Kaalameghaa (Andrographis paniculata)

Kaalameghaa (Andrographis paniculata)

Introduction

Kaalamegha or Kalmegh (Andrographis paniculata), an herbaceous annual is a much esteemed medicinal plant in Ayurveda. It was used for centuries in place of or as an alternative to antibiotics before hardcore antibiotics were evolved. It has been used primarily to treat cold, PUO and liver diseases as well as for its bitter   tonic properties. It is one of the prominent ingredients in 28 different polyherbal patent formulations in vogue in the Ayurvedic system of medicine. 

It has been used in China, Thailand, South East Asia and other Asian countries. In 1992 Kaalamegha (Andrographis paniculata) was officially listed in the Pharmacopoeia of the Peoples Republic of China as a “Cold Property” herb, used to rid the body of heat as in fevers and to dispel toxins from the body. 

Ayurvedic and Traditional Chinese Medicine (TCM) doctors have been using Kaalamegha to treat various diseases for over 1000 years. [1]

In Scandinavian countries, it is commonly used as a prophylactic and therapeutic agent for common cold. Kan Jang is an immunostimulant preparation containing Kaalamegha (Andrographis paniculata) and Eleutherococcus (Siberian Ginseng) used in Scandinavian countries for 20 years. 

Traditionally, in Malaysia, Hempedu Bumi (Andrographis paniculata) is used to treat skin eruptions and scabies. It has a host of other medicinal uses as well.  

Kaalamegha is also popular in the East Indies, West Indies and Mauritius.Various proprietary preparations of Kaalamegha are manufactured and marketed in the US.

Kaalamegha, quite a name to live up to, for, literally it means “black cloud” or “dark cloud” perhaps attesting to its harvest time just before winter or flowering time from September to December. The plant is known in north-eastern India as Mahaa-tikta which literally means "king of bitters". Its another epithet is ‘Bhoo-Nimba’ or ‘Bhui-Neem’ where bhoo stands for earth or ground and nimb or neem refers to Neem tree (Azadirachta indica) . The term therefore means ‘Neem of the earth’ or ‘Neem of the ground’ referring to its neem like bitter taste and effects.

In Malaysia, it is known as Hempedu Bumi, which literally means 'bile of earth' referring to the fact that it is one of the most bitter medicinal plants. In fact it is nicknamed ‘King of Bitters’. [2], [3]  

Research conducted in the '80's and '90's has confirmed that Kaalamegha (Andrographis paniculata), properly administered, has a surprisingly wide range of pharmacological effects. Kaalamegha (Andrographis paniculata) is introduced from the countries in Southeast Asia and cultivated in the southern part of China.

In studies conducted earlier in China and Taiwan and in recent studies, it was demonstrated that Kaalamegha (Andrographis paniculata) can indeed reduce the severity of symptoms associated with cold and flu. In some controlled studies on Kaalamegha (Andrographis paniculata) it was found that in 83% of patients with cold, body ache and fever, the body temperature returned to normal in 48 hours, compared to the patients in control group and those treated with placebo. [4]

From January 1918 to December 1919 there was an influenza pandemic involving H1N1 influenza virus. It infected 500 million people across the world and killed 50 to 100 million of them.  

It is said, in India Kaalamegha (Andrographis paniculata) was used to treat influenza patients which saved many patients from death. In India, the death toll was 17 million. Thanks to Kaalamegha (Andrographis paniculata) [5], [6], [7]   

Other Names

Botanical: Andrographis paniculata Nees

Sanskrit: Kaalamegha (Kalmegh), Bhoonimba

English: Green chirayata, Creat, King of bitters, Andrographis, India echinacea

Assamese: Chirota

Bengali: Kalmegh

Gujarati: Leelukariyaatu, Kirayat, Kariyatu

Hindi:  Kaalamegha, Kiraayat

Kannada: Nelabevu

Marathi: Kadu, Kiraayata, Kadu Kiraayata, Oli-kiryata

Malayalam: Nilaveppu, Kiriyatta

Oriya: Bhuinimba

Punjabi:  Chooraita

Tamil: Nilavempui

Telugu: Nela Vemu

AKA Chuan Xin Lian  [8], [9] 

Taxonomic classification 

Kingdom:  Plantae

Unranked: Angiosperms

Unranked: Eudicots

Unranked: Asterids

Order:        Lamiales, Tubiflorae

Division:     Angiospermae

Class:         Dcotilydonae

Family:      Acanthaceae      [10] 

The total number of species in the genus Andrographis varies in different reports; however accepted number of species as of today is 28.They are mainly distributed in tropical Asia. Of these species very few are of medicinal value; Andrographis paniculata Nees being the most useful and popular too. 

For long, there was dispute among herbalists and taxonomists as well regarding the identity of Kaalamegha and Kiratatikta. Both the plants are often called by a common name ‘Bhoonimba’. The taxonomists have however resolved the issue by identifying the former as Andrographis paniculata Nees and the latter as Swertia chirata.  [11], [12], [13] 

Geographical Distribution 

The plant is widely distributed in tropical Asian countries, often in isolated patches. Native population is spread throughout south India and Sri Lanka which probably represents the center of origin and diversity of the species. It also occurs in Hong Kong, Thailand, Brunei, Singapore and other parts of Asia. However it may or may not be native to them. It is introduced  in Java, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Thailand, Vietnam, West Indies, Christmas Island and elsewhere in the America.   

It can be found in a variety of habitats, such as plains, hillsides, coastlines, and disturbed and cultivated areas such as roadsides, farms, and wastelands. As it grows in soil types where almost no other plant can be cultivated, particularly “serpentine soil” (soil containing a rock formed by hydration and metamorphic transformation of a rock with low silica and rich minerals) it is cultivated for its medicinal properties.

It is now cultivated on wide range of soils from loam to lateritic soils (soil types rich in iron and aluminium) with moderate fertility as well. It is indigenous to India.  It grows throughout India in moist and shaded places; throughout the hotter and tropical parts from Uttar Pradesh (UP), Madhya Pradesh (MP), Bihar, Andhra Pradesh, Gujarat, Rajasthan, Tamilnadu, Kerala, Punjab, Haryana etc. It is cultivated as an annual herb to some extent in Assam and Bengal.  [14], [15]

Plant Morphology

                                            

                                                 Kaalamegha (Andrographis paniculata) Plant

                   

          

                             Kaalamegha (Andrographis paniculata) Stem

                                                        

                              

                                          Kaalamegha (Andrographis paniculata) Leaf

                                                       

                     

                                       Kaalamegha (Andrographis paniculata) Flower

                         

                      Kaalamegha (Andrographis paniculata) Fruit (Pods)

                                                                                                               

                                                    

                                     Kaalamegha (Andrographis paniculata) Seeds 

Macroscopic 

Plant  Andrographis paniculata is an annual, branched erect plant growing to a height of 30-110 cm. 

Stem is erect, 0.3- 1.0 m in height, 2- 6 mm in diameter, slender, dark green, quadrangular in cross-section with longitudinal furrows and wings along the angles of the younger parts, multi-branched branches,  slightly enlarged, knob point at the nodes, easily broken 

Leaves are up to 8.0 cm long and 2.5 cm broad, opposite, lanceolate or elliptical, pinnate; both surfaces green, dark green above, gray-green below, glabrous (smooth, hairless) blades, apex accuminate, base cuneate, margine shallow undulate, venation of leaf is unicostate, reticulate and mid-rib is centrally grooved.

Flowers are 7.5-10 cm in length, small, white in color with rose-purple spots on the petals; axillary and terminal racemes or panicles, bracts and bracteoles small, lanceolate, calyx 5-parted, outside covered with glandular hairs; corolla purplish white, two-lipped, upper lip and outside bracteoles small, lanceolate; corolla tube length same as lip; two stamens outstretched, anther two, one small, another large; base covered with beard filaments, hairy; calyx covered with glandular hairs      

Fruit is a linear-oblong capsule acute at both ends, 1.9 cm x 0.3 cm slightly glandular.

Seeds are numerous, sub quadrate, yellowish brown or red in color extremely bitter in taste. [18]

Microscopic structure 

Root- Conspicuous cork is composed of 8–10 layers. Outer 2–3 layers are thick walled cells filled with reddish-brown content, followed by 6–7 layers of thin walled square or rectangular cells, a narrow band of parenchyma interior to the cork has numerous sclereids aligned in more or less a ring and pit apertures about 2.17 µm in diameter. Wood is very prominent and occupies the major portion of the root. Wood consists of a large number of vessels. Vessels are mostly solitary and small sized, majority of them are arranged in radial rows. The vessel groupings of radial multiples of four or more are quite common. Vessels groupings in radial multiples of two and three were also occasionally found. Vessels are circular, elliptical or polygonal in shape. The Diameter of vessel lumen ranges from 12.61 µm to 39.6 µm. Mean number of vessels per square millimeter of the wood was found to be 417.4 (ranges 389.8 to 425.4) Tylosis are occasionally found. The bulk of the wood is constituted by fibers (Figure 7f). Medullary rays are very conspicuous and many in number. Medullary rays are mostly uniseriate and biseriate Cells of the xylem vessels contain prismatic crystals of calcium oxalate 

Stem- T.S. of the stem possesses a quadrangular outline with dense collenchyma strands at the four angles of the stem. Epidermis is composed of single layer of rectangular cells. There is a group of 2–3 layered collenchymous cell zone with secretary cavities having white colored deposition are present under the epidermis. Cortex forms a narrow zone, composed of 5–6 layers of parenchyma cells with chloroplast. Solitary sclereids and a group of sclereids of 4–6 are present in the cortex followed by a layer of thick-walled endodermis and parenchyma contains chloroplastid. Solitary sclereids are present in secondary phloem tissues. Xylem is very prominent and occupies the major portion of the stem.  Vessels are mostly solitary and small sized, majority of them are arranged in radial rows. Vessels are circular or polygonal in shape. The Diameter of vessel lumen ranges from 18.3 µm to 35.8 µm. Mean number of vessels per square millimeter of the xylem was found to be 393.8 (ranges 419.8 to 345.4). Wood with spiral, reticulate and pitted xylem vessels were revealed. The vessels with bordered pits and intervessel pitting were of alternate position were observed. The bulk of the xylem is constituted by fibers. Medullary rays are very conspicuous and many in number. Rays are mostly unistriate biseriate rays are also found occasionally. Centrally placed pith with large parenchymatous cells and cells are polygonal in shape. Some of the pith cells contain crystals crystals of calcium oxalate linear-oblong capsule acute at both ends, 1.9 cm x 0.3 cm slightly glandular.

Leaves-The leaf is microphyll, which consists of an average length of 5.3 cm and width of 1.2 cm. Leaf is dorsiventrally differentiated. The shape of the T.S. of midrib is characteristic, which projects strongly at two corners on the lower side with a prominent ridge having shallow groove in the middle on the adaxial side. Lamina is flat and much reduced in dimension. Midrib consists of epidemics, collenchyma, mesophyll and vascular tissues. Collenchymatous hypodermis comprises 7–8 layers. A chlorenchyma zone consists of 2–3 layers are located beneath the hypodermis, which is followed by parenchymatous ground tissues. The midrib possesses an arc of xylem lies in the middle of the ground tissue. Xylem vessels (30–35 µm in diameter) arranged in radial rows of 5–6 and phloem lies on abaxal side. Both the epidermis of the lamina is uniseriate, composed of compactly arranged rectangular cells with cuticle in the outer walls. Cells of the upper epidermis are larger in size than the lower surface. The mesophyll is divided into upper palisade and lower spongy tissues. A single layer of columnar palisade, cells are filled of plenty of chloroplasts. The palisade ratio was found to be about 2. Spongy parenchyma cells are 3 layered, cells of the spongy mesophyll are loosely arranged with wide intercellular spaces. 

Epidermal Characters- Surface features of both upper and lower epidermis revealed many fairly large cystoliths measuring an average length of 38.9 µm and width 16.5 µm (ranges 31.6–46.6 µm in length × 13.9–19.2 µm

in width). The adaxial epidermis is devoid of stomata, the abaxial (lower) epidermis shows diacytic stomata. The mean length and breadth of stoma was observed as16.9 µm × 8.2 µm and Guard cell area (GCA) was found to be 107.3 µm2 . Mean density of abaxial (lower) stomata per square millimeter area of leaf was found to be 172.1. Epidermal cells were wavy in nature. The number of abaxial epidermal cells per square millimeter area of the leaf was observed as 1110.9 and stomatal index for the lower surface was found to be 13.4. 

Petiole- In cross sectional view, the petiole has a characteristic structure with shallow adaxial grooves. A chlorenchyma zone consisting of 2–3 layers are located beneath the epidermis, which is followed by parenchymatous ground tissues. The 15–16 vascular bundles are arranged in crescent shape, lies in the middle of the ground tissue. Each vascular strand is separated from one another by wide areas of ground tissues. Xylem vessels are aligned in radial rows of 5–6 and phloem lies on abaxal side. Some of adaxial epidermal cells of the petiole are provided with non-glandular trichomes. Trichomes are uniseriate and 3-celled.

Venation Pattern- Leaf architectural characters could provide useful anatomical information for characterization of the taxon. Venation patterns of cleared leaves were studied and terminologyused for description of architecture is as per Hickey. Petiolate simple leaves with entire margins had observed eucamptodromous pinnate venation under low (× 2) magnification. Areolation was poorly developed. Areoles are small, area of areoles ranges from 0.96 to 1.07 mm and areoles are polygonal in shape. Within the areoles terminal vein-endings was absent. Marginal ultimate veins were looped. The minor venation pattern viz. mean number of vein islet number/mm2 of leaf was found to be 0.756. Veinlets termination number/mm2 were found 0.864 and average size of areoles was observed as 1.02 mm. The number of areoles/mm2 was found to be 0.324 when critically analyzed microscopically. [19] 

Parts Used 

Mostly the leaves and roots are used but sometimes the stem and whole plant is used.     

Phytochemistry 

The herb owes its medicinal properties and actions to the chemicals it contains. They are diterpene lactones. Of many diterpene lactones, Andrographolide was isolated first. Later, neoAndrographolide, deoxy-didehydroAndrographolide, deoxy-oxoAndrographolide and deoxyAndrographolide, were isolated. They are isolated from the whole plant and leaves. Of these Andrographolide is referred to as a 'bitter' principle. It was isolated in pure form by Gorter (1911). Modern chemists too call Andrographis paniculata as the 'King of Bitters'. 

Chemical constituents isolated in recent times are: Andrographolides, kalameghin, andrographin, andrographidine A, B, C, D, E & F, andrographoside, neoAndrographolide, paniculides etc. 

Chemical constituents isolated from the roots are: andrographin, panicolin, apigenin 4, 7 dimethyl ether; new flavone glucosides B, C, D, E, and F. 

In experimental studies when callus cultures of the plant (cultures of the plant tissues for plant regeneration) were investigated Andrographolide and the other diterpenes were not produced. Instead, the sesquiterpenes paniculides A-C were found. Other constituents found were various flavones. [20], [21], [22] 

                  Chemical constituents in various parts of the plant: 

Tissue Culture	5-Hydroxy-7,8, 2’-Trimethoxyflavone
Whole plant	Andrographolide, NeoAndrographolide, Paniculide-A, B, C,14- Deoxy-11-dehydroAndrographolide, 14- Deoxy-11-oxoandroAndrographolide, 5-Hydroxy-7.8,2’,3’ Tetramethoxyflavone
Leaves	A bicyclic diterpenoid lactone, flavones: oroxylin and wogonin
Stem	Glycosides, flavonoids, gums, phytosteroids, terpenoids, tannins, saponins and phenolic compounds
Root	Andrographine, panicoline, flavonones, andrographidines A-F, Α-sitosterol
Arial parts	Four lactones: Chuaxinlian A (deoxyAndrographolide), B (Andrographolide), C (neoAndrographolide), D (14-deoxy-11, 12-didehydroAndrographolide)

                                                                                                                   [23]   

Identity, Purity and Strength

Foreign organic matter: Not more than 2 percent

Total ash: Not more than 20 percent

Acid-insoluble ash: Not more than 5.1 percent

Alcohol-soluble extractive: Not less than 24 percent

Water-soluble extractive: Not less than 20 percent.  [24] 

Tests accepted recently---- 

Kaalmegha contains: Not less than 1.0 per cent of Andrographolide, calculated on the dried basis.

