Background
Andrographis paniculata, (AP), also known commonly as "King of Bitters," is a member of the plant family Acanthaceae, and has been used for centuries in Asia to treat GI tract and upper respiratory infections, fever, herpes, sore throat, and a variety of other chronic and infectious diseases. It is found in the Indian Pharmacopoeia and is the prominent in at least 26 Ayurvedic formulas; whereas in Traditional Chinese Medicine (TCM), Andrographis is an important "cold property" herb: it is used to rid the body of heat, as in fevers, and to dispel toxins from the body. In Scandinavian countries, it is commonly used to prevent and treat common colds. Research conducted in the '80's and '90's has confirmed that Andrographis, properly administered, has a surprisingly broad range of pharmacological effects, some of them extremely beneficial:
* Abortifacient (can abort pregnancy... although ayurvedic tradition allows it to be taken for short duration during pregnancy. We advise all women to avoid its use during pregnancy as a precaution. In almost every other respect Andrographis has an extremely low toxicity.)
* Acrid (hot: in this case, slightly rubifacient to the skin)
* Analgesic (pain killer)
* Anti-inflammatory (reduces swelling and cuts down exudation from capillaries... antiflammatory action probably mediated, in part, by adrenal function)
* Antibacterial (fights bacterial activity... although Andrographis appears to have weak direct antibacterial action, it has remarkably beneficial effect in reducing diarrhea and symptoms arising from bacterial infections.)
* Antiperiodic (counteracts periodic/intermittent diseases, such as malaria)
* Antipyretic (fever reducer - both in humans and animals, caused by multiple infections or by toxins)
* Antithrombotic (blood clot preventative)
* Antiviral (inhibits viral activity)
* Cancerolytic (fights, even kills, cancer cells)
* Cardioprotective (protects heart muscles)
* Choleretic (alters the properties and flow of bile)
* Depurative (cleans and purifies the system, particularly the blood)
* Digestive (promotes digestion)
* Expectorant (promotes mucus discharge from the respiratory system)
* Hepatoprotective (protects the liver and gall bladder)
* Hypoglycemic (blood sugar reducer)
* Immune Enhancement (increases white cell phagocytosis, inhibits HIV-1 replication, and improves CD4+ and T lymphocyte counts)
* Laxative (aids bowel elimination)
* Sedative (a relaxing herb, though not with the same effect as the accepted herbal sedatives: valerian root, hops, skullcap, etc.)
* Thrombolytic (blood clot buster)
* Vermicidal (kills intestinal worms)
Andrographis has been used as a medicinal herbs for centuries in not one, but several different medical traditions, which is the subject of other sections below.
Morphology / Chemistry
Andrographis paniculata is an annual - branched, erect - running 1/2 to 1 meter in height. The aerial parts of the plant (leaves and stems) are used to extract the active phytochemicals. It grows abundantly in southeastern Asia: India (and Sri Lanka), Pakistan and Indonesia - but it cultivated extensively in China and Thailand (1), the East and West Indies, and Mauritius (2). Normally grown from seeds, Andrographis is ubiquitous in its native areas: it grows in pine, evergreen and deciduous forest areas, and along roads and in villages. Because of its well-known medicinal properties, it is also cultivated - quite easily, because it grows in all types of soil. Moreover, it grows in soil types where almost no other plant can be cultivated, particularly "serpentine soil," which is relatively high in aluminum, copper and zinc. Such hardiness helps account for its wide distribution.
The leaves contain the highest amount of andrographolide (2.39%), the most medicinally active phytochemical in the plant, while the seeds contain the lowest. (3). The other medicinal chemicals are also bitter principles: diterpenoids viz. deoxyandrographolide, -19ß-D-glucoside, and neo-andrographolide, all of which have been isolated from the leaves. (4).
andrographolide - called The primary medicinal component of Andrographis is andrographolide. It has a very bitter taste, is a colorless crystalline in appearance, and is called a "diterpene lactone" - a chemical name that describes its ringlike structure (see diagram at left). Besides the related bitters cited above, other active components include 14-deoxy-11,12- didehydroandrographolide (andrographlide D), homoandrographolide, andrographan, andrographon, andrographosterin, and stigmasterol - the last of which was isolated from an Astrographis preparation (5).
Both growing region and seasonality play a role as to the concentration of these diterpene lactones. Andrographis appears to grow best in the tropical and subtropical areas of China and Southeast Asia. The highest concentration of the active components is found just before the plant blooms, making early fall the best time to harvest. In those parts of Asia where Andrographis is sold commercial as medicine, a variety of lab methodologies are used to ensure a standardized level of andrographolides: thin-layer chromatography, ultraviolet spectrophotometry, liquid chromatography, and volumetric and colorimetric techniques.
Extraction is usually performed using ethanol, and liquid extracts or tinctures are the most common form of dispensing the product. When consumed, andrographolides appear to accumulate in organs throughout the viscera. In one study, after 48 hours, the concentration of labelled andrographolide was 20.9%, brain; 14.9%, spleen; 11.1%, heart; 10.9%, lung; 8.6%, rectum; 7.9%, kidney; 5.6%, liver; 5.1%, uterus; 5.1%, ovary; and 3.2%, intestine. (6). Absorption and excretion is rapid: 80% is removed within eight hours via the kidney (urine) and G.I. tract. Ninety percent is eliminated within forty-eight hours.
Known Mechanisms of Action
Andrographis paniculata has been extensive studied, most of it in the last half of the 20th century, and much of it concentrating on "AP's" pharmacological composition, safety, efficacy, and mechanisms of action. (1,7,8). A good deal of this research has centered around a screening technique called signal transduction technology - probably best explained in a seminal work by Jean Barilla, M.S.:
"All cells in the body contain receptors on the surface of the cell membrane that surrounds the cell. These receptors function to bind hormones, growth factors, neurotransmitters, and other molecules that regulate (or in the case of cancer, disturb) cell function. Once a molecule binds to the receptor, a chemical message is transmitted to targets in the cell or to other molecules in the cell, which carry the message further. The message will eventually reach the nucleus of the cell where the genetic material (the DNA) is stored. The DNA will be activated and the cell will respond according to what type of cell it is. An example would be a message to make a particular protein, such as insulin, by a cell in the pancreas. The receptor, its cellular target, and any intermediary molecules are referred to as a "signal transduction pathway." Signal transduction technology involves the study of these pathways that affect cell function. Any point in this pathway may be affected by cancer-causing toxins or by viruses. In the case of cancer, changes in the components or in the timing of cellular events can cause abnormal cell division. Uncontrolled cell division results in a tumor or in the spread of cancerous cells. Other diseases can also develop when the signals are disturbed.
