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This document discusses herbal approaches for treating liver disorders. It notes that over 600 herbal formulations are sold worldwide for claimed hepatoprotective effects. Four plants - Silybum marianum, Glycyrrhiza glabra, Picrorhiza kurroa, and Phyllanthus amarus - have been scientifically proven to have hepatoprotective, anti-inflammatory, and immune-modulating effects. However, many herbal preparations still lack standardization, randomized clinical trials, and toxicological evaluation needed for universal acceptance in chronic liver disease treatment. The liver's vital functions are also summarized, including roles in metabolism, glycogen storage, hormone production, and detoxification.
This document discusses herbal approaches for treating liver disorders. It notes that over 600 herbal formulations are sold worldwide for claimed hepatoprotective effects. Four plants - Silybum marianum, Glycyrrhiza glabra, Picrorhiza kurroa, and Phyllanthus amarus - have been scientifically proven to have hepatoprotective, anti-inflammatory, and immune-modulating effects. However, many herbal preparations still lack standardization, randomized clinical trials, and toxicological evaluation needed for universal acceptance in chronic liver disease treatment. The liver's vital functions are also summarized, including roles in metabolism, glycogen storage, hormone production, and detoxification.
This document discusses herbal approaches for treating liver disorders. It notes that over 600 herbal formulations are sold worldwide for claimed hepatoprotective effects. Four plants - Silybum marianum, Glycyrrhiza glabra, Picrorhiza kurroa, and Phyllanthus amarus - have been scientifically proven to have hepatoprotective, anti-inflammatory, and immune-modulating effects. However, many herbal preparations still lack standardization, randomized clinical trials, and toxicological evaluation needed for universal acceptance in chronic liver disease treatment. The liver's vital functions are also summarized, including roles in metabolism, glycogen storage, hormone production, and detoxification.
1. INTRODUCTION There are numerous plants and traditional formulations available for the treatment of liver diseases. About 600 commercial herbal formulations with claimed hepatoprotective activity are being sold all over the world. Around 170 phyto constituents isolated from 110 plants belonging to 55 families have been reported to possess hepatoprotective activity. In India, more than 93 medicinal plants are used in different combinations in the preparations of 40 patented herbal formulations3. However, only a small proportion of hepatoprotective plants as well as formulations used in traditional medicine are pharmacologically evaluated for their safety and efficacy. Some herbal preparations exist as standardized extracts with major known ingredients or even pure compounds which are being evaluated. The use of natural remedies for the treatment of liver diseases has a long history, starting with the Ayurvedic treatment, and extending to the Chinese, European and other systems of traditional medicines. The 21 st century has seen a paradigm shift towards therapeutic evaluation of herbal products in liver diseases by carefully synergizing the strengths of the traditional systems of medicine with that of the modern concept of evidence-based medicinal evaluation, standardization of herbal products and randomized placebo controlled clinical trials to support clinical efficacy. The present review provides the status report oil the scientific approaches made to herbal preparations used in Indian systems of medicine for the treatment of liver diseases. In spite of the availability of more than 300 preparations for the treatment of jaundice and chronic liver diseases in Indian systems of medicine using more than 87 Indian medicinal plants, only four terrestrial plants have been scientifically elucidated while adhering to the internationally acceptable scientific protocols. In-depth studies have proved Syllabus Mariana to beatnik-oxidative, anti-lipid per-oxidative, anti-fibrotic, anti- inflammatory and liver regenerative. Glycyrrhiza glabralias been shown to be hepatoprotective and capable of inducing an indigenous interferon. Picrorhiza kurroa is proved to be anti-inflammatory, hepatoprotective and immune modulatory. Extensive studies on Phyllan thusamarus have confirmed this plant preparation as being antiviral against hepatitis B and C viz-uses, hepato protective and immune modulating, as well as possessing anti-inflammatory properties. 1 Herbal Approaches For Liver Disorder
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The use of herbal medicine can be traced back to 2100 BC in ancient China at the time of Xia dynasty, and in India during the Vedic period. The first written reports are timed to 600 BC with Charaka samhita of India, and in China the same became systematic by 400 BC. The basic concept in these medicinal systems is that the disease is a manifestation of a general imbalance of the dichotomous energies that govern life as a whole and human life in particular, and they focus on medicine that can balance these energies and maintain good health. In Ayurvedha of India, the forces are said to be agni (strength, health and innovation) and ama (weakness, disease and intoxication). In India there are also other systems of traditional medicine besides Ayurvedha and these are called Siddha, which originated almost at the same time as Ayurvedha from southern India, and Unani, which entered India during the Mogul dynasty periods. Like Ayurvedha, practitioners of Siddha medicine believe in a perfect balance of three doshas known as vatha (space and air elements), pitta (fire and water elements) and kapha (water and earth elements). All these Indian systems of medicine have primarily claimed a curative potential for their medicinal preparations for all kinds of liver diseases. 18 In spite of the significant popularity of these medicinal systems, they are still to be recognized as being universally acceptable treatment modalities for chronic liver disease. The limiting factors that contribute to such an eventuality are (i) lack of standardization of the herbal drugs; (ii) lack of randomized placebo controlled clinical trials; and (iii) lack of traditional toxicologic evaluations.
