Acth Herb information, tips and advice

Since Andrographis is energetically 'cold,' it is preferably taken in combination with 'warm' herbs when used during winter as a preventative treatment, especially if the user has a 'cold' constitution. Warming herbs include Echinacea spp., Zingiber officinalis (ginger), Astragalus membranaceus and Ocimum sanctum (holy basil).

Adverse Reactions

High doses may cause gastric discomfort, anorexia and emesis (vomiting), but generally there are few side effects associated with its use and it is not toxic. Generally Andrographis has been well tolerated in clinical trials. Two cases (8% of patients) of urticaria were reported in one trial investigating respiratory infections (1) and in another trial one patient in a treatment group of 90 reported adverse effects (unpleasant sensations in the chest and intensified headache). (2) A high incidence of adverse effects was reported in a trial involving HIV patients (3) but the dosage of pure andrographolide which was administered was very high compared to the normal therapeutic dosages of Andrographis extract.

Contraindications & Cautions

The antifertility effect in female mice (albeit at high doses) suggests that Andrographis should not be used during human pregnancy, especially in the first trimester. However it has been suggested that the risks associated with its use during pregnancy are low. (4)

Traditional Uses

In Ayurvedic medicine, the herb is used for its bitter tonic, stomachic, antipyretic and laxative properties. It is said to increase appetite, strengthen digestion and diminish flatulence, hyperacidity and biliousness. (5)

It is also utilized for treatment of many conditions, including diabetes, debility and hepatitis. (6) The roots and leaves have a reputation for being alterative and anthelmintic. (7) In traditional Chinese herbal medicine, Andrographis is bitter and cold, and is used to clear Heat from the Blood (especially in the lungs, throat and urinary tract) and to detoxify Fire Poison (manifesting as skin sores and carbuncles). In addition to gastrointestinal complaints, it is prescribed for throat infections, cough with thick sputum and snake bites. (8,9) As Andrographis is regarded as a 'cold' herb, it is ideally suited to treating acute infections, which are 'hot' conditions.

Scientific Studies

Constituents

The main active constituent is the bitter diterpenoid lactone, andrographolide. Other constituents include other diterpene lactones, diterpene glucosides (which are also lactones, such as neoandrographolide (nonbitter)), (10) diterpene dimers, (11) and flavonoids. (12)

Anti-infective and Immunostimulating Activity

Although Andrographis is widely used in infections and infestations, the weight of evidence is that its value here is mainly as an immune-enhancing treatment.

Early reports in China attributed an antibacterial activity to Andrographis which has not been confirmed since. The andrographolides are devoid of antibacterial activity. (9) Direct antibacterial activity against a number of organisms was not demonstrated in vitro (aqueous extract), in vivo (oral Andrographis, .24 g/kg over a 6-month period) or in serum taken from 10 healthy volunteers after a single oral dose of Andrographis (ranging from 1 g to 6g). (13) However, alcoholic extract of Andrographis did show significant activity against an E. coli enterotoxin-induced secretory response (which causes diarrhea) in in vivo models. (14)

Fluid extract of Andrographis root demonstrated strong in vitro antihelmintic activity against human Ascaris lumbricoides. (13) In vitro studies with aqueous extracts of Andrographis showed little or no inhibition of HIV-1. (15)

An immunostimulant action, especially on phagocytosis has been demonstrated for a decoction of Andrographis in vitro, and in viva by injection of the soluble derivatives. (9) Isolated andrographolide and Andrographis fluid extract stimulated both antigen-specific and non-specific immune responses in mice. The fluid extract produced stronger immunostimulation. (16) Prolonged survival in animals after snakebite was observed after pretreatment with Andrographis extract. (17)

Hepatoprotective and Choleretic Activity

Andrographis or its isolated diterpenes have shown protective activity against experimentally-induced hepatotoxicity in vitro, (18) or in viva after oral (19) or intraperitoneal administration. (20-22) The activity was comparable to silymarin (18,20,21) and is likely to be due to antioxidant activity. (21)

Hepatoprotective activity has been exhibited in vivo for acute hepatitis after oral andrographolide treatment, (23) and for alcohol-induced toxic liver damage. (24) Pre- and post-treatment with oral doses of Andrographis ( g/kg/day) normalized alcohol-induced increases in serum transaminase activity in rats. (24)