"Many of the steps are involved in signal transduction are well understood, although research can be done to fine-tune an understanding, of these pathways. Investigating what can go wrong at such a basic level (inside the cell) allows researchers to detect diseases at a much earlier stage -- before there are obvious symptoms and when there is still a good chance to correct the problem.
"Scientists at many U.S. companies are using signal transduction technology to determine the effects of natural and synthetic components on the signal transduction pathways in the cell, in particular those involved in cell division... Several applications of signal transduction technology in the development of compounds with therapeutic potential have been reviewed in an excellent editorial published in Genetic Engineering News in January 1996. (9)
"One of the criticisms made by the conventional medical and scientific community regarding dietary supplements is that their development and use have been based on folklore, not science. Using signal transduciton technology to investigate the effect on a botanical or other nutrition supplement on the cell-level processes of cells is good science. This approach will legitimize the nutritional approach to the prevention and treatment of disease and speed the process of development of new and more effective supplements. Importantly, this technology avoids the use of animal testing, which often lasts for years before a supplement is approved for human use; not using animals is an additional benefit those who consider animal testing to be inhumane. In addition to saving time and animals, this technology reduces the costs involved in getting a supplement to market - a saving which will be passed on to consumers...
"Using signal transduction technology, extracts of AP (Andrographis paniculata) have been found to counteract interference with the cell cycle. Such interference is the basis for the development of cancer or infection with viruses such as HIV-1. Andrographolides are thought to enhance immune system functions such as production of white blood cells (scavengers of bacteria and other foreign matter), release of interferon, and activity of the lymph system. Interferon is a protein (called a cytokine) made by cells in response to viruses. It is a potent antiviral agent and is also antiproliferative (stops the growth of viruses). The lymph system is an important part of the immune system. Briefly, it is another circulatory system (like the vascular system) that carries a fluid, the lymph. The lymph carries away the by-products of cellular metabolism and also acts as a shuttle for invading bacteria and viruses, taking them to the lymph nodes where the white blood cells (lymphocytes) destroy them. Andrographis, a superb immune system enhancer, is even more effective when combined with immune stimulators, such as the herb Echinacea, and with zinc and vitamin C... Andrographolides may also be useful in cancer therapy [see below].
"Several studies have looked at the disposition of andrographolide in various organs of the body.(10) Biodistribution experiements have been done in experimental animals. Following injection of radioactively labeled andrographolide, this compound appears to be widely distributed in the body. High concentrations are noted in the central nervous system (brain and spinal cord) and other organs with high blood flow, including the colon, spleen, heart, lungs, and kidneys. Andrographolide appears to have a relatively short half-life of approximately two hours. The term "half-life" refers to the time when the concentration of the compound in the body is half of what it originally was when it entered the body. This is what is left after the compound has been metabolized (broken down), changed into other forms (called metabolites), and excreted by one of several routes (urine, feces, exhaled air, sweat, or other body excretions). Compounds with short half-lives need to be given often since they do not stay in the body for long. Andrographolides are excreted fairly rapidly from the body via the urine and gastrointestinal tract. In some studies, 80 percent of the administered dose of andrographolide is removed from the body within eight hours, with excretion rates of more than 90 percent of the compound within forty-eight hours.
The wide tissue and organ distribution and the immune-stimulating and regulatory actions of AP make it an ideal candidate in the prevention and treatment of many diseases and conditions. Some of the biological effects and potential treatment properties of extracts of AP are summarized above in the Background section." (11)
Immunological Benefits: Cancer
Mice studies have shown that Andrographis paniculata is a potent stimulator of the immune system in two ways: (1) Antigen-specific response: antibodies are made to counteract invading microbes, and (2) Nonspecific immunse response: macrophage cells scavenge and destroy invaders. AP activates both responses - making it effective against a variety of infectious and oncogenic (cancer-causing) agents. (12).
The initial interest at Alpha Omega Labs in AP was two-fold: its hepatoprotective (liver protecting), as well as its anti-cancer properties. Our internet domain name (altcancer.com) was chosen in 1995 because of the high priority we set on finding alternatives (the "alt" in "altcancer") to the traditional, expensive, and often fatal therapies that modern medicine has chosen to attack cancer: chemotherapy, radiation, and surgery. Our conviction in a conspiracy to suppress inexpensive, effective cancer therapies has been rooted in the undeniable fact that after many billions of dollars has been spent in the supposed quest for effective cancer treatment, the best solution that modern medicine can come up with is chemotherapy: an indiscriminate killer of cells that kills over 66% of all patients within 5 years of administration (source: Harvard Medical School study - cited in Hoxsey movie). Compare this to the record of Cansema, a simple herbal formula, based on a healing tradition going back over 100 years that has provided effective results for the majority of its users.
Similarly, AP has a record of effective treatment rooted in its mechanisms of immune boosting. Cancer results when cells do not respond to signals that are intended to limit growth. When cells develop normally, at each stage of development the cells become more specialized in order to be able to perform the duties of that particular cell. For example, cells that will make insulin will develop the cellular machinery to do so. When cancer upsets normal development, cells do not mature -- they more closely resemble immature body cells. The more they resemble immature cells, the more unfavorable the outcome: the cancer grows and spreads (metastasizes) more rapidly.
If a cancer cell can be made to mature (or differentiate), it will not have the ability to grow out of control. Researchers are therefore searching for substances that can cause cancer cells to mature. In one study of mice, researchers searched for naturally occurring substances that would cause differentiation of leukemia cells. Leukemia is a cancer of the white blood cells. AP was chosen becaues it contained substances (terpenes) that were similar to substances found in other plants and were known to cause differentiation of cancer cells. The results of the study demonstrated that AP had potent cell differentiation-inducing activity on leukemia cells. (13)
In addition to causing cancer cell maturity or differentiation, AP extracts from the leaves of the plant are also cytotoxic (cell-killing) against cancer cells. This cancer cell-killing ability was demonstrated against human epidermoid carcinoma (squamous cell carcinoma) of the skin lining of the nasopharynx and against lymphocytic leukemia cells. (14). It was the andrographolide component that was found to have the cancer cell-killing ability. This ability for killing cancer cells was superior to the levels of the effectiveness recommended by the National Cancer Institute for a cytotoxic substance.
