INTRODUCTION

Andrographis is an erect, branched annual that prefers shady, moist locations. It grows to a height of one to three feet (30-90 cm) and produces small, pink or white flowers with brown or purple spots.^1,2 The flowers are followed by oblong seed capsules containing six to 12 yellow-brown, flat, ovoid seeds.^1,3 The entire herb has been used medicinally in India,^1,4 but the dried leaves or aerial parts — which are harvested in the fall when the flowers appear — are used more commonly.^5,6

Andrographis is native to the Indian subcontinent (India, Pakistan, and Bangladesh) and Sri Lanka, and it has been introduced to the islands of the Caribbean and West Indian Ocean, China (specifically Guangdong, Guangxi, Fujian, Yunnan, Sichuan, Jiangsu, and Jiangxi provinces), Indonesia, Laos, Malaysia, Myanmar, Thailand, Vietnam, and Mesoamerica.^7,8 Its natural habitat in India comprises five of India’s 15 specified agro-climatic zones including the “Middle Gangetic Plains Region” in the states of Bihar and Uttar Pradesh; the “Upper Gangetic Plains Region” in the states of Uttar Pradesh and Delhi; the “Eastern Plateau and Hill Region” in the states of Bihar, Orissa, and Madhya Pradesh; the “Central Plateau and Hill Region” in the states of Madhya Pradesh, Uttar Pradesh, and Rajasthan; and the “East Coast Plains and Hill Region” in the states of Orissa, Andhra Pradesh, and Tamil Nadu.⁹ Commercial plant material is obtained mainly from wild collection, but it also is sourced from new cultivation projects in India.¹⁰

HISTORY AND CULTURAL SIGNIFICANCE

Other common names for andrographis include king of bitters, kalmegh (Bengali, Hindi, Unani), kirta or kirata (Sanskrit),⁵ kiryata (Hindi), creat, green chiretta, Indian chiretta,¹¹ and hinbinkohomba (Sinhalese).³ It has been called chirayta or chirayita desi (“southern chirata”) because it is used in India as a substitute for the bitter herb Swertia chirayita (Gentianaceae).^2,5 Common names used specifically in the Indian Ayurvedic medicine tradition also include bhunimba and mahatikta (Sanskrit).^1,11 In traditional Chinese medicine (TCM), andrographis is known as chuan xin lian (“thread-the-heart lotus”), chuan-hsin-lien, or i-chien-hsi.^5,6,11,12 In Japanese it is known as senshinren,⁵ and, in Korean, ch’onsimyon.⁶

Andrographis has been used traditionally as an antiplatelet, antipyretic (fever reducer), anti-inflammatory, a bitter tonic (herb that strengthens and tones specific organs or the entire body), choleretic (bile stimulator), hepatoprotective agent, immunostimulant, and, possibly, as an adaptogen.^5,13 In addition, it is believed to protect against free radical damage and help normalize blood sugar.⁵

Traditionally, the plant has been used to treat a wide range of conditions, including atonic dyspepsia (indigestion with impaired stomach muscle tone), bowel conditions in children, diabetes, diarrhea, dysentery, flatulence, gastroenteritis, general debility, loss of appetite, poor liver function (including toxic liver damage and liver infections), to aid recuperation from fever, and for respiratory and skin conditions.^5,13

In TCM, andrographis, or chuan xin lian, is said to have bitter, cold properties and is believed to clear heat and eliminate toxins, dry dampness, stop diarrhea, and enter the lungs, stomach, bladder, and channels of the large and small intestines.^5,12,14,15 The plant is thought to have antibacterial, antiviral,¹² abortifacient, antipyretic, anti-inflammatory, antivenom, antihypotensive, immunostimulant, hepatoprotective, and cholagogic properties.^13,16 It has been used in TCM for cold, influenza, sore throat, fever, headache, acute and chronic cough, colitis, snake bites, eczema, sores, carbuncles, acute enteritis, bronchitis, dysentery, infectious diseases, nephritis, pneumonia, purulent otitis media, pustular dermatitis, tonsillitis, and urethritis.^12,14,16 Curiously, one source claims that andrographis does not appear in any traditional Chinese herbal text.¹²