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2. EFFICACY AND SAFETY OF HERBAL PRODUCTS Any evaluation of herbal products faces major problems. The first is the use of mixed extracts (concoctions) and variations in methods of harvesting, preparing, and extracting the herb, which can result in dramatically different levels of certain alkaloids. The biologically active substances have been structurally defined and standardized for only a few of the herbs. Even then, it may not be known if this molecule is the sole active principle or if efficacy depends on the mixture of compounds. The second problem is a lack of randomized, placebo-controlled clinical studies. Traditional Eastern medicine relies on empiricism and a holistic philosophy, and controlled studies are considered unnecessary. This is a view shared by many Western supporters of alternative medicine. Also, trials may not use end points, such as death from liver disease, histological fibrosis or inflammation, cancer, and transplantation. 15
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3. LIVER The Liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemical necessary for digestion. The liver is necessary for survival; there is currently no way to compensate for the absence of liver function long term, although liver dialysis can be used short term. This organ plays a major role in metabolism and has a number of functions in the body, including glycogen storage, decomposition of red blood cells, plasma protein synthesis, hormone production, and detoxification. It lies below the diaphragm in the abdominal-pelvic region of the abdomen. It produces bile, an alkaline compound which aids in digestion via the emulsification of lipids. The various functions of the liver are carried out by the liver cells or hepatocytes. Your entire blood supply passes through your liver several times a day. Your liver keeps you alive and healthy by metabolizing the food you eat, by breaking it down and digesting fatty acids. The liver produces bile and stores it in the gall bladder until it is needed. It produces blood-clotting factors, and also converts sugar into glycogen, which it stores until the muscles need energy and it is secreted into the blood stream as glucose. It synthesizes proteins and cholesterol and converts carbohydrates and proteins into fats, which are stored for later use. 2
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4. FUNCTION OF LIVER The liver is thought to be responsible for up to 500 separate functions, usually in combination with other systems and organs. The various function of liver is as follow: The liver performs several roles in carbohydrate metabolism. Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol). Glycogenolysis (the breakdown of glycogen into glucose). Glycogenesis (the formation of glycogen from glucose)(muscle tissues can also do this). The liver is responsible for the mainstay of protein metabolism, synthesis as well as degradation. The liver also performs several roles in lipid metabolism. Cholesterol synthesis. Lipogenesis, the production of triglycerides (fats). A bulk of the lipoproteins is synthesized in the liver. In the first trimester fetus, the liver is the main site of red blood cell production. By 32 nd
week of gestation, the bone marrow has almost completely taken over that task. The liver produces and excretes bile (a yellowish liquid) required for emulsifying fats. Some of the bile drains directly into the duodenum, and some is stored in the Gall bladder. The liver also produces insulin-like growth factor 1 (IGF-1), a polypeptide protein hormone that plays an important role in childhood growth and continues to have anabolic effects in adults. The liver is a major site of thrombopoietin production. Thrombopoietin is a glycoprotein hormone that regulates the production of platelets by the bone marrow. 5
The liver stores a multitude of substances, including glucose (in the form of glycogen), vitamin A (1-2 years' supply), vitamin D (1-4 months' supply), vitamin 1312 (1-3 years' supply), iron, and copper. The liver is responsible for immunological effects the reticuloendothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system. The liver produces albumin, the major osmolar component of blood serum. Herbal Approaches For Liver Disorder
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The liver synthesizes angiotensinogen, a hormone that is responsible for raising the blood pressure when activated by renin, an enzyme that is released when the kidney senses low blood pressure. 4
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5. THE DISEASES OF THE LIVER There are more than a hundred kinds of liver disease. The most widely spread are as follows: Hepatitis, inflammation of the liver, is caused mainly by various viruses (viral hepatitis) but also by some liver toxins (e.g. alcoholic hepatitis), autoimmunity (autoimmune hepatitis) or hereditary conditions. Alcoholic liver disease is any hepatic manifestation of alcohol overconsumption, including fatty liver disease, alcoholic hepatitis, and cirrhosis. Analogous terms such as "drug-induced" or "toxic" liver disease are also used to refer to the range of disorders caused by various drugs and environmental chemicals. Fatty liver disease (hepatic steatosis) is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells. Non-alcoholic fatty liver disease is a spectrum of disease associated with obesity and metabolic syndrome, among other causes. Fatty liver may lead to inflammatory disease (i.e. steato hepatitis) and, eventually, cirrhosis. Cirrhosis is the formation of fibrous tissue (fibrosis) in the place of liver cells that have died due to a variety of causes, including viral hepatitis, alcohol overconsumption, and other forms of liver toxicity. Cirrhosis causes chronic liver failure. Primary liver cancer most commonly manifests as hepatocellular carcinoma and/ or cholangio carcinoma; rarer forms include angio sarcoma and hemangio sarcoma of the liver. (Many liver malignancies are secondary lesions that have metastasized from primary cancers in the gastrointestinal tract and other organs, such as the kidneys, lungs, breast, or prostate). Primary biliary cirrhosis is a serious autoimmune disease of the bile capillaries. Primary sclerosing cholangitis is a serious chronic inflammatory disease of the bile duct, which is believed to be autoimmune in origin. Centrilobular necrosis of liver can be caused by leakage of enteric toxins into circulation. Salmonella toxins in ileum have been shown to cause severe damage to liver hepatic cells. BuddChiari syndrome is the clinical picture caused by occlusion of the hepatic vein, which in some cases may lead to cirrhosis. Herbal Approaches For Liver Disorder
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Hereditary diseases that cause damage to the liver include hemochromatosis, involving accumulation of iron in the body, and Wilson's disease, which causes the body to retain copper. Liver damage is also a clinical feature of alpha 1-antitrypsin deficiency and glycogen storage disease type II. In transthyretin-related hereditary amyloidosis, the liver produces a mutated transthyretin protein which has severe neurodegenerative and/or cardiopathic effects. Liver transplantation can provide a curative treatment option. Gilbert's syndrome, a genetic disorder of bilirubin metabolism found in about 5% of the population, can cause mild jaundice. There are also many pediatric liver diseases including: biliary atresia, alpha-1 antitrypsin deficiency, Alagille syndrome, and progressive familial intrahepatic cholestasis. 6
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6. CAUSES FOR LIVER DISORDER The liver can be damaged in a various ways: Cells can become inflamed (such as in hepatitis: hepar=liver + itis=inflammation). Bile flow can be obstructed (such as in cholestasis: chole=bile + stasis=standing). Cholesterol or triglycerides can accumulate (such as in steatosis; steat=fat + osis=accumulation). Blood flow to the liver may be compromised. Liver tissue can be damaged by chemicals and minerals, or infiltrated by abnormal cells. Alcohol is directly toxic to liver cells and can cause liver inflammation, referred to as alcoholic hepatitis. In chronic alcohol abuse, fatty accumulation (steatosis) occurs in liver cells causing the cells to malfunction. Liver cells may become temporarily inflamed or permanently damaged by exposure to medications or drugs. E.g. taking excess amounts of acetaminophen (Tylenol, Panadol) can cause liver failure that is permanent, Statin medications are commonly prescribed to control elevated blood levels of cholesterol. Even when taken in the appropriately prescribed dose, liver inflammation may occur and can be detected by blood tests that measure liver enzymes. Hepatitis is a viral infection that is caused primarily through the fecal-oral route when small amounts of infected fecal matter are inadvertently ingested. 4
6.1 Prevention Some, but not all, liver diseases can be prevented. For example, hepatitis A and hepatitis B can be prevented with vaccines. Other ways to decrease the risk of infectious liver disease include: Practicing good hygiene, such as washing hands well after using the restroom or changing diapers. Avoiding drinking or using tap water when traveling internationally. Avoiding illegal drug use, especially sharing injection equipment. Practicing safest sex. Practicing safer sex provides less protection. Herbal Approaches For Liver Disorder
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Avoiding the sharing of personal hygiene items, such as razors or nail clippers. Avoiding toxic substances and excess alcohol consumption. Using medications only as directed. Using caution around industrial chemicals. Eating a well-balanced diet following the food guide pyramid. Getting an injection of immune globulin after exposure to hepatitis A. Using recommended safety precautions in healthcare and day care work. 19
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7. DIAGNOSTIC CHECK LIST FOR LIVER DISORDER 1. Indigestion of all kinds, especially epigastric fullness after meals, intolerance of fatty foods, and nausea without vomiting. 2. General aches and pains from toxins not clearing. Full headaches. 3. Low energy and lethargy, especially if worse in the morning. 4. Aches and pains over the liver area. 5. Gall bladder problems, from poor and too thick bile flow, leads to pains around the right shoulder blade and tenderness on palpating the gall bladder. 6. Bile flow congestion leading to jaundice, yellow skin and conjunctiva, bitter tastein the mouth, generalized itching, and chronic constipation. 7. Blood protein imbalance leading to generalized water retention. 8. Venous return blockage leading to hemorrhoids, pelvic congestions, and a heavy, erratic menstrual flow. 9. Heat accumulation leading to hot skin and rashes. 10. Lack of joy, irritability, and quick anger. 11. Intolerance of alcohol. 12. Drug taking, medical or recreational, strains the liver. 13. Blood sugar imbalances including reactive hypoglycemia and diabetes (Type II). 14. Allergies and food sensitivities can arise from liver congestion or may cause it. Skin rashes, migraines, abdominal bloating, and colic. 15. Tongue softness on the right side.