Japanese researchers have reported that AP stopped stomach cancer cells from multiplying. After three days, there were less than 8 cancer cells growing in the presence of AP while the untreated cancer cells numbered 120. Another group of Japanese researchers tested AP on sarcoma cells. These usually very malignant cancers affect muscle, connective tissue, and bones. When tumor samples were examined under the microscope, AP was found to inhibit the growth of the tumors. Laboratory tests conducted in Buffalo, New York, demonstrated that AP inhibited the growth of human breast cancer cells at levels similar to the drug tamoxifen. Extracts of AP are much less toxic than most chemotherapeutic agents used to fight cancer. Although more studies need to be done to determine just which types of cancer respond to AP, the results so far have been promising.
In 1977, a human study was conducted using AP in sixty skin cancer patients, including forty-one with confirmed metastases (the cancer was spreading). As reported in the Journal of Chinese Medicine, twelve patients given AP and its compounds alone, recovered. All other patients were given AP along with standard drugs; there was no tumor regrowth in forty-seven of these patients. Based on this report, American investigators obtained investigational new drug status from the FDA to test AP extract. In 1996, early trials showed that the extract safely and effectively blocked growth of both prostate and breast cancer, as well as non-Hodgkin's lymphomas. Based on the results of using AP on breast cancer cells grown in the laboratory, researchers believe that AP probably inhibits synthesis of cancer cell DNA. Additional details of cancer trials are given in the book, Miracle Herbs by Stephen Holt, M.D., wherein cancer studies done at Roswell Park Cancer Institute in Buffalo, New York, showed that AP extract has an antiprostate cancer action comparable to that of the widely used and highly toxic agent cisplatin - without the toxicity.
Immunological Benefits: HIV & Other Viruses
Immune deficiency is at the root of susceptibility to a variety of infections, and it is the basis of the Acquired Immune Deficiency Syndrome (AIDS). Impairments of immune function result in variable clinical symptoms. To understand how to treat the disease and why infection with the human immuno-deficiency virus (HIV-1) is resistant to conventional and alternative therapies, we need to understand just what AIDS is.
AIDS appears to have first arisen in Africa. It may have started when the HIV virus that previously only affected African primates most likely mutated and was able to infect humans. In this modern age of fast intercontinental travel, the virus spread all over the world. The initial cases in North America were reported in 1981, before the condition had even been named. Studies of hospital records and frozen tissue samples, however, indicate that AIDS was present as early as 1969. Two strains of HIV have been since identified: HIV-1 and HIV-2 (which seems confined to Africa).
HIV, like all viruses, cannot reproduce itself or even live, without using the resources of other cells. When HIV virus finds a suitable cell, it attaches to the cell, using proteins on its cell surface. In the case of human cells, the HIV virus enters the cells by binding two molecules on the cell's surface. The first of these to be identified was CD4; other, more recently identified molecules are CCR5 and CXCR4.
The brain and certain skin tissues are areas where the HIV virus tends to concentrate. HIV also attacks and debilitates cells in the immune system. Helper T cells - the "T" represents the thymus gland where the cells are produced -- are a main target of the virus. These cells signal the lymph nodes and the spleen to produce more antibodies against the NIV virus. Once the antibodies inactivate the virus, suppressor T cells produce chemicals that stop further production of antibodies. The HIV virus, however, attaches itself to the helper T cell. Through a series of manipulations of the helper cell's genetic machinery, the virus tricks the cell into producing chemicals that the virus needs. HIV takes over the "machinery" of the helper T cell and thus becomes a virus production factory that is no longer part of the immune system. Without the T-cells, the other components of the immune system do not receive any messages to produce antibodies and resistance to HIV is seriously compromised.
Conventional treatment consists of a combination of drugs designed to achieve maximum viral suppression. Often referred to as a "cocktail," this mixture consists of compounds called protease inhibitors and reverse transcriptase inhibitors. Without going into detail, a protease is an enzyme needed by the HIV virus for replication and assembly of new virus parts. Reverse transcriptase is another enzyme that the HIV virus uses to copy its genetic material when inside the T cell. While inhibiting these enzymes has been effective treatment in many cases, reducing the amount of HIV in the blood does ot mean that a patient will suffer from fewer AIDS-related diseases. Researchers are not certain how long a new combination of drugs will work before virus strains become resistant to the treatment. It is always the case with drug treatment that a few resistant virus particles will survive and go on to reestablish the infection. Protease inhibitors (Invirase, Norvir, Viracept, and Crixivan) do not work on everyone and are not well absorbed. Large doses (36 pills a day) may be required with costs as high as $16,000 a year. Dangerous side effects, such as diabetes and hypertension, can develop or become worse in patients taking protease inhibitors.
Another therapy: AZT -- an antiviral that can slow the HIV infection -- has limited use because of the high incidence of side effects, which include kidney stones, bone marrow depression and brain and liver toxicity. Scientists are therefore looking for better therapies. Protease inhibitors are abundant in plants: soybeans, rice, corn, beans, wild tomatoes, and other vegetables. Reverse transcriptease inhibitors are also found in nature. Quercetin, a bioflavonoid found in red applies and red onions, has activity against viruses that cause AIDS, herpes, and polio. The long history of using herbs with immune-enhancing properties in TCM prompted scientists to look further into this area of potential therapies.
Exciting recent research has indicated that extracts of AP may have great promise for interfering with the viability of the HIV virus. Scientists now believe that AP can join with modern technology in the fight against AIDS. An important place to look for a way to stop HIV was in the human cell where the virus was using the cell's machinery to reproduce itself. Cells, when they grow and reproduce, go through a series of steps collectively termed the "cell cycle." During this process, chemical messages are carried to various parts of the cell in order to "turn on" functions. This process is called "signal transduction." The HIV virus actually subverts the cell's messengers, tricking them into producing more viral particles. Using signal transduction technology (methods to investigate cell message systems), scientists found that AP contained substances that destroyed the virus's communcations mechanism. One component of the herb -- andrographolide -- prevented transmission of the virus to other cells and stopped the progress of the disease by modifying cellular signal transduction. Andrographolide probably does this by inhibiting enzymes that facilitate the transfer of phosphates. Phosphates are molecules that are the energy storehouses of the cell. During the cell cycle, phosphates are created or chemically changed and energy is produced. This energy is used in the regulation of the cell cycle and for the many cellular functions that go on during reproduction of the cell. AP can thus interfere with key enzymes that result in viral reproduction. (15).