Description: Taste, intensely bitter 

Foreign organic matter: Not more than 2.0 per cent

Ethanol-soluble extractive: Not less than 3.0 per cent

Water-soluble extractive:   Not less than 12.0 per cent

Total Ash: Not more than 15 per cent

Acid-insoluble ash: Not more than 3.0 per cent

Heavy metals: 1.0 g complies with the limit test for heavy metals

Loss on drying Not more than 12.0 per cent, determined on 5 g by drying in an oven at 105⁰ C

Microbial contamination complies with the microbial contamination tests.

Assay-- Determine by liquid chromatography [25] 

Chromatographic Identity

By using high performance liquid chromatography coupled with diode array detector (HPLC-DAD) technique researchers, standardized qualitatively and quantitatively phytochemicals found in Kaalamegha (Andrographis panaculata) [26], [27]

The Determination of "Bitterness" Value

Many phytochemicals found in plants have bitter taste. These phytochemicals  are called “bitters”. They are valued medicines. They stimulate appetite by increasing secretion of gastric juice. The bitterness is subjective. Hence it is necessary to determine bitterness of drugs by comparing it to some standard, threshold bitter compound. The standard, threshold bitter is quinine hydrochloride. Thus,

One unit of bitterness = bitterness of a solution containing 1gram of quinine hydrochloride in 2000 mL of water.

The chief bittet principle in Kaalamegha (Andrographis paniculata) is Andrographolide. Without entering into complicated calculations it can be said, the bitterness of Andrographolide is about 112x103 units/g or 56% w/w of the bitterness of quinine.

Thus the epithet “Mahaa-Tikta”, “King of bitters” behooves to the plant. [28], [29]

Chromosomal Identity

25 chromosomes in Andrographis paniculata [30], [31]

Genetic Identification 

Recently by using simple sequence repeats (SSR), amplified fragment length polymorphism (AFLP) and random amplified polymorphic DNA (RAPD) marker system the genetic identity of Kaalamegha (Andrographis paniculata) has been established. [32]

Properties and Pharmacology

Ayurvedic Properties

Ganas (Classical Categories) 

Charak Ganas: None

Sushruta Ganas: None

Energetics

Rasa (Taste): Tikta (Bitter)

Weerya/ Virya: (Energy State): Ushna (Hot)

Wipaaka (End result, Post Digestive Effect): Katu (Acrid, Pungent, Piquant)

Prabhaawa(Special Effect, Prominant Effect): None 

Gunas (Qualities): Laghu (Light), Rooksha (Dry), Teekshna (Penetrating)

Effects on Doshas: Pitta-hara, Kapha-hara

Actions on Dhatus (Tissues): Rasa (Lymph), Rakta (Blood)

Actions on Srotas (Systems): Rasawaha (Lymphatic system), Raktawaha (Hemopoetic System)

Ayuevedic Actions

Daahaprashamana – Respites, allays burning sensation

Deepana - Aappetizer

Jwarghna - Anti pyretic

Kaasahara - Antitussive

Krimighna – Anthelmintic, Antimicrobial

Kushthaghna -Antileprotic

Lekhana – Reduces weight, reduces fat

Paachana –Digestive (Digestant)

Pittashaamak: Passifies pitta (Anti-histaminic)

Raktapitta - Gout

Raktashodaka - Purifies blood

Shothahara – Respites swelling, (Anti-inflammatory), Relieves edema

Trishaghna – Quenches thirst

Udara hara – Allays ascites

Yakriduttejaka –Stimulates the functions of the liver 

Kaalamegha improves the texture of the skin

It is diaphoretic

It is immunomodulator

It is laxative and anthelmintic [33]

Modern View

Bitter in taste, pungent in the post digestive effect and has hot potency. It is appetizer, digestive, febrifuge, alterative and anthelmintic. It alleviates cold, respiratory catarrh. Bitter herbs generally have an affinity for the heart, liver and gall bladder. Many have cooling effect on the body as they act as antipyretic. 

Research conducted in ‘80’s and ‘90’s on Kaalamegha (Andrographis paniculata) has confirmed that the plant has a broad range of pharmacological effects. They are: 

Bitter-Acrid: Bitter, pungent in taste

Rubefacient: Produces redness locally when applied to the skin    

Anti-inflammatory: Reduces redness and swelling caused by an irritant

Immunomodulator: Enhances immunity to fight diseases (increases white blood cell count, T lymphocyte count and improves CD4 count)

Analgesic: Relieves pain

Antiperiodic: Counteracts periodically repeating illnesses such as malaria.

Antipyretic: Reduces fever

Antibacterial: Counteracts bacterial activities to relieve infections

Antiviral: Inhibits viral activity to relieve viral infections

Anthelmintic: Kills intestinal worms

Antithrombotic: Prevents clotting of blood in the blood vessels

Thrombolytic: Bursts blood clot

Analgesic: Relieves pain

Sedative: Calms nervous system

Antitussive: Relieves cough

Expectorant: Promotes mucus discharge and bringing out phlegm from respiratory system

Cardioprotective: Protects heart muscle

Digestive: Promotes digestion

Laxative: Aids evacuation of the bowel

Detoxicant: Neutralises toxins

Hepatoprotective: Protects liver from toxins

Choleretic: Promotes bile flow

Hypolipidemic: Lowers lipids

Hypoglycemic: Lowers raised blood sugar 

Abortifacient: Induces abortion

Anti-tumor/ Anti-cancer: Fights against tumors and cancers [34]

Andrographolide

Molecular formula: C₂₀H₃₀O₅                       

Structural formula:

                                      [35]

Andrographolide is a bitter water-soluble lactone. It is the chief constituent extracted from the leaves of A. paniculata. This was isolated in pure form by Gorter in 1911.

Phorbol

Molecular formula: C₂₀H₂₈O₆

Structural formula:

                       

Phorbol is a natural, organic compound derived from plants. It was first derived and isolated from the seeds of Croton tiglium in 1934. Various esters of phorbol have important biological properties. The phorbol esters are amphiphilic; i. e. they possess both hydrophilic and lipophilic properties. They have tendency to bind to phospholipid membrane receptors. Usually they are the primary targets for the phorbol esters. Their effects on the membrane include modification in activities of cell receptors, enhanced intake of 2-deoxyglucose and other nutrients, altered cell adhesion, induction of arachidonic acid release and prostaglandin synthesis, inhibition of binding of epidermal growth factor to cell surface receptors, and altered lipid metabolism. It has been proposed that the phorbol esters cause irreversible damage to the cell membrane.

Andrographolide antagonizes these activities of the phorbol esters. It prevents the formation of phorbol ester-induced reactive oxygen species. It thus acts as free radical scavenger and anti-inflammatory molecule and immune modulating and anti-tumor agent as well. The benevolent effects and the mechanism of action of Andrographolide are described in detail below in respective sections. 

In fact all pharmacological actions of Kaalamegha (Andrographis paniculata) are due to  Andrographolide. (for details see below)                                                                                                       

To summarize, Andrographolide is antiinflammatory, immunomodulator, antimicrobial, antiallergic, hepatoprotectant and cytotoxic to tumor cells. 

However a group of researchers has raised the need for caution because Andrographolide-enhanced Stromal Cell-Derived Factor-1 (SDF-1)-chemokine activity might induce tumor cell metastasis. Also, A. paniculata extract has induced cell differentiation in mouse myeloid leukemia cells, a point to ponder. [36] 

Mechanisms of Action of Kaalamegha (Andrographis paniculata): 

All the body cells have receptors on the cell membrane. Various chemicals such as neurotransmitters, growth factors, hormones and many other molecules bind to these receptors. Once a molecule binds to the receptor a chemical message is transmitted to the targets in the cell. The message will eventually reach the genetic material stored in DNA. The DNA is activated. The cell then reacts or responds accordingly. The receptor, its cellular target and intermediary molecules are referred to as a “Signal transduction pathway”. Diseases develop when the signals in this pathway are disturbed. Interestingly corrections in the disturbances can ‘cure’ diseases. In the case of cancer these changes cause abnormal cell division. Genetic engineers can detect 

these changes much early before the disease can manifest. Hence prevention and treatment of diseases especially cancers has become easy. [37]   

Using signal transduction technology it was found that Kaalamegha (Andrographis paniculats) binds to the receptors, prevents the changes occurring in the cell due to the binding of disease inducing molecules, stabilizes the milieu interne of the cell. Andrographolides found in the plant enhance the function of immune system such as production of large number of white blood cells, release of interferon and increase the activity of lymph system. Interferon is a potent anti-viral and anti-proliferative agent. The lymph carries away the by-products of cellular metabolism, carries invading bacteria and viruses to lymph nodes where the white blood cells destroy them. Thus Kaalamegha (Andrographis paniculata) is an immune system enhancer par excellence.   Kaalamegha (Andrographis paniculata) becomes even more effective when combined with zinc and vitamin C. [38]

14-DeoxyAndrographolide

Molecular formula:  C₂₀H₂₈O₄    

Structural formula:

    [39] 

In laboratory experiments on rats, 14-deoxyAndrographolide inhibited contractions of isolated thoracic aorta induced by phenylephrine and high K+ (80 mmol/L) in the concentration-dependant manner in endothelium-intact aorta. Like verapamil, it is a great vasorelaxant. It antagonizes Ca++ induced vasocontractions in the concentration dependant manner. It suppresses contractions induced by caffeine (10 mmol/L) and nor adrenaline (1 micromol/L). The vasorelaxant activity of 14-deoxyAndrographolide is mediated through activation of NOS (Nitric Oxide System) and guanylate cyclase, as well as the blockade of Ca++ channels. [40]

Two medicinally important diterpenoids isolated from A. paniculata are 14-deoxyAndrographolide and 14-deoxy-11, 12-didehydroAndrographolide. stimulate Nitric Oxide (NO) release from cultured human endothelial cells. Of the two, DDA (14-deoxy-11, 12-didehydroAndrographolide) caused greater production of NO than DA (14-deoxyAndrographolide). Needless to say then, this NO production is responsible for vasodilator and hypotensive effects of the plant. [41]

The data collected from laboratory experiments on rat-uterus suggests that 14-DAP (14-deoxyAndrographolide) blocks the calcium channels to induce the smooth muscle relaxation of the uterus. [42]

DA (14-deoxyAndrographolide) desensitizes the liver cells to TNF alpha induced apoptosis. [43]

Probably by virtue of Ca++ channel blocking property, 14-DAP (14-deoxyAndrographolide) exhibits a potent PAF antagonistic activity. [44]

NeoAndrographolide

Molecular formula: C₂₆H₄₀O₈

Structural formula:

         [45]

It is a non-bitter constituent. Andrographolide and neoAndrographolide exhibit a significant dose dependent choleretic effect in rats and guinea pigs. Following administration of these compounds, the flow of bile rich in bile salts and bile acids increased significantly. Pre treatment with Andrographolide and neoAndrographolide prevented Paracetamol induced reduction in bile flow. This effect was more potent than Silymarin a known hepatoprotective agent. [46]

Andrographolide, andrographiside and neoAndrographolide when administered intraperitoneally at 100mg/kg to mice, they not only prevented the liver damage but also protected the liver from CCl₄ and terbutyl hydroperoxide insult. Andrographolide and neoAndrographolide exhibit activity against lipid peroxidation. [47]

NeoAndrographolide though a non-bitter compound; exhibits many other pharmacological actions which are similar to the bitter compounds mentioned above.

Paniculides

Paniculide-A

Molecular formula:  C₁₅H₂₀O₄               

Structural formula:

         

Paniculide-B 

Molecular formula: C₁₅H₂₀O₅

Structural formula:

  

[49]

Kalameghin 

Paniculides and Kalameghin are synergistic to other active compounds contained in the plant.

Andrographin

Molecular formula: C₁₈H₁₆O₆

Structural formula:

        [51]

Andrographin is anti-inflammatory, immunostimulant, antibacterial, stomachic, cholagogue and hepatoprotective. It is principally used for typhoid and jaundice.  [52]

Some testimonials from modern research:

General Pharmacology 

When administered Andrographolide is widely distributed in the body. Its concentrations in various organs are very high. Its half life is very short, about two hours, hence the need for frequent administration of the drug. Andrographolides are excreted via gastrointestinal tract and urine. 

The wide tissue distribution and the immune-stimulating actions of Kaalamegh (Andrographis paniculata) for prevention and treatment of many diseases. [53], [54] 

Following oral administration of 20mg/kg bodyweight in rats of extract of Kaalamegh (Andrographis paniculata) and fixed combination Kan Jang tablets Andrographolide was quickly and completely absorbed. However when a 10-times higher dose was used its bioavailability was decreased. Since 55% of Andrographolide is bound to plasma proteins, very little can enter cells. [55] 

Anti-Inflammatory Activity   

In an in vitro study the methanol extract of Kaalamegha (Andrographis paniculata) inhibited the formation of reactive oxygen species (ROS) and inhibited carrageenan induced inflammation [56] 

In experimental studies at a dose of 200mg/kg body weight Kaalamegha (Andrographis paniculata) was found to reduce inflammatory edema by 60 to 62% [57] 

Kaalamegha (Andrographis paniculata) significantly reduces the inflammation caused by croton oil (hemolytic necrosis), histamine, dimethyl benzene and acute pneumocystis produced by adrenaline. [58]  

Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a protein complex that controls the transcription of DNA. NF-kB is found in all animal cells. It is involved in cellular responses to stimuli such as free radicals and oxidative injuries, bacterial and viral infections, exposure to antigens, radiation injuries, stress etc. NF-kB plays a key role in regulating cellular response and immune response. Incorrect regulation of NF-kB has been linked to inflammations, autoimmune diseases, septic shock cancer and many more afflictions. Andrographis paniculata is said to have a direct inhibitory effect on NF-kB.  

The anti-inflammatory effect of Kalamegha (Andrographis paniculata) is due to Andrographolide, neoAndrographolide, deoxyAndrographolide and dehydroAndrographolide. Of these dehydroAndrographolide shows maximum activity followed by neoAndrographolide and Andrographolide. This effect is due to the effect of Kaalamegh (Andrographis paniculata) on increasing the synthesis and release of adrenocorticotrophic hormone (ACTH) by pituitary gland. ACTH signals the adrenal gland to release cortisol, a natural anti-inflammatory hormone. The effect is absent in adrenalectomized experimental animals. [59], [60], [61]   

The four diterpenes contained in the plant show anti-inflammatory and antipyretic activity at the dose 1g/kg given orally. In this regard water extract was more effective than extracts in other solvents. The anti-inflammatory effect was not observed in adrenalectomized animals suggesting that the anti-inflammatory effect was mediated through adrenal gland. [62], [63], [64]  

Excessive amounts of nitrous oxide, prostaglandin E2 and cyclo-oxygenase-2 (COX-2) play an important role in the process of inflammation. Lipopolysaccharide (LPS) stimulates secretion of pro-inflammatory cytokines from macrophages resulting in increased production of nitric oxide. Incubation of macrophages with methanol-extract of Kaalamegh (Andrographis paniculata), phytochemicals Andrographolide and neoAndrographolide of Kaalamegh (Andrographis paniculata) inhibits production of nitric oxide. These phytochemicals also inhibited PGE2 synthesis and TNF-α in lipopolysaccharide (LPS)- stimulated macrophages. [65], [66], [67], [68], [69], [70] 

Anti-oxidant Activity 

Flavonoids found in plants are well known for their free radical scavenging property. The flavonoids found in the leaves of Kaalamegh (Andrographis paniculata) exhibit free radical scavenging and antioxidant activity. [71], [72] 

By employing 2, 2-diphenyl-1-picrylhydrazyl (DPPH), Lipid Peroxidation and DNA cleavage protective assay Sangeeta Huidrom and Manab Deca determined the free radical scavenging and anti-oxidant property of Kaalamegha (Andrographis paniculata) [73]

Aqueous and ethanol extracts of Kaalamegha (Andrographis paniculata) or Andrographolide protected the rat’s brain from free radical injury. The aqueous extract was superior to ethanol extract in this regard. This is because of higher flavonoid content in aqueous extract than in ethanol extract [74], [75] 

Immunomodulatory activity 

To study antigen specific and nonspecific immune responses, the ethanolic extract of Kaalamegha (Andrographis paniculata)  and Andrographolide were administered in mice. The ethanolic extract was found to be more potent than Andrographolide suggesting that some other constituents of the herb hitherto unidentified and unnamed may be expressing immunomodulatory effect.