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8. LAB TESTS FOR LIVER DISEASE 8.1 Aspartate Aminotransferase (ASAT) It is found practically in every tissue of the body, including RBCs. Its concentration is particularly high in cardiac muscle and liver, intermediate in skeletal muscle and kidney, and much low in other tissues. The measurement of the serum ASAT level is helpful for the diagnosis and following of cases of myocardial infarction, hepatocellular diseases and skeletal muscle disorders. Reference Interval: 6-25 U/L. 8.2 Alanine Aminotransferase (ALAT) The concentration of ALAT is not really as great as for ASAT. It is present in moderately high concentration in liver, but is low in cardiac and skeletal muscles and other tissues. Its use for clinical purposes is primarily for the diagnosis of liver diseases and to resolve some ambiguous increase in serum ASAT and ALAT. The liver is the primary source of these enzymes. If the serum ASAT is elevated while ALAT remains within normal limits, it is a case of suspected myocardial infarction. Reference Interval: 3-30 U/L. 8.3 Alkaline Phosphatase (ALP) Alkaline phosphatase is a group of enzymes that hydrolyzes monophosphate esters at an alkaline pH. The enzyme has been identified in most body tissues and is generally localized in the membrane. Eleven different isoform of this enzyme have been identified in serum. Reference Interval: 40-223 U/L. 8.4 Lactate Dehydrogenase (LDH) Lactate dehydrogenase is localized in the cytoplasm of the cells and this is extruded into the serum when the cells are damaged or necrotic. When only a specific organ, such as liver is known to be involved, the measurement of total LDH is useful. Reference Interval: 125-290 U/L. 8.5 Total Cholesterol Serum cholesterol comprises two forms, free cholesterol and esterified cholesterol. In jaundice and paranchymatous liver disease, serum cholesterol level will fall. Drug Herbal Approaches For Liver Disorder
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administration will rectify the defective mechanism associated with carbon tetrachloride administration. Reference Interval: <200 mg/dL. 8.6 Triglycerides (TGL) Immediately after carbon tetrachloride administration, the triglycerides level in the liver is elevated. The defect in the transport of triglycerides into the plasma is the cause for accumulation of lipids in the liver during carbon tetrachloride intoxication. Within 3-5 hours after administration of carbon tetrachloride, decrease in serum triglyceride level occurs in rats. Carbon tetrachloride intoxication evokes a defect in the secretory mechanism of triglycerides in the liver, resulting in accumulation of lipid in liver. A reduction in the synthesis of lipoproteins will result in the lower transport of triglycerides, which is associated with lipoprotein. Reference Interval: 35-200 mg/dL. 8.7 Total Protein (TP) A healthy functioning of the liver is required for the synthesis of the serum proteins, except for the gamma globulins. The proteins synthesized in the liver are usually decreased in hepatocellular disease, but the immunoglobulins are increased in viral hepatitis and chronic liver infections. Reference Interval: 6-8.2 g/dL. 8.8 Albumin Albumin is decreased in chronic liver diseases and is generally accompanied by an increase in the beta and gamma globulins as a result of production of IgG and IgM in chronic active hepatitis and of IgM and IgA in biliary or alcoholic cirrhosis, respectively. Reference Interval: 3.5-5.2 g/dL. 8.9 Total Bilirubin (TB) Bilirubin has been used to evaluate chemically induced hepatic injury. It is the principle pigment in the bile, and is derived from the breakdown of heamoglobin when senescent RBCs are phagocytozed. As most of the liver diseases are accompanied by jaundice, the differential diagnosis of jaundice plays an important role in elucidating hepatic dysfunction. Herbal Approaches For Liver Disorder
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An elevated level of serum bilirubin may be produced. It shows severe parenchymal injury. Reference Interval: < 1 mg/dL. 8.10 Direct Bilirubin (DB) Unconjugated bilirubin is not water-soluble. It is transported in the blood stream bound to albumin. It accounts for 30-50% of bilirubin rise in hepatocellular disease or cholestasis. Unconjugated hyper-bilirubenemia is most often due to either haemolysis, or Gilberts syndrome, an inherited abnormality of bilirubin metabolism. Reference Interval: < 0.25 mg/dL.