HIV alters regulation of the cell cycle by causing the process to stop at a particular phase. What the virus specifically does is to alter the action of a central information-processing enzyme that coordinates all events relating to cell division. This regulatory enzyme (actually a class of enzymes) is called cyclin-dependent kinase (CDK). A particular CDK -- CDK-1 -- is the prime target of HIV. When the cell moves through its cycle, all information about cellular activities is sent to CDK-1. Several diseases in addition to AIDS, such as cancer, heart disease, and viral infections, are associated with aberrant functioning of CDK-1. The virus causes CDK-1 to misfunction by attaching molecules to it -- a process called phosphorylation. Agents that can prevent this phosphorylation can less the severity of AIDS. The new class of antiviral compounds with this ability is called tyrosine kinase inhibitors. This class includes the andrographolides. Work done by researchers at the National Institutes of Health (NIH - USA) in 1995 showed that T-cells infected with HIV accumulate high levels of overphosphorylated CDK-1. An extract of AP can, in fact, inhibit CDK-1 that has been altered by HIV. In April 1992, NIH researchers reported that these inhibitors could halt the disease-causing components of HIV. These compounds are amino acids that can inhibit the viral enzymes involved in the production of high-energy phosphates.
Cooperative research at the National Cancer Institute has shown that andrographolide can also inhibit HIV's toxic effect on cells. It does this by inhibiting c-mos, a genetic component involved in HIV propagation and T-cell death. C-mos is integrated into the DNA of the cell and usually is inactive. Normally found only in reproductive system cells, c-mos is not expressed in CD4 cells or other body cells. When CD4 cells are infected by the HIV virus, c-mos expression is activated. For this to happen, an enzyme (c-mos kinase) is needed. Andrographis extract can inhibit this enzyme and so can support normal immune function. A hypothesis for the mechanism of action of AP in AIDS is that the herbal extract appears to induce apoptosis or programmed cell death. In this process, cells break up into particles which are then scavenged by immune system cells. The HIV virus may generate apoptotic signals to uninfected immune cells. This would explain the extensive T-cell destruction caused by HIV infection, which is far more than the amount of virus present.
Testing of AP done at the Frederick Research Center demonstrated that extracts of AP increased AZT's ability to inhibit replication of HIV. The effect of the combination was greater than that of either compound alone. An added benefit is that lower doses of AZT could be used. Some researchers believe that AP extracts may also be useful in combating other viruses, including the Ebola virus and the viruses associated with herpes, hepatitis, and influenza. In a study examining 27 types of "heat clearing" and detoxifying medicinal herbs, researchers at the China Academy of Traditional Chinese Medicine in Beijing reported that AP wasone of the herbs that had an inhibitory effect on HIV replication. (7). Leukemia cells in particular have been shown to be very sensitive to the efffects of andrographolide. (13).
The Common Cold, Fever & Inflammation
The prevention of the common cold with an extract of AP was shown in a pilot double-blind study. Students were given Kan Jang, a formulation of AP produced by the Swedish Herbal Institute, and were diagnosed for the presence or absence of colds during a three-month period. (16). A dose of 200 mg/day was given to the study group. After one month there was no signficant difference in the number of colds. However, after the third month of intake of Kan Jang there was a significant decrease in the incidence of colds as compared to the placebo group. The students that got the Kan Jang had a rate of incidence of colds of 30% compared to 62% for students that received the placebo. The relative risk of catching a code indicated that the preventive effect could be due to the presence of andrographolide, which hasknown immunostimulant effects.
The amount of Kan Jang used in the previous study was much less than used in a previous study that produced quicker results. In this study, patients were divided into two groups, one of which received 1,200 mg/day of Kan Jang. (17). These patients already had colds with symptoms including nasal discharge, nasal stuffiness, sore throat, earache, cough, fever, headache, and malaise. At the beginning of the study, the patients receiving Kan Jang, and those receiving a placebo had similar symptoms. The symptoms, such as tiredness, shivering, sore throat, and muscular aches, diminished significantly on the fourth day of treatment with Kan Jang. The researchers concluded that treatment with Kang Jang (standardized to 4 percent andrographolides) accelerated the recuperation of patients from the common cold.
AP is also used as a folk medicine remedy for fever, pain reduction, and disorders of the intestinal tract. The ability of AP to lower fever has been demonstrated independently in several laboratories. Rat studies done in China have shown that andrographolide, neoandrographolide, and dehydroandrographolide can lower the fever produced by different fever-inducing agents, such as bacterial endotoxins (toxic chemicals released from bacteria), pneumococcus, hemolytic streptococcus, typhoid, paratyphoid, and the chemical 2,4-dinitrophenol. (19).
Researchers tested AP to try and determine whether it did, in fact, work in these conditions. (20). 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 found that 300 mg/kg body weight of andrographolide was as effective as the same amount of aspirin, in fact, the AP extract was found to possess antiulcerogenic activity. It reduced the development of ulcers by 31%, while the standard ulcer drug, cimetidine had an 85.43% reduction rate. Andrographolide caused a significant decrease in total stomach acidity and acid stomach juice secretion, without the cost and side effects associated with ulcer therapy.
In another study, AP extracts were found to produce results comparable to 200 mg of aspirin/kg. body weight. (21). The researchers also established that there was a wide margin of safety in using AP extracts, an indication of the lack of toxicity.
The anti-inflammatory effects of various AP compounds have been shown in many studies in which the inflammation was produced by chemicals. Inflammation caused by histamine, dimethyl benzene, croton oil (hemolytic necrosis), and acute pneumocystis produced by adrenaline was significantly reduced or relieved. (22). This effect was observed for all major andrographolides: deoxyandrographolide, andrographolide, neoandrographolide, and dehydroandrographolide. Dehydroandrographolide had the most pronounced effect, followed by neoandrographolide and andrographolide. This anti-inflammatory effect seemed to work by a mechanism that involved the adrenal glands. The effect disappeared when adrenal glands were removed from experimental animals. (23). Further study confirmed that the anti-inflammatory action of dehydroandrographolide was due to its effect on increasing the synthesis and release of andrenocorticotrophic hormone (ACTH) of the pituitary gland of the brain. ACTH signals the adrenal gland to make cortisol, a natural anti-inflammatory. (19).
In research done on the anti-inflammatory activity of naturally occurring products, AP was found to inhibit edema (swelling due to fluid trapped in tissues). At a concentration of 200 mg/kg body weight, AP significantly inhibited (by 60%) edema at three hours. With 400 mg/kg body weight, 62.7 percent was inhibited. (24).