  

It is suggested that Kaalamegha (Andrographis paniculata) regulates the cytokine receptors and the synthesis of histocompatibility molecules thus improving the cellular response.  

Some scientists have discovered that Kaalamegha (Andrographis paniculata) boosts the immune system by stimulating the production of antibodies and macrophages. 

The decoction of Kaalamegha (Andrographis paniculata) enhanced leucocytic phagocytosis of Staphylococcus aureus in vitro. This activity was inhibited by leucocytic phagocytosis inhibitors such as gentamycin, tetracycline and erythromycin. [76], [77], [78] 

Oral administration of ethanolic extract of the aerial parts of the plant (25mg/kg) or purified Andrographolide (1mg/kg) stimulated antibody production and the delayed type hypersensitivity response to sheep RBCs. The extract alone was more effective in this regard than purified Andrographolide alone or purified neoAndrographolide alone. The extract also stimulated a nonspecific response in mice. [79] 

Antibacterial Activity 

The ethanol Extract of leaves of Kaalamegh (Andrographis paniculata) inhibited the growth of E. coli  and reduced the effects of enterotoxin induced diarrhea in rabbit and guinea pig models. This effect was attributed to Andrographolide and other three related diterpenes contained in the plant. The extract also inhibited the growth of Staphylococcus aureus. The 50% methanol extract of leaves of Kaalamegh (Andrographis paniculata) inhibited the growth in vitro of proteus vulgaris. However no antibacterial activity was observed when dried powder of the leaves was tested. [80], [81], [82]

The phenolics found in plants are most important in the plant defense. Tannins act as antiseptic agents because of the presence of phenol group. The presence of alkaloids, phenolics and tannins may explain the antibacterial, antiviral and antifungal activity exhibited by the leaves of Kaalamegh (Andrographis paniculata) [83], [84]

In laboratory experiment the decoction of A. paniculata inhibited the growth of Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Shigella dysenteriae and Escherichia coli. This activity was attributed to flavones. But the extract was ineffective in treating dysentery. On the other hand water-insoluble terpene lactones exhibited therapeutic effect against many infectious diseases but did not show antibacterial activity in laboratory experiments. NeoAndrographolide had a better effect in dysentery than chloramphenicol and furazolidone. Andrographolide was also effective in the treatment of dysentery. Both neoAndrographolide and Andrographolide were also effective in URTI. [85], [86], [87] 

Several studies have reported that Kaalamegh (Andrographis paniculata) is useful for the treatment of leptospirosis. The herbal therapy is effective in approximately 80% of patients treated with deoxyAndrographolide, Andrographolide and neoAndrographolide tablets. [88] 

Aqueous extract of leaves of Kaalamegh (Andrographis paniculata) was found to have antibacterial activity against Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa but not against E. Coli and Klebsiella. [89] 

Investigations carried out by filter plate disc-agar diffusion and hexane and chloroform extracts were found to inhibit MRSA, Pseudomonas aeruginosa, Clostridium perfriengens, Serratiamarcescens, Bacillus subtilis, Enterbacter aeruginosa, Shigellaflexneri, Staphylococcus aureus and Salmonella typhi.   

The antibacterial activity of the plant was attributed to the combined effect of Andrographolides, arabinogalactan proteins, terpenoids, coumarins and steroids found in the plant. [90], [91] 

In laboratory experiment the decoction of  Kaalamegh (Andrographis paniculata) inhibited the growth of Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Shigella dysenteriae and Escherichia coli. This activity was attributed to flavones. But the extract was ineffective in treating dysentery. On the other handwater-insoluble terpene lactones exhibited therapeutic effect against many infectious diseases but did not show antibacterial activity in laboratory experiments. NeoAndrographolide had a better effect in dysentery than chloramphenicol and furazolidone. Andrographolide was also effective in the treatment of dysentery. Both neoAndrographolide and Andrographolide were also effective in URTI. 

Extracts of   A. paniculata may have a synergistic effect with isoniazid. [92], [93], [94], [95]

Antiviral Activity

All medical students remember the adage: “Treated cold lasts for seven days and untreated lasts for a week!” In a small clinical study Kaalamegh (Andrographis paniculata) shortened the duration of common cold and allayed the acute attack of cold.

In the world history, the global pandemic of influenza of 1918 was one of the most devastating outbreaks of viral infection, killing 50 million people worldwide. No country escaped its onslaught, but in India Kaalamegha was credited with halting the spread of the deadly virus.

Kaalamegh (Andrographis paniculata) is said to act against herpes zoster. [96], [97]

Extracts of  Kaalamegha (Andrographis paniculata)  shown modest activity in vitro against HIV; however, a phase 1 clinical study of the herb showed no effect on viral replication, CD4 count increase; and the trial was abandoned after six weeks because of adverse effects. However succinylated derivatives of Andrographolide which have protease-inhibitor properties did show anti-HIV activity in vitro. A study conducted at Bastyr University, showed a significant rise in the mean CD4 count of HIV subjects after administration of 10 mg/kg Andrographolide. 

   

In another study for the efficacy of the herb against HIV, the herb prevented the virus from infecting healthy T cells and inhibited the spread of infection. In some other studies the herb was able to fight HIV infection similar to AZT.  

To declare Kaalamegha (Andrographis paniculata) as a ‘proved’ (proven), ‘effective’ and ‘curative’ drug for HIV more study is essential. [98], [99] 

In a study, 25 patients of viral hepatitis A were treated with decoction of Kaalamegha (Andrographis paniculata) equivalent to 40g of crude compound for over 24 days.

On the basis of clinical findings and blood biochemistry 80% patients were considered ‘cured’. In China 112 patients treated in the similar way. They reported 83% patients were ‘cured’ [100], [101]       

Antimalarial and Antifilarial activity 

Although herbal formulations are not substitutes for the treatment of malaria and filariasis, according to Dr. Stephen Holt, herbal formulations may be very good adjuvants for the modern drugs prevailing today. Extracts of Kaalamegha (Andrographis paniculata) produce considerable inhibition of Plasmodium berghei. 

NeoAndrographolide and deoxyAndrographolide were most effective of the four compounds present in Kaalamegha (Andrographis paniculata). Pretreatment of the experimental animals for 21 days was more effective than the treatment started after infection.

Extracts of Kaalamegha (Andrographis paniculata) were effective in killing microfilariae. 

Extracts of Kaalamegha (Andrographis paniculata) were devoid of any side effects. [102] 

In an in vitro study methanolic extract of Kaalamegha (Andrographis paniculata) was found to be effective against chloroquin sensitive and chloroqin resistant malarial parasite Plasmodium falsiparum. It was more effective when combined with curcumin than when used singly. The extracts of Andrographis paniculata and Hedyotis corymbosa were found to inhibit the ring stage of the parasite. They did not show any in vivo toxicity. [103] 

Larvicidal and Ovicidal Activity 

Many phytochemicals show larvicidal and ovicidal activities. Thus they are useful to prevent vector-borne diseases.

Different products of Kaalamegha (Andrographis paniculata) greatly affect the larval growth of Anophelis stephensi and cause malformation and mortality in a dose dependent manner. Kaalamegha (Andrographis paniculata) also shows larvicidal activity against Culex mosquito, a vector of filariasis. [104], [105]

The ethanolic extract of Kaalamegha (Andrographis paniculata) kills all stages of development of Aedis stephensi (i.e. larva, pupa and adult insect) thus suppressing the vector population and adversely influencing transmission of the disease pathogen [106] 

Benzene, methane, hexane, chloroform and ethyl acetate extract of Kaalamegha (Andrographis paniculata) exhibit ovicidal and larvicidal activity against Culex quinquefasciatus Say and Ades aegypti L. Of these methanol and ethyl acetate extracts of the plant show only ovicidal activity against these mosquitoes. The extract of the leaf of Kaalamegha (Andrographis paniculata) may have the potential to be used to control the Culex mosquito. [107]

Antifungal Activity 

Hexane, dichloromethane (DCM) and methanol extracts of  Kaalamegha (Andrographis paniculata) exhibited antifungal activity against Candida albicans and Aspergillus niger. [108] 

Actions on the Skin 

Aoueous and dichloromethane extracts of Kaalamegha (Andrographis paniculata) whole plant showed the significant antibacterial activity against gram positive and gram negative organisms causing skin infections [109]

Actions on the Hematopoetic System 

Activation of platelets and platelet aggregation are common denominators in thrombotic events and inflammatory diseases and immunity. Therefore antiplatelet agents inhibit thrombosis and complications of thrombosis. [111], [112]

Thisoda et al reported that at the dose of 10-100 µg/mL, Kaalamegha (Andrographis paniculata) significantly inhibited platelet aggrgation. This activity was found to be due to Andrographolide present in Kaalamegha (Andrographis paniculata) through activation of the eNOs-NO/ cyclic GMP pathway [113], [114] 

DDA (14-deoxy-11, 12-dide-hydroAndrographolide), Andrographolide and aqueous extract of Kaalamegha (Andrographis paniculata) inhibit thrombin-induced platelet aggregation in time and concentration manner. Extracts with higher concentration of DDA have less inhibitory activity than extracts with lower concentrations of DDA.

This shows that other water soluble phytochemicals present in water extract possess antiplatelet aggregation activity.  

An added effect of Andrographolide present in Kaalamegha (Andrographis paniculata) is that it activates fibrionolysis, the natural process in the body that dissolves clots. [115], [116]

Andrographolide present in Kaalamegha (Andrographis paniculata) inhibits platelet-activating factor (PAF)-induced platelet aggregation without affecting biosynthesis of eicosanoids. An extract of Kaalamegha (Andrographis paniculata) significantly inhibited ADP-induced platelet aggregation in patients with cardiac and cerebro-vascular disease. This effect is dependent on dose used. [117], [118] 

In another study, Kaalamegha (Andrographis paniculata) extracts were found to produce results comparable to 200 mg of aspirin/kg body weight. [119] 

Actions on Nervous system 

Analgesic and Antipyretic Activity

Fever was induced in rats. There was a reduction in rectal body temperature for 30, 100, and 300 mg. of Andrographolide/kg body weight. While the analgesic (painkilling) activity of Andrographolide extracted from AP was weak compared to aspirin, the anti-pyretic (fever-reducing) activity was comparable to that of aspirin. 

The study showed that the dose of 300mg/kg body weight of Andrographolide was as effective as the same amount of aspirin. While aspirin is gastric irritant, the extract of Kaalamegha (Andrographis paniculata) was gastroprotective. The plant extract reduced the development of gastric ulcers by 31%, while cimetidine had an 83% reduction rate. [120] 

Andrographolide, neoAndrographolide, deoxyAndrographolide and 14-deoxy-11, 12-didehydroAndrographolide found in Kaalamegha (Andrographis paniculata) reduced the fever in rabbits caused by typhoid and paratyphoid vaccine. They also reduced the fever in rats caused by 2, 4-dinitrophenol. Of the four phytochemicals, 14-deoxy-11, 12-didehydroAndrographolide had the highest antipyretic activity followed by deoxyAndrographolide, neoAndrographolide and Andrographolide. [121], [122] 

DeoxyAndrographolide, neoAndrographolide and Andrographolide can lower fever produced by various fever inducing agents such as bacterial endotoxins, Pneumococcus, Hemolytic Streptococcus, Typhoid-Paratyphoid organisms and the chemical 2, 4-dinitrophenol. [123]

Intraperitoneal administration of ethanolic extract of Kaalamegha (Andrographis paniculata) significantly delayed the occurrence of respiratory failure and death of mice poisoned with cobra venom. Kaalamegha (Andrographis paniculata) inhibited the frog heart in situ. This inhibition could be blocked by atropine. From this finding it could be concluded that the herb did not activate nicotinic receptors, but produce a muscarinic effect, which accounts for action against cobra venom. [124], [125] 

Andrographolide found in Kaalamegha (Andrographis paniculata) penetrates blood brain barrier and concentrates in the brain and spinal cord thus protecting the entire nervous system. [126] 

Kaalamegha (Andrographis paniculata) has a sedative effect in mice. The sedative action lasts longer than that of barbital. [127] 

The studies indicate that AP products may act at the barbital receptors in the brain.  

Actions on Endrocrine system 

At high dose the four lactones found in Kaalamegha (Andrographis paniculata) caused atrophy of the thymus in infant mice. The phytochemical 14-deoxy-11, 12-didehydroAndrographolide hemisuccinate (DAS) found in Kaalamegha (Andrographis paniculata) also caused atrophy of the thymus in infant mice and reduced the vitamin C content in the adrenal glands in rats. This effect was completely abolished in hypophysectomised rats. DAS suppliment could not prolong the survival time of adrenalectomized infant rats. These results suggest that DAS does not have adrenocorticoid-like effect but is able to activate anterior pituitary function and consequently adrennocortical function. Other Andrographolide derivatives found in Kaalamegha (Andrographis paniculata) also exhibit similar effects on pituitary-adrenocortical function. [128] 

Actions on Cardiovascular system 

In experimental studies on animal models aqueous extract of Kaalamegha (Andrographis paniculata) produced fall in systolic blood pressure in both hypertensive and normotensive Wistar-Kyoto rats. This effect was dose dependent. This effect was mediated via angiotensin converting enzyme (ACE) system and lipid peroxidation in kidneys in hypertensive rats treated with the extract of the herb. This activity was not significant in normotensive rats suggesting that the hypotensive effect in hypertensive rats and normotensive rats is not mediated through identical mechanism. [129] 

The hypotensive effect of n-butanol and aqueous fractions of the crude extract of Kaalamegha (Andrographis paniculata) is antagonized or attenuated by phentolamine, hexamethonium, pyrilamine and cimetidine but not by propranolol or atropine. [130] 

The hypotension produced by DDA (14-deoxy-11, 12-didehydroAndrographolide), a diterpenoid found in Kaalamegha (Andrographis paniculata) in anaesthetized Sprague-Dawley rats was attenuated by propranolol, hexamethonium. DDA also antagonized the positive chronotropic effect of isoproterenol on the isolated rat right atria in a non-competitive and dose-dependent manner. [131] 

A study on negative chronotropic effects of DDA (14-deoxy-11, 12-dide-hydroAndrographolide) suggests that DDA has direct action on vascular smooth muscle. [132] 

In a study in rats, Andrographolide present in Kaalamegha (Andrographis paniculata) fully restored the contractile response of thoracic aorta to phenylephrine. Thus it restores the mean arterial blood pressure. [133] 

A refined extract API0134 of Kaalamegha (Andrographis paniculata) significantly reduced the activities of lipid peroxide and endothelin in rabbits, thus protecting the animals against atherosclerosis. [134] 

Aqueous extract of Kaalamegha (Andrographis paniculata) administered intravenously one hour after myocardial infarction in dogs restricted the infarct size. Similar results were observed in animals treated with flavones extracted from the root of Kaalamegha (Andrographis paniculata). [135], [136]

  

Treatment with extract of Kaalamegha (Andrographis paniculata) protected the experimental animals (dogs) from myocardial ischemia-reperfusion injury. 