Significant activity was demonstrated for an alcohol extract of Andrographis and the diterpenes, andrographolide and neoandrographolide, against hepatotoxicity caused by Plasmodium berghei infection in animals. The protective effect of Andrographis may be due, in part, to reactivation of superoxide dismutase which counteracts peroxidative damage. Andrographis may also cause induction of hepatic drug metabolizing systems which detoxify hepatotoxins. (25)

Administration of Andrographis ( g/kg per day) or andrographolide ( mg/kg per day) to rats for 7-30 consecutive days caused a significant induction of the liver microsomal drugmetabolizing enzymes aniline hydroxylase, N-demethylase and O-demethylase. However, a single dose only caused inhibition of aniline hydroxylase activity. (26)

Andrographolide produced a dose-dependent choleretic effect (increased bile flow, bile salt and bile acids) in animals after oral administration. The effect was stronger than silymarin. Oral administration of aqueous extract of Andrographis ( mL/kg) increased bile flow and liver weight. The maximal increase in flow and weight was reached after two days and levels remained constant after longer treatment periods. (27) Pretreatment at the same dose for 5 days shortened experimentally-induced sleeping time in mice. This provides further evidence that Andrographis may cause induction of hepatic drug metabolizing enzymes. (28)

Antifertility Activity

Oral administration of Andrographis leaf powder (20 mg/ day for 60 days) to male rats produced an antifertility effect, possibly due to an antispermatogenic and/or antiandrogenic mechanism. (29) Using levels of 10 mg and 20 mg per day for 24 and 48 days resulted in biochemical changes in the testes and male accessory organs. (30) These results were not duplicated in a similar study using a standardized dried ethanol extract of Andrographis at 20, 200 and 1000 mg/kg per day for 60 days. The authors concluded that the variation in results may be due to differences in plant material used in the two studies . dried leaf powder and a dried ethanol extract. Andrographis did not produce subchronic testicular toxicity. (31)

A controlled experiment in female mice fed with 2g/kg per day found Andrographis prevented pregnancy in 100% of those treated. (32)

Other Activity

Several in vivo studies have shown antipyretic and anti-inflammatory effects for andrographolides (by oral administration or injection). The anti-inflammatory activity of andrographolides may be due to promotion of ACTH and consequently enhancement of adrenocortical function. (9) Andrographolide administered orally (30, 100 and 300 mg/kg) significantly reduced inflammation in a number of animal models including adjuvant-induced arthritis. (33)

Oral doses of andrographolide at 300 mg/kg demonstrated analgesic activity; at 100 and 300 mg/kg significant antipyretic effects were also observed after 3 hours. In addition, this dose had significant antiulcerogenic activity against aspirin-induced ulceration in rats. (34)

Aqueous extract of Andrographis (10 mg/kg) was found to prevent glucose-induced hyperglycemia in rabbits, but it failed to prevent hyperglycemia induced by adrenalin, suggesting that the herb prevents glucose absorption from the gut. (35)

Andrographis extract reduced fasting serum glucose and increased the activity of antioxidant enzymes in an experimental model of diabetes when given orally. It had no effect on nondiabetic animals. Results were comparable to metformin (a hypoglycemic drug). (36)

Oral administration of Andrographis extract and andrographolide produced a dose- and time-dependent activation of brush-border membrane-bound hydrolases (lactase, maltase, sucrase) in rats. This suggests Andrographis accelerates intestinal digestion and absorption of carbohydrate (as opposed to simple glucose) by activation of disaccharidases. (37)

Methanol extract of Andrographis showed potent cell differentiation-inducing activity on mouse leukemia cells in vitro. (This implies anticarcinogenic activity.) Some of the isolated diterpenes also demonstrated activity. (11)

Andrographis

Pharmacokinetics

Intragastric administration of radio-labelled andrographolide to mice was rapidly absorbed and distributed to organs, especially gallbladder, kidney, ovary and lung. Approximately 90% was excreted in the urine and feces after 24 hours and 94% after 48 hours. At 48 hours, radio-labelled andrographolide only accounted for approximately 11% of urine and liver fractions, the remainder consisted of metabolites. (38)