In Ayurveda, andrographis has been used for centuries for intermittent fevers and jaundice, and it is an ingredient in more than half of the multi-ingredient herb formulations used in India for treating liver conditions.¹ The leaves and roots have been used in Ayurvedic medicine as an adjunct treatment for cholera, diabetes, dysentery, enteritis, gastritis, malaria, pneumonia, pyelonephritis, and rabies.¹ The leaf juice has been utilized as an alterative (i.e., a plant that gradually restores body functions), a tonic, to relieve pain and stomach distress, to expel parasites, to promote bile flow, to reduce fever, and as an antiseptic, antispasmodic, and laxative.^1,3 As a traditional household remedy, the leaf juice is used for diarrhea, dysentery, dyspepsia, general debility, and loss of appetite.³

Andrographis is used as a substitute for chirata (Swertia spp., Gentianaceae) — which is scarce in the northern Himalayas — particularly in southern parts of India where andrographis is relatively abundant.¹⁷ Andrographis and chirata exhibit similar therapeutic actions (anti-inflammatory, hepatoprotective, antidiarrheal, antiviral, and antimalarial), and they share the name Kiriyattu in Malayalam and Kiratatikta (“black-colored with bitter taste”) in Sanskrit.¹⁷ Furthermore, adding to continued likelihood of acceptable substitution, chirata is considered to be critically endangered and possibly on the verge of extinction.¹⁸ Known as say-gha-gyi in the Burmese language, andrographis reportedly grows wild throughout Myanmar where an aqueous decoction or whole-plant powder is used in Myanmar traditional medicine for treating fevers, malaria, paresis, and paralysis, among other conditions.¹⁹

English-language Andrographis paniculata monographs have been published in the Hong Kong Chinese Materia Medica Standards (Volume 3, 2010),²⁰ Indian Pharmacopoeia (7th edition, 2014),²¹ Malaysian Herbal Monograph (Volume 1, 1999),²² Medicinal Plants of Myanmar (Volume 1, 2008),²³ Pharmacopoeia of the People’s Republic of China (PPRC, 2010),²⁴ Thai Herbal Pharmacopoeia (Volume 1, 1995),²⁵ and WHO Monographs on Selected Medicinal Plants (Volume 2, 2002),²⁶ as well as in the United States Pharmacopeia (USP 37).²⁷

CURRENT AUTHORIZED USES IN COSMETICS, FOODS, AND MEDICINES

In countries where the Ayurvedic system of medicine is recognized and practiced (e.g., India, Bangladesh, Bhutan, Malaysia, Nepal, and Sri Lanka), the dried leaves and tender shoots of kalmegh are used as a component of preparations indicated for treating a range of conditions including the following: burning sensation, chronic fever, malaria, intermittent fever, inflammation, cough, bronchitis, skin diseases, intestinal worms, dyspepsia, flatulence, colic, diarrhea, dysentery, and hemorrhoids.²

In China and other countries where TCM is recognized and practiced (e.g., Malaysia, Taiwan, and Singapore, as well as a few Western countries), andrographis herb is indicated for treating influenza with fever, sore throat, ulcers in the mouth or on the tongue, acute or chronic cough, colitis, dysentery, urinary infection with difficult or painful urination, carbuncles, sores, and venomous snake bites.²⁸

“Herba Andrographis” is classified as a medicinal ingredient in Canada where it is listed in Table 1 (General Medicinal Ingredients) of the Natural Health Product (NHP) Traditional Chinese Medicinal Ingredients monograph.²⁹ At the time of this writing, there were nearly 100 licensed NHPs containing A. paniculata as a medicinal ingredient.³⁰

In the United States, although andrographis herb is not classified as a generally recognized as safe and effective (GRASE) active ingredient for use in over-the-counter drug products, it is within the scope of practice of certain licensed healthcare practitioners — such as licensed acupuncturists (LAc) and naturopathic doctors (ND) — to dispense andrographis-containing preparations to their patients. For example, a popular and frequently dispensed TCM formulation for soothing severe sore throat with swollen glands is a traditional three-herb combination containing andrographis herb (50%), Mongolian dandelion (Taraxacum mongolicum, Asteraceae) whole plant (25%), and isatis (Isatis indigotica, Brassicaceae) root (25%).