In another study pretreatment of rat cardiomyocytes with Andrographolide protected them against hypoxia-re-oxygenation injury in a time dependent manner. This happens due to up-regulation of reduced levels of glutathione and antioxidant enzyme activities by Andrographolide present in Kaalamegha (Andrographis paniculata) [137], [138], [139]

To evaluate the effect of a refined extract of Kaalamegha (Andrographis paniculata) (API0134) on left ventricle after ischemia, the extract was administered intravenously in dogs 45 minutes after the ischemia. The extract prevented increase in the left ventricle end diastolic pressure, preserved normal cardiac output and cardiac rhythm in dogs with experimental ischemia-reperfusion myocardial injury. [140] 

  

In a study hydroalcoholic extract of Kaalamegha (Andrographis paniculata) prevented isoproterenol induced increase in lipid peroxidation. The extract increased the activities of antioxidant enzymes viz. super oxide dismutase, catalase, glutathione peroxidase and the levels of reduced glutathione in hearts. The extract also prevented the leakage of LDH (lactate dehydrogenase) from heart and salvages the heart from isoproterenol-induced myocardial ischemic injury. [141] 

Pretreatment with extract of Kaalamegha (Andrographis paniculata) prevented atherosclerotic iliac artery stenosis in rabbits. Extract of Kaalamegha (Andrographis paniculata) also prevented the restenosis after experimenta angioplasty. The extract inhibited cell growth and DNA synthesis in a dose dependent manner. This is similar to the mechanism of drug eluting stents. [142], [143]  

Andrographolide found in Kaalamegha (Andrographis paniculata) ameliorates the progression of aneurism of the abdominal aorta by inhibiting inflammatory cell infiltration through down-regulation of cytokine and integrin expression. [144] 

Intra-arterial or retrograde injections of extract of Kaalamegha (Andrographis paniculata) were found to be effective in thrombo-angiitis obliterans [145] 

Actions on Respiratory System 

To evaluate the preventive activity of Kaalamegha (Andrographis paniculata) extract against common cold a double-blind pilot study was carried out on student volunteers. For three months the students were given Kan Jang, a formulation of Kaalamegha (Andrographis paniculata) produced by the Swedish Herbal Institute. The results showed that the extract was useful in the prevention of common cold. [146] 

  

A dose of 200mg/day of Kan Jang was given to the study group. After a month’s treatment there was no significant change in the number of volunteers catching cold. However after the third month there was a significant decrease in the number of volunteers catching cold. This effect was attributed to the phytochemical Andrographolide, a known immunostimulant present in the plant. [147] 

In another study the patients already suffering from cold, nasal discharge, nasal stuffiness, sore throat, fever etc were included. They were administered Kan Jang. On forth day there was a significant improvement in the symptoms. This showed that Kaalamegha (Andrographis paniculata) was useful in the treatment of common cold. [148]

Andrographolide found in Kaalamegha (Andrographis paniculata) was useful to treat tonsillitis and other respiratory infections. The therapy was successful in 65percent of patients suffering from acute tonsillitis. [149] 

For a clinical study in 1991 by Thamlikitkul et al, 152 adult patients with pharyngotonsillitis were recruted. Some received paracetamol and others received 3g/day or 6g/day for 7 days Kaalamegha (Andrographis paniculata). In terms of symptomatic relief from throat pain, sore throat and fever the efficacy of paracetamol and high doses of Kaalamegha (Andrographis paniculata) were significantly more than the low dose of Kaalamegha (Andrographis paniculata). In each group minimal and self-limiting side effects were observed in about 20% of patients.  [150]   

Andrographolide was used to treat 49 patients of pneumonia. Of these 35 recovered completely. In another study Andrographolide was used to treat 111 patients with pneumonia and 20 patients with bronchitis. The overall effectiveness of Andrographolide was 91 percent. In a study 2.5% of Andrographolide solution (i. e. Andrographolide: 50 to 80 mg/kg body weight) was injected once a day for two months to patients with tuberculosis. Of seventy cases of tubercular meningitis 30% patients were cured. The combination of Andrographolide with rifampicin resulted in a 2.6 fold decrease in fatality rates. [151]  

Actions on GI System 

In a randomized, double-blind, multicentre study conducted in 2011, Kaalamegha (Andrographis paniculata) was found to be as effective as mesalazine (mesalamine) used in ulcerative colitis. 

Ethanol, chloroform or 1-butanol extract of the aerial parts of Kaalamegha (Andrographis paniculata) at 300mg/ml inhibited E. coli enterotoxin-induced diarrhea in rabbit and guinea pig ileal loop assay. But the aqueous extract of the aerial parts of the herb was inactive in this regard. This activity was attributed to the potent antisecretory activity of diterpene lactones, Andrographolide and neoAndrographolide against E. coli enterotoxin-induced  diarrhea.  Andrographolide and neoAndrographolide 1 mg each per loop were as effective as loperamide. These compounds inhibit the secretory response induced by enterotoxins through the stimulation of adenylate cyclase. [152], [153]

In the treatment of diarrhea, Andrographolide and neoAndrographolide showed similar activity to loperamide. 

In acute bacterial diarrhea, a total dose of 500mg of Andrographolide divided in three equal doses per day for six days combined with oral rehydration cures infective diarrhea. [154] 

In another study C was used to treat 1611 cases of bacterial dysentery and 955 cases of diarrhea with overall 91.3% effectiveness [155]  

It had been ‘believed’ that Kaalamegha (Andrographis paniculata) was effective against bacillary dysentery and diarrhea because it was ‘antibacterial’. But this ‘belief’ was not supported and confirmed by scientific study. However Andrographolides were very effective in stopping the diarrhea. How is this accomplished is not completely understood at present. [156]   

Kaalamegha (Andrographis paniculata) extract shows antisecretory and gastroprotective effect. The extract strengthens the gastric mucosa, decreases the acidity in gastric juice and pepsin activity. Thus the extract of the herb has gastroprotective anti-ulcerogenic activity. The effect is dose dependent. [157] 

Hepatoprotective Activity 

The aqueous extract of Kaalamegha (Andrographis paniculata) protects the liver damage induced by hexachlorocyclohexane in mice. Several diterpenes isolated from the herb protect the liver damage induced by acetaminophen, CCl₄, in rats and guinea pigs. The extract of the herb was more effective in this regard than the compounds isolated in pure forms.  

Kaalamegha (Andrographis paniculata)  improves gall bladder function, (increases the gall bladder contractility), increases bile flow thereby improves digestion.  

Pretreatment with a single dose of Kaalamegha (Andrographis paniculata) leaf extract, 500 mg/kg or Andrographolide 5ml/kg prevented CCI₄-induced liver damage and decreased the elevated levels of SGOT and SGPT enzymes in dog.

Administration of a single dose of aqueous extract of Kaalamegha (Andrographis paniculata) leaves protects the liver from CCl₄ insult. However, long term administration (15 consecutive days) of the extract of the herb or the Andrographolide did not decrease CCl₄-induced hepatic microsomal lipid peroxidation.

Pretreatment of mice with diterpenes (I, II, III; 100mg/kg, IP) for three consecutive days produced a significant reduction in malondialdehyde formation, reduced glutathione depletion and enzymatic leakage of glutamic-pyruvate transaminase and alkaline phosphatase in hepatotoxin-treated animals.   

Alcohol, carbontetrachloride, galactosamine and many other toxic chemicals damage the liver by causing lipid peroxidation. In this process, the free radicals produced by the chemical attack destroy cell membrane. When compounds of Kaalamegha (Andrographis paniculata) were administered to animals three days before the toxic chemicals, a significant hepatoprotective effect was observed. The hepatoprotective effect was attributed to the antioxidant property of these phytochemicals especially that of Andrographolide which was as effective as Silymarin.  [158], [159] 

Kaalamegha (Andrographis paniculata) increased biliary flow in rats and decreased hexabarbital-induced sleeping time [160], [161], [162] 

Oral dose of 0.5g/kg/day of Kaalamegha (Andrographis paniculata) not only protects the liver from alcohol induced toxic damage but also cures it. [163] 

The alcoholic extract of Kaalamegha (Andrographis paniculata) and its two diterpenes (Andrographolide and neoandrographolids) protect the liver against the toxicity caused by Plasmodium burghei infection in animals. The hepatic damage is thought to be mediated through free radical damage. The protection is thought to be due to scavenging of free radicals through activation of SOD [164] 

Bile is produced in the liver and stored in the gall bladder. When paracetamol is administered to a patient the bile production is diminished and gall bladder contraction becomes sluggish. Andrographolide prevents and improves this decrease in bile production and improves the contractility of the gall bladder. In this regard, Andrographolide is more potent than Silymarin.  

Ayurvedic physicians used to treat Jaundice (infective hepatitis, now called viral hepatitis) with monoherbal or polyherbal therapy. One of them was Kaalamegha (Andrographis paniculata). The results of evaluation of the use of the decoction or infusion of Kaalamegha (Andrographis paniculata) for the treatment of viral hepatitis showed that there was a marked improvement in the clinical picture (appetite improved on the fifth day, fever subsided in 7 days, yellow discoloration of eyes and skin completely disappeared in 24 days). There was proportionate improvement in liver function tests. These effects were attributed to Andrographolide present in the plant. [165]

Andrographolide stimulates the function of gallbladder. It significantly increases the contractility of gallbladder, and bile flow and prevents the stasis of bile. Thus it might be useful to prevent the formation of gallstones.  [166], [167]  

A comparative study on the effect of extract of leaf of Kaalamegha (Andrographis paniculata)/ Andrographolide on low concentration-carbontetrachloride-induced hepatotoxicity (microsomal lipid peroxidation) revealed that a single oral dose of the extract and of Andrographolide had hepatoprotective effect. However, while the high concentration-carbontetrachloride-induced microsomal lipid peroxidation was completely protected by the extract but not by Andrographolide. This indicates that the hepatoprotective effect of Kaalamegha (Andrographis paniculata) is not solely due to the presence of Andrographolide. [169]   

Mechanism of Hepatoprotection 

The mechanism of hepatoprotection by Kaalamegha (Andrographis paniculata) is probably multi-factorial and is attributed to--

1. Anti-inflammatory, anti-oxidant and free-radical scavenging activities of the plant

2. Cell membrane stabilizing property of the plant

3. Reduction of glutathione (GSH) in the liver and in intestinal mucosa

4. Improvisation of liver function and restoration of liver enzymes (ALT, AST, GGT etc) to normal levels

5. Choleretic and anti-cholestatic activity 

See above: Pharmacology of chemical constituents of Kaalamegha (Andrographis paniculata)

Various extracts of Kaalamegha (Andrographis paniculata) and its constituents were used to evaluate hepatoprotective effects. The total extract and its individual constituents used singly exhibited the same hepatoprotective effects. Kaalamegha (Andrographis paniculata) extracts also showed benefits against liver damage caused by hepatotoxic agents with different hepatotoxic mechanisms. This suggests that the plant and its phytochemicals exert a broad spectrum hepatoprotective effect. Their action is not agent-specific.  [170], [171], [172]

Actions on Lipid Metabolism

A recent study demonstrates that Kaalamegha (Andrographis paniculata) has a potent hypolipidemic effects. It lowers total cholesterol, LDL and triglycerides. [173]   

The ethanol extract of Kaalamegha (Andrographis paniculata) at the dose of 400mg/kg body weight administered orally twice a day for 14 days to streptozotocin-induced diabetic rats produced a 49.8 percent reduction in serum triglyceride levels. This was 27.7 percent greater than the reduction achieved with metformin. [174] 

Anti-diabetic Activity

In a study on non-diabetic rabbits, aqueous extract of Kaalamegha (Andrographis paniculata) prevented hyperglycemia when glucose was administered orally. [175]  

At a dose of 50mg/kg body weight, aqueous extract of Kaalamegha (Andrographis paniculata) resulted in 52.9 % decrease in blood glucose levels in streptozotocin-induced diabetic rats. Where as freeze-dried extract of Kaalamegha (Andrographis paniculata) decreased blood glucose by 61.8% at a very lower dose of 6.25 mg/kg body weight. [176] 

In another study Dandu and Inamdar administered 400mg/kg body weight of aqueous extract of leaves of Kaalamegha (Andrographis paniculata) to streptozotocin-induced diabetic animals. This dose reduced blood sugar and increased activity of superoxide dismutase significantly. Oral administration of the decoction of the plant also reduced blood glucose levels in alloxan-induced diabetic rats. [177] 

However, ethanol extract of Kaalamegha (Andrographis paniculata) administered orally twice a day for 14 days to streptozotocin-induced diabetic rats significantly lowered fasting blood sugar but increased body weight in a dose dependent manner. [178] 

The hypoglycemic activity of Kaalamegha (Andrographis paniculata) in normal and diabetic rats was attributed to Andrographolide present in the plant. The glucose lowering effect of Andrographolide is due to better utilization of glucose by skeletal muscles. After in vitro experiments Wibudi et al concluded that the hypoglycemic activity of Kaalamegha (Andrographis paniculata) was due to release of insulin from β-cells of pancreas through ATP-sensitive potassium channels. [179], [180]

After in vitro experiments conducted by Subramaniam et al suggested that hypoglycemic activity of Kaalamegha (Andrographis paniculata) might be due to the inhibition of α-glucosidase and α- amylase enzymes. [181] 

Available evidence suggests that hypoglycemic activity of the extract of Kaalamegha (Andrographis paniculata) and Andrographolide may involve different mechanisms in non-diabetic and diabetic subjects.  

Actions on Urinary System 

In treating acute pyelonephritis, Kaalamegha (Andrographis paniculata) was found to be as effective as nitrofurantoin. The herb did not show any side effects. [182] 

Uncontrolled diabetes is the root cause of many life threatening complications. Diabetic nephropathy is one of them. 

In an experimental study on alloxan-induced diabetic rats the chloroform extract of roots of Kaalamegha (Andrographis paniculata) at 300mg/kg body weight for 4 weeks controlled diabetes and prevented diabetic nephropathy as was evident by well controlled blood levels of glucose, protein, albumin and creatinine. The extract significantly inhibited the induction of proteinuria and uremia. This study suggests that Kaalamegha (Andrographis paniculata) might be useful in preventing some complications of diabetes. [183] 

A water-soluble polysaccharide (AAP) was isolated from Kaalamegha (Andrographis paniculata). A study on streptozotocin-induced diabetic mice showed that AAP plus Andrographolide from Kaalamegha (Andrographis paniculata) prevented the progerssion of diabetic renal complications. This study suggests that the combination of AAP and Andrographolide can be of value in prevention and treatment of diabetic nephropathy. [184]

Actions on Male Reproductive System 

Administration of powdered stem of Kaalamegha (Andrographis paniculata) to male Wister mice had antifertility effect, but no effect on fertility in female mice. [185], [186]

Administration of powder of dry leaf of Kaalamegha (Andrographis paniculata) at 20 mg daily for 60 days to male albino rats resulted cessasion of spermatogenesis, degenerative changes in the seminiferous tubules, regression of Leyding cells and degenerative changes in the epididymis, seminal vescicle and prostate gland, coagulating gland and reduction in the weight and fluid content of accessory glands. [187]

(The function of coagulating gland is to secrete fluids to form the copulatory plug/ mucus plug to help ensure fertilization. The plug has two purposes: (1) to hold the sperm in the female’s vagina; and (2) to prevent other males from impregnating the female.) [188], [189] 

When administered orally to male Wister rats for 48 days, Andrographolide from 
Kaalamegha (Andrographis paniculata) decreased the sperm count and sperm motility. Some sperm abnormalities were also noted. [190]

However Burgos et al did not find testicular toxicity in male Sprague dawley rats after treatment with a standardized dried extract in doses up to 1,000 mg/kg body weight for 60 days. Their analysis was based on testosterone levels, testicular weight, ultrastructural analysis and histology. [191]    

Actions on Female Reproductive System 

Decoction of Kaalamegha (Andrographis paniculata) administered orally to alloxan-induced diabetic rats could restore impaired estrous cycle. [192] 

When administered orally to pregnant does (doe= female rats) during first 19 days of pregnancy in doses of 200, 600 and 2000mg/kg body weight the extract of Kaalamegha (Andrographis paniculata) did not affect progesterone levels. [193] 

The Chinese researchers reported that administration of Kaalamegha (Andrographis paniculata) to pregnant does (doe= female rabbits) resulted in abortion. 