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9. HERBAL TREATMENT FOR LIVER DISORDER According to the principles of all Herbal medicine, health exists when the body is balanced and its energy is freely flowing. The term energy refers to Qi, the life energy that is said to animate the body. The term balance refers to the relative factors of yin and yangthe classic Taoist opposing forces of the universe. The expression in various subsidiary antagonists such as cold vs. heat, dampness vs. dryness, descending vs. ascending, at rest vs. active, and full vs. empty. Herbal medical diagnosis and treatment involves identifying the factors that are out of balance and attempting to bring them back into harmony. Diagnosis is carried out by means of listening to the pulse (in other words, taking the pulse with extraordinary care and sensitivity), observing and palpating various parts of the body, and asking a long series of questions. It is important to realize that diagnosis according to herbal system differs greatly from Western diagnosis. To understand this, consider two hypothetical patients with the single Western diagnosis of migraine headaches. The first might be said to have dryness in the liver and ascending while another might be diagnosed with exogenous wind-cold. Based on these differing diagnoses, entirely different remedies might be applied. The herbal formulas used in herbal system consist of four categories of herbs. Ministerial, deputy, assistant, and envoy. The ministerial herb addresses the principal pattern of the disease. Deputy herbs assist the ministerial herb or address coexisting conditions. Assistant herbs are designed to reduce the side effects of the first two classes of herbs, and envoy herbs direct the therapy to a particular part of the body. For example, in the case of dryness in the liver and ascending described above, an herbalist might employ a ministerial8 herb to reverse ascending Qi, a deputy herb to exert a moistening effect, an assistant herb to prevent the stagnation of Qi (Qi stagnation is said to be a side effect of moistening herbs), and an envoy to carry these effects to the liver. 8 CLASSIFICATION: These are generally classified into 3 categories without any strict delineation amongst them. 9.1 Anti-hepatotoxic agents: These generally antagonise the effects of any hepatotoxin causing hepatitis or any liver disorder or disease. Herbal Approaches For Liver Disorder
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9.2 Hepatotropic agents: These generally support or promote the healing process of the liver. In practice these two activities cannot be easily distinguished from each other. 9.3 Hepatoprotective agents: These generally prevent various types of liver affections prophylactically. In general any hepatoprotective agent can act as an anti-hepatotoxic or hepatotropic agent but the vice versa is always not true. PLANTS USED IN THE TREATMENT OF LIVER DISEASE (HEPATOPROTECTIVE NATURAL PLANTS): Some of the crude drugs with activity against liver diseases are: Eclipta alba (Asteraceae), Glycyrrhiza glabra (Leguminosae), Boerhaavia diffusa (Nyctaginaceae), Phyllanthus amarus (Euphorbiaceae), Silybum marianum (Compositeae), Uncaria gamber (Rubiaceae), Andrograhis paniculata (Acanthaceae). Table 9.1 Plants with hepatoprotective activity Botanical name Family Parts Used Areca catechu Linn Arecaceae Inflorescence Arenga wightii Griff Arecaceae Inflorescence and fruit husk Aristolochia indica Linn Aristolochiaceae Roots (tender) Asparagus racemosus Willd Liliaceae Roots Herbal Approaches For Liver Disorder
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Azadirachta indica A. Juss Meliaceae Root Bark Centella asiatica Urban Apiaceae Whole Plant Ceratopteris siliquosa (L) Copel Ceratoptendaceae Whole Plant Cuminum cyminum Linn Apiaceae Fruit Curcuma domestica Val Zingiberaceae Fresh rhizome Desmodium biflorum Linn Fabaceae Whole plant Elettaria cardamomum Maton Zingiberaceae Seed Ficus glomerata Roxb Moraceae Fruit Ficus racemosa Linn Moraceae Tender root Hibiscus lampas Cav. Malvaceae Fresh root Ixora coccinea Linn Rubiaceae Fresh root Impatiens henslowiana Arn Balsaminaceae Flowers and leaves Momordica subangulata Bl. Cucurbitaceae Fruits (tenders) Moringa oleifera Lam Moringaceae Stem bark Naregamia alata W & A Meliaceae Whole plant Phyllanthus fratenus Webst. Euphorbiaceae Whole plant Piper longum Linn Piperaceae Stem Ricinus communis Linn Euphorbiaceae Tender Leaves Herbal Approaches For Liver Disorder
Some of the reported constituents with pharmacologically/ therapeutically proved claims may be enlisted as, was also reported for its hepatoprotective properties. Silymarin Glycyrrhizin (+) Catechin Saikosaponins Curcumin Picrolive I and II Gomosin(Wagner et al.,1998) Acetyl bergenin (Lim et al., 2000) Kolaviron (Oluwatosin and Edward, 2006) 14
9.3.1Silybum marianum: Synonyms: Carduus marianus, mariane thistle. Common name: Milk thistle Family: Asteraceae Origin: indigenous to the Mediterranean region, North Africa & Western Asia. Parts used: Aerial parts Herbal Approaches For Liver Disorder
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Chemical constituents: The active constituents of milk thistle are flavonolignans including silybin, silydianin, and silychristine, collectively known as silymarin. Silybin is the component with the greatest degree of biological activity, and milk thistle extracts are usually standardized to contain 70-80 percent silybin. Silymarin is found in the entire plant but is concentrated in the fruit and seeds. Silybum seeds also contain betaine (a proven hepatoprotector) and essential fatty acids, which may contribute to silymarin's anti-inflammatory effect. Active ingredients: Silymarin a flavolignin (hepatoprotective), lipids, proteins. Milk seeds also contain other flavonolignans namely dehydrosilybin, desocysilycristin, desoxysilydianin, silyhermin, neosilyhermi, silybinome, and silandrin. Use: Silybum marianum is currently the most well researched plant in the treatment of liver disease. Also use in the dyspepsia, disorders of biliary system, liver disorder. It is used as hepatoprotective and in chronic inflammatory hepatic disorders including hepatitis, cirrohis and fatty infiltration which occur due to industrial pollutants and alcohol. It has also been found to be effective against liver poisioning due to alpha-galactosamine, carbontetrachloride and tioacetamide. It has reported that therapeutic utility of silymarin is due to stabilization of cell membrane, stimulation of protein synthesis and accelerating the process of regeneration of hepatic cells. The mechanism of hepatoprotective effect of silymarin has been suggested variously like antioxidant activity by trapping superoxide anions, stimulation of RNA synthesis and in case of amanita phalloides poisioning, blocking the receptor sites of outer liver cell membranes Silymarin is preferably given by parantral route, due to low water solubility of flavonoligans if taken orally, only 20-50% is absorbed. Herbal Approaches For Liver Disorder