Although andrographis is not classified as generally recognized as safe (GRAS) for use in food products in the United States, it is permitted as a component of dietary supplement products, which require FDA notification within 30 days of marketing if a “structure-function” claim is made and product manufacturing according to current Good Manufacturing Practices (cGMPs).³¹ The USP has developed dietary supplement quality standards monographs for “Andrographis” (dried stems and leaves), “Powdered Andrographis,” and “Powdered Andrographis Extract.” These USP monographs are acceptable for the verification of dietary supplement component specifications and quality control testing before use in a product.³²

The situation is different in the EU, where the Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency (EMA) began to develop a labeling standards monograph to be used by applicants for the labeling of andrographis “leaf” herbal medicinal products. In February 2011, the EMA requested submissions of scientific data to be used in the assessment of andrographis as part of the establishment of a community herbal monograph and/or community list entry.³³ However, following the assessment process, EMA announced in September 2013 that a community herbal monograph on A. paniculata leaf could not be established because certain basic requirements for the development of a monograph (e.g., whether for traditional use or well-established use) were not fulfilled. Importantly, although the EMA requested data on andrographis “leaf,” most of the information that the agency received and assessed concerned the primary material of commerce: aerial parts, including leaf and stem. The plant did not qualify as a Traditional Herbal Medicinal Product (THMP) — due to a lack of evidence of any single-component andrographis preparations with 15 years of medical use in the EU — or as a Well Established Use Herbal Medicinal Product (WEU-HMP), due to a lack of studies required for WEU-HMP marketing authorization.³⁴

According to the August 2014 EMA final assessment report, there are no known andrographis single-herb preparations with marketing authorizations granted in EU member states.³⁵ There is, however, an andrographis-containing combination product registered in Denmark, Kan Jang^® coated tablets (Swedish Herbal Institute; Vallberga, Sweden). Each tablet contains 33-35 mg andrographis herb dry extract with 5.7 mg dry extract of eleuthero (Eleutherococcus senticosus, Araliaceae) root. A Swedish product by the same name — Kan Jang coated tablets (Bringwell AB*; Stockholm, Sweden) — is registered as a THMP; however, it does not contain andrographis herb.

There is just one andrographis ingredient approved for use in cosmetic products by the European Commission Health and Consumers Directorate General: “Andrographis Paniculata Leaf Extract,” which is listed as an astringent and skin-conditioning substance.³⁶

MODERN RESEARCH

The main known chemical components of A. paniculata are diterpene lactones, collectively referred to as andrographolides, which include aglycones (e.g., andrographolide; shown to be responsible for much of the herb’s anti-inflammatory activity) and glucosides (e.g., neoandrographolide and andrographoside), diterpine dimers, and flavonoids, as well as xanthone in the roots.⁵

At least two studies have evaluated the efficacy of A. paniculata extract (HMPL-004, a 90/10 v/v ethanol/water leaf extract; Hutchison MediPharma Ltd.; Shanghai, China) in treating mild-to-moderate ulcerative colitis. The first, published in 2011, was an eight-week, randomized, double-blind, multicenter, parallel-group study wherein 120 patients in five locations were randomized and given either 1200 mg/day HMPL-004 or 4500 mg/day slow-release mesalazine (i.e., a conventional ulcerative colitis drug also known as mesalamine).³⁷ Colonoscopy scores at baseline were compared to those performed at the end of the eight-week study, and mucosal healing was compared. At week eight, 21% of patients in the HMPL-004 group were in remission compared to 16% in the mesalazine group. An additional 36% in each group were in partial remission, defined as a 50% reduction in symptoms. The overall efficacy — which included remission, partial remission, and/or improvement — was calculated as 76% for the HMPL-004 group and 82% for the mesalazine group. In this study, at this dose, HMPL-004 was determined to be similar to mesalazine in efficacy, and adverse events were rare and limited to allergic reactions (urticaria/hives).