Intraperitoneal injection of decoction of aerial parts of Kaalamegha (Andrographis paniculata) to female albino mice prevented implantation and caused abortion at different periods of gestation. Intravenous, intramuscular and subcutaneous administration in early pregnancy resulted in abortion. Administration of progesterone or leutinizing hormone-releasing hormone antagonized this activity of the plant extracts. [194]

To evaluate contraceptive activity of Kaalamegha (Andrographis paniculata), Zoha et al fed female mice sun-dried powder of the plant at a dose of 2 g/kg body weight/day for six weeks. When mated with males of proven fertility pregnancy was inhibited in 100 percent of the animals. [195]

By blocking calcium channels, dried extract of Kaalamegha (Andrographis paniculata) induces relaxation of uterine muscle. [196] 

As existing evidence is inconsistent, Kaalamegha (Andrographis paniculata) cannot be used as a dependable contraceptive. 

Antitumor Activity 

Most anti-cancer agents employed in modern medicine aim at inducing apoptosis, necrosis, cell cycle arrest, cell differentiation or proliferation of cancer cells, improving host immunity, arresting vascularization of tumors or killing cancer inducing agents like viruses or microorganisms like H. pylori. The compounds that inhibit multiple procancer events are of greater interest as they are likely to inhibit wider range of cancers. In this context, Andrographolide exerts both a direct and indirect action on cancer cells.    

Methanolic extract of Kaalamegha (Andrographis paniculata) shows toxicity against human epidermoid leukemia, lymphocytic leukemia breast cancer, lung cancer and melanoma cells. This effect of the plant is due to Andrographolide found in the plant which is cytotxic to these cells lines. By inhibiting cell proliferation and inducing apoptosis in cancer cells Andrographolide is highly cytotoxic to many cancers including drug resistant cancers. Andrographolide   The activity is dose dependent. [197], [198]

Andrographolide induces cell-cycle arrest in cancer cells at G0/G1 stage. It inhibits cell-cycle progression by modulating the expression of cell-cycle related proteins. When treated with Andrographolide, human acute myeloid leumic cells demonstrated a significant decrease at S and G2/M phase. 

Andrographolide exhibits a potent growth inhibitory effect in acute promyelocytic leukemia cells by inducing retinoic acid receptor-independent cell differentiation and apoptosis. [199], [200], [201], [202], [203]

To induce apoptotic cell death in certain human cancer cells types, Andrographolide activates the extrinsic death receptor pathway including caspase-3 and caspase-8. 

Zhou et al demonstrated this type of activity of Andrographolide in cervical, breast and hepatoma cell lines. [204], [205]

Andrographolide enhances tumor necrosis factor-α (TNF- α)   related apoptosis inducing ligand (TRAIL) an important member of extrinsic apoptosis pathway in various human cancer cell lines. TRAIL is an important anti-cancer agent. It can selectively kill cancer cells amongst normal cells. [206], [207]

Some kinds of cancers develop resistance towards TRAIL. However molecules like Andrographolide can enhance TRAIL expression and re-sensitize resistant cancer cells to TRAIL and induce apoptosis in cancer cells. Thus, in future, Andrographolide may be developed as as a sensitizer to induce apoptosis in various kinds of cancers. [208], [209], [210]

Recent in vitro studies have demonstrated that Andrographolide has the capabilities of inducing cell-cycle arrest and apoptosis in a variety of cancer cells. Andrographolide also exhibits potent immunomodulatory and anti-angiogenic activities in cancerous tissues. This makes Andrographolide a strong anticancer agent of tomorrow. [211]

Andrographolide is also effective in combination with other anticancer agents such as 5-fluouracil, cisplatin and adriamycin. In fact when combined with other anticancer agents, Andrographolide increases the rate of apoptosis and prevents multidrug resistance of cancer cells. [212] 

Andrographolide suppresses adhesion of gastric cancer cells which express high-level sialyl Lewis X to human vascular endothelial cells by blocking E-selectin expression.

(E-selectin is also known as endothelial-leukocyte adhesion molecule-1. It plays an important part in inflammation. In humans E-selectin mediates the adhesion of tumor cells to endothelial cells, by binding to E-selectin ligands expressed by neutrophils, monocytes, eosinophils, memory-effector T-like lymphocytes, natural killer cells or cancer cells. This interaction is associated with metastatic dissemination) [213], [214]

A patient of anal tumor treated with decoction of Kaalamegha (Andrographis paniculata) was said to have recovered “satisfactorily” [215]

Andrographolide exhibits anti-invasive activity against colon cancer cells via inhibition of matrix metalloproteinase-2 (MMP-2) [216]

In one study, sixty patients with chorioepithelioma, hydatidiform mole were treated with Kaalamegha (Andrographis paniculata) and compounds derived from the plant. Of these, forty one patients had metastasis. Twelve patients treated with Kaalamegha (Andrographis paniculata) alone recovered completely; four of them became pregnant. Remaining patients treated with Kaalamegha (Andrographis paniculata) and other drugs did not show recurrence during the time of the study. [217]   

Individually as well as in synergy with 5- Fluorouracil, Andrographolide induces apoptosis in human hepatocellular carcinoma cells. [218]

Ras is a family of related proteins which is ubiquitously expressed in all cell lineages and organs. They are involved in transmitting signals within cells (cellular signal transduction). When Ras is ‘switched on’ by incoming signals, it subsequently switches on other proteins. Because these signals result in cell growth and division, overactive Ras signalling can ultimately lead to cancer. [219]

While treating cancers with radiation therapy supplementation of Andrographolide was found to sensitize Ras-transformed cells and significantly delay tumor growth.  [220] 

Individually as well as in synergy with Taxifolin, Andrographolide inhibited human prostate cancer. [221]

By inhibiting interleukin-6 and androgen receptor expression, Andrographolide suppresses the growth of human prostate cancer. Andrographolide targets androgen receptor pathway in castration-resistant prostate cancer [222]

Apart from inducing apoptosis, Andrographolide is able to induce cell differentiation in proliferating cancer cells. In experiments on mice, following treatment with Andrographolide, the myeloid leukemia cells were directed to differentiate into phagocytes. This activity being rarely found in plant derived anti-cancer agents is of special inerest to researchers and to pharmaceuticals interested in the development of a new drug. [223]

Sheeja and Kuttan demonstrated that the extract of Kaalamegha (Andrographis paniculata) or Andrographolide could stimulate killer T lymphocyte production through enhanced secretion of Interleukin-2 and Interferon-c thereby inhibiting tumor growth in vivo. Inhibition of angiogenesis is a promising strategy in treating cancers. In recent studies Kaalamegha (Andrographis paniculata) was found to inhibit tumor-specific angiogenesis by pro and anti-angiogenic factors. A recent studydemonstrated that Andrographolide inhibited breast cancer cell proloferation, migration and cell cycle arrest at G2/M phase and induced apoptosis through caspase-independent pathway. In experimental studies Andrographolide was found to attenuate endothelial cell motility and tumor-endothelial cell interaction. [224], [225]

Culinary uses

Not used.

Adverse effects and Toxicity

In therapeutic doses, Kaalamegha (Andrographis paniculata) shows very little toxicity. However large doses cause gastric discomfort, nausea, vomiting and loss of appetite. They are due to the bitter taste of Andrographolide. If the crude drug extract is injected, anaphylactic reactions may occur. [226] 

Joanna et al, concluded that Kaalamegha (Andrographis paniculata) is safe and efficacacious for the treatment of uncomplicated upper respiratory diseases. The herb has insingificant adverse events. [227]

A phase-I clinical trial was undertaken in 2000 by Calabrese et al to evaluate anti-HIV activity of Andrographolide from Kaalamegha (Andrographis paniculata). After six weeks the trial was interrupted due to moderate to severe adverse events including an anaphylactic reaction in one patient. Howevr all adverse reactions resolved by the end of observation. [228]  

In a study in 2005, treatment with Kaalamegha (Andrographis paniculata) in patients with type 2 diabetes for twelve weeks did not show adverse effects [229]    

An acute toxicity study reported that LD50 of Kaalamegha (Andrographis paniculata) was too high to be determined. A chronic toxicity on dogs did not show toxicity after administering 15 times the clinical dosage of Andrographolide. In animal studies Andrographolide is associated with fetrility issues but not in human studies. No adverse events were noticed in patients treated with 1200mg/day of Kaalamegha (Andrographis paniculata)

In a study, female rats treated with a formulation containing Andrographolide, at 5000mg/kg for 14 days, did not show toxic effects. [230], [231] 

In a toxicity study carried out by Burgos et al in 1997, the standardized dried extract of Kaalamegha (Andrographis paniculata) did not show testicular toxicity in male Sprague-Dawley rats with the treatment at doses of 20, 200 and 1000 mg/kg body weight for 60 days. [232], [233]

Drug Interactions

Andrographolide and Kaalamegha (Andrographis paniculata) significantly increase the clearance of theophylline. The elimination half life of theophylline was shortened by 14% and 17% respectively. However some phytochemicals contained in Kaalamegha (Andrographis paniculata) extract may interact with theophylline and retard its elimination when it was administered at high dose. [234]

Kaalamegha (Andrographis paniculata) when administered with anticoagulants there may be increased risk of bleeding. Kaalamegha (Andrographis paniculata) may inhibit the action of immuno-suppressants [235], [236], [237]

The simultaneous administration of Kan Jang and Warfarin did not produce significant effects on the pharmacokinetics and pharmacodynamics of Warfarin [238]

Contraindications

Kaalamegha (Andrographis paniculata) should not be used during pregnancy as it is abortifacient [239], [240]

Medicinal Actions and Uses

Kaalamegha (Andrographis paniculata) is used to treat skin-infections, leprosy, PUOs, leptospirosis, pharyngo-tonsillitis, ottitis media, respiratory infections and allergies, tuberculosis, bacillary dysentery, entero-colitis, typhoid fever, hepatitis (jaundice), pyelonephritis, pelvic inflammations, induction of labour, thromboangitis obliterans (TAO) [241]

Traditional Uses

The Tamils have been using it for centuries.

Common cold, respiratory infections, fevers, jaundice, as anti-snake venom in snake bite.

Recently in Siddha medicine, it is used to treat fevers like chikungunya, swine-flu, typhoid etc.

Usages in Ayurveda 

It is used for jaundice, fevers, diabetes, worm infestation, anemia, wounds etc.

Usages in Modern Medicine 

In modern medicine, Kaalamegha (Andrographis paniculata) is used to treat skin-infections, leprosy, PUOs, leptospirosis, pharyngo-tonsillitis, ottitis media, respiratory infections and allergies, tuberculosis, bacillary dysentery, entero-colitis, typhoid fever, hepatitis (jaundice), pyelonephritis, pelvic inflammations, induction of labour, thromboangitis obliterans and to boost immunity [242]

Preparations and dosages

Powder of whole Plant: 0.5 to 1.5 g.

Juice: 2 to 4 ml.

Powder: 3 to 6 g of the crude powder, some recommend 6 to 9 g.

Decoction: 30 to 60 ml, (20 to 40 ml.)

Paste of Kaalamegha: 5 g mixed with sugar and honey given for vomiting.

Crude drug, capsules, tablets and pills are also available in some countries. (Store in a well-closed container, protected from light and moisture)

For common cold, PUO, influenza: Crude powder-1.2 g daily.

Purified Andrographolide: 40mg. Some recommend 1.5–3.0 g powdered crude drug three times daily, after meals and at bedtime

For diarrhea: Decoction from 3–9 g crude drug as a single dose as needed, or two tablets of 500 mg four times daily, after meals and at bedtime

For fever with rigors: mixture of Kaalamegha and Pepper is used es daily, after meals and at bedtime SA'>Andrographolide: 40mg. Some recommend 1.5–3.0 g powdered crude drug three times daily, after meals and at bedtime

Kaalamegha Kwaatha: 20 to 40 ml

Kaalamegha Swarasa: 5 to 10 ml [243]

Panchaanga Choorna: 0.5-1.25 gm b.i.d. [244], [245]

References:

[1]http://www.huffingtonpost.com/richard-palmquist-dvm/andrographis_b_1221334.html 

[2] http://en.wikipedia.org/wiki/Andrographis_paniculata 

[3]http://library.everyonehealthy.com/library/treatmentcategory/Alternative% 20and%20Complementary%20Therapy/Andrographis%20Paniculata 

[4]  Melchior J, Palm S, Wikman G, Phytomedicine 1997, 3: 4 Feb, 1997, pages 315-318 

[5] http://en.wikipedia.org/wiki/1918_flu_pandemic

[6]http://virus.stanford.edu/udahttp://www.planetayurveda.com/andrographis_paniculata.htm 

[7] Andrographis, In-depth review, http://www.altcancer.com/andcan.htm 

[8] http://en.wikipedia.org/wiki/Andrographis_paniculata 

[9] http://www.hort.purdue.edu/newcrop/CropFactSheets/andrographis.html 

[10] http://en.wikipedia.org/wiki/Andrographis_paniculata 

[11] http://www.herbaxisnutrition.com/wp-content/uploads/2012/09/Bioactivity-of-Andrographis-Paniculata.pdf 

[12]B. Parixit et al, The genus Andrographis- A review, International Journal of Pharmaceutical Sciences, Volume 4, No. 1, pp. 1835- 1856, 2012

[13] S. K. Roy, P. Datta, Chromosomal biotypes of Andrographis pniculata in India and Bangladesh, Cytologia, Volume 53, No. 2, pp. 369-378, 1988

[14]Aromatic and Medicinal plants of Central India, http://www.jnkvv-aromedicinalplants.in/front/Plant_Details/index.php?pid=14

[15] Wu Z et al,  Flora of China; Cucurbitaceae Through Valerinaeceae with Annonaceae and Berberidaceae. Beijing, China: Science Press; 1996 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408759/ 

[16]Google images        

[17] http://en.wikipedia.org/wiki/Andrographis_paniculata 

[18] Botanical Morphology of Andrographis paniculata

http://www.mdidea.com/products/proper/proper10302.html

[19] Sudhakaran MV, Department of Drug Standardisation, Government Ayurveda College, Thiruvananthapuram-695 001, Kerala, India; Botanical pharmacognosy of Andrographis paniculata (Burm. F.) Wall. Ex. Nees; Submission Date: 9-5-2012; Review Completed: 30-5-2012; Accepted Date: 19-7-2012 

[20] Priyanka Das, Alok Kumar Srivastav, Phytochemical Extraction and Characterization of the Leaves of Andrographis Paniculata for Its [21]AntiBacterial, Anti-Oxidant, Anti-Pyretic and AntiDiabetic Activity,  International Journal of Innovative Research in Science, Engineering and Technology, Volume 3, Issue 8, August 2014 

[22] Shirishta K et al, Andrographis paniculata and its bioactive phytochemical constituents for oxidative damage: A systemic review, Pharmacophore 2013, Volume 4 (6): 212-225 

[23] Goodman, S., L., and Gilman, A. The Pharmacological Basis of Therapeutics, IX edition-Macmillan Publishing Co Inc, New York: 959- 975.2000

[24] www.books.google.co.in        

[25] http://ipc.nic.in/writereaddata/linkimages/Admin9640017989.pdf 

[26] HJ Dong et al, Chemical fingerprinting of Andrographis paniculata (Burm. F.) Ness by HPLC and hierarchical clustering analysis, Journal…..2009, Chromsci.oxfordlournals.org    

[27] Sharma A. L. et al, 1992, Standardization of the Indian crude drug Kalmegh by high pressure liquid chromatographic determination of Andrographolide, Phytochemical analysis, 3:129-31 

[28] Sunday J Ameh et al, Quality Control Tests on Andrographis paniculata Nees (Family: Acanthaceae) – an Indian ‘Wonder’ Plant Grown in Nigeria, Tropical Journal of Pharmaceutical Research August 2010; 9 (4): 387-394

[29] http://download.fa.itb.ac.id/filenya/Handout%20Kuliah/Analytical%20Pharmacognosy/07.%20Physical%20and%20chemical%20parameters%20of%20crude%20drugs%20and%20their%20products.pdf 

[30] B. Parixit et al, The genus Andrographis- A review, International Journal of Pharmaceutical Sciences, Volume 4, No. 1, pp. 1835- 1856, 2012 

[31] S. K. Roy, P. Datta, Chromosomal biotypes of Andrographis pniculata in India and Bangladesh, Cytologia, Volume 53, No. 2, pp. 369-378, 1988

[32] Wijarat P et al, Genetic evaluation of Andrographis paniculata (Burm. F.) Ness revealed by SSR, AFLD, and RAPD markers, Journal of Medicinal Plants Research Volume 6 (14), pp. 2777-2788, 16 April, 2012

[33] http://www.ayurwiki.info/wiki/kalemegha, www.evaidyaji.com 

[34] Andrographis, In-depth review, http://www.altcancer.com/andcan.htm 

[35] http://en.wikipedia.org/wiki/Andrographolide 

[36] http://en.wikipedia.org/wiki/Phorbol 

[37] Signal Transduction Companies (editorial). 1996. Genetic Engineering News 16(1), 1 January 

[38] Tang, W., and G. Eisenbrandt. 1992. Chinese drugs of plant origin: Chemistry, pharmacology, and use in traditional and modern medicine. New York: Springer-Verlag.  