Toxicology

No toxic effect was observed after administration of a water decoction of Andrographis leaves to rabbits. (39) The LD5O values of the andrographolides and their derivatives indicate Andrographis has a low toxicity: g/kg for oral administration of the total andrographolides, greater than 40 g/kg for oral andrographolide. (9)

Clinical Studies

Respiratory Infections

Chinese clinical studies in both bacterial and viral respiratory infections demonstrated good effects for oral administration of Andrographis or andrographolides, implying an immunostimulant action. (9)

Investigations from the Sichuan Traditional Medicine Research Institution showed Andrographis has a beneficial effect in the treatment of infectious diseases associated with cold symptoms. In particular, Andrographis lowered body temperature within 48 hours: of 84 cases of common cold, 70 achieved normal body temperature within 48 hours. (40)

A randomized, double blind study on 152 patients with pharyngotonsillitis found 6g per day of Andrographis for a week to be as effective as paracetamol in providing relief of fever and sore throat. For both groups the difference between baseline symptoms and final evaluation were significant (p< 1). Lower doses of Andrographis were not as effective. (41)

Tablets containing a total of 1200 mg Andrographis extract (standardized to 4% andrographolides) or placebo were given to 61 patients suffering symptoms of common cold in a double blind, placebo-controlled clinical trial. After 4 days of treatment, measured symptoms were significantly reduced in the Andrographis-treated group compared to placebo (strength of disease (p=), tiredness (p=), sweating/shivering (p=), sore throat (p=), and muscular ache (p=)). For the clinical signs (rhinitis, sinus pain and headaches, lymphatic swellings) there was no significant difference between the treated and placebo groups at day 4. However, if the groups are compared over time (. day 0 versus day 4) there was a significant decrease in the intensity of these signs only for the Andrographis-treated group (p<). (The overall reduction in the symptom score over time was also significant (p<).) The authors concluded that Andrographis treatment can significantly shorten the course and duration o f the common cold. (42) In an earlier controlled trial, improvement of hospital in-patients suffering from common cold and sinusitis was significantly better in the Andrographis group compared to placebo (p<). (43)

In a randomized, double blind, placebo-controlled, clinical trial, 107 healthy children received either Andrographis tablets (200 mg per day of extract, standardized to mg andrographolide) or placebo for 3 months during the winter season. This corresponds to about 1 g of the original herb. Analysis after the first month indicated no significant change for Andrographis treatment. However, by the third month there was a significant decrease in the incidence of colds compared to placebo (30% versus 62%; p<). The relative risk of catching a cold was times lower for the Andrographis group. (44)

In a randomized, double blind, placebo-controlled, pilot study conducted by the Swedish Herbal Institute, 50 outpatients with symptoms of common cold were treated with tablets containing Andrographis extract (1020 mg per day, about 6g of herb). After 5 days of therapy, subjective evaluation demonstrated a significantly reduced number of sick leave days (p<), improved symptoms (p<) and hastened recovery (p<). Side effects were few and mild. (45)

Tiredness, sleeplessness, sore throat and nasal secretions were significantly decreased by the second day of treatment with Andrographis extract (1200 mg/day for 5 days; standardized to 5% andrographolides) compared to placebo in a randomized, double-blind trial involving 158 patients with the common cold. By day 4 all measured symptoms (including headache, earache, expectoration, frequency of cough, intensity of cough) were significantly decreased compared to placebo. (46)

Enteric Infections

Many Chinese studies using oral administration of Andrographis or andrographolides in acute bacillary dysentery and enteritis have shown a marked benefit. (9)

Patients with acute diarrhea were treated with powdered leaves and stems of Andrographis. The Andrographis was more effective in reducing the number of Shigella, but was less effective for cholera compared to tetracycline. Oral administration of 1 g every 12 hours for 2 days was more effective than giving a dose of 500mg every 6 hours for 2 days. (47)

Other Conditions

Andrographolide (5 mg/kg for 3 weeks, then 10 mg/kg for 3 weeks) significantly increased mean [.+] lymphocyte levels from baseline in 13 HIV positive patients. Mean plasma HIV-1 RNA levels did not significantly change. Antiretroviral medications were not used by patients during the trial. Twelve of the 13 patients reported at least one adverse event during the treatment. 3)