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Active constituents The active constituents of milk thistle are flavonolignans including silybin, silydianin, and silychristine, collectively known as silymarin. Silybin is the component with the greatest degree of biological activity, and milk thistle extracts are usually standardized to contain 70- 80 percent silybin. Silymarin is found in the entire plant but is concentrated in the fruit and seeds. Silybum seeds also contain betaine (a proven hepatoprotector) and essential fatty acid which may contribute to the silimarins anti-inflammatory effect. Pharmacokinetics Silymarin is not water soluble and so cannot be taken as a tea. It is typically administered as an encapsulated standardized extract. The absorption with oral administration is rather low with only two to three percent of the silybin recovered in 24 hours from rat bile. The peak plasma levels after an oral dose are achieved in four to six hours in both animals and humans. Silymarin is cleared from the body predominantly via the bile and to a lesser extent the kidney. The clearance half-life is six to eight hours. 8
9.3.2 Taraxacum officinale: Synonyms: Dandelion Family: Asteraceae Origin: All parts of the northern hemisphere. Parts used: Leaves & roots. Chemical constituents: Bitter constituents like taraxecerin and taraxcin are active constituents of the medicinal herb. Other Active ingredients: sesquiterpene lactones, phenolic acid, inulin, K. Use: Hepatic & biliary disorders, kidney stones. Traditionally taraxacum officinale has been used as a remedy for jaundice and other disorders of the liver and gallbladder, and as a remedy for counteracting water retention. Herbal Approaches For Liver Disorder
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Generally, the rrots of the plants have the most activity regarding the liver and gallbladder. Oral administration of extracts from the roots of taraxacum officinale has been shown to act as a cholagogue, increasing the flow of bile. Action: diuretic, tonic. 9.3.3 Cichorium intybus: Synonyms: Cichory. Common name: Kasni Family: Compositae (asteraceae) Chemical constituents: A bitter glucoside, Cichorin has been reported to be the active constituent of the herb. Use: Use for the treatment of liver diseases. It is commonly known as kasni and is part of polyherbal formulations used in the treatment of liver diseases. In mice, liver protection was observed at various doses of Cichorium intybus but optimum protection was seen with a dose of 75 mg/kg given 30 minutes after CCl4 intoxication. In preclinical studies an alcoholic extract of the Cichorium intybus was found to be effective against chlorpromazine-induced hepatic damage in adult albino rats. 9.3.4 Solanum nigrum: Synonyms: Black nightshade. Ayurvedic name: Kakamachi. Family: Solanaceae. Chemical constituents: Main active constituents are solamargine, andsolasonine. Herbal Approaches For Liver Disorder
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Use: Aromatic water extracted from the drug is widely prescribed by herbal vendors for liver disorders. Although clinical documentation is scare as far as hepatoprotective activity is concerned, but some traditional practitioners have reported favorable results with powdered extract of the plant. It is in treatment of cirrhosis of the liver. Also used as an emollient, diuretic, antiseptic, and laxative properties. Antimicrobial, antioxidants, cytotoxic properties. It is also have anti ulcerogenic activity and hepatoprotective activity. 9.3.5 Glychyrrhiza glabra: Synonyms: Liquorice Family: Leguminosae Chemical constituents: Licorice contains triterpene saponin, known as glycyrrhizin, which has potential hepatotprotective activity. It belongs to a group of compounds known as sulfated polysaccharides. Glycyrrhizin is potassium and calcium salt of Glycyrrhizinic acid. Glycyrrhizinic acid is a glycoside and on hydrolysis yields glycyrrhetinic acid which has a triterpenoid structure. Other constituents are glucose, sucrose, bitter principle glycyramarin resin, aspargin and fat. Another chemical aspects of liquorice is prencence of flavonoids(liquiritin and isoliquiritin) which cauce antigastric effect and are useful in peptic ulcer treatment.
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Use: Glycyrrhizin use for anti-viral. It has potential for therapeutic use in liver disease. Experimental hepatitis and cirrhosis studies on rats found that it can promote the regeneration of liver cells and at the same time inhibit fibrosis. Glycyrrhizin can alleviate histological disorder due to inflammation and restore the liver structure and function from the damage due to carbon tetrachloride. The effects including: lowering the SGPT, reducing the degeneration and necrosis and recovering the glycogen and RNA of liver cells. Effects of glycyrrhizin has been studied on free radical generation and lipid peroxidation in primary cultured rat hepatocytes. Favorable results have been reported in children suffering from cytomegalovirus aftrer treating with glyrcyrrhizin. 9 9.3.6 Wilkstroemia indica: Synonyms: Aradon indica, wilkstromia. Family: Thymelaeaceae Chemical constituents: A dicoumarin, daphnoretin is the active constituent of the herb. The drug has shown to suppress HbsAG in Hep3B cells. Use: W. indica is a Chinese herb and has been evaluated in patients suffering from hepatitis B. It is said to activator of protein kinase C. 9.3.7 Curcuma longa: Synonyms: Curucuma, turmeric, Indian saffron Herbal Approaches For Liver Disorder
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Family: Zingiberaceae Chemical constituents: Diarylhepatonoids including Curcumin is the active constituent of the plant. It contains yellow colour substances known as curcuminoids. Curcuminoids is responsible for yellow colour. Curcuma species contain volatile oil, starch etc. Use: Like silymarin, turmeric has been found to protect animal livers from a variety of hepatotoxic substances, including carbon tetrachloride,galactosamine, pentobarbitol, 1- chloro-2,4-dinitrobenzene,7 4-hydroxy-nonenal,1and paracetamol. Diarylhepatonoids. Curcumin has been proved as anti-inflamatory drug. 9.3.8 Tephrosia purpurea: Synonyms: basterd indigo, hoary pea. Ayurvedic name: sharpunkha Family: Fabaceae. Chemical constituents: The roots, leaves and seeds contain tephrosin, deguelin and quercetin. The hepatotprotective constituent of the drug is still to be proved. Use: Alkali preparation of the drug is commonly used in treatment of liver and spleen diseases. In animal models, it offered protective action against carbon tetrachloride and D- galalactosamine poisoning. 9.3.9 Fumaria officinalis: Synonyms: Fumatory Herbal Approaches For Liver Disorder
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Family: Papaveraceae Chemical constituents: Alkaloids, flavonoids Origin: Europe, Mediterranean, Middle East, but has now become a weed all over the world. Parts used: aerial parts Actions: Cholagogue, anti-spasmodic Uses: Biliary & dyspeptic disorders, especially spastic discomfort of the GIT, the gall-bladder & bile ducts 9.3.10 Peumus boldus: Synonyms: Boldo Family: Monimiacee Parts used: Leaf Chemical constituents: Alkaloids, volatile oils, flavonols and their glycosides. Origin: Chile and other South American regions. Actions: Choleretic, diuretic, stomachic, mild sedative. Use: Dyspepsia, spastic complaints. It is the traditional anthemintic in Chile. It is also used in pharmaceutical slimming mixtures. 9.3.11 Chionanthus virginicus: Synonyms: Fringe tree, old mans beard. Family: Oleaceae Parts used: Dried root bark Herbal Approaches For Liver Disorder