The second study, in 2013, was a randomized, double-blind, placebo-controlled trial wherein patients with diagnosed ulcerative colitis (n=224), most of whom were failing first-line therapy with mesalazine, were randomized to receive either 1200 or 1800 mg daily HMPL-004 in three divided doses, or placebo for eight weeks.³⁸ At week eight, 45% of patients taking 1200 mg and 60% taking 1800 mg daily HMPL-004 experienced a clinical response, compared with 40% of those taking placebo. Additionally, at week eight, 34% of patients taking 1200 mg and 38% taking 1800 mg daily HMPL-004 were in clinical remission, compared to 25% taking placebo. Adverse events consisted mainly of a mild, reversible rash in 8% of participants. The authors stated that while treatment with HMPL-004 was more effective than placebo in mucosal healing of mild-to-moderate active ulcerative colitis in this short-term study, additional clinical trials are needed to evaluate the safety and efficacy of higher doses of HMPL-004 in both ulcerative colitis and other conditions such as Crohn’s disease.

An andrographis leaf extract has been evaluated for its role in the relief of rheumatoid arthritis (RA). A 2009 prospective, randomized, double-blind, placebo-controlled study investigated the efficacy of 30 mg Paractin^® (dried extract, 30% andrographolides; Farmindustria SA; Santiago, Chile) three times per day for 14 weeks.⁴⁶ Sixty women were randomized into two groups, one receiving Paractin, and the other receiving placebo. The Paractin group experienced a significant reduction in tender joints, number of swollen joints, and total grade of tender joints.

A number of clinical studies have investigated A. paniculata’s effectiveness, alone or in a combination product, in treating upper respiratory infections (URI), colds, and pharyngotonsillitis. At least one study has examined its efficacy in the prevention of colds, and one evaluated its usefulness in treating influenza.

In a 2010 double-blind, placebo-controlled clinical study, 223 patients were randomized to receive either 200 mg/day KalmCold™ (100 mg A. paniculata leaf extract standardized to 31.30% andrographolide content; M/s Natural Remedies Pvt. Ltd.; Bangalore, India) or placebo for five days.³⁹ KalmCold was found to be 52.7% more effective than placebo; the KalmCold group experienced significantly reduced symptoms — including cough, expectoration, nasal discharge, headache, fever, sore throat, malaise/fatigue, and sleep disturbance, but not earache — whereas the symptoms in the placebo group were either unchanged or worsened after the third day of the study period. Adverse effects were minor with no significant difference between groups.

The leading clinically tested andrographis-containing product is the andrographis/eleuthero fixed combination product, Kan Jang (Swedish Herbal Institute; Vallberga, Sweden; 85 mg A. paniculata extract, SHA-10, containing 5.25 mg andrographolide, deoxyandrographolide [with precisely 5 mg andrographolide], and 9.7 mg E. senticosus extract). It should be noted that results from Kan Jang studies do not reflect or correspond directly with the clinical efficacy of andrographis extract alone.

A 2004 three-arm study compared Kan Jang with an echinacea product (Immunal^® drops; Ljubljana, Slovenia; 80 ml Echinacea purpurea expressed juice from freshly collected flowering plants and 20 ml ethanol) for the treatment of uncomplicated upper respiratory disease in children.⁴⁰ Children aged four to 11 (n=133) with symptoms of headache, cough, rhinitis, sore throat, hoarseness, and fever for less than 24 hours were randomized to receive two tablets Kan Jang three times per day for 10 days (n=53), 10 drops Immunal three times per day for 10 days (n=41), or standard care including throat gargles, antiseptic nose drops, and acetaminophen at 500 mg three times daily as needed for headache and fever (n=39). All three groups improved by day two or three, but the Kan Jang group had an increased rate of recovery on the second and third examination, with virtually no symptoms by the third exam.

At least four additional studies between 1995 and 2002 evaluated 1200 mg daily Kan Jang for URI and found statistically significant results.^41-44 Two studies evaluated adults with URI symptoms of fewer than three days duration,^41,43 and another investigated the use of Kan Jang in adults with URI symptoms for fewer than two days.⁴² In yet another study, adult patients were started on Kan Jang treatment within 36 hours of symptom onset. In the last study, patients had symptoms for “several” days and suspected sinusitis.⁴⁴

Additionally, andrographis has been evaluated in at least two studies for its effectiveness in treating influenza.⁴⁵ In a pilot study from 1999, 540 patients were randomized to receive either Kan Jang (two tablets three times per day for three to five days) or conventional therapy (acetaminophen for fever and the antiviral agent amantadine). In the second study, 66 patients were randomized to receive the same dosage of Kan Jang as in the pilot study or conventional therapy. Kan Jang-treated subjects recovered from symptoms (headache, throat pain, cough, and rhinitis) faster than the control group, suffered fewer post-influenza complications, and were able to return to work sooner. The study authors also reported that Kan Jang’s effects were consistent in patients with different types of influenza.