Antibacterial / Antimalarial & Filaricidal
The potential use of AP and its components are important especially because bacteria are showing resistance to drugs. Each time bacteria are exposed to an antibiotic, most are killed, but a few survive. These survivors go on to multiply and establish infections that cannot be treated with the original antibiotic, and in some cases there are no existing drugs to stop the bacteria. Although AP and other herbs are not substitutes for antibiotics, these plants and other herbs could have a complementary effect when used along with antibiotics. In fact, according to Dr. Stephen Holt, we may be seeing natural remedies combined with synthetic medications being used in therapies that are more effective and safer.
Malaria is still a prevalent disease in many tropical and subtropical countries. It is difficult to eradicate because the parasites that carry malaria become resistant to the drugs used to treat the disease. Extracts of AP containing the four active components previously mentioned were evaluated for antimalarial activity against Plasmodium berghei, one of the parasites that transmit malaria. The extract was found to produce considerably inhibition of multiplication of the parasites. (25). Two of the AP components, neoandrographolide and deoxandrographolide, were found to be the most effective of the four. Pretreating animals with neoandrographolide for fifteen to twenty-one days prior to exposure as well as after infection was found to be more effective than treatment started only after infection. Effects were better than treatment after infection with chloroquine, a commonly used antimalarial drug. In a subsequent study, researchers repeated the effects of AP and indicated that the protective action of AP may be due to reactivation of superoxide dismutase (SOD), a key antioxidant enzyme that protects the liver (Chander 1995).
AP extracts are also efffective in killing filaria (microscopic worms) that obstruct lymph channels in the body, leading to gross swelling termed elephantiasis. The study was done in dogs. Since no toxic effects were apparent, researchers believed that the AP plant extract would be safe for humans. No plant has previously been shown to have antifilarial action.
Antidiarrheal & Intestinal Effects
Experiments on animals demonstrate that AP can prevent or stop diarrhea. Diarrhea-type diseases are one of the top ten causes of death worldwide and are a leading cause of death in children in developing countries, especially those that are under five years of age. The use of antibiotics is producing antibiotic-resistant strains of bacteria. While there are many drugs used to relieve the symptoms of diarrhea (kaolin-pectin, bismuth, Lomotil, loperamide hydrochloride, and others), many have undesirable side effects. An inexpensive and easily obtained herbal remedy would benefit many, especially people in developing countries where diarrheal disease is almost catastrophic. Extracts of AP have been shown to have significant effects against the diarrhea associated with E. coli bacterial infections. (2). The AP components, andrographolide and neoandrographolide, showed similar activity to loperamide (Imodium), the most common antidiarrheal drug.
Acute bacterial diarrhea in patients was treated with a total dose of 500 mg andrographolide divided over three dosing periods per day for six days (2.5 to 3.0 mg/kg of body weight). This regimen was combined with rehydration. There were 66 cures of 80 patients treated -- an 82.5% cure rate. Seven additional patients responded favorably to the treatment and only seven patients (8.8%) did not respond. The effectiveness of the treatment was confirmed by laboratory tests of stool samples. (23). In another study, AP was used to treat 1,611 cases of bacterial dysentery and 955 cases of diarrhea with overall effectiveness of 91.3%. (22).
It had been believed that AP was effective against bacterial dysentry and diarrhea because it was antibacterial, but studies could not confirm this effect. However, the andrographolides were very effective in stopping the diarrhea. How this is accomplished is not completely understood at present.
Chronic inflammation of the colon was treated with a combination of AP (60 g) and Rehmannia glutinosa (30 g), decocted. Rehmannia is a Chinese herb used to treat anemia, fatigue, and to promote the healing of injured bones. It is also a demulcent. The liquid part of the mixture was used as an enema at doses of 100 to 150 ml each night for fourteen days. Of a total of 85 patients, 61 (72%) were considered clinically cured and 22 (26%) had symptomatic relief. (23).
Cardiovascular Benefits
In 1964, angioplasty was developed. This technique has been used to treat blocked blood vessels (usually arteries). A balloon is inserted into the artery and then inflated to clear away fatty deposits, widen the artery, and improve blood flow. In 1967, surgeons at the Cleveland Clinic developed another treatment for coronary artery obstructions: bypass surgery. In this procedure, a new vein (from another part of the body, from an animal, or a synthetic) replaces the obstructed artery. Today, angioplasty and bypass surgery are routine, with about 800,000 such procedures done in the United States each year. These treatments are not, however, a cure-all. For, with angioplasty, restricted blood flow recurs in 30 percent of patients within six months; 50 percent of patients will require a repeat procedure. Many of these patients eventually require bypass surgery, which is successful in only 50 to 65% of cases.
Clot-dissolving drugs used in the emergency treatment of heart attacks appear to be as effective as angioplasty and may prevent some of the heart attacks or strokes that occur within one month of angioplasty. The process of blood clotting in the body is not yet fully understood. It is a delicate balance between the clotting necessary to achieve healing and processes that will cause abnormal and unwanted clotting. Research to understand the signals involved in bleeding and blood vessel development is making use of signal transduction technology (previously described). It has been demonstrated that extracts of AP can increase the time it takes for blood clots to form, thus decreasing the risk of subsequent closing of blood vessels (restenosis) seen after angioplasty procedures. In studies done on rabbits given angioplasty procedures. In studies done on rabbits given angioplasty, AP extracts was shown to significantly prevent constriction of blood vessels. The rabbits received AP for three days before angioplasty and for four weeks after surgery. While the arterial narrowing occurred in 100% of animals not given AP, only 70% of those receiving AP showed narrowing. (28). Narrowing caused by injury to the inner lining of the blood vessel and by high cholesterol in the diet was also found to be decreased by AP. It appears that AP may be quite effective in preventing repeated narrowing of vessels after coronary angioplasty.
In 80 to 90% of patients with destroyed heart muscle resulting from an acute myocardial infarction (heart attack), clots are found in the heart shortly after the beginning of symptoms. When heart muscle is deprived of its blood supply, and therefore of oxygen, the tissue dies. Physicians and researchers believe that the best treatment is to limit the size of the myocardial infarction (the area of tissue damage) in order to preserve the pump function of the heart. Agents that dissolve the clots and increase blood flow through the blocked artery are constantly being sought. AP may have the potential to be part of the treatment plan in such cases.
