Herbal Drug Development For Liver Disorders And Hyperlipidemia

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Nanjaian Mahadevan

Dr.Nanjaian Mahadevan

1. Herbal medicine

India is the birth place of renowned system of indigenous medicine such as Ayurveda, Siddha and Unani. The country is enriched with flora and, therefore, plant remedies have been used since ancient times for the treatment of human ailments.  The knowledge of these valuable plant remedies have not been documented and was orally dissipated by the tribal populations.  But these tribals possessed remarkably accurate knowledge about the medicinal use of the plants around them.

With the advent of modern synthetic drugs and their convenience of standardized dosage forms, dramatic efficacy in acute conditions and simplicity of usage, there was a decline in the use of plant remedies till recently. Further, there has been a deep scepticism in doctors trained in modern medicine about herbal drugs other than serving as a placebo or palliative. In recent times, however, a large volume of work aimed at scientific validation of the efficacy of herbal remedies has been carried out coinciding with the world wide popular perception of herbal drugs as safe and effective alternatives or adjuncts to modern medicine.  This interest in herbal drugs also stems from the fact that modern medicine does not have a suitable answer for many conditions such as liver disorders, heart diseases and for chronic conditions such as arthritis, asthma and many skin conditions1. Further, inspite of the advances made in modern system of medicine, tropical diseases, viral diseases, herpes, AIDS, cancer, mental deficiency, parkinsonism are yet to be tackled.

Traditional systems of medicine remain the major source of health care for more than two thirds of the world's population and impressive progress has been made in certain developing countries like China through integration of traditional systems with western systems and the application of modern science and technology to the promotion and development of traditional medicine. Ayurveda, practiced in India, perhaps is the only organised science in the world that deals with the ecological development, cultivation of medicinal plants, harvesting specific parts of plants, processing, preserving, diagnosis and treatment.

Development of quality control methods of plant drugs with adoption of good manufacturing practices and validation of the claims of their therapeutic efficacy are the challenges in the years ahead, if the resurgence of global interest in these drugs is to be further strengthened.

1.1 Phytochemicals

There are several areas wherein plant derived drugs are used. Some of them have antiprotozoal activity like quinine from Cinchona, berberine from Berberis, harmaline from Peganum, artemisin from Artemesia for fever and malaria.  Allicin from garlic is antifingal, ricin from castor is specific immunotoxin against protozoa and liquorice is used in cleansing inflammed stomach. Oleanolic acid, sericic acid, quillia saponins and nimbidine from the seed oil of Azadirchta indica, catechin from Acacia catechu and lapachol from common teak have antiulcer activity. Colenol from Coleus forskohli is a hypotensive drug.  Digitalis and yellow oleander are cardiotonics. Some of the anticancer drugs such as vinca alkaloids, ochrosia species, podophyllum resin, tenoposide and etoposide and taxol are obtained from plant sources only. Bacoposides from Bacopa moniera is a memory enhancer. The current available drugs for treatment of rheumatism show toxicity and reappearance of symptoms.  Effective plant drugs available are nimbidine from neem oil and oleogum resin of Boswellia serrata.

A variety of drugs are available as antiasthmatic such as lobeline from Lobelia, ephedrine from Ephedra and vasicine from Vasaka.  Catharanthus roseus,Gymnema sylvestris, Pterocarpus marsupium are antidiabetics. Flowers of Sambucus nigra, aerial parts of Hypericum perforatum and roots of Saponaria officinalis have antiviral properties.  Hepatoprotectives, sedatives, laxatives, sweeteners, antioxidants and several other plant drugs are being investigated today. Inspite of so much potential and scope for future development of plant drugs, a mere 2 % of the total flora provided by nature is being used today.  The major pitfalls in plant drug research include lack of standardization, confusion in nomenclature, controversial botanical identification, and danger of extinction of some of the plants due to extensive exploitation, lack of proper dosage formulations and frustrating experiences of searching for a single active principle2.

Experiments and clinical trials can be conducted after careful study of how the plants are being used in Ayurveda and other traditional system of medicine. The results of these carefully planned studies can perhaps lead to their wide applicability. Historically and traditionally, the approaches towards evaluating medicinal plants have been based on chemical extracts from plants known to possess pharmacological properties or therapeutic effects. The extracts are then tested on animal models3.

2 .Liver disorders

Hepatitis:It is an inflammation of the liver that may be caused by viral and bacterial infections, chemical toxicity (primarily drugs), or autoimmune hypersensitivity reactions4-7.

Viral hepatitis:Viral hepatitis is a major health concern worldwide. The categories of viral agents currently implicated in hepatitis are hepatitis-A virus (HAV), hepatitis-B (HBV), hepatitis-C (HCV), hepatitis-D (HDV), hepatitis-E (HEV) and hepatitis-F (HFV).

Acute viral hepatitis: As many viral infections, acute viral hepatitis is a self-limiting disorder. No specific treatment is available. Drugs are of little value and do not alter the severity or time course of the disease.

Chronic hepatitis: Chronic liver disease is defined as inflammation of the liver that persists for over six months. It is associated with permanent structural changes within the liver secondary to long-standing cell damage. The main causes of chronic liver disease are alcoholism, viral hepatitis, immunological diseases, vascular diseases, metabolic diseases due to genetic factors and infectious diseases. Chronic hepatitis represents a medical challenge. The goal of any treatment plan is to halt the progression to cirrhosis, liver failure and death.

Drugs induced hepatitis:Modern day medicines have become the leading cause of liver failure (30-50% of cases) and serious drug induced liver injury is the main reason that drugs are withdrawn from the market8,9. The recent withdrawal of nefazodone from the European market due to drug induced liver injury, once again focuses the attention of the pharmaceutical industry, regulators and doctors on the hepatotoxicity of drugs. Regulatory authorities in USA and Europe have become very sensitive to drug induced liver changes after the troglitazone experience.

Two major types of hepatotoxicity have been noted. They are direct toxicity, also called predictable toxicity and idiosyncratic and nonpredictable toxicity. Idiosyncratic reactions are sometimes referred to as hypersensitivity reactions.

Disruption of metabolic process, toxic destruction of essential cell structures, induction of immunologic reactions, carcinogenic effect, transmission of infections, exacerbation of underlying disease are some of the basic mechanisms of drug induced hepatic injury. Table 1 shows the characteristic morphologic lesions seen in drug induced injury related to these mechanisms.

Jaundice:Jaundice is a general condition that results from abnormal metabolism or retention of bilirubin. Jaundice causes a yellow coloration of the skin, mucous membranes and sclera. The three principle types of jaundice are prehepatic, hepatic and post hepatic7.

Prehepatic jaundice: This is the result of acute and chronic hemolytic anemia.

Hepatic jaundice: This includes disorders of bilirubin metabolism and transport defects. Levels of unconjugated bilirubin are elevated in this disorder.

Post hepatic jaundice:  It is also known as cholestatic and obstructive jaundice. This is generally caused by biliary obstructive disease resulting from spasms of the biliary tract, ductal occlusions by stones or compression by neoplastic disease. The major increase is in the conjugated fractions.

Table 1. Morphological changes induced by frequently encountered drugs

Morphology

Drug class

Examples

Necrosis

Mushroom

Metals

Hydrocarbon

Analgesics

Anesthetics

Amanite phalloides

Phosphorus

Carbon tetra chloride

Paracetamol

Halothane

Hepatitis

Anesthetics

Antitubercular

Antihypertensive

Chemotherapeutic

Halothane

INH

Methyl dopa

Nitrofurantoin

Steatonecrosis

Anticholesterol

Sedative

Chemotherapeutic

Cardiovascular

Levostatin

Alcohol

Methotrexate, tetracycline

animodarone

Cholestatis

Chemotherapeutic

Antipsychotic

Hormones

Cardiovascular

Anticonvulsant

Erythromycin

Chloropromazine

Oral contraceptives

Catopril, verapamil

Carbamazepine

Granulomas

Xanthine oxidase inhibitor

Chemotherapeutic

Anti-inflammatory

Allopurinol

 

Sulphonamides

Phenylbutazone

Hepatic injury: From a morphologic standpoint, the liver is an inherently simple organ, with a limited repertoire of responses to injurious events. Regardless of the cause, the general responses are necrosis, fatty liver, cholestasis and cirrhosis

Necrosis involves the death of hepatocytes caused by progressive enzymatic degradation. It may affect group of cells or part of a structure or an organ. Fatty liver (Steatonecrosis) is due to the microvesicular fat accumulation in the hepatocytes. Alcohol is the most common cause of this type of lesion. Cholestasis is due to the hepatic obstruction of biliary micelle by drugs.

Cirrhosis is characterized by a diffuse increase in the fibrous connective tissue of the liver, with areas of both necrosis and regeneration of paranchymal cells imparting a nodular or glandular texture. In later stages, cirrhosis leads to such deformity of the liver that it interferes with hepatobiliary function and the circulation of blood both to and from the liver.

2.1 Hepatotoxicity induction and evalution9-11

Carbon tetrachloride (CCl4) induced toxicity model, is the most widely accepted model by most of the scientists for inducing liver damage. This toxicant has been found to induce extensive liver damage within a period of 24 hours following intraperitoneal administration12. Research carried out earlier, involved acute exposure of high dose of toxicant agent like CCl4 and paracetamol in experimental animals. Hepatoprotection was shown against these chemicals. But in realistic situation, the patient neither consumes directly CCl4 like chemicals nor does overdose himself with paracetamol. To create analogy to clinical situation, antitubercular treatment induced hepatotoxicity in the clinically relevant doses is selected.

Isoniazid (INH) induced hepatitis is the most frequent toxic effect. There is increase in liver aminotransferases. Clinical hepatitis with loss of appetite, nausea, vomiting and jaundice, occur in 1% of INH recipients. There is histologic evidence of hepatocellular damage and necrosis. Rifampicin may cause cholestatic jaundice and occasionally hepatitis. Major adverse effect of pyrazinamide is hepatotoxicity. Oxidation stress has been found to be the most important mechanism in hepatotoxicity of antitubercular drugs.

2.1.1 Invitro evaluation of hepatic injury

In vitro systems offer the possibility of assessing liver injury in the absence of extra hepatic factors, such as absorption, distribution and extrahepatic metabolism of the chemical, humoral factors and toxic effects caused at other sites. In vitro approaches available to assess hepatotoxic properties of chemical agents encompass different levels of organization ranging from isolated hepatocytes and cell cultures to precision cut liver slices and isolated livers. Liver cell organization is not disrupted in these four in vitro systems, such that the injury caused by chemical results from the overall effects of phase I and II biotransformation reaction, defense and repair systems and cellular processes. Isolated hepatocytes offer the advantages such as relative ease to prepare without sophisticated equipments. Further, large number of experiments can be performed with the liver of one animal, serving as its own control and sampling throughout the experiment is feasible.

2.1.2 In vivo evaluation of hepatic injury

The major tests that have proved useful for the evaluation of experimental hepatic injury in laboratory animals can be placed in four primary categories such as

·serum enzyme techniques

·hepatic excretory test

·alteration in the chemical constituents of the liver

·histological analysis of liver injury

Serum enzyme techniques: Determination of activity of hepatic enzymes released into blood by the damaged liver is one of the most useful tools in the study of hepatotoxicity. The application of serum enzyme methodology to the detection of liver injury was introduced during 1930’s.

2.1.3 Alteration in chemical constitution of liver

In addition to producing elevation in serum enzyme activities and altering hepatocytes transport process, chemical hepatotoxicants can produce changes in structural and functional hepatic constituents. Hepatic lipid content, lipid peroxidation, hepatic glucose-6-phosphate activities, triglycerides and hepatic collagen contents have been found useful for detecting and qualifying the degree of liver injury produced. 

2.1.4  Liver function tests
i) 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.

ii) 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.

iii) 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.

iv)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.

v)Total Cholesterol

          Serum cholesterol comprises two forms, free cholesterol and esterified cholesterol. In jaundice and paranchymatous liver disease, serum cholesterol level will fall. Drug administration will rectify the defective mechanism associated with carbon tetrachloride administration. Reference Interval: <200 mg/dL.

vi) 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.

vii) 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.

viii)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.

ix)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. An elevated level of serum bilirubin may be produced. It shows severe parenchymal injury. Reference Interval: < 1 mg/dL.

x) 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 hyperbilirubenemia is most often due to either haemolysis, or Gilbert’s syndrome, an inherited abnormality of bilirubin metabolism. Reference Interval: < 0.25 mg/dL.

2.2 Currently available modern medicine for liver disorders and their limitations

Only a few modern drugs are available for treating liver diseases. Drugs such as tricholine citrate, trithioparamethoxy phenyl propene, essential phospholipids, combination of L-Ornithine L-aspartate and pancreatin, silymarin and ursodesoxy cholic acid are generally prescribed for hepatitis, cirrhosis and other liver diseases. However, these modern medical treatments are still far from satisfactory.

Hepatitis C is an infectious viral disease of the liver that affects more than 150 million people worldwide. Of these almost 15-20% people develop chronic liver disease, liver cirrhosis and liver cancer. However, this condition has not received as much attention as other infectious conditions, notably AIDS, because of ignorance about the disease and the absence of effective treatment options. In India, approximately 18 million people are estimated to be infected.

The main form of treatment of hepatitis C virus (HCV) infection is through drugs like Interferon, Amantadine and Ribavarin. A combination therapy of Interferon and Ribavarin for 6 months is most commonly used for HCV treatment. However, there are certain conditions in which therapy should be used with utmost caution such as

·kidney failure/transplant

·HIV infection

·children

·blood disorders and

·chemotherapy or other immunosuppressive treatment.

The combination of interferon and ribavirin used for the treatment of hepatitis C is very expensive.

Ribavarin is the drug of choice along with Interferon for HCV treatment, but it is not used in conditions like pregnancy, heart and kidney problems and psychological illnesses. Some categories of people do not respond to treatment at all and in such patients alternatives need to be sought. Elderly and overweight (>95 kg) patients and those with advanced fibrosis do not respond to this drug therapy. Patients who respond well to medication during the first week are also more likely to respond later and thus have a better prognosis.

The current status of HCV vaccine is not too optimistic due to certain obstacles in the path of development of potent vaccines. There are too many diverse strains of the Hepatitis C virus to be responsive to one vaccine. Even within an individual, the virus changes and evolves thus making its isolation and treatment difficult. No small animal models are currently available for vaccine testing. In most cases, jaundice is treated with antibiotics, a mild case usually resolves on its own. The disease leaves a lot of weakness in its wake and thus recuperation may take a long time.

Interferon alphas have been widely used to treat chronic hepatitis C virus infection. These include recombinant interferons, or purified natural leucocyte or Lymphoblastoid interferon. Interferon alpha is usually administered by subcutaneous or intramuscular injection. The terminal half-life of interferon alpha is 4-5 hours. Renal excretion is the predominant route of elimination. Early flu-like side effects are predictable and are encountered in the majority of patients. These tend to occur within 6-8 hours after starting treatment and are worst with the first injections. These side effects include fever, malaise, tachycardia, chills, headache, arthralgias, and myalgias. However, they are usually acceptable at doses of 3-6 million units (MU) of interferon alpha, and tachyphylaxis generally develops after the first few injections. These side effects are ameliorated by paracetamol. Side effects also develop after some days. These include fatigue, malaise, apathy, and cognitive changes. Between 10 and 15 percent of patients find the chronic side effects intolerable and discontinue treatment. Higher doses (above 5-6 MU three times weekly) tend to give higher rates of adverse events.

Therapy for chronic hepatitis B and C is evolving and may include interferon antiviral and immune-modulating drugs. Autoimmune hepatitis is usually treated with corticosteroids, such as prednisone.

With several grams of choline per day, some people will experience abdominal discomfort, diarrhea, or nausea. Supplementing choline in large amounts (over 1,000 mg per day) can lead to a fishy body odor. Depression has been reported as a side effect in people taking large amounts of choline, such as 9 grams per day.

Antibiotics may cause stomach upset or allergic reactions. A liver transplant can cause many problems, including failure or rejection of the new liver. After a liver transplant, a person will need to take powerful antirejection medications for the rest of his or her life. Side effects of these medications increase the person's risk for infections, certain cancers, and other problems.

Side effects of ursodeoxycholic acid include bladder pain, bloody or cloudy urine, difficult and burning or painful urination, dizziness, fast heartbeat, frequent urge to urinate, indigestion, lower back or side pain, severe nausea, shortness of breath, skin rash or itching over the entire body, stomach pain, vomiting, weakness and wheezing.

2.3 Plant remedies for liver diseases

Ayurveda and other traditional medical practitioners the world over have claimed for centuries that extracts from plants can be effectively used for the alleviation of different types of liver diseases. Most of the claims, however, are anectodal and very few have received adequate medical or scientific evaluation. Except for the use of appropriate vaccine for the treatment of hepatitis caused by viral infection, very few effective treatments are available today to cure liver diseases. It is not surprising, therefore, that a considerable interest has been taken by researchers to examine these numerous traditional plant remedies, used for treating liver disorders. In recent years, investigations have been carried out to provide experimental evidence, confirming that many of these plants do indeed have hepatoprotective properties. Recent progress in the study of such plants has resulted in the isolation of about 170 different phytoconstituents from plants belonging to about 55 families, which exhibit hepatoprotective activity13.

3  Hyperlipidemia

Major lipids found in blood stream are triglycerides, phospholipids, cholesterol and cholesterol esters and free fatty acids. The function of cholesterol is to help carry fat in the body, because fat being insoluble in water cannot travel on its own in the blood stream. Cholesterol associates with fat and protein and comes out of the liver as lipoprotein.  There are several types of lipoproteins for the transport of fatty material in the body such as chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), intermediate density lipoproteins (IDL) and high density lipoproteins (HDL). Each has a different function in the transport system. VLDL are responsible to carry endogenous triglycerides from the liver into the blood stream and to other parts of the body. Lipoprotein lipase catalyses triglycerides degradation to generate VLDL remnants which are further degraded by hepatic glyceride hydrolase to generate LDL. It easily adheres along the walls of the arteries and, therefore, called as bad cholesterol. There are different types of HDL like HDL1, HDL2 and HDL3. It is called good cholesterol as it finds and removes stuck LDL of peripheral cells and bring them back to liver. Hyperlipidemia, the elevation of lipid concentration in plasma, is the manifestation of a disorder in the synthesis and degradation of plasma lipoproteins14,15. Primary type hyperlipidemia can be treated with drugs but the secondary type originating from diabetes, renal lipid neprosis or hypothyrodism demands the treatment of original disease rather than hyperlipidemia.

3.1  Classification of hyperlipidemia

Type I hyperlipidemia: It is characterised by high concentration of blood chylomicrons. Currently there are no drugs available for treating this type.

Type II hyperlipidemia: Itis subdivided into Type II A hyperlipidemia and TypeII B hyperlipidemia. Type II A hyperlipidemia is characterized by high LDL and cholesterol levels with a slight increase in blood triglycerides. Type II B hyperlipidemia is characterized by the elevation of triglycerides, serum cholesterol, LDL and VLDL.

Type III hyperlipidemia: It shows elevated levels of triglycerides and IDL. A blockade in the normal conversion of VLDL to LDL results in accumulation of IDL. Controlled diet is the treatment of this type of hyperlipidemia.

Type IV hyperlipidemia: It is the sequel to high concentration of triglycerides and VLDL and often faulty carbohydrate metabolism. Both diet and drug therapy is recommended for this type of hyperlipidemia.

Type V hyperlipidemia: It shows elevated levels of chylomicrons, VLDL and triglycerides resulting from faulty carbohydrate metabolism.

A major concern in patients with hyperlipidemia is the increased risk of atherosclerosis resulting in heart diseases. The aim of treating the patients with hyperlipidemia is to reduce serum cholesterol and/or improve the HDL cholesterol by maintaining a high ratio of HDL to LDL cholesterol level thereby reducing the risk of developing heart disease or the occurrence of further cardiovascular or cerebrovascular events.

3.2 Currently used modern drugs to treat hyperlipidemia and their limitations

Modern drugs of first choice for elevated LDL cholesterol are the HMG CoA reductase inhibitors, like lovastatin, pravastatin and simvastatin. These drugs are not totally free from side effects particularly when used for prolonged periods. Statin drugs are very effective for lowering LDL cholesterol levels and have very few immediate short-term side effects. They are easy to administer, have high patient acceptance and have few drug-drug interactions. Patients who are pregnant, have active or chronic liver disease, or who are allergic to statins shouldn't use statin drugs. The most common side effects are gastrointestinal, including constipation and abdominal pain and cramps. These symptoms are usually mild to severe and generally subside as therapy continues.

Another class of drugs for lowering LDL is the bile acid sequestrants, cholestyramine and colestipol and nicotinic acid (niacin). These have been shown to reduce the risk for coronary heart disease in controlled clinical trials. Both classes of drugs appear to be free of serious side effects. But both can have troublesome side effects and require considerable patient education to achieve adherence. Nicotinic acid is preferred in patients with triglyceride levels that exceed 250 mg/dl because bile acid sequestrants tend to raise triglyceride levels. Other available drugs are gemfibrozil, probucol and clofibrate. Gemfibrozil and clofibrate are most effective for lowering high triglyceride levels. They moderately reduce LDL cholesterol levels in hypercholesterolemic patients. If a patient does not respond adequately to single drug therapy, combined drug therapy should be considered further to lower LDL cholesterol levels. For patients with severe hypercholesterolemia, combining a bile acid sequestrant with either nicotinic acid or lovastatin has the potential to markedly lower LDL cholesterol. For hypercholesterolemic patients with elevated triglycerides, nicotinic acid or gemfibrozil should be considered as one agent for combined therapy. But these synthetic drugs possess side effects such as bloating, constipation, muscle pain, progression of cataract, cutaneous flushing, skin disorders nausea, gastrointestinal, hepatobiliary neoplasms and cardiac arrhythmias.

The action of most synthetic drugs discussed above is intended to be powerful and singular. In other words, they usually affect a specific problem with a strong action. As the chemicals in these drugs are concentrated, their action is strong and focused. Consequently, they can also produce nasty side effects.

Plant remedies for hyperlipidemia

A number of plant preparations such as Allium sativum, Cicer arientinum, Inula recemosa, Terminalia arjuna, Trigonella foenum graecum, Commiphora mukul, green tea and curcumin have been reported to have hypolipidemic actions. Few of these also, possess certain other beneficial properties like antianginal and antiplatelet actions15. Plant preparations contain many compounds that work synergistically on multiple parts of the body. For example, garlic is not only antibacterial, but antifungal, and helps to lower cholesterol. This synergy of chemicals helps to balance the overall activity of the herb. Since the chemicals in herbs are non-specific and unconcentrated, there are generally fewer side effects from herbs than from manufactured drugs. Further, according to a study published in the April 15, 1998 issue of the Journal of the American Medical Association, the fifth leading cause of death in the United States in 1994 was adverse drug reactions of modern medicine, an excess of 100,000 deaths16. By contrast, there have been less than 100 adverse reactions and only one death attributed to herbs in Canada since 1990. Most reactions to herbs have to do with an individual allergic reaction to the herb or to an interaction with prescription drugs.

4 Development of standardized herbal formulations

The quality control of herbal crude drug and their bioconstituents is of paramount importance in justifying their acceptability in modern system of medicine. One of the major problems faced by users in industry is non availability of rigid quality control profiles for herbal raw materials and their formulation. With the advent of new analytical techniques and sophisticated instrumental technology, it is possible to suggest a practicable quality assurance profile for a crude drug or its bioactive constituents17.

With the ever increasing demand for herbal medicines, commercial establishments have proliferated and, therefore, a greater need for proper standardization has arisen. At present most of the commercial supplies of herbs are made by traders who have limited knowledge of these plant materials. To check any adulteration or non deliberate mixing in the commercial batches, specifications must be laid down for each herb. With the commercialization of herbal medicines it has become necessary to undertake systematic studies on their efficacy levels along with parameters to assess their quality. One of the most important methods of standardization is marker based standardization with one or more constituents used as standards.

Herbal medicines can be relevant today only if they are applied and tested within the frame work of modern medicine and subjected to the most rigorous criteria for quality, safety and efficacy. However, due to lack of proper quality control tests often ineffective and toxic herbal formulations are marketed and in the case of polyherbal formulations, the label claims can not be verified. The conventional analytical parameters like ash value, loss on drying, acid value, saponification value and other physical parameters hardly provide any clue to the exact identity of the herbal materials. It is necessary that some simple and reliable methods using instruments like HPLC, HPTLC and GC should be used so that the identity of each herb in the formulation could be verified. Quality maintenance of herbal drugs is possible, if care is taken right from the collection of raw materials, to their processing, preparation of rational combinations and keeping pharmacological parameters and specific bioeffective chemical markers of each herb as a part of quality control test.

Standardization of herbal preparations is an important issue but not an easy one because herbal preparations are a combination of several herbs and each herb comprises of several chemical constituents. In many cases, the overall pharmacological effects are not due to single compound but several compounds causing synergistic effects. This indicates that standardization should calibrate more than one component. It is difficult to quantify all these constituents in the formulation. A finger print chromatogram of the extracts or preparation is, therefore, very often used. This finger print should represent identity, purity and therapeutic efficacy of extracts from the same herbs18.

One of the major difficulties in standardization of herbal preparations is the limited knowledge of the active ingredients. Further, the secondary constituents of medicinal plants are influenced by various factors like heredity, ontogeny, environment, methods of collection etc. This also makes the standardization of herbal medicines a difficult task. For standardization of polyherbal preparations, which contain number of ingredients, it is very difficult to set parameters to control these preparations. There is no problem to quantify a single principal active constituent. If a preparation contains more than four herbal extracts, each extract may be characterized before mixing and after mixing to establish the identity of the product. Toxicity studies are very pertinent to indicate the safety of the product. Simple bioassay for biological standardization of herbal drugs should be incorporated to develop animal models for toxicity and safety evaluation. Some of the bottlenecks in standardization of herbals are,

·Non availability of library of marker compounds isolated from herbs in their pure form to be used for analytical purposes. It is tedious job to isolate every marker compound in its purest form for testing purposes by the testing laboratories itself. 

·Poor availability of public test houses to support the industry in day to day analysis.

·Non availability of a system where standard or properly identified herbs are available for the industry.

·High cost involved in the procurement of sophisticated imported instruments like HPTLC, HPLC, LCMS etc.

One of the best methods of standardizing herbs and herbal formulations based on the modern scientific tools is chromatography. It not only helps in establishing the correct botanical identity but also helps in regulating the chemical sanctity of the herbs. One such technique is marker compound testing and fingerprint analysis. Different chromatographic methods are used to analyze the marker compounds in herbs with the help of modern sophisticated tools. HPTLC is most frequently used where only finger printing of the herbs is required without quantifying the compound though the same can also be quantified with the help of a densitometer19.

A list of plants that reported to possess hepatoprotective activity is given in table 2.

Table 2. 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

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

Allium cepa

Alliaceae

Bulbs

Allium sativum

Alliaceae

Bulbs

Aphanamixis polystachya

Meliaceae

Stem, Root bark, Seeds

Apium graveolens

Apiaceae

Seeds

Arbutus unedo

Ericaceae

Leaves, Stem Bark.

Argemone mexicana

Papaveraceae

Yellow juice

Aspargus officinalis

Liliaceae

Root

Azadirachta indica

Meliaceae

Leaves

Boerhaavia diffusa

Nyctaginaceae

Whole plant with root

Calotropis gigantean

Asclepiadaceae

Leaves

Carica papaya

Caricaceae

Milky juice

Centella asiatica

Apiaceae

Whole plant with root

Cichorium intybus

Asteraceae

Leaves and root

Cynara scolymus

Asteraceae

Leaves and root

Daucus carota

Apiaceae

Fruit and root

Eclipta prostrata

Asteraceae

Whole plant

Foeniculum vulgare

Apiaceae

Seeds

Fumaria officinalis

Fumiriaceae

Whole plant

Glycosmis pentaphylla

Rutaceae

Leaves

Iris germanica

Iridaceae

Rhizome

Fumaria parviflora

Fumaricaceae

Whole plant

Lobelia inflata

Lobeliaceae

Whole plant

Lycopodium clavatum

Lycopodiaceae

Plant and spores

Moringa pterygosperma

Moringaceae

Leaves, stem, root and gum

Myristica fragrans

Myristicaceae

Fruit

Myrtus communis

Myrtaceae

Leaves

Phyllanthus emblica

Euphorbiaceae

Root

Primula obconica

Primulaceae

Whole plant

Raphanus sativus

Brassicaceae

Whole plant

Ruscus aculeatus

Ruscaceae

Whole plant with root

Santolina chamaecyparissus

Asteraceae

