General features: The botanical name of this Asian herb is Andrographis Paniculata (Kalamegh in Hindi, Kalomegh in Bengali), an annual herbaceous plant, and 25 – 50 inches high that grows in moist and shaded condition of tropical climate, belonging to the Acanthaceae family. The stem is dark green slender by appearance and the leaves are hairless lance shaped 3 – 4 inches long and 2 – 3 inches wide. The flowers are racemes by nature and white – pinkish in color. The plant is a native of India, Sri Lanka and South East Asian tropical nations also grown in the Caribbean islands of West Indies. In recent days, it is much cultivated for the medicinal uses. Approximately, ~ 5500 tons are annually traded in India in the trade name of Kalmegh which is sold in the form of alcoholic extract or tincture commonly used as a part of the traditional home remedy to cure cold, cough, infections or other diseases. Besides India, it is seen to be used in China and other far eastern countries as a folk medicine. In China it is named as Chuanxinlian, Yijianxi or Lanhelian and is considered to be antipyretic, anti-inflammatory, detoxicant and detumescent. Usually, aqueous and alcoholic extract of the leaves or roots or both are used for medicinal reasons. Owing to the extreme bitterness it is titled as “King of bitters”. The Chirota / Swertia Chirayta also bears similar bitterness. Like S Chirayta, A Paniculata / Kalmegh is also an adaptogen enabling to prevent any physical or biochemical stress of the body. Additionally, it also behaves as antifungal, antibacterial, antiviral, choleretic, hypoglycemic, hypocholesterolemic agent. It is considered to be a good liver tonic which was even mentioned in the ancient Ayurvedaincluding its neoplastic role also.
Uses: For the sake of home use, herb is sold in the form of dried powdered leaves or alcoholic or hydro-alcoholic extracts which is often taken at daily morning under fasting condition. The powdered leaves or tincture is adequately diluted with water for consumption which would contain 100 – 200 mg by weight of dry leaf. Besides the above ailments, it finds applications to prevent or cure neonatal annular subcutaneous ulcer, vaginitis, chicken pox, herpes zoster, mumps, neurodermatitis, eczema, burns, pelvic inflammation and cervical erosion. The aqueous extract of fresh leaves is often given to the children in case of appetite loss, bowel irregularities or griping. It is also frequently offered for the relief of dyspepsia, distension and convalescence due to fever or dysentery. In recent days pharmacological studies indicates its further roles which have been identified to be anti-neoplastic, anti-HIV and antithrombotic agent benefiting cardiovascular and numerous drastic diseases.
Pharmacological event: The bioavailability or absorption of A Paniculata is higher at low doses but the event falls following the increment of drug concentrations which could be due to excessive flux of P-glycoprotein since incubation with Verapamil, the P-glycoprotein inhibitor increases the level of absorption. The primary metabolite 14 – deoxy-12 (R) – sulfo-andrographolide traced in the urine behaves like anti-inflammatory drug. The clearance rate through urine is although significant but presumably most of it may pass through the feces via intestinal absorption. Andrographolide is distributed throughout the body by binding to human serum albumin (Cmax ~ 1. 3 µg / ml at Tmax ~ 2.5 hrs. and for decay t1/2 ~ 2.4 hrs). In human, after an oral ingestion about less than 10 % permeates into the circulation of which ~ 55 % binds with the albumin at that physiological concentration but its accumulation in tissues levels within 1.5 – 3 hrs and to a different extent.
Important phytochemicals and their medicinal actions: The major physiologically active constituents of A Paniculata / Kalamegh consist of varieties of di-terpenoids, lactones and flavonoids. The flavonoids are mostly synthesized in the roots but a significant amount grows inside the leaves also. The bitterest compound in A Paniculata / Kalamegh is andrographolide lactone which is considered to be the main bioactive ingredient (~ 70 mg / g). The content varies from 1 – 6 % by weight of the dry leaves. Additional bioactive derivatives of andrographolide are identified to be Neo-andrographolide (~17 mg / g), Iso-andrographolide, 14 – deoxy – andrographolide (~ 20 mg / g), 14, deoxy – 11, 12 di-dehydro-andrographolide (highest level in the young leaves ~ 25 mg / g). The other notable compounds are Andrograpanin, Skullcapflavone, 7 – O – methylwogonin, several isomers of methoxy flavones, 3, 4 – Dicaffeoylquinic acid, onysilin and number of sterols like β – sitosterol, stigmasterol, ergosterol peroxide etc. Few di-terpenoids like bis-andrographolides A, B and C are also isolated from the leaves. Among the di-terpenoids, bis-andrographolide A is a potent agonist (EC50 ~ 0.8 – 0.95 µM) toward the receptor, TRPV4 (one of the six membered superfamily of transient receptor potential belonging to vanilloid subfamily) which on activation enhances intracellular Ca+2 and subsequently regulates vascular tone, osmoregulation, nociception and temperature control. Interestingly, the compound shows no affinity toward TRPV1, TRPV2 or TRPV3 receptor. Normally, TRPs are involved during sensing the changing events of extra and intra-cellular conditions. Many plant products can activate various TRP channels. For example capsaicin, the hot ingredient of chili activates TRPV1 creating hot sensation. The four isomers TRPV1 – TRPV4 are involved in the heat sensation and bear the sequence homology whereas TRPV5 and TRPV6 are quite different being highly selective for the Ca+2 homeostasis and mostly located on the apical membrane surface of kidney and intestinal cells. They belong to the family of Calcium channels and take part in the Ca+2 transport helping calcium reabsorption subsequently maintaining the level of Vitamin D3 and Parathyroid hormone. Below is the picture showing the role of few TRP receptors by the various external stimuli. Besides bis-andrographolide A no other andrographolide are active to any TRPV receptor.