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Chemical constituents: Saponins, lignin glycoside. Origin: Southern parts of Northern America. Actions: Cholagogue, liver tonic, bitter tonic, anti-emetic, laxative. Use: Liver & gall bladder ailments (gall stones, hepatitis, jaundice & other ailments associated with poor liver function). It is also thought to be useful as a general tonic, diuretic & febrifuge. It is also used for minor wounds, sores, bruises, inflammation, & infected wounds. Traditional uses: American Indians used the herb for malaria & wound healing. Homeopathic uses: migraine, headache, liver & gall bladder disorders & symptoms of depression. 9.3.12 Andrograhis paniculata: Synonyms: Kalmeg. Family: Acanthaceae. Parts used: Andrographis leaves, as well as the fresh juice of the whole andrographis plant, have been used in a variety of cultures. Chemical constituents: Kalmegh contains bitter principles andrographolide, a bicyclic diterpenoid lactone and Kalmeghin (upto 2.5%). Andrographis contains andrographolide, deoxyandrographolide and neoandrographolide. Andrographis contains many flavonoids. Use: Andrographis dispels heat i.e., is antipyretic. Herbal Approaches For Liver Disorder
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It removes toxins, which makes it a good treatment for infectious fevercausing diseases. It has been used in bacterial dysentery, arresting diarrhea and in upper respiratory infections, tonsillitis, pharyngitis, laryngitis, pneumonia, tuberculosis, and pyelonephritis. It has also been used in herpes, skin infections, and in helminthic (parasitic) infections. Finally, it has been used for conditions as diverse and unrelated as snakebites and diabetes, as well as terminating pregnancies. 9.3.13 Elipta alba: Synonyms: Eclipta arecta, eclipta prostata. Family: Compositae(asteraceae). Chemical constituents: It contain resins and a alkaloid known as ecliptin, nicotin, glucoside, alkaloids Use: Viral hepatitis, liver disorders, skin- and hair care, improves complexion, calm the mind, memory disorders, swollen glands, due to upper respiratory viral infection, strengthen spleen, general tonic The tincture has a neutralizing effect on the venom of South America rattle snakes. The alcoholic extracts of the entire plant has been reported to have antiviral activity against Ranikhet disease virus. Aqueous extracts of the plant showed subjective improvement of vision in the cases of refractive errors. The alcoholic extract of the plant shows protective effects on experimental liver damage in rats and mice. 9.3.14 Phyllanthus niruri/amarus: Synonyms: Phyllanthus emblica, jonesiansoca. Family: Euphorbiaceae Herbal Approaches For Liver Disorder
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Chemical constituents: Constituents of this plant are numerous, and include flavonoids and alkaloids. Use: Liver & gall bladder ailments (gall stones, hepatitis, jaundice & other ailments associated with poor liver function). It is also thought to be useful as a general tonic, diuretic & febrifuge. Standardization of phyllanthus amarus In order to determine the reasons for variation in the in vitro efficacy of different collections of P. amarus made from different parts of India,in vitro analysis for biological properties was done. It revealed that the quantitative HBsAg binding ability and HBV DNA polymerase inhibition ability varied significantly in different plant collections, and some of them did not possess demonstrable anti-hepatitis B properties. When the extracts of these collections were analyzed by HPLC profiles, there were similar variations of diminished elution peaks or even absence of such peaks that could be correlated with the absence of biological properties. These observations were considered along with the report of Mitra and Jain on the botanical survey of India, which stated that the P. niruri is a mixture of three distinct species, namely P. amarus Schum and Thonn, P. fraternus Webster and P. debilis Kleinx Wild.From the reports it is now understood that the variety that is predominant in South India is P. amarus only. Based on these observations it was necessary to define a multistep standardization procedure for assuring the reproducible, maximized bio-efficacy of P. amarus when used in the treatment of chronic liver disease with special reference to chronic HBV infection. These steps are: (i). Taxonomic identification of the specific variety of P. amarus as the source material; (ii). Preparation of the soil for the optimum growth of the selected P. amarus variety; (iii). A formulation of the combination of specific extracts that will possess the following six demonstrablein vitro activities: (a) HBsAg binding property, which will facilitate the inactivation of the virus in circulation, ultimately leading to viral clearance; Herbal Approaches For Liver Disorder
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(b) HBV-DNA polymerase enzyme-inhibiting potential, thus acting as an antiviral and preventing the multiplication of HBV; (c) Reverse transcriptase enzyme inhibition, also required for the prevention of initiation of HBV replication; (d) Inhibition of HBsAg secretion from HBV-transinfected liver cells, thus possessing activity against virus-infected chronic liver disease conditions; (e) Hepatoprotective and antihepatotoxic properties against the liver cell toxicity brought about by all hepatitis viruses (A,B,C,D,E) and other hepatotoxic agents; and (f) Immunomodulating property to potentiate the immune system of HBV-infected patients towards virus clearance and protective antibody (anti-HBs) responses; and (iv) A chemobiological finger printing methodology using the aforementioned six biological tests along with a matching HPLC profile to assess batch-to-batch in vitro reproducibility. The evaluation of herbal products face several major problems. The first is the use of mixed extracts (concoctions) and variations in methods of harvesting, preparing and extracting the herb, which can result in dramatically different levels of certain alkaloids. The biologically active substances have been structurally defined and standardized for only a few of the herbs. Even then it may not be known whether this is the sole active principal or if efficacy depends on the mixture of compounds. Second, there is a lack of randomized placebo controlled clinical trials for many of these preparations using end-points of treatment efficacy such as viral clearance, and histological improvement. Numerous reports on toxic effects contradict the popular view that herbal drugs are natural and are harmless. A survey by the National Poison Information Service for the years 1991 1995 documented 785 cases of possible or confirmed adverse reactions to herbal drugs, among which hepatotoxicity was the most frequent. Hence, safety studies are needed to generate scientifically sufficient data that may serve as a basis for future herbal drug development. In addition to the well-accepted laboratory parameters as described here using P. amarus as an example, if the aforementioned three aspects viz., herbal drug standardization, randomized controlled clinical trials and well-designed safety studies are incorporated as integral Herbal Approaches For Liver Disorder
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components, then herbal drug development, potent, safe and acceptable herbal drugs can be launched for the treatment of acute and chronic liver diseases. The drug development of P. amarus in India may be an example of such an effort in an international setting. 9.3.15 Picrorrhiza kurrora: Synonyms: Indian gentian, kutki. Family: Scrophulariaceae Chemical constituents: It is found to contain irridoid bitter substances picroside, picroside and kutkoside. Picroside and kutkosides are C9 monoterpene glycosides with an epoxy oxides in ring. Use: Picrorrhiza is used as valuable bitter tonic, antiperiodic, febrifuge and stomachic and laxative in large doses. Alcoholic extract of root is found to have antibacterial effect. The drug is found to useful in treatment of jaundice Kutkoside has been found to be a potential hapatoprotectant. 17 Table 9.2 Plants with Hypolipidaemic activity Sl.No Name of Plant Family Common/ Indian vernacular names Plant parts Sponsored Links