Leptospirosis, snake bite, acute pyelonephritis, tuberculosis and leprosy have responded to treatment with Andrographis. (9)

An open study in Thailand compared parameters of urinary tract infection in patients undergoing shock wave dissolution of kidney stones (lithotripsy). The study found that 1 g of Andrographis was as effective as the antibiotics cotrimoxazole and norfioxacin in the reduction of pyuria and hematuria. (48)

Sixty-three patients with cardiac and cerebral vascular diseases were observed at 3 hours and/or one week after taking Andrographis extracts. Results showed that platelet aggregation induced by ADP was significantly inhibited (p<). The aggregation rate was lower at one week. In other volunteers taking Andrographis, serotonin release from platelets was decreased (p<), but plasma serotonin levels remained unchanged. A rise in platelet cyclic AMP levels might be the mechanism behind the antiplatelet activity of Andrographis. (49)

A majority of twenty patients with infective hepatitis showed marked improvement in symptoms after an average of 24 days' treatment with Andrographis decoction (equivalent to 40 g of herb per day). Significant decreases in various liver function tests was observed. Overall, 80% of cases were cured and 20% were relieved. (50)

Andrographis has been used as part of a protocol for treating late stage cancers which resulted in a significant increase in NK (natural killer cell) function. (51)

FNIMH = Fellow, National Institute of Medical Herbalists (UK)

FNHAA = Fellow, National Herbalists Association of Australia

Acknowledgment

The contribution of Michelle Morgan in the preparation of this article is gratefully acknowledged.

References

(1.) Melchior J, Palm S, Wikman G. Phytomed 1996/73(4): 315-318

(2.) Melchior J, Spasov AA, Ostrovskij OV et al. Phytomed 2000; 7(5): 341-350

(3.) Calabrese C, Berman SH, Babish JG et al. Phytother Res 2000; 14(5): 333-338

(4.) Panossian A, Kochikian A, Gabrielian E et al. 1999; 6(3): 157-161

(5.) A Panel of Vaidyas. Clinical Application of Ayurvedic Remedies. Indian Medical Science Series No. 3, 4th Edition. Delhi: Sri Satguru Publications, 1998: p 100

(6.) Kapoor LD. CRC Handbook of Ayurvedic Medicinal Plants. Boca Baton: CRC Press, 1990: p 39

(7.) Chopra RN, chopra IC, Handa KLet al. Chopra's indigenous Drugs of India, 2nd Edition Reprint. Calcutta: Academic Publishers, 1982: p 278

(8.) Bensky D, Gamble A. Chinese Herbal Medicine Materia Medica. Seattle: Eastland Press, 1986: p 136

(9.) Chang H, But P. Pharmacology and Applications of Chinese Materia Medica, Vol 2. Singapore: World Scientific, 1987: p 918-928

(10.) Tang W, Eisenbrand G. Chinese Drugs of Plant Orgin, Berlin: Springer Verlag, 1992: pp 97-103

(11.) Matsuda T, Kuroyanagi M, Sugiyama S et al. Chem Pharm Bull 1994; 42 (6): 1216-1225

(12.) Zhu PY, Liu GQ. Chin Trod Herb Drugs 1984; 16: 373-376

(13.) Leelarasamee A, Trakulsomboon S, Sittisomwong N. J Med Assoc Thai 1990; 73(6): 299-304

(14.) Gupta S, Chaudhry MA, Yadava JNS. Int J Crude Drug Res 1990;28(4): 273-283

(15.) Collins RA, NgTB, Fong WP et al. Life Sc 1997; 60(23): 345-301

(16.) Puri A, Saxena R, Saxena RP et al. J Nat Prod 1993; 56(7): 995-999

(17.) Martz W. Toxicon 1992; 30(10): 1131-1142

(18.) Visen PK, Shukla B, Patnaik GK et al. J Ethnopharmacol 1993; 40(2): 131-136

(19.) Choudhury BR, Poddar MK. Methods Find Exp Clin Pharmacol 1984; 6(9): 481-485