The other di-terpenes offer various hepatoprotection against the effects of any toxins and others. For example, derivatives of andrographolide provide protection from the Hepatitis B virus. In all cases, it systematically lowers the toxin or virus induced increase of transaminases, alkaline phosphatases, and bilirubin and hepatic triglyceride levels to a significant extent. Additionally, the crude extracts or some of its individual components, like Andrographolide and its isomers inhibit the reduction of hepatic antioxidant enzyme (Superoxide dismutase, Catalase and glutathione peroxidase) and glutathione levels. Experiments on isolated rat hepatocytes or entire animal using intra-peritoneal injections also establish the similar facts. Injecting 50 % ethanol extract to the mice dosedependently elevates the level of acid soluble sulfhydryl components, cytochrome P450, Cytochrome P450 reductase, Cytochrome b5 reductase, Glutathione S transferase, and superoxide dismutase. The elevation of catalase, glutathione peroxidase and glutathione reductase occurred only at large doses. It is further noticed that derivatives of andrographolide have immunomodulatory effect. For example, 14 – deoxy – 14, 15 – dehydro-andrographolide can block NF – κβ production in LPS challenged macrophages (IC50 ~ 2µg / ml). Mice injected with crude extract of Ethyl acetate reduces the fatality due to LPS challenge but occurs only at the higher doses (> 6.25 mg / Kg). In that way it may exert the anti-inflammatory actions. Andrographolide increases the lymphocyte proliferation as well as the IL – 2 secretion at ~ 1 µM concentration. Among the derivatives, andrographolide A is the most potent one in that role. Similar compounds are also identified in the extracts which also display the similar immune-modulatory role. The compound, Andrographolide has also unique ability to decrease the count of CD4+ T- cells in normal subjects but to the contrary for HIV infected patients it increases the count to similar extent (~ 24 %) after six weeks of administration. In most cases, the extract or its main component, Andrographolide acts mostly via anti-oxidant role in cooperation with the others. Its protection toward the liver against oxidative toxins is very comparable to the Sylmarins / Silibinin (flavo-lignan compound from Milk thistle) which also often acts as an anti-cancer agent working by inhibiting the STAT3 signaling pathway.
Further, the extract is very effective toward patients who has undergone Extra-corporeal shock wave lithotripsy (kidney stone treatment) causing significant reductions of hematuria, proteinuria and post-ESWL pyuria. The efficiency is same as Cotrimoxazole or Norfloxacin. The extract of A Paniculata or Andrographolide is also effective against Ulcerative Colitis whose possible action could be by inhibiting the CD4+ T cell differentiation. No testicular dysfunction, toxicity or sperm counts are noticed after heavy dosing of A Paniculata (1000mg / Kg) having ~ 6 % Andrographolide for at least two weeks. The compound synergizes cytotoxic role of many anti-cancer drugs like 5 – fluorouracil, Adriamycin or Cisplatin, even in the case of multi-drug resistance cancer cells. It has been noticed that in most cancer cells it upregulates the Death receptor 4 (DR4) that initiates TRAIL (TNF related apoptosis inducing ligand which is a potent apoptosis inducer specifically for cancer cells but not in normal ones) mediated apoptosis.
Effect on blood pressure, platelets and cardiac tissues – One of the analogs in A Paniculata extracts, 14-deoxy-11, 12-didehydo-andrographolide causes dosedependent lowering of blood pressure (ED50 ~ 3.4 nmol / kg in anesthetized rats). So care should be taken during its consumption concerning the doses in order to avoid any fatal incident of hypotension. In that regard, 14-deoxy-11, 12-di-dehydo-andrographolide is seen far more effective than the Andrographolide. The effect is mediated via adreno-receptors while acting as a potent β – blocker. In case of platelets, Andrographolide, being an effective NF – κβ inhibitor induces apoptosis dosedependently (25 – 100 µM). The disruption of mitochondrial membrane potential or the involvement of Caspase – 8 pathway are identified to be the leading cause since Z-IETD-fmk, the Caspase inhibitor blocks the incidence. So logically, the extract of A Paniculata / Kalomegh has the potential to prevent thrombosis. Concerning cardiac tissues, 14-deoxy-11,12-didehydo-andrographolide accumulates within heart muscle more effectively than the Andrographolide causing reduction of heart rate / atrial beating in a dose-dependent manner (5 – 320 µM).