The literature is replete with experimental studies using herbs of largely unknown composition. The following are those preparations for which human studies or mechanistic data exist. 9.1 Compound 861: Known as cpd 861, this is an aqueous extract of 10 defined herbs based on traditional Chinese medicine. The aim of traditional Chinese medicine is resolution of blood stasis and liver stagnation, two conditions that form the basis of liver pathology and patient discomfort.The chief herbs used in cpd 861 are Salvia miltiorrhiza, Astragalus Herbal Approaches For Liver Disorder
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membranaceous, andSpatholobus suberectus.Rats with experimental liver fibrosis showed a 50% reduction of the 5-fold increased hepatic collagen level when cpd 861 was administered daily by gavage.This was accompanied by a comparable down-regulation of hepatic messenger RNA for transforming growth factor 1 and for procollagens I, III, and IV, as well as by increased hepatic collagenase activity. Because procollagen messenger RNAs, major effectors of liver fibrogenesis, were also down-regulated in cultures of hepatic stellate cells, a direct antifibrotic effect was proposed.From 1993 to 1995, 60 patients with chronic hepatitis B were treated in an open trial with cpd 861.After 2 years, subjective improvement was reported by 50 patients (83%), and this was accompanied by a reduction in spleen size in 41% and a decrease in liver enzyme levels and serum fibrosis markers such as PIIINP and laminin. In a nonrandomized controlled trial, 22 patients with chronic hepatitis B were treated with cpd 861 for 6 months and compared with 12 matched patients receiving a control herbal medicine.Follow-up liver biopsy results showed a statistically significant improvement in both histological inflammation and fibrosis in the cpd 861 group but no change in the control subjects. 9.2 LI V.52: An extract of several plants prepared for ayurvedic medicine has been marketed in the West as LIV.52. Standardization, chemical characterization, functional, and pharmacological studies are not well documented. The extract was reported to improve serum biochemistry values in rats with toxic liver damage,and uncontrolled observations in patients with liver disease seemingly gave similar results.Furthermore, it lowered circulating levels of acetaldehyde in healthy adults consuming alcohol.Therefore, Fleig et al.performed a randomized, placebo-controlled, 2-year clinical trial in 188 patients with alcohol-related cirrhosis. LIV.52 did not affect the survival rate of Child class A and B patients but increased mortality among the 59 Child class C patients (81% in the treated group, compared with 40% in the placebo group). Twenty-two of 23 deaths in the LIV.52 group were related to bleeding or liver disease compared with only 3 of 11 deaths in the placebo group. This result led to immediate withdrawal of the drug. It highlights the danger of ill-defined herbal preparations and the necessity for in-depth preclinical testing.
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10. CASES OF HEPATIC DISORDER AND HERBAL TREATMENT 10.1 Case 1: Liver Strengthening Male 37 years old, general aches and pains, leg cramps, tendency to diarrhoea or constipation, nausea, erratic appetite, occult blood in stools, indigestion with colicky pains low energy, prone to minor infections, several lymph nodes swollen, lumps on akin inc fatty nodule, skin puffy and somewhat greyish. Overweight. "I need to make BMW changes, would like to detoxify." Generally an anxious and obsessively hard-working person. Tongue covered with thick, greyish fur. 10 Herbal treatment: Tincture: Taraxacum officinalis (dandelion root) Salvia off (Sage) 20 ml Calendula off (Marigold) 20 ml Sambucusnigra (elder flowers) 20 ml Thujaoccidentalis (thuja) 120 ml Phytolaccadecandra (poke root) 5 ml Sig 15 nil twice a day. The sage and the thuja were for general energy and to strengthen the immune system. The elder flower was for sinusitis. The marigold and poke root were for skin and lymphatic cleansing.
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10.2 Case 2: Liver herbs in pregnancy Strong liver cleansing herbs are generally contraindicated in pregnancy. They are excessively cooling and downward-moving. Strategies in pregnancy should concentrate on building up with gentle warming and gentle cleansing where appropriate. If liver cleansing is needed, dandelion root (Taraxacumofficinalis) is the herb of choice. Yellow dock (Rumexcrispus) root is the strongest herb I use, in this category. Yellow dock also has a traditional reputation for helping conception. Patient A woman of 28 years with chronic constipation. Feels "stuck in life at the moment." Medical history Bulemia, vaginal thrush, severe PMS made worse by the contraceptive pill, irregular cycle, lumpy breasts, generalized water retention, depression, anxiety, insomnia, cystitis triggered by sexual activity, poor skin tone with lots of spots. Tongue pale, soft, and wobbly. Cold. Diet Mostly vegetarian, occasional fish, no milk, occasional bread. Modified after following an anti-candida diet for some years. Supplements included acidophilus and evening primrose oil. Notes This patient originally presented with depression and anxiety. There were obviously issues arising around her history to be dealt with. She had taken a psychology degree, "in order to understand myself better," which didn't work. The liver is not the only organ affected here, but plays a central role in reestablishing proper bowel function." Treatment: Initial prescription Aloe (Aloe yen) leaf Rhubarb (Rheum officinalis) Tincture, 20-35 ml per week On these and other herbs she showed slow but steady improvement in all her symptoms, over a period of three years. Her life then had improved enough for her to consider motherhood. Herbal Approaches For Liver Disorder
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New prescription:Tincture Dandelion root (Taraxacumofficinalis) Yellow dock (Rumexcrispus) She became pregnant very quickly, and her constipation rapidly got worse. After some experimentation with dosage we settled on a tincture mixture of: Mallow (Althea officinalis) 20 ml Yellow dock (Rumexcrispus) 40 ml Dandelion root (Taraxacumofficinalis) 40 ml Sweet fennel essential oil (Foeniculumvulgare) 1 drop Dose: 5 ml three times a day, increasing to 15 ml if necessary Her average dose over her pregnancy was around 20 ml/day Comments Fennel oil is contra-indicated in pregnancy, but this dosage level is OK. I often use it with dock or rhubarb root tinctures. It improves the flavor, takes the edge off their coldness, and relieves griping. 12
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11. CONCLUSION Out of the several leads obtained from plant sources as potential hepatoprotective agents, silymarin, andrographolide, neoandrographolide, curcumin, picroside, kutkoside, phyllanthin, hypophyllanthin, and glycyrrhizin have been established as potent hepatoprotective agents. The hepatoprotective potential of several herbal medicines has been clinically evaluated. Significant efficacy has been seen with silymarin, glycyrrhizin and Liv- 52 in treatment of hepatitis, alcoholic liver disease and liver cirrhosis.
