer adverse effects.6 Intra-arterial or erative changes in the epididymis, seminal vesicle, retrograde intravenous injections of the herb were ventral prostate, and coagulating glands.89 reportedly effective in thromboangiitis obliterans, Andrographolide also produced similar results especially of “heat toxic type.”6 Ten cases of viper when orally administered to male Wistar albino bites were reportedly cured in 3-5 days by a rats for 48 days. Sperm count and sperm motility compound formula that had A. paniculata as the were decreased and sperm abnormalities were chief constituent.6 noted.90 However, Burgos et al found no testicular A phase I, dose-escalating clinical trial of toxicity in male Sprague Dawley rats after treat- andrographolide was conducted in 13 HIV-positive ment with a standardized dried extract in doses of patients and five HIV-negative healthy volunteers. up to 1,000 mg/kg daily for 60 days. "eir analysis "e planned protocol was to start with a dose of 5 was based on testicular weight and histology, mg/kg body weight for the first three weeks, ultrastructural analysis of Leydig cells, and increase to 10 mg/kg body weight for three weeks, testosterone levels.91 Extract of A. paniculata also and then to 20 mg/kg body weight for a final three did not affect the progesterone levels in pregnant weeks. Andrographolide administration signifi- rats when administered orally in doses of 200, 600, cantly improved the CD4+ lymphocyte count from and 2,000 mg/kg daily during the first 19 days of a baseline mean of 405 cells/mm3 to 501 cells/mm3 pregnancy.92 Burgos et al reported that dried in HIV-positive patients. "ere was no statistically extract of A. paniculata induces uterine relaxation significant change in mean plasma HIV-1 RNA by blocking voltage-sensitive calcium channels.93 A levels. "is trial was stopped after six weeks phase I clinical study on Kan-Jang (a combination because of adverse events.13 of A. paniculata and Eleutherococcus senticosus) A. paniculata has been used for uncomplicated reported no significant negative effects on sperm upper respiratory tract infections (URTIs). "ere quality and fertility of healthy adult males.94 appears to be differences in the degree of therapeu- Existing evidence is too inconsistent, with some tic effect based upon the kind of preparation used findings directly contradicting others, to reach any and duration of treatment. Pills (made from the definitive conclusion about the reproductive effects whole powdered plant with water) and tablets of A. paniculata. "e existing evidence does suggest (made from the water extract of the herb) produced that A. paniculata is unlikely to be an effective form aggregate effective rates of 88 percent and 61 of birth control. Further studies on short- and percent in URTI, respectively.6 In a randomized, long-term effects on fertility are warranted. double-blind, controlled study, "amlikitkul et al

gave A. paniculata at a dose of 6 g/day for seven alternative treatment for uncomplicated URTIs days to 152 "ai adults suffering from pharyngo- compared to placebo.100,101 tonsillitis. Efficacy was comparable to acetamino- "e results from these Kan Jang trials, in both phen in relieving symptoms of fever and sore adults and children, cannot be attributed exclu- throat.95 A study of 158 adult patients suffering sively to the effects of A. paniculata, since it was from common cold used a standardized A. panicu- given in combination with E. senticosus. "e lata dried extract SHA-10 (1,200 mg/day) for five majority of other clinical trials have been published days. "e extract significantly decreased the in Chinese journals and lack sufficient details to intensity of the symptoms of tiredness, sleepless- determine actual efficacy, especially since many ness, sore throat, and nasal secretion, starting from conditions studied are self-limiting. More clinical the second day of treatment.96 Self-limiting side research is required before A. paniculata can be effects were reported in 20 percent of patients deemed efficacious for conditions other than URTI. from both groups in the former study and no significant adverse effects were reported in the Toxicity and Dosing

latter study. "e LD50 of the alcohol extract, obtained by cold 28 A commercial preparation consisting of a maceration, is 1.8 g/kg. "e LD50 of androgra- standardized extract of A. paniculata in a fixed pholide (yield 0.78% w/w from whole plant) in combination with Eleutherococcus senticosus (Kan male mice through intraperitoneal route is 11.46 g/ Jang) has been tested in uncomplicated URTIs. kg.29 Two randomized, double-blind, placebo-controlled In the study on HIV-positive patients a dose of parallel group trials were conducted in Sweden. 1,500-2,000 mg of andrographolides was given One was a pilot study that involved 46 patients daily for six weeks. Side effects were common and who were treated with Kan Jang three times daily the study was discontinued early despite some for a minimum of three days and a maximum of improvements in CD4+ counts.13 eight days; the other was a phase III study of 179 Until definitive information on A. paniculata and patients for three days. Patients’ self-evaluation in its constituents on reproduction is available, it regard to muscle aches, cough, sore throat, head- would be prudent for both men and women to ache, nasal discharge, eye symptoms, and fever avoid this herb during desired conception and for served as the primary outcome measures. "roat women during pregnancy. symptom relief was highly significant in treated "e majority of studies for common colds and groups compared to placebo-treated groups in both URTI used a patented product – Kan Jang – which studies.97 In a similar Armenian study, 95 patients combines A. paniculata and E. senticosus. with acute URTIs, including sinusitis, were treated Andrographis used in this product is standardized with Kan Jang for five days, while a group of 90 to contain 4-6 percent andrographolides and the patients served as control. A highly significant dose used provided anywhere from 60-72 mg per improvement in headache, nasal and throat day (low range) up to about 300 mg per day symptoms, and general malaise was reported in the (highest dose). Existing evidence suggests that best treated groups, including the sinusitis subgroups, results might be obtained if taken within the first while cough and eye symptoms did not differ 24 hours of URTI symptoms. significantly from the placebo group.98 Effects of Kan Jang on uncomplicated respira- Conclusions and Other Potential Uses tory disease have also been studied in children "e hepatoprotective effects of pretreatment (ages 4-11 years). In a three-arm study, a group with various extracts and constituents of A. treated with standard common cold treatment paniculata are very consistent. Moreover, its served as a control. In two groups, Kan Jang or an inclusion in effective polyherbal formulations for Echinacea preparation was added as an adjunct to liver ailments not amenable to any modern standard treatment for 10 days. Patients receiving intervention lends support to its potential effec- Kan Jang as adjunct to standard therapy at an early tiveness. Before definitive conclusions can be stage of the common cold showed less severe drawn, it would be prudent to study the effects of symptoms, especially nasal congestion and A. paniculata or its constituents under experimen- secretions, faster recovery, and a significantly lower tal conditions of post-hepatic damage to determine need for standard medication.99 Two systemic if and how they reverse the pathological changes reviews of randomized, controlled trials concluded and which form is the most effective. More that A. paniculata was a safe and efficacious research is needed to determine the effects of this

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