[39] http://www.chemicalbook.com/ChemicalProductProperty_EN_CB6735337.htm 

[40] PMID: 9673817, PubMed- indexed for MEDLINE 

[41] PMID: 10190192, PubMed - indexed for MEDLINE 

[42] Burgos RA et al, PMID: 14595578 PubMed - indexed for MEDLINE 

[43] DN Roy, S Mandal, G Sen, S Mukhopadhyay, T Biswas, British Journal of Pharmacology, Volume 160, Issue 7, August 2010 

[44] PMID: 16041644      

[46] C. P. Khare, Indian Herbal Remedies: Rational Western Therapy, Ayurvedic and Other Traditional Usage, Botany  

[47] Simon Mills and Kerry Bone, Principles and Practice of Phytotherapy: Modern Herbal Medicine

[48] https://commons.wikimedia.org/wiki/File:paniculide_A.png

[49] kanaya.naist.jp/knapsack_jsp/information.jsp?word=C00011908 

[50] http://www.ebuychem.com/product/21764-32-9.html 

[51] http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5318506 

[52]C. P. Khare-2004-medical, http://books.google.co.in

[53] Jean Barilla, M.S., 1999. Andrographis paniculata: Can herbs fight common ailments, cancer, and chronic viral infections?, A Keats Good Health Guide, p. 17-20. 

[54] Andrographis, In-depth review, http://www.altcancer.com/andcan.htm 

[55] Panossian A et al, Pharmacokinetic and oral bioavailability of Andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human, Phytomedicine 2000; 7: 351-64 

[56] Sheeja K, Shihab PK, Kuttan G. Antioxidant and anti-inflammatory activities of the plant Andrographis paniculata Nees. Immunopharmacol Immunotoxicol 2006; 28:129-140. 

[57] Manez S et al, 1990, Selected extracts from medicinal plants as anti-inflammatory agents,  Andrographis,

In-depth review, http://www.altcancer.com/andcan.htm 

[58] Deng WL 1978. Outline of current clinical and pharmacological research on Andrographis paniculata in China. Newsletters of Chinese  Herbal Med. 10:27-31  

[59] Yin J, Guo L, 1993, Contemporary traditional Chinese medicine. Beijing: Xie Yuan 

[60] Deng WL, 1978. Preliminary studies on the pharmacology of the Andrographis product dihydroAndrographolide sodium succinate. Newsletters of Chinese Herbal Med. 8:26-28   

[61] Abu-Ghefreh AA, Canatan H, Ezeamuzie CI. In vitro and in vivo anti-inflammatory effects of Andrographolide. Int Immunopharmacol 2009;9:313-318 

[62] Herbal Research- Menolyte Chuan Xin Lian 

[63] Herbal Research- Menolyte Chuan Xin Lian; http://www.chineseherbshealing.com/andrographis-paniculata-chuan-xin-lian/ 

[64] http://diagnostiki.gr/herbal/menolyte_08.shtml 

[65] Batkhuu J, Hattori K, Takano F, et al. Suppression of NO production in activated macrophages in vitro and ex vivo by neoAndrographolide isolated from Andrographis paniculata. Biol Pharm Bull 2002;25:1169-1174. 

[66]  Chiou WF, Lin JJ, Chen CF. Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipo-polysaccharide. Br J Pharmacol 1998;125:327-334. 

[67]  Chiou WF, Chen CF, Lin JJ. Mechanism of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by Andrographolide. Br J Pharmacol 2000;129:1553-1560.

[68] Liu J, Wang ZT, Ji LL, Ge BX. Inhibitory effects of neoAndrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage. Mol Cell Biochem 2007;298:49-57.

[69] Shen YC, Chen CF, Chiou WF. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol 2002; 135:399-406. 

[70] Liu J, Wang ZT, Ji LL. In vivo and in vitro anti-inflammatory activities of neoandro-grapholide. Am J Chin Med 2007;35:317-328. 

[71] A. Kar. Pharmaocgnosy and Pharmacobiotechnology (Revised-Expanded Second Edition). New Age International Limted Publishres New Delhi. 2007, 332-600. 

[72] S. D. Sarker, & Nahar L. Chemistry for Pharmacy Students General, Organic and Natural Product Chemistry. England: John Wiley and Sons. 2007, 283-359. 

[73] Sangeeta Huidrom* and Manab Deka, Determination of antioxidant property of Andrographis paniculata Indian Journal of Drugs and Diseases Vol.1 No.1 (Apr 2012) 

[74] Das S, Gautam N, Dey SK, et al. Oxidative stress in the brain of nicotine-induced toxicity: protective role of Andrographis paniculata Nees and vitamin E. Appl Physiol Nutr Metab 2009; 34:124-135. 

[75] Lin FL, Wu SJ, Lee SC, Ng LT. Antioxidant, antioedema and analgesic activities of Andrographis paniculata extracts and their active constituent Andrographolide. Phytother Res 2009; 23:958-964 

[76] Herbal Research- Menolyte Chuan Xin Lian 

[77] Herbal Research- Menolyte Chuan Xin Lian; http://www.chineseherbshealing.com/andrographis-paniculata-chuan-xin-lian/ 

[78] http://diagnostiki.gr/herbal/menolyte_08.shtml 

[79] Puri A et al, Immunostimulant agents from Andrographis paniculata. Journal of Natural Products, 1993, 56: 995-999

Experimental pharmacology, ayurnepal.com/ Andrographis paniculata 

[80] George M, Pandalai KM, Investigations on plant antibiotics. Part IV. Further search for antibiotic substances in Indian medicinal plants, Indian Journal of Medical Research, 1949, 37: 169-189 

[81] Nakanishi K et al, Phytochemical survey of Malaysian plants: perliminary chemical and pharmacological screening, Chemical and pharmaceutical Bulletin, 1965, 13: 882-890  

[66]  Chiou WF, Lin JJ, Chen CF. Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipo-polysaccharide. Br J Pharmacol 1998;125:327-334. 

[67]  Chiou WF, Chen CF, Lin JJ. Mechanism of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by Andrographolide. Br J Pharmacol 2000;129:1553-1560.

[68] Liu J, Wang ZT, Ji LL, Ge BX. Inhibitory effects of neoAndrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage. Mol Cell Biochem 2007;298:49-57.

[69] Shen YC, Chen CF, Chiou WF. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol 2002; 135:399-406. 

[70] Liu J, Wang ZT, Ji LL. In vivo and in vitro anti-inflammatory activities of neoandro-grapholide. Am J Chin Med 2007;35:317-328.  

[71] A. Kar. Pharmaocgnosy and Pharmacobiotechnology (Revised-Expanded Second Edition). New Age International Limted Publishres New Delhi. 2007, 332-600. 

[72] S. D. Sarker, & Nahar L. Chemistry for Pharmacy Students General, Organic and Natural Product Chemistry. England: John Wiley and Sons. 2007, 283-359. 

[73] Sangeeta Huidrom* and Manab Deka, Determination of antioxidant property of Andrographis paniculata Indian Journal of Drugs and Diseases Vol.1 No.1 (Apr 2012)  

[74] Das S, Gautam N, Dey SK, et al. Oxidative stress in the brain of nicotine-induced toxicity: protective role of Andrographis paniculata Nees and vitamin E. Appl Physiol Nutr Metab 2009; 34:124-135. 

[75] Lin FL, Wu SJ, Lee SC, Ng LT. Antioxidant, antioedema and analgesic activities of Andrographis paniculata extracts and their active constituent Andrographolide. Phytother Res 2009; 23:958-964 

[76] Herbal Research- Menolyte Chuan Xin Lian 

[77] Herbal Research- Menolyte Chuan Xin Lian; http://www.chineseherbshealing.com/andrographis-paniculata-chuan-xin-lian/ 

[78] http://diagnostiki.gr/herbal/menolyte_08.shtml 

[79] Puri A et al, Immunostimulant agents from Andrographis paniculata. Journal of Natural Products, 1993, 56: 995-999, Experimental pharmacology, ayurnepal.com/ Andrographis paniculata 

[80] George M, Pandalai KM, Investigations on plant antibiotics. Part IV. Further search for antibiotic substances in Indian medicinal plants, Indian Journal of Medical Research, 1949, 37: 169-189  

[81] Nakanishi K et al, Phytochemical survey of Malaysian plants: perliminary chemical and pharmacological screening, Chemical and pharmaceutical Bulletin, 1965, 13: 882-890  

[66]  Chiou WF, Lin JJ, Chen CF. Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipo-polysaccharide. Br J Pharmacol 1998;125:327-334. 

[67]  Chiou WF, Chen CF, Lin JJ. Mechanism of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by Andrographolide. Br J Pharmacol 2000;129:1553-1560.

[68] Liu J, Wang ZT, Ji LL, Ge BX. Inhibitory effects of neoAndrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage. Mol Cell Biochem 2007;298:49-57.

[69] Shen YC, Chen CF, Chiou WF. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol 2002; 135:399-406.  

[70] Liu J, Wang ZT, Ji LL. In vivo and in vitro anti-inflammatory activities of neoandro-grapholide. Am J Chin Med 2007;35:317-328. 

[71] A. Kar. Pharmaocgnosy and Pharmacobiotechnology (Revised-Expanded Second Edition). New Age International Limted Publishres New Delhi. 2007, 332-600.  

[72] S. D. Sarker, & Nahar L. Chemistry for Pharmacy Students General, Organic and Natural Product Chemistry. England: John Wiley and Sons. 2007, 283-359.  

[73] Sangeeta Huidrom* and Manab Deka, Determination of antioxidant property of Andrographis paniculata Indian Journal of Drugs and Diseases Vol.1 No.1 (Apr 2012) 

[74] Das S, Gautam N, Dey SK, et al. Oxidative stress in the brain of nicotine-induced toxicity: protective role of Andrographis paniculata Nees and vitamin E. Appl Physiol Nutr Metab 2009; 34:124-135.  

[75] Lin FL, Wu SJ, Lee SC, Ng LT. Antioxidant, antioedema and analgesic activities of Andrographis paniculata extracts and their active constituent Andrographolide. Phytother Res 2009; 23:958-964  

[76] Herbal Research- Menolyte Chuan Xin Lian  

[77] Herbal Research- Menolyte Chuan Xin Lian; http://www.chineseherbshealing.com/andrographis-paniculata-chuan-xin-lian/ 

[78] http://diagnostiki.gr/herbal/menolyte_08.shtml 

[79] Puri A et al, Immunostimulant agents from Andrographis paniculata. Journal of Natural Products, 1993, 56: 995-999;  Experimental pharmacology, ayurnepal.com/ Andrographis paniculata 

[80] George M, Pandalai KM, Investigations on plant antibiotics. Part IV. Further search for antibiotic substances in Indian medicinal plants, Indian Journal of Medical Research, 1949, 37: 169-189 

[81] Nakanishi K et al, Phytochemical survey of Malaysian plants: perliminary chemical and pharmacological screening, Chemical and pharmaceutical Bulletin, 1965, 13: 882-890  

[66]  Chiou WF, Lin JJ, Chen CF. Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipo-polysaccharide. Br J Pharmacol 1998;125:327-334.  

[67]  Chiou WF, Chen CF, Lin JJ. Mechanism of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by Andrographolide. Br J Pharmacol 2000;129:1553-1560. 

[68] Liu J, Wang ZT, Ji LL, Ge BX. Inhibitory effects of neoAndrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage. Mol Cell Biochem 2007;298:49-57.

[69] Shen YC, Chen CF, Chiou WF. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol 2002; 135:399-406. 

[70] Liu J, Wang ZT, Ji LL. In vivo and in vitro anti-inflammatory activities of neoandro-grapholide. Am J Chin Med 2007;35:317-328. 

[71] A. Kar. Pharmaocgnosy and Pharmacobiotechnology (Revised-Expanded Second Edition). New Age International Limted Publishres New Delhi. 2007, 332-600. 

[72] S. D. Sarker, & Nahar L. Chemistry for Pharmacy Students General, Organic and Natural Product Chemistry. England: John Wiley and Sons. 2007, 283-359.  

[73] Sangeeta Huidrom* and Manab Deka, Determination of antioxidant property of Andrographis paniculata Indian Journal of Drugs and Diseases Vol.1 No.1 (Apr 2012)  

[74] Das S, Gautam N, Dey SK, et al. Oxidative stress in the brain of nicotine-induced toxicity: protective role of Andrographis paniculata Nees and vitamin E. Appl Physiol Nutr Metab 2009; 34:124-135.  

[75] Lin FL, Wu SJ, Lee SC, Ng LT. Antioxidant, antioedema and analgesic activities of Andrographis paniculata extracts and their active constituent Andrographolide. Phytother Res 2009; 23:958-964  

[76] Herbal Research- Menolyte Chuan Xin Lian  

[77] Herbal Research- Menolyte Chuan Xin Lian; http://www.chineseherbshealing.com/andrographis-paniculata-chuan-xin-lian/  

[78] http://diagnostiki.gr/herbal/menolyte_08.shtml  

[79] Puri A et al, Immunostimulant agents from Andrographis paniculata. Journal of Natural Products, 1993, 56: 995-999; Experimental pharmacology, ayurnepal.com/ Andrographis paniculata 

[80] George M, Pandalai KM, Investigations on plant antibiotics. Part IV. Further search for antibiotic substances in Indian medicinal plants, Indian Journal of Medical Research, 1949, 37: 169-189 

[81] Nakanishi K et al, Phytochemical survey of Malaysian plants: perliminary chemical and pharmacological screening, Chemical and pharmaceutical Bulletin, 1965, 13: 882-890  

[66]  Chiou WF, Lin JJ, Chen CF. Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipo-polysaccharide. Br J Pharmacol 1998;125:327-334.  

[67]  Chiou WF, Chen CF, Lin JJ. Mechanism of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by Andrographolide. Br J Pharmacol 2000;129:1553-1560.

[68] Liu J, Wang ZT, Ji LL, Ge BX. Inhibitory effects of neoAndrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage. Mol Cell Biochem 2007;298:49-57.

[69] Shen YC, Chen CF, Chiou WF. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol 2002; 135:399-406. 

[70] Liu J, Wang ZT, Ji LL. In vivo and in vitro anti-inflammatory activities of neoandro-grapholide. Am J Chin Med 2007;35:317-328.  

[71] A. Kar. Pharmaocgnosy and Pharmacobiotechnology (Revised-Expanded Second Edition). New Age International Limted Publishres New Delhi. 2007, 332-600. 

[72] S. D. Sarker, & Nahar L. Chemistry for Pharmacy Students General, Organic and Natural Product Chemistry. England: John Wiley and Sons. 2007, 283-359.  

[73] Sangeeta Huidrom* and Manab Deka, Determination of antioxidant property of Andrographis paniculata Indian Journal of Drugs and Diseases Vol.1 No.1 (Apr 2012)  

[74] Das S, Gautam N, Dey SK, et al. Oxidative stress in the brain of nicotine-induced toxicity: protective role of Andrographis paniculata Nees and vitamin E. Appl Physiol Nutr Metab 2009; 34:124-135.  