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12. REFERENCES 1. Saliou C, Rihn B, Cillard J, Okamoto T, Packer L. Selective inhibition of NF-B activation by, the flavonoid hepatoprotector silymarin in HepG2. FEBS Lett 1998; 440: 8-12. 2. Salmi HA, Sarna S. Effects of silymarin on chemical, functional and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 1982; 17: 517- 21. 3. Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybummarianum) for the therapy of liver disease. J Gastroenterol 1998; 93: 139-43. 4. Luper S. A review of plants used in the treatment of liver diseases: Part 1. Altern Med Rev 1998; 3: 410-21. 5. Barzaghi N, Crema F, Gatti G, Pifferi G, Perucca E. Pharmacokinetic studies on Idb 1016, a silybin phosphatidyl choline complex, in healthy human subjects. Eur J Drug Meta Phannacokinet 1990; 15: 333-8. 6. Saraswat B, Visen PKS, Patnaik GK, Dhawan BN. Effect of andro grapholide against galactosamine-induced hepatotoxicity. Fitoterapia 1995; 66: 415-20. 7. Bhattacharya A, Ramanathan M, Ghosal, Bhattacharya SK.Effect of Withania Somnifera glycol with anolides on iron induced hepatotoxicity in rats. Phytother Res 2000; 14: 568-70. 8. Lirussi F, Okolicsanyi L. Cyto protection in the nineties: experience with ursodeoxycholic acid and silymarinin chronic liver disease. ActaPhysiol Hung 1992; 80: 363-7. 9. Gebhardt R. Oxidative stress, plant-derived antioxidants and liver fibrosis. Planta Med 2002; 68: 289-96. 10. Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: A systematic review. J Viral Hepatitis 2005; 12: 559-67. 11. Wiseman H. Dietary influences on membrane function: Importance in protection against oxidative damage and disease. J NutrBiochem 1996; 7: 2-5. 12. Dehmlow C, Eahard J, Goot HD. Inhibition of Kupffer cells as an explanation for the hepatoprotective properties of silibinin. Hepatology 1996; 23: 749-54. Herbal Approaches For Liver Disorder
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13. Chen HC, Chou CK, Kuo YH, Yeh SF. Identification of a protein kinase C (PKC) activator, dephnoretin, that suppresses hepatitis B virus gene expression in human hepatoma cells. Biochem Pharmacol 1996; 52:1025-1032. 14. Duke JA (1985) Die amphocholeretische Wirkung der Fumaria officinalis .Z Allg Med 34:1819. 15. Srinivas L, Shalini VK. DNA damage by smoke: Protection by turmeric and other inhibitors of ROS. Free Radical Biol Med 1991; 11:277-283. 16. Selvam R, Subramanian L, Gayathri R, et al. The anti-oxidant activity of turmeric (Curcuma longa). J Ethnopharmacol 1995; 47:59-67. 17. M.Sree Rama Murthy, M.Srinivasan, R&D Department, TTK Pharma Limited. Hepatotprotective Effect of Tephrosia pupurea in experimental animals. Indian Journal of Pharmacology 1993; 25:34-36. 18. Adzet T, Camarasa J, Laguna JC. Hepatoprotective activity of polyphenolic compounds from Cynara scolymus against CCl4 toxicity in isolated rat hepatocytes. Departamento de Farmacognosia y Farmacodinamia, Facultad de Farmacia, Nucleo Universitario de Pedralbes, Barcelona, Spain. J Nat Prod 1987 Jul-Aug; 50(4): 612-7. 19. Datta S, Sinha S, Bhattacharyya P. Hepatoprotective activity of a herbal protein CI-1, purified from Cajanus indicus against beta-galactosamine HCl toxicity in isolated rat hepatocytes. Department of Chemistry, Bose Institute, 93/1, A.P.C. Road, Calcutta 700009, India. Phytot1her Res 1999 Sep; 13(6): 508-12. 20. Reddy PB, Reddy CK, Rambhau D, Venkateshvarala V, Murthy VN. Anti hepatoprotective activity of some Ayurvedic preparations. Indian J Pharm Sci 1993;55:137- 40. 21. Gonzalez FJ. The molecular biology of cytochrome P450s. Pharmacol Rev 1988;40:243- 88. 22. Mac Cay PB, Lai EK, Poyer JL. Oxygen and carbon center free radical formation during carbon tetrachloride metabolism observation of lipid radical in-vivo and in- vitro . J Biol Chem 1984;259:2135-43. Herbal Approaches For Liver Disorder
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23. Pandey Govind P. Pharmacological studies of Livol(R) with special reference to liver function. MVSc & AH thesis. Jabalpur, MP, India: JNKVV; 1980. 24. Pandey Govind, Medicinal plants against liver diseases. International research journal of pharmacy. 2011; 2 (5): 115-121.
Summary of Fiber Fueled: by Will Bulsiewicz MD - The Plant-Based Gut Health Program for Losing Weight, Restoring Your Health, and Optimizing Your Microbiome - A Comprehensive Summary
An Evaluation of The Hypolipidemic Effect of An Extract of Hibiscus Sabdariffa Leaves in Hyperlipidemic Indians: A Double Blind, Placebo Controlled Trial