Researchers at the Tongi Medical University in China have demonstrated that AP given to dogs one hour after developement of myocardial infarction decreased the damage that occurred to the heart muscle. (29). Such damage occurs after the blood supply is restored to the muscle. This is due to a sudden influx of oxygen (which produces free radicals that damage tissue) and abnormally high amounts of calcium. In subsequent studies at the same university, the researchers demonstrated by electrocardiograph that abnormal changes in heart readings were prevented by pretreatment with AP. Also, clumping of platelets (the blood particles that initiate clotting) was inhibited and no clot (thrombus) that could cause infarction was induced. (29). An added effect of AP was that it activated fibrionolysis, the natural process in the body that dissolves clots. (18).
Another way to prevent cardiovascular disease is to correct high blood pressure. Researchers have reported that an extract of AP produced antihypertensive (blood pressure lowering) effects. (18). The extract was given intravenously to hypertensive rats. Noradrenaline, a hormone secreted by the brain, acts to constrict blood vessels and increase heart rate, blood pressure, and blood sugar levels. AP inhibited the increase in blood pressure that is caused by noradrenaline. Researchers believe that AP has this antihypertensive effect because it relaxes the smooth muscle in the walls of blood vessels. This relaxation prevents the blood vessel from constricting and limiting blood flow to the heart, brain, and other organs in the body. AP keeps blood, and therefore oxygen, flowing to the brain. Diminished blood flow to the brain can cause short-term memory loss, ringing in the ears, dizziness, headaches, depression, and impaired mental performance. The effects of AP are produced without toxicity and at a reasonable cost, making this miracle herb a good option for cardiovascular therapy.
Fertility Effects
AP has clear antifertility as well as pregnancy-terminating effects. In India, where AP is used for common ailments such as diarrhea, fever, and other digestive disorders, it is recommended that the herb be used only for short-term treatment. This is due to the content of compounds that are contraceptive in nature. To determine the actual effects on fertility, studies were done in male rats. In one study, it was found that AP, given as dry leaf powder (105 mg. of powder/kg body weight) each day for 60 days, stopped spermatogenesis (development and maturation of sperm cells). (30). The authors concluded that the observations suggested an antispermatogenic (sperm production blocking) or antiandrogenic (blocking effects of androgens) ability of the plant. It should be noted that many herbal extracts have effects on reproductive functions and thus should not be used during pregnancy.
Studies by Zoha and colleagues, also in India, reported antifertility effects on female mice. (31. When 2 grams per kilogram body weight of sun-dried AP powder were given to the rats every day for six weeks, none of the animals were pregnant after mating (five times) with proven fertile males who did not recieve the AP. The mice who did not recieve the AP had normal litters when bred with similar males. According to the researchers, the effect of AP may have been to prevent ovulation. The potential for its use as an antifertility agent in Bangladesh, where the plant is easily available, motivated scientists to perform these experiments.
Studies done in cultured human placental tissue showed that andrographolide sodium succinate (derived from AP) was effective in inhibiting human progesterone production. (23). This hormone is necessary for pregnancy to be successful. The form of AP used was tissue specific, meaning it only affected the tissue it was intended for. There were no detrimental effects on other normal human tissue, even at the highest doses tested. The researchers concluded that the derivatives appeared to be promising contraceptives. Other studies in female mice using dehydroandrographolide indicated that the dose required to affect pregnancy was 250 mg/kg. of body weight. This amount of pure compound would not be found in the 105 mg/kg. body weight dose of AP given to male animals or the 2g (2,000 mg/kg body weight) given to the female animals in the studies described above. Thus, it appears unlikely that the active compound in AP causing infertility is a member of the andrographolide series of compounds.
Liver & Gallbladder Protection
In Ayurvedic medicine (a system used in India), there are 26 different formulations containing AP that are used to treat liver disorders. AP's four related medicinal compounds were tested for a protective effect against liver toxicity produced in mice by giving them carbon tetrachloride (a cleaning solvent), alcohol, or other toxic chemicals. (26). These chemicals damage the liver by causing lipid peroxidation. This is a process whereby free radicals (reactive molecules) produced by the chemical attack and destroy cellular membranes that surround liver cells. When the AP compounds were given to animals three days before the toxic chemicals, there was a significant protective effect in the liver. This effect was attributed to the antioxidant ability of the AP compounds, which was effective as silymarin (another plant antioxidant from milk thistle).
In another study, andrographolide from AP was shown to produce a significant increase in bile flow. (27). Bile is produced in the liver and stored in the gallbladder and aids in digestion. When a chemical, paracetamol, was given to animals pretreated with andrographolide, the usual decrease in bile production seen with this chemical was prevented. In this case. andrographolide was more potent than silymarin.
Infective hepatitis is an acute inflammatory condition of the liver. It is often followed by liver cirrhosis and may progress to a coma and death. In India, where ancient physicians used AP to treat similar liver ailments, a study was conducted to evaluate the effect of AP in infective hepatitis. There was marked improvement in the majority of patients tested, when given a decoction or infusion of AP. Appetite improved on the fifth day of treatment, jaundice (yellow color of conjunctive of the eye and skin) gradually diminished and completely disappeared within 24 days, and fever subsided after 7 days on average. Other indications of effectiveness of AP included improvement in liver function tests. The researchers concluded that AP was a useful remedy for treatment of infective hepatitis.
The andrographolides present in AP are potent stimulators of gallbladder function. In animal experiments, those that received andrographolides for seven consecutive days showed an increase in bile flow, bile salts, and bile acids. These increases are beneficial and result in enhanced gallbladder function. Use of AP might, therefore, decrease the probability of gallstone formation and might also aid fat digestion. The andrographolides also prevented decreases in the amount of bile that are caused by acetaminophen toxicity. (15).
Nervous System Effects
Many compounds do not penetrate the blood-brain barrier. However, andrographolide does so and concentrates in the brain and particularly in the spinal cord. (7). Several studies have shown that AP products have a sedative effect. In mice given barbital as anesthesia, the animals became sedated more quickly and the anesthesia lasted longer. Also, it was possible to give less of the anesthesia if it was given along with AP. (19). The studies indicate that AP products may act at the barbital receptors in the brain.
Respiratory System Effects
Andrographolide has been used to treat tonsilitis, respiratory infections, and tuberculosis. In one study, AP was used to treat 129 cases of acute tonsilitis. Sixty-five percent of patients responded to the therapy. (32). The same authors used andrographolide to treat 49 pneumonia patients. Thirty five cases were found to show positive changes and nine patients completely recovered. In another study, andrographolide was used to treat 111 patients with pneumonia and twenty with chronic bronchitis and lung infection. The overall effectiveness of AP treatment was 91%. Fever subsided within three days in 72% of the patients and 40% of these patients had smaller areas of infection within one week.