[75] Lin FL, Wu SJ, Lee SC, Ng LT. Antioxidant, antioedema and analgesic activities of Andrographis paniculata extracts and their active constituent Andrographolide. Phytother Res 2009; 23:958-964  

[76] Herbal Research- Menolyte Chuan Xin Lian  

[77] Herbal Research- Menolyte Chuan Xin Lian; http://www.chineseherbshealing.com/andrographis-paniculata-chuan-xin-lian/ 

[78] http://diagnostiki.gr/herbal/menolyte_08.shtml  

[79] Puri A et al, Immunostimulant agents from Andrographis paniculata. Journal of Natural Products, 1993, 56: 995-999; Experimental pharmacology, ayurnepal.com/ Andrographis paniculata 

[80] George M, Pandalai KM, Investigations on plant antibiotics. Part IV. Further search for antibiotic substances in Indian medicinal plants, Indian Journal of Medical Research, 1949, 37: 169-189 

[81] Nakanishi K et al, Phytochemical survey of Malaysian plants: perliminary chemical and pharmacological screening, Chemical and pharmaceutical Bulletin, 1965, 13: 882-890 

[82] Leelarasamee A et al, Undetectable antibacterial activity of Andrographis paniculata (Burm) Wall. Ex Ness. Journal of the Medical Association of Thailand, 1990, 73: 299-304.  

[83] S. D. Sarker, & Nahar L. Chemistry for Pharmacy Students General, Organic and Natural Product Chemistry. England: John Wiley and Sons. 2007, 283-359.  

[84] Harborne J.B. Biochemistry of phenolic compounds. academic, London.1964, 511-543. 

[85] Herbal Research-Menolyte Chuan Xin Lian  

[86] Herbal Research- Menolyte Chuan Xin Lian; http://www.chineseherbshealing.com/andrographis-paniculata-chuan-xin-lian/  

[87] http://diagnostiki.gr/herbal/menolyte_08.shtml  

[88] Shanghai City Andrographis Research Group, 1976. A study on water-soluble Andrographolide. Newsletters of Chinese Herbal Med. 3:10-18.  

[89] ZaidanM.R. et al, In vitro screening of five local medicinal plants for anti]acterial activity using disc diffusion method, Trop Biomed, 2005; 22:165-170.  

[90] Sukesh K. et al, J. Phytochemical investigation and antibacterial activity of Gymnemasylvestre and Andrographis paniculatafrom western ghats, Int. J. Phytomedicine 3. 2011, 254- 260. 

[91] Singha P.K. et al, Protective activity of Andrographolide and arabinogalactan proteins from Andrographis paniculataNees against ethanol-induced toxicity in mice. J Ethnopharmacol. 2007, 111, 13-21.  

[92] Herbal Research-Menolyte Chuan Xin Lian  

[93] Herbal Research- Menolyte Chuan Xin Lian; http://www.chineseherbshealing.com/andrographis-paniculata-chuan-xin-lian/ 

[94]http://diagnostiki.gr/herbal/menolyte_08.shtml  

[95] www.vitaminherbuniversity.com  

[96] https://en.wikipedia.org/wiki/1918_flu_pandemic  

[97] www.equilibrauk.com/Andrographis.pdf  

[98] Weibo L, 1995.Prospect for study on treatment of AIDS with traditional Chinese medicine, J TradeChinese Med, 15(1): 3-9

[99] Holt, Stephen MD, Linda Comac, Miracle Herbs: How Herbs combine with Modern Medicine to Treat Cancer, Heart Disease, AIDS and More, Caro Publishing Group, 1998

[100] Chturvedi, G.N., G.S. Tomar, S.K. Tiwari, and K.P. Singh. 1983. Clinical studies on Kalmegh (Andrographis paniculataNees) in infective hepatitis. Journal of International Institute of Ayurveda 2:208-11.   

[101] Deng, W.L. 1978. Outline of current clinical and pharmacological research on Andrographis paniculata in China, Newsletters of Chinese Herbal Med. 10:27-31.  

[102] Misra, P., N.L. Pal, P.Y. Guru, J.C. Katiyar, V. Srivastava, J.S. Tandon. 1992. Antimalarial activity of Andrographis paniculata (Kalmegh) against Plasmodim berghei NK 65 in Mastomys natalensis. Int. J. Pharmacog. 30(4): 263-74. ra K, Dash AP, Swain BK, Dey N, Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combinations with curcumin, Malar J 2009 Feb 12; 8: 26  

[103] Mishra K, Dash AP, Swain BK, Dey N, Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combinations with curcumin, Malar J 2009 Feb 12; 8: 26

[104] C. Kuppusamy and K. Murugan, “Mosquitocidal effect of Andographis paniculata Nees against the malaria vector, Anopheles stephensi Liston (Diptera: culicidae),” International Journal of Integrative Biology, vol. 5, no. 2, pp. 75–81, 2009.

[105] B. D. Sheeja, D. Sindhu, J. Ebanasar, and S. Jeeva, “The Larvicidal activity of Andrographis paniculata(Burm. f) Nees against Culex quinquefasciatus Say (Insecta: Diptera-Culicidae), a filarial vector,” Asian Pacific Journal of Tropical Disease, pp. S574–S578, 2012

[106] K. Chenniappan and M. Kadarkarai, “Oviposition deterrent, ovicidal and gravid mortality effects of ethanolic extract of Andrographis paniculata Nees against the malarial vector Anopheles stephensi Liston (Diptera: Culicidae),” Entomological Research, vol. 38, no. 2, pp. 119–125, 2008

[107] M. Govindarajan, “Evaluation of Andrographis paniculata Burm.f. (Family:Acanthaceae) extracts against Culex quinquefasciatus (Say.) and Aedes aegypti (Linn.) (Diptera: Culicidae),” Asian Pacific Journal of Tropical Medicine, vol. 4, no. 3, pp. 176–181, 2011

[108] B. D. Sheeja, D. Sindhu, J. Ebanasar, and S. Jeeva, “The Larvicidal activity of Andrographis paniculata(Burm. f) Nees against Culex quinquefasciatus Say (Insecta: Diptera-Culicidae), a filarial vector,” Asian Pacific Journal of Tropical Disease, pp. S574–S578, 2012; http://www.hindawi.com/journals/ecam/2013/846740/ 

[109] Suparna Deepak et al, Study of antioxidant and antimicrobial activities of Andrographis paniculata, Asian J. Plant Sci. Res., 2014, 4(2):31-41

[110] Abubkar Sule et al, Bacteriostatic and bactericidal activities of Andrographis paniculata extracts on skin disease causing pathogenic bacteria, Journal of Medicinal Plants Research Volume 5(1), pp. 7-14, 4 January, 2011 

[111] P. von Hundelshausen and C. Weber, “Platelets as immune cells: bridging inflammation and cardiovascular disease,” Circulation Research, vol. 100, no. 1, pp. 27–40, 2007 

[112] E. Amroyan, E. Gabrielian, A. Panossian, G. Wikman, and H. Wagner, “Inhibitory effect of Andrographolide from Andrographis paniculata on PAF-induced platelet aggregation,” Phytomedicine, vol. 6, no. 1, pp. 27–31, 1999

[113] W. J. Lu, K. H. Lin, M. J. Hsu, D. S. Chou, G. Hsiao, and J. R. Sheu, “Suppression of NF-κB signaling by Andrographolide with a novel mechanism in human platelets: regulatory roles of the p38 MAPK-hydroxyl radical-ERK2 cascade,” Biochemical Pharmacology, vol. 84, pp. 914–924, 2012

[114] http://www.hindawi.com/journals/ecam/2013/846740/ 

[115] Thisoda P, Rangkadilok N, Pholphana N. et al. Inhibitory effect of Andrographis paniculata extract and its active diterpenoids on platelet aggregation. Eur J Pharmacol 2006; 553:39-45. 

[116] Huang LY 1987. The effects of Andrographolides on experimental deficiency of cardiac muscle, Chinese Herbal Med, 18(7): 26-28 

[117] Amroyan E, Gabrielian E, Panossian A, et al. Inhibitory effect of Andrographolide from Andrographis paniculata on PAF-induced platelet aggregation. Phytomedicine 1999; 6:27-31.  

[118] Zhang YZ, Tang JZ, Zhang YJ. Study of Andrographis paniculata extracts on antiplatelet aggregation and release reaction and its mechanism. Zhongguo Zhong Xi Yi Jie He Za Zhi 1994; 14:28-35  

[119] Vedavathy, S. and K.N. Rao. 1991. Antipyretic activity of six indigenous medicinal plants of Tirumala Hills, Andhra Pradesh, India. Ethnopharmacology 33:193-96.  

[120] Vedavathy S, and K. N. Rao 1991. Antipyretic activity of six indigenous medicinal plants of Tirumala Hills, Andhra Pradesh, India. Ethnopharmacology 33: 193-96     

[121] Wang Y.S. (1983) Pharmacology and Applications of Chinese Materia Medica, pp. 822-836; people’s Health Publisher

[122] Deng WL, Nie RJ, Liu JY (1982), Comparison of pharmacological effect of four Andrographolides. Chinese Pharmaceutical Bulletin, 17, 195-198 

[123] Deng, W.L. 1978. Preliminary studies on the pharmacology of the Andrographis product dihydroAndrographolide sodium succinate. Newsletters of Chinese Herbal  Med. 8:26-28.  

[124] Wang YS (1983) Pharmacology and Applications of Chinese Materia Medica PP. 822-836. Beijing: people’s Health Publisher

[125] http://diagnostiki.gr/herbal/menolyte_08.shtml

[126] Weibo L 1995, Prospect for study on treatment for AIDS with traditional Chinese medicine, J Trad Chinese Med, 15 (1): 3-9

[127] Deng WL 1978, Preliminary studies on the pharmacology of Andrographis product dihydroAndrographolide sodium succinate, Newsletters of Chinese Herbal Med, 8:26-28

[128]Wang YS (1983) Pharmacology and Applications of Chinese Materia Medica PP. 822-836. Beijing: people’s Health Publisher;  http://diagnostiki.gr/herbal/menolyte_08.shtml

[129] Zhang CY Tan BK, Hypotensive activity of aqueous extract of andrographis paniculata in rats, Clin Exp Pharmacol Physiol 1996; 23: 675-678  

[130] Zang CV, Tan BK, Mechanism of cardiovascular activity of Andrographis paniculata in anaesthetized rats. J. Ethnopharmacol 1997; 56: 97-101  

[131] Zhang CY, Kuroyangi, Tan BK, Cardiovascular activity of 14-deoxy-11,,12-didehydro-Andrographolide in anaesthetized rat and isolated right atria, Pharmacol Res 1998; 38: 413-417   

[132] Yoopan N et al, Cardiovascular effects of 14-deoxy-11, 12-dide-hydroAndrographolide and Andrographis paniculata extracts. Planta Med 2007; 73: 503-511.  

[133] Chiou WF, Lin JJ, Chen CF. Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipo-polysaccharide, Br J Pharmacol 1998; 125:327-334.  

[134] Wang HW, Zhao HY, Xiang SQ. Effects of Andrographis paniculata component on nitric oxide, endothelin and lipid peroxidation in experimental atherosclerotic rabbits. Zhongguo Zhong Xi Yi Jie He Za Zhi 1997;17:547-549. [Article in Chinese] 

[135] Zao HY, Fang WY, protective effects of Andrographis paniculata Ness. On post-infarction myocardium in experimental dogs. J Tongji Med Univ 1990; 10: 212-217   

[136] Zao HY, Fang WY, Antithrombic effects of Andrographis paniculata Ness. in preventing myocardial infarction. Chinese Med J (Engl) 1991; 104:770-775 

[137] Guo ZL, Zao HY, Zheng XH, The effect of Andrographis paniculata Ness. (APN) in alleviating the myocardial ischemic reperfusion injury. J Tongji Med Univ 1994; 14: 49-51 

[138] Guo ZL, Zao HY, Zheng XH, An experimental study of the mechanism of Andrographis paniculata Ness. (APN) in alleviating the Ca2+ overloading in the process of myocardial ischemic reperfusion. J Tongji Med Univ 1995; 15: 205-208 

[139] Woo Ay et al, Andrographolide up-regulates cellular reduced glutathione level and protects cardiomyocytes against hypoxia / re-oxygenation injury. J Pharmacol Exp Ther, 2008; 325: 226-235 

[140] Guo ZL, Zhao H, Fu L, protective effect of API0134 on myocardial ischemia and reperfusion injury. J Tongji Med Univ 1996; 16: 193-197  

[141] S.K. Ojha, M. Nandave, S. Kumari and D.S. Arya 1 Antioxidant Activity of Andrographis paniculata in Ischemic Myocardium of Rats Global Journal of Pharmacology, 3 (3): 154-157, 2009  

[142] Wang DW, Zhao HY, Experimental studies on prevention of atherosclerotic arterial stenosis and restenosis after angioplasty with Andrographis paniculata Nees and fish oil. J Tongji Med Univ 1993; 13:193-198.  

[143] Wang DW, Zhao HY, Prevention of atherosclerotic arterial stenosis and restenosis after angioplasty with Andrographis paniculata Nees and fish oil. Experimental studies of effects and mechanisms. Chinese Med J (Engl) 1994; 107:464-470.  

[144] Jun Ren et al, The Journal of Pharmacology and Experimental Therapeutics,

http://jpet.aspetjournals.org/content/suppl/2015/10/20/jpet.115.227934.DC1/2279 34_suppl_figs.pdf  

[145] Chang HM, But PPH. Pharmacology and Applications of Chinese Materia Medica. English translation by Shem Chang-Shing Yeung, Sih Cheng-Yao and Lai-Ling Wang (Chinese Medicinal Material Research Centre, The Chinese University of Hong Kong), Singapore: World Scientific Publishing Co. Pte. Ltd; 1987; 2:918-928  

[146] Caceres D.D. , J.L. Hancke, R.A. Burgos, and G.K. Wikman. 1997. Prevention of common colds with Andrographis paniculatadried extract: A pilot double-blind trial. Phytomedicine. 4(2): 101-4.  

[147] Burgos R.A., and D.D. Caceres. A double-blind study with a new mono drug: Kan-Jang: decrease of symptoms and enhancement of resistance in common colds. Research performed at the University of Chile, Departments of Pharmacology and School of Public Health, Santiago, Chile and funded by the Swedish Herbal Institute. August 1994.

[148] Deng, W.L. 1978. Preliminary studies on the pharmacology of the Andrographis product dihydroAndrographolide sodium succinate,  Newsletters of Chinese Herbal  Med. 8:26-28.  

[149] Second traditional Chinese medicine pharmaceutical factory in Shanghai test and manufacture of the water-soluble Andrographolide injections. 1976. Med. Industry 1:24-31.  

[150] Thamilitkul V et al, Efficacy of Andrographis paniculata, Ness for pharyngotonsillitis in adults, J Med Assoc Thai 1991; 74: 437-42   

[151] Department of the Infectious Disease of the People's Hospital of Shantou Prefecture. 1977. Clinical observation of seventy cases of tubercular meningitis treated with Andrographis and rifampin. New Med. 1:14-15.  

[152] Gupta S, Antisecretory (antidiarrhoeal) activity of Indian medicinal plants against Escherichia coli enterotoxin-induced secretion in rabbits and guinea-pig ileal loop models. International Journal of Pharmacognosy, 1993, 31:198-204 

[153] Gupta S, Antidiarrhoeal activity of diterpenes of Andrographis paniculata (kalmegh) against Escherichia coli enterotoxin in invitro models, International Journal of Crude Drug Research, 1990, 28: 273-283 

[154] Yin J, L. Guo, 1993, Contemporary traditional Chinese medicine, Beijing: Xie Yuan 

[155] Deng, W.L. 1978. Outline of current clinical and pharmacological research on Andrographis paniculata in China.Newsletters of Chinese Herbal Med. 10:27-31. 

[156] Yin J, L. Guo, 1993, Contemporary traditional Chinese medicine, Beijing: Xie Yuan 

[157] Ambreen Shoaib et al, Antiulcerogenic activity of hydromethanolic extract of Andrographis paniculata in Indomethacin plus pylorus ligation induced gastric ligation in rats,

http://www.jbiopharm.com/index.php/ajbps/article/view/635  

[158] Shukla B et al, 1992, Choleretic effect of Andrographolide in rats and guinea pigs, Planta Med, 58: 146-48  

[159] Handa SS, Sharma A. Hepatoprotective activity of Andrographolide against galactosamine and paracetamol intoxication in rats. Indian J Med Res 1990; 92:284-292. 33.  