Effect on diabetes – The anti-diabetic role of Andrographolide has been well studied using various animal models. It is noticed that the compound or A Paniculata extract protects pancreatic β cells from high glucose induced oxidative damage by down regulating NF – κβ signaling pathway. Additionally, it stimulates the translocation of glucose transport protein 4 (Glut 4) in the muscle membrane. The studies also show that in the overall process, serum insulin level is significantly increased resulting hypoglycemia. The mechanistic interpretation along with age-old observation indicates that it is a good agent either to prevent or treat the diabetes.
Effect on Infections – Daily intake of A Paniculata reduces pharyngo-tonsillitis and fever. The efficiency is very comparable to the Tylenol after day three of treatment. The extract is further effective in lowering simple cases of upper respiratory infections providing comfort to the subjects troubled with cough, headache, fever and fatigue. The effective component is seen to be Andrographolide. Ingestion of A Paniculata extract for two days often reduces the symptoms of common cold and coughing.
Effect on Rheumatoid Arthritis – At moderately high doses (~ 100 mg) having ~ 30 % Andrographolide reduces the swelling, tenderness and pain after two weeks of use. The lowering of IgA and C4 complement is noticed in the patient’s serum.
Effect on Colon cancer – Seemingly, this herbal extract could be effective in controlling the colorectal cancer. When tested in isolated colon cancer cells (Lovo, SW620, HCT116, HT29, KM12 and COLO205) it shows great potential to stop the cell proliferation. The notable component has been identified to be Andrographolide which shows near complete inhibition after ~ 48 hours of incubations (IC50 < 1 µM). The other compounds present in the extract like various flavones or di-terpenes even with less potency also participate in that inhibitory act through their anti-oxidant role.
Effect on Breast cancer – Studies performed by using the isolated breast cancer cell lines (MCF -7, TD – 47, MDA-MB-457, MCF7/ADR, T47D and NCI/ADR-RES) show potential inhibitory effect on cell growth exerting apoptosis and imposing DNA fragmentation within 24 hours of exposure in case of extracts or Andrographolide at different doses. After 72 hours of incubation with Andrographolide (~ 1.4 µM) more than 99 % cell death is noticed. The di-terpenes, 14- deoxy-11, 12 di-dehydro-andrographolide and few analogs act with similar potency and in identical manners via the gene modifications involving cell cycles, tumor suppression factors, cell growth, apoptosis, vesicle transport and protein and DNA degradtions etc. The major signaling pathways are seen to be associated with PI3K/Akt and also suppressing the angiogenic factors like VEGF and Osteopontin.
Effect on Leukemia – In leukemic cells (HL60, RPMI8226, CCRF-CEM), only Andrographolide is found to be effective exerting cytotoxic actions. Interestingly, anti-proliferative role of Andrographolide occurs at low doses but the event of apoptosis occurs at higher doses. Studies further showed that the compound can enforce cell differentiation when applied to the mice myeloid leukemia cell line (M1) imposing phagocytic actions. The event is rare for any daily usable plant product.
Effect on Lung cancer – Andrographolide is able to inhibit proliferation of various lung carcinoma cells (A549, NCI-H23, HOP62, MES-SA, H522 and MES-SA-DX5) efficiently (IC50 ~ 6 – 16 µM). In most situations it increases HLJ1 promoter actions which is secondary to JunB activation causing MMP2 suppression thus lowering the event of cancer cell proliferation.
Effect on CNS cancer – Andrographolide also prevents proliferation (IC50 ~ 5 – 15 µM) of CNS cancer cell lines (U251, SF268, SNB19 and U87) without enforcing any cytotoxicity. The event is associated with G2/M arrest by downregulating Cdc25C and CdK1along with the partial inhibition of PI3K/Akt. Interestingly, co-incubating with the PI3K/Akt inhibitor (Wortmannin or LY294002) synergizes the inhibitory effect particularly in case of glioblastoma cells.
Effect on Melanoma – The inhibitory / anti-proliferative role of Andrographolide (IC50 ~ 5 – 15 µM) Andrographolide is also viewed in several cultured melanoma cell lines (A431, M14, UACC62). The compound exerts its anti-cancer actions by arresting the cell cycle at Go/G1 phase by inducing the inhibitory protein p27 while decreasing the expression of cyclin-dependent kinase 4, CDK4. The compound can be accounted to be an anticancer therapeutic agent.
Effect on Prostate, Ovarian and Renal cancers – Andrographolide is also effective against various prostate (DU145, PC3), ovarian (ES2, SKOV3, OVCAR8, PA-1) and renal cancer cell lines (ACHN, A498) having IC50 ~ 5 – 15 µM.
Conclusion: Among the household Indian herbs, A Paniculata displays possibly the largest effectivity toward number of diseases either for its control or remedy purposes. The bioactive components can be largely extractible in both aqueous and hydro-alcoholic media. It is by far the most common herb used in the household as a home remedy especially within the villages. The remedial efficiency along with the cost effectiveness makes it perhaps the most attractive alternative medicine in rural India.