In 2013, Omeros^® Corporation, a Seattle-based biopharmaceutical company, submitted a patent application to the United States Patent and Trademark Office for its invention claiming methods and compositions of A. paniculata for the treatment or prevention of addiction and impulse control disorders.⁴⁷

FUTURE OUTLOOK

Of the estimated 960 medicinal plant species that form the source of 1,289 botanical raw drugs in trade in India, A. paniculata is among the top 117 species, the annual domestic consumption of which exceeds 100 metric tons (MT).10 In 2008, ranking at number nine in terms of volume, Indian domestic consumption of andrographis was estimated at 3,279 MT, of which about 51% was consumed by large herbal manufacturing units and the rest by small or very small companies.

While much of the commercial supply is wild collected, the Indian government’s National Medicinal Plants Board (NMPB) has included andrographis in its “State wise list of plants recommended for cultivation and development,” and farmers who cultivate it through the NMPB scheme are eligible for a 20% subsidy.2 NMPB has included a chapter on agronomic practices for andrographis in the second volume of its publication Agro-techniques of Selected Medicinal Plants. The information provided is based on an agro-technique study carried out by the Centre for Advanced Studies in Botany at the University of Madras in Chennai. According to NMPB, andrographis can be grown easily through seed and vegetative methods, although for commercial cultivation, propagation through seed is more economical. The crop is grown during the cooler season and remains in the field for 120 days. Cultivation in a cooler climate helps the plant produce a higher level of bitter principles that are associated with efficacy.

Following NMPB guidelines, whole-plant yield should be 2.5 tons (dry weight) per hectare and should provide a reasonable profit to growers. The farmer’s cost of cultivation per hectare is estimated to be 25,000 Indian rupees (Rs), or about $400. A 2014 news report indicated a market price paid to Indian farmers of 60 Rs/kg,⁴⁸ while the Indian Council of Agricultural Research (ICAR) reported summer 2014 farmgate prices of 15 Rs/kg for fresh leaf and 40 Rs/kg for dried leaf.⁴⁹

Similarly, in China, current market prices for dried andrographis herb produced in the Guangxi Zhuang Autonomous Region range from 4.5 Chinese yuan (CNY)/kg ($0.73/kg) at the Chengdu TCM Market in the Sichuan province to 6 CNY/kg at the Anguo TCM Market in the Hebei province.⁵⁰

According to a November 2014 market research survey of 27 Chinese businesses trading in andrographis herb, 26% reported that the current market for andrographis was better than had been expected, 55% worse than expected, and 19% just as expected. Regarding market outlook, none of the companies expected upward price movement, 26% expected downward price movement, and 74% of companies predicted no change

Production, price, and availability of andrographis herb appear stable in the countries where it is most widely used such as in China and India, where traditional herbal medicines are a big part of the national healthcare systems. India’s 20% subsidies to farmers willing to cultivate andrographis may indicate an increasing demand for the herb or a transition from reliance on wild collection. Outside of India, andrographis-based medicinal products are licensed, listed, or registered in several member states of the Commonwealth of Nations, including Australia, Canada, Malaysia, and Sri Lanka.

Market access to medicinal andrographis preparations in the European Union and United States remains complicated due to its lack of recognition as a safe and effective active ingredient. Thus, while the prospect of gaining marketing authorization for the sale of andrographis medicinal products in the EU and US is very low at the present time, there is still a way into these markets through the health practitioner market and authorized clinics, dispensaries, or pharmacies where patients can obtain TCM prescriptions. In the United States, it can be possible to label and market andrographis as a dietary supplement product without making reference to its traditional uses in the Chinese or Indian systems of medicine, which are, for the most part, disease treatment indications.

—Gayle Engels and Josef Brinckmann

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