[160], Choudhary BR, Poddar MK. Andrographolide and Kalmegh (Andrographis paniculata) extract: in vivo and in vitro effect on hepatic lipid peroxidation. Methods Find Exp Clin pharmacol 1984, 6, 481-485

[161] Aruna Kapil, I. B. Koul, S. K. Banerjee, B. D. Gupta, Antihepatotoxic effects of major diterpene constituents of Andrographis paniculata, Biochemical Pharmacology, Volume 46, issue 1, July 6 1993, Pages 182-185 

[162] Kapil A, Koul IB, Banerjee SK, Gupta BD Antihepatotoxic effects of major diterpenoid constituents of  Andrographis paniculata Biochem Pharmacol 1993, 46, 182- 185  

[163] Choudhary BR, Poddar MK. Effect of alcohol induced liver damage in rats by Andrographis paniculata Methods Find Exp Clin pharmacol 1983, 5, 727-730  

[164] Chander R, Srivastava V, Tandon SK, Kapoor NK, Antihepatotoxic activity of diterpenes of Andrographis paniculata (Kalmegh) against Plasmodium burghei- induced hepatic damage in Mastomys natalensis. Int J of Pharmacolog 1995, 33, 135-138  

[165] Holt, Stephen M.D., Linda Comac, Miracle Herbs: How Herbs Combine with Modern Medicine to Treat Cancer, Heart Disease, AIDS, and More, Caro Publishing Group, 1998. 

[167] Holt, Stephen M.D., Linda Comac, Miracle Herbs: How Herbs Combine with Modern Medicine to Treat Cancer, Heart Disease, AIDS, and More, Caro Publishing Group, 1998. 

[168] Shukla, B., P.K.S. Visen, G.K. Patnaik, and B.N. Dhawan. 1992. Choleretic effect of Andrographolide in rats and guinea pigs. Planta Med. 58:146-48. 

[169] W. L. Deng, Outline of current clinical and pharmacological research on Andrographis paniculata in China, Newsletters Chinese Herbal Medicine, Vol. 10, pp 27-31; 1978 

[170] Shahid Akbar, MD, PhD, Andrographis paniculata: A Review of Pharmacological Activities and Clinical Effects, Alternative Medicine Review, Volume 16, Number 1   

[171] http://www.altmedrev.com/publications/16/1/66.pdf 

[172] http://www.altcancer.com/andcan.htm, Andrographis: in depth review

[173] T. Yang, H. X. Shi, Z. S. Wang, and Z. H. Wang, “Hypolipidemic effects of Andrographolide and neoAndrographolide in mice and rats,” Phytotherapy Research, 2012. 

[174] Zhang XF, Tan BK. Antidiabetic property of ethanolic extract of Andrographis paniculata in streptozotocin-diabetic rats. Acta Pharmacol Sinica 2000; 21:1157-1164.

[175] Borhanuddin M, Shamsuzzoha M, Hussain AH. Hypoglycemia effects of Andrographis paniculata Nees on non-diabetic rabbits. Bangladesh Med Res Counc Bull 1994; 20:24-26.

[176] Husen R, Pihie AH, Nallappan M. Screening for antihyperglycemic activity in several local herbs of Malaysia. J Ethnopharmacol 2004; 95:205-208 

[177] Dandu AM, Inamdar NM. Evaluation of beneficial effects of antioxidant properties of aqueous leaf extract of Andrographis paniculata in STZ-induced diabetes. Pak J Pharm Sci 2009; 22:49-52. 

[178] Zhang XF, Tan BK. Antihyperglycemic and anti-oxidant properties of Andrographis paniculata in normal and diabetic rats. Clin Exp Pharmacol Physiol 2000; 27:358-363. 

[179] Yu BC, Hung CR, Chen WC, Cheng JT. Antihyperglycemic effect of Andrographolide in streptozotocin-induced diabetic rats. Planta Med 2003; 69:1075-1079. 

[180] Wibudi A, Kiranadi B, Manalu W, et al. th traditional plant, Andrographis paniculata (Sambiloto), exhibits insulin-releasing actions in vitro. Acta Med Indones 2008; 40:63-68 

[181] Subramanian R, Asmawi MZ, Sadikun A. In vitro alpha-glucosidase and alpha-amylase enzyme inhibitory effects of Andrographis paniculata extract and Andrographolide. Acta Biochim Pol 2008; 55:391-398 

[182] Shahid Akbar, MD, PhD Andrographis paniculata: A Review of Pharmacological Effects, Alternative Medicine Review Volume 16, Number 1; http://www.altmedrev.com/publications/16/1/66. pdf 

[182] Department of the Infectious Disease of the People's Hospital of Shantou Prefecture. 1977. Clinical observation of seventy cases of tubercular meningitis treated with Andrographis and rifampin. New Med. 1:14-15.  

[183] Nalamolu Koteswara Rao, Anti-Hypergylcemic and Renal Protective Activities of Andrographis paniculata Roots Chloroform Extract, Indian Journal of Pharmacology & Therapeutics 5: 57-50. 2006  

[184] Xu J et al, Synergetic effect of Andrographis paniculata polysaccharide on diabetic nephropathy with Andrographolide, Int J Biol Macromol, 2012, Dec; 51(5): 738-42. 

[185] Shamsuzzoha M, Rahman MS, Ahmed MM, Islam AK. Anti-fertility effect in mice of medicinal plant of family Acanthaceae. Lancet 1978; 2:900.  

[186] Shamsuzzoha M, Rahman MS, Ahmed MM. Antifertility activity of a medicinal plant of the genus Andrographis Wall (family Acanthaceae). Part II. Bangladesh Med Res Counc Bull 1979; 5:14-18.  

[187] Akbarsha MA, Manivannan B, Hamid KS, Vijayan B. Anti-fertility effect of Andrographis paniculata (Nees) in male albino rats. Indian J Exp Biol 1990; 28:421-426. 

[188] http://ratguide.com/breeding/anatomy/mal...      

[189] http://ratguide.com/breeding/pregnancy/d

[190] Akbarsha MA, Murugaian P, Aspects of the male reproductive toxicity/male antifertility property of Andrographolide in albino rats: effect on the testes and the cauda epididymidal spermatozoa. Phytother Res 2000; 14:432-435. 

[191] Burgos RA, Caballero EE, Sanchez NS, et al. Testicular toxicity assessment of Andrographis paniculata dried extract in rats. J Ethnopharmacol 1997; 58:219-224. 

[192] Reyes BA et al, Anti-diabetic potentials of Momordica charantia and Andrographis paniculata and their effects on estrous cyclicity of alloxan-induced diabetic rats, J Ethnopharmacol, 2006, Apr 21; 105(1-2): 196-200  

[193] Panossian A, Kochikian A, Gabrielian E, et al. Effect of Andrographis paniculata extract on progesterone in blood plasma of pregnant rats. Phytomedicine 1999; 6:157-161. 

[194] Chang HM, But PPH. Pharmacology and Applications of Chinese Materia Medica. English translation by Shem Chang-Shing Yeung, Sih Cheng-Yao and Lai-Ling Wang (Chinese Medicinal Material Research Centre, The Chinese University of Hong Kong), Singapore: World Scientific Publishing Co. Pte. Ltd; 1987; 2:918-928 

[195] Zoha MS, Hussain AH, Choudhury SA. Antifertility effect of Andrographis paniculata in mice. Bangladesh Med Res Counc Bull 1989; 15:34-37 

[196] Burgos RA, Aguila MJ, Santiesteban ET, et al. Andrographis paniculata (Ness) induces relaxation of uterus by blocking voltage operated calcium channels and inhibits Ca(+2) influx. Phytother Res 2001; 15:235-239

[197] Siripong P et al, Cytotoxic diterpenoid constituents from Andrographis paniculata Ness. Leaves, Journal of the Science Society of Thailand. 1992; 18:187-194  

[198] Rajagopal S et al, Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata, Journal of Experimental Therapeutics and Oncology, 2003, 3 (3):147-158

[199] Geethangili M et al, Cytotoxic constituents from Andrographis paniculatainduce cell cycle arrest in Jurkat cells. Phytotherapy Research. 2008;22(10):1336–1341

[200]Rajagopal S et al, Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata, Journal of Experimental Therapeutics and Oncology, 2003, 3 (3):147-158

[201] Shi M-D et al, Inhibition of cell-cycle progression in human colorectal carcinoma Lovo cells by Andrographolide, Chemico-Biological Interactions, 2008;174(3):201–210

[202]Cheung H-Y, Cheung S-H, Li J, et al. Andrographolide isolated from Andrographis paniculata induces cell cycle arrest and mitochondrial-mediated apoptosis in human leukemic HL-60 cells. Planta Medica.2005; 71(12):1106–1111

[203] S. D. Manikam, J Stanslas, Andrographolide inhibits growth of acute promyelocytic leukemia cells by inhibiting retinoic acid receptor-independent cell differentiation and apoptosis, The journal of Pharmacy and Pharmacology, Volume 61, No. 1, PP 69-78, 2009

[204] Kim TG et al, Morphological and biochemical changes of Andrographolide-induced cell death in human prostatic adenocarcinoma PC-3 cells, In Vivo, 2005, 19(3):551–558

[205] Zhou J, Zhang S, Ong CN, Shen H-M. Critical role of pro-apoptotic Bcl-2 family members in Andrographolide-induced apoptosis in human cancer cells, Biochemical Pharmacology, 2006; 72(2):132–144 

[206] Zhou J et al, Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation, Molecular Cancer Therapeutics, 2008;7(7):2170–2180

[207] Burns TF, El-Deiry WS. Identification of inhibitors of TRAILinduced death (ITIDs) in the TRAIL sensitive colon carcinoma cell line, SW480, using a genetic approach, Journal of Biological Chemistry, 2001; 276(41):37879–37886

[208] Jin Z et al, Deficient tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis,  Journal of Biological Chemistry, 2004;279(34):35829–35839 

[209] Wang S. The promise of cancer therapeutics targeting the TNF-related apoptosis-inducing ligand and TRAIL receptor pathway, Oncogene, 2008; 27 (48): 6207-6215

[210] Zhou J et al, Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation, Molecular Cancer Therapeutics, 2008, 7(7):2170–2180

[211] Astha Varma, Harish Padh, Neeta Shrivastava, Andrographolide: A New Plant-Derived Antineoplastic Entity on Horizon, Evid Based Complement Alternet Med. 2011; 2011: 815390, Published online 2011 Feb 10 

[212] Han Y et al, Modulation of multidrug resistance by andrographolid in a HCT-8/5-FU multidrug-resistant colorectal cancer cell line, Chinese Journal of Digestive Diseases, 2005; 6(2):82–86 >(7):2170–2180

[213] C. G. Jiang et al, Andrographolide inhibits the adhesion of gastric cancer cells to endothelial cells by blocking E-selectin expression, Anticancer Research, Volume 27, No. 4 B, PP 2439-2447, 2007 

[214] https://en.wikipedia.org/wiki/E-selectin 

[215]Hueng, S.J. 1991. Treating anal tumor by washing using Andrographis paniculata extractions plus vinegar, Chinese J. Anal. Intest. Dis. 11(2):40 

[216] Chao HP et al, Andrographolide exhibits anti-invasive activity against colon cancer cells via inhibition of MMP 2 activity. Planta Med 2010 Nov; 76(16): 1827-1833 

[217] Department of Gynecology and Obstetrics of the People's Hospital in Meixian Prefecture. 1977. Summary of the effects ofAndrographis paniculata on 60 cases of chorioepithelioma and malignant hydatidiform mole. Chinese J. of Med. 12:755 

[218] Yang L et al, Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrial pathway involving p53 participation in hepatocellular carcinoma (SMMC-7721) cells. Cancer Letters, 2009; 276(2):180–188

[219] http://en.wikipedia.org/wiki/Ras_subfamily 

[220] S. K. Hung, Andrographolide sensitizes Ras-transformed cells to radiation in vitro and in vivo, International Journal of Radiation Oncology Biology Physics, Volume 77, no. 4, pp 1232-1239 

[221] Zhong Rong Zhang et al, Taxifolin Enhances Andrographolide-induced Mitotic arrest and Apoptosis in Human Prostate Cancer Cells via Spindle Assembly Checkpoint Activation, PLoS One, 2013; 8 (1): e54577. Published on line 2013 Jan 28 

[222] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111248/?tool=pubmed

[223] Matsuda T et al, Cell differentiation-inducing diterpenes from Andrographis paniculata Ness. Chemical and Pharmaceutical Bulletin, 1994; 42(6): 1216-1225

[224] K. Sheeja, G. Kuttan, Activation of cytotoxic T lymphocyte responses and attenuation of tumor growth in vivo by Andrographolide paniculata extract and Andrographolide, Immunology and Immunotoxicology, Volume 29, no. 1, pp. 81-83, 2007

[225] S. Kumar et al, Andrographolide inhibits osteopontin expression and breast tumor growth through down regulation of PI3 kinase/Akt expression signaling pathway, Current Molecular Medicine, Volume 12, no. 8, pp. 952-966, 2012

[226] WHO Monographs on selected medicinal plants, Volume 2, Geneva: AITPBS Publications and Distributors; 2004, p. 12-34

[227] Coon JT, Ernst E, Andrographis paniculata in the Treatment of Upper Respiratory Infections: A Systematic review of Safety and Efficacy, Planta med, 2004; 70: 293-298

[228] Calabrese C et al, A phase I trial of Andrographolide in HIV positive patients and normal volunteers, Phytother Res 2000; 333-338

[229] Agrawal R et al Open label clinical trial to study adverse effects and tolerance to dry powder of aerial part of Andrographis paniculata in patients type 2 with diabetes mellitus, Malays J Med Sci, 2005; 12: 13-9

[230] Hanke J et al, A double-blind study with a new monodrug Kan Jang: Decrease of symptoms and improvements in the recovery from common colds, Phytother Res 1995; 9 (8): 559- 562 

[231] Chandrasekharan CV et al, Evaluation of the genotoxic potential and acute oral toxicity of standardized extract of Andrographis paniculata (Kalm Cold). Food Chem Toxicol 2009: 47: 1892-902 

[232] Burgos RA et al, Testicular toxicity assessment of Andrographis paniculata dried extract in rats. J. Ethnopharmacol 1997; 58: 219-24

[233] Allen JJ et al, Reproductive and fertility effects of Andrographis panaculata in male Wistar rats, Int J Toxicol 2009; 28: 308-17

[234] Chien CF et al, Herb-drug interaction of Andrographis paniculata extract and Andrographolide on the pharmacokinetics of theophllline in rats, Chem Biol Interact 2010; 184: 458-465

[235] Puri A. et al, Immunostimulant agents from Andrographis paniculata, J Nat Prod, 1993; 56: 995-999

[236] Ernst E., The desktop guide to complimentary medicine: An evidence based aproach. St Louis: Mosbey; 2001

[237] Mills S, Bone K principles and practice of phytotherapy, London: Churchil Livingstone; 2000

[238] Hovhannisyan AS et al, The effect of Kan Jang Extract on the pharmacokinetics and pharmacodynamics of warfarin in rats, Phytomedicine, 2006; 13: 318- 23

[239] Hencke J, Reproductive toxicity study of Andrographis paniculata extract by oral administration of pregnant Sprague- Dawley rats, de Chile: Santiago, pontifica Univer; 1997

[240] Panossian A et al, Effect of Andrographis paniculata extract on progesterone in blood plasma of pregnant rats, Phytomedicine; 1999; 6: 157-161

[241] http://diagnostiki.gr/herbal/menolyte_08. shtml 

[242] http://diagnostiki.gr/herbal/menolyte_08. shtml

[243] http://www.ayurwiki.info/wiki/kalemegha, www.evaidyaji.com

[244] www.rahulpharmacy.com/bhoonimb.html 

[245] http://diagnostiki.gr/herbal/menolyte_08. shtml