(20.) Kapil A, Koul IB. Hepatoprotective agents from Indian traditional plants. In: Pushpangadan P et al (ado). Glimpses of Indian Ethnophormacology (Proceedings of the First National Conference on Ethnopharmacology). Kerala, India: Tropical Botanic Garden and Research Institute, 1995: pp 283-297

(21.) Kapil A, Koul IB, Banerjee SKet al. Biechem Pharmacol 1993; 46(1): 182-185

(22.) Handa SS, Sharma A. Indian J Med Res 1990; 92: 276-283

(23.) Handa SS, Sharma A. Indian J Med Res 1990; 92: 284-292

(24.) Chaudhury BR, Poddar ME. Methods Find Exp Clin Pharmacol 1983; 5(10): 727-730

(25.) Chander R, Srivastava V, Tandon JS. Int J Pharmacog 1995; 33 (2): 135-138

(26.) Choudhury BR, Haque SJ, Poddar MK. Planta Med 1987; 53(2):135-140

(27.) Shukla B, Visen PKS, Patnaik GK et al: Planta Med 1992; 58(2): 146-149

(28.) Chaudhuri SK. Indian J Exp Biol 1978; 16: 830-832

(29.) Akbarsha MA, Manivannan B, Hamid KS et al. Indian J Exp Biol 1990; 28(5): 421-426

(30.) Akbarsha MA, Manivannan B. Indian J Comparative Animal Physiol 1993; 11(2): 103-108

(31.) Burgos RA, Caballero EE, Sanchez NS. J Ethnopharmacol 1997; 58(3): 219-224

(32.) Zoha MS, Hussain AH, Choudhury SA. Bangladesh Med Res Coune Bull 1989; 15(1): 34-37

(33.) Madav S, Tandan SK, Lal J. Fitoterapia 1996; 67(5); 452-458

(34.) Madav S, Tripathi HC, Tandan. Ind J Pharm Sci 1995; 57(3): 121-125

(35.) Borhanuddin M, Shamsuzzoha M, Hussain AH. Bangladesh Med Res Counc Bull 1994; 20(1): 24-26

(36.) Zhang XF, Tan BK. Clin Exp Pharmacol Physiol 2000; 27(5-6): 358-363

(37.) Choudhury BR, Poddar ME. Methods Find Exp Clin Pharmacol 1985; 7(12): 617-621

(38.) Zheng ZY, Wan YD, He GX. Chin Trod Herb Drugs 1982; 13: 417-420

(39.) Dutta A, Sukul NC. J Helminthol 1982; 56(2): 81-84

(40.) Pharmacology Department, Sichan, 1975, cited in Melchior J, Palm S, Wikman G. Phytomed 1996/7; 3(4): 315-318

(41.) Thamlikitkul V. Dechatiwongse T, Theerapong S et al. J Med Assoc Thai 1991; 74(10): 437-442

(42.) Hancke J, Burgos R, Careres D. Phytother Res 1995; 9: 559-562

(43.) Hancke J, Ibarra M. Article under publication, cited in Melchior J, Palm S, Wikman G. Phytomed 1996/7; 3(4): 315-318

(44.) Caceres DD, Hancke JL, Burgos RZ et al. Phytomed 1997; 4(2): 101-104

(45.) Melchior J, Palm S, Wikman G. Phytomed 1996/7; 3(4): 315-318

(46.) Caracas DD, Hancke JL, Burgos RA et al. Phytomed 1999; 6(4): 217-223

(47.) Thamlikitkul V, Dechatiwongse T, Theerapong S et al. J Med Assoc Thai 1991; 74(10): 437-442

(48.) Muangman V, Viseshsindh V, Ratana-Olarn K et al. J Med Assoc Thai 1995; 78(6): 310-313

(49.) Zhang YZ, Tang JZ, Zhang YJ. Chung-Kuo Chung Hsi I Chieh Ho Tao Chin 1994; 14(1): 28-30

(50.) Chturvedi GN, Tomar GS, Tiwari SK et al. Ancient Sri Life 1982; 2: 208-215

(51.) See D, Mason S. Roshan R. Immunol Invest 2002; 31(2): 137-163