Tuberculosis is usually treated within the antibiotic rafampin. When used alone, rifampin therapy still results in 22.5% of patients dying. In a study using an injectable solution of 2.5% andrographolide given so as to provide 50 to 80 mg/kg. body weight per day for two months, results were improved. Of seventy cases of tubercular meningitis, 30% of patients were considered cured with a fatality rate of 8.6%. 33. The combination of andrographolide plus rifampin resulted in a 2.6-fold decrease in fatality rates.
Other Diseases, Effect on
Leptospirosis is a disease caused by the bacterium Leptospira interrogens. Infection with this organism results in fever, hemorrhagic (blood-containing) lesions, central nervous system dysfunction, and jaundice. Several studies have reported efficacy in approximately 80% of patients treated with deoxyandrographolide, andrographolide, and neoandrographolide tablets. (34).
In a study reported from India, twenty cases of infective hepatitis (hepatitis A) in men and women were treated with a decoction of AP (Kalmegh) equivalent to 40 g of the crude compound for over twenty-four days. In all twenty patients, the yellowing of the conjunctiva of the eye and of the urine returned to normal coloration. Ninety percent of the patients regained their appetite and 83% had relief from general depression. Overall, 80% of the patients were considered cures and 20% improved bbased on biochemical tests and changes in symptoms. (35). In a similar study in China, 112 cases of hepatitis were successfully treated in 83% of patients. (22).
Acute pyelonephritis is an inflammation of the kidney, particularly due to local bacterial infection. In a study evaluating the effectiveness of AP in treating this disease, AP was compared with nitrofurantoin, a standard clinical drug for pyelonephritis therapy. AP was found to be as effective as the standard drug, but with fewer side effects. (36).
Chorioepithelioma is a highly malignant tumor derived from the placenta. It is surrounded by "lakes" of blood. Hemorrhagic metastases develop relatively early in the course of the illness, and are frequently found in the lungs, liver, brain, vagina, and various other pelvic organs; one where a hydatidiform mole is present. The malignant cells that form the placenta. AP was found to have a unique effect on these conditions. In one study, sixty patients with these conditions were treated with AP and AP-derived compounds. Forty-one of these patients had confirmed metastasis (spread of the cancer) of the lesions. Twelve patients treated with AP alone recovered. Of these patients, four women subsequently became pregnant (this condition usually results in difficulties in trying to get pregnant). Of patients treated with other drugs in addition to AP, forty-seven did not experience a regrowth of the tumor during the time of the study. (37).
In a case study of patient with an anal tumor, results were reported as "satisfactory" when the tumor was treated with a decoction of AP. In this therapy, a 500 ml. decoction was prepared from 100 g of AP and 1,000 ml water, filtering out residue, and mixing the liquid with 10 ml of vinegar. When the temperature of the liquid was below 40 degrees C., the anal tumor was treated in a sitz bath for fifteen minutes twice daily. (38).
Additional diseases reported to be effectively treated by herbal combinations that include AP are Japanese B encephalitis, cervical erosion, pelvic infection (23), otitis media purulence, cutaneous gangrene in infants (39), vaginitis (40), leprosy (41), herpes (42, 43), chicken pox, and mumps (43), neurodermatitis, eczema, and burns (44). When cobra venom was given to mice, AP prolonged survival time and postponed the occurrence of respiratory failure caused by the venom (45).
Safety & Contraindications
In Traditional Chinese Medicine (TCM) and in systems of healing in Thailand and India, AP has long been perceived as safe. Although trial and error in humans may not be considered scientific, it is a way of determining whether a substance is effective or harmful. When scientists began to investigate the safety of AP, formal toxicological studies in animal models and in animal and human clinical trials confirmed that andrographolide and other members of this AP family of compounds have very low toxicity. In mice that received oral extracts of AP (10 g/kg body weight) once a day for seven days, none of the mice died (46). This very high amount did produce decreased activity and general lethargy. Heart, kidney, liver, and spleen were found to be normal in these animals. When 500 mg/kg of AP were given daily for ten days to mice, there was no effect on growth, appetite, or stool production. The animals were energetic and results of complete blood counts were normal. In rabbits given intravenous andrographolide (10 mg/kg.), there were no abnormal cardiovascular responses. Liver enzyme tests and heart, liver, kidney, and spleen were normal in these animals (47). In other tests for toxicity, rats or rabbits received 1 g/kg orally of andrographolide or neoandrographolide for seven days. This amount did not affect body weight, blood counts, liver or kidney function, or other important organs (23, 30).
Rarely, people who use AP experience dizziness and heart palpitations. As with all herbs, some people will have an allergic reaction to AP. The other side effect, as discussed above, is antifertility. Overall, evidence to date indicates that andrographolides are naturally occurring compounds with low toxicity when used appropriately.
The use of AP has been associated with allergic reactions ranging from minor skin rashes to more serious anaphylaxis, which is a potential problem at high doses. Whether or not these reactions are due to AP per se or other matter in herbal preparations is not clearly understood.
Footnotes
1 Sandberg, F. 1994. Andrographidis herba Chuanxinlian: A review. Gothenburg, Sweden: Swedish Herbal Institute. Available from the American Botanical Council (USA).
2 Gupta, S., M. A. Choudhry, J.N.S. Yadava, V. Srivastava, and J.S. Tandon. 1990. Antidiarrheal activity of diterpenes of Andrographis paniculata (Kalmegh) against Escherichia coli enterotoxin in in vivo models. Int. J. Crude Drug Res. 28; 4:273-83.
3 Sharma, A., L. Krishan, and S.S. Handa. 1992. Standardization of the Indian crude drug Kalmegh by high pressure liquid chromatographic determination of andrographolide. Phytochemical analysis 3:129-31
4 Chem Weiming and Liang Xiaotion. Deoxyandrographolide 19ß-D-glucoside from the leaves of A. paniculata, Planta Medica 1982; 15: 245-246.
5 Siripong, P., B. Kongkathip, K. Preechanukool, P. Picha, K. Tunsuwan, and W.C. Taylor. 1992. Cytotoxic diterpenoid constituents from Andrographis paniculata, Nees leaves, J. Sci. Soc. Thailand 18(4):187-94.
6 Zheng, Z.Y. 1982. Pharmacokinetic studies on 3H-andrographolide. Chinese Herbal Med. 13(9):33-36.
7 Weibo, L. 1995. Prospect for study on treatment of AIDS with traditional Chinese medicine. J. Trad. Chinese Med. 15(1):3-9.
8 Wang, Y.H. 1983. The pharmacology and application of traditional Chinese medicine. Beijing: People's Health Press.
9 Signal Transduction Companies (editorial). 1996. Genetic Engineering News 16(1), 1 January.
10 Tang, W., and G. Eisenbrandt. 1992. Chinese drugs of plant origin: Chemistry, pharmacology, and use in traditional and modern medicine. New York: Springer-Verlag.
11 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.
12 Puri, A., R. Saxena, R.P. Saxena, and K.C. Saxena. 1993. Immunostimulant agents from Andrographis paniculata. J. Natural Products 56(7):995-99.
13 Matsuda, T., M. Kuroyanagi, S. Sugiyama, K. Umehara, A. Ueno, and K. Nishi. 1994. Cell differentiation-inducing diterpenes from Andrographis paniculata Nees. Chem. Pharm. Bull (Tokyo) 42(6):1216-25.
14 Talukdar, P.B., and S. Banerjee. 1968. Studies on the stability of andrographolide. Indian J.Chem. 6:252-54.
15 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.
16 Caceres D.D., J.L. Hancke, R.A. Burgos, and G.K. Wikman. 1997. Prevention of common colds with Andrographis paniculata dried extract: A pilot double-blind trial. Phytomedicine. 4(2): 101-4.
17 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.
18 Huang, L.Y. 1987. The effects of andrographolides on experimental blood deficiency of cardiac muscle. Chinese Herbal Med. 18(7): 26-28.
19 Deng, W.L. 1978. Preliminary studies on the pharmacology of the Andrographis product dihydroandrographolide sodium succinate. Newsletters of Chinese Herbal Med. 8:26-28.
20 Madav. H.C., T. Tripathi, and S.K. Mishra. 1995. Analgesic, antipyretic, and antiulcerogenic effects of andrographolide. Indian J. Pharm. Sci. 57(3):121-25.
21 Vedavathy, S. and K.N. Rao. 1991. Antipyretic activity of six indigenous medicinal plants of Tirumala Hills, Andhra Pradesh, India. Ethnopharmacology 33:193-96.
22 Deng, W.L. 1978. Outline of current clinical and pharmacological research on Andrographis paniculata in China. Newsletters of Chinese Herbal Med. 10:27-31.
23 Yin, J., and L. Guo. 1993. Contemporary traditional Chinese medicine. Beijing: Xie Yuan.
24 Manez, S., J.J. Alcaraz, J. Paya, J.L. Rios, and J.L. Hancke. 1990. Selected extracts from medicinal plants as anti-inflammatory agents.
25 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.
26 Kapil, A., I.B. Koul, S.K. Banerjee, and B.D. Gupta. 1993. Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata. Biochemical Pharmacology 46(1):182-85.
27 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.
28 Wang, D., and H. Zhao. 1993. Experimental studies on prevention of atherosclerotic arterial stenosis and restenosis after angioplasty with Andrographis paniculata Nees and fish oil. J. of Tongji Medical University 13(4):193-98.
29 Zhao, H., and W. Fang. 1990. Protective effects of Andrographis paniculata Nees on post-infarction myocardium in experimental dogs. J. of Tongji Medical University 10(4):212-17.
30 Akbarsha, M.A., B. Manivanan, K.S. Hamid, and B. Vijayan. 1990. Antifertility effect of Andrographis paniculata (Nees) in male albino rat. Indian Journal of Experimental Biology. 28:421-26.
31 Zoha, M.S., A.H. Hussain, and S.A. Choudhury. 1989. Antifertility effects of Andrographis paniculata in mice. Bangladesh Med. Res. Council Bull. 15:34-37.
32 Second traditional Chinese medicine pharmaceutical factory in Shanghai test and manufacture of the water-soluble andrographolide injections. 1976. Med. Industry 1:24-31.
33 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.
34 Shanghai City Andrographis Research Group, 1976. A study on water-soluble andrographolide. Newsletters of Chinese Herbal Med. 3:10-18.
35 Chturvedi, G.N., G.S. Tomar, S.K. Tiwari, and K.P. Singh. 1983. Clinical studies on Kalmegh (Andrographis paniculata Nees) in infective hepatitis. Journal of International Institute of Ayurveda 2:208-11.
36 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.
37 Department of Gynecology and Obstetrics of the People's Hospital in Meixian Prefecture. 1977. Summary of the effects of Andrographis paniculata on 60 cases of chorioepithelioma and malignant hydatidiform mole. Chinese J. of Med. 12:755.
38 Hueng, S.J. 1991. Treating anal tumor by washing using Andrographis paniculata extractions plus vinegar. Chinese J. Anal. Intest. Dis. 11(2):40.
39 Qi, w.C. 1965. Investigations of forty-five cases of infant cutaneous gangrene treated by Yi-Jian-Xi cream. Traditional Chinese Med. in Fujian 4:32.
40 Lingtang Town Hospital of Gaoyou County. 1975. Treating vaginitis using Andrographis paniculata. Jiangshu Med. 6:45-46.
41 No. 31 Field Hospital of the People's Liberation Army. 1975. A summary of the clinical effects of Andrographis paniculata and andrographolide on 112 leprosy cases. J. Protection and Cure of Dermal Diseases 2:158-164.
42 Huang, Q.Z. 1974. Treating herpes using Andrographis paniculata products. Guangxi Health 5:43.
43 Huang, Q.Z. 1978. Treating herpes, chicken pox, mumps, and neurodermatitis using Andrographis paniculata products. J. Barefoot Doctor Guangxi 9:21.
44 Cooperative Clinic of Zuoqiao, Sanca, Douchang, Jiangxi. 1975. Treating burns using pumpkin pump plus Andrographis paniculata powder. J. Barefoot Doctor 4:11.
45 Huang, T.K. 1994. Handbook of compositions and pharmacology of traditional Chinese medicine. Beijing: China Medical and Technology Press.
46 Chung, Y. 1979. Andrographis paniculata. Handbook of traditional Chinese medicine. Guangzhou.
47 Guo, S.Y., D.Z. Li, W.S. Li, A.H. Fu, and L.F. Zhang. 1988. Study of the toxicity of andrographolide in rabbits. J. Beijing Med. Univ. 5:422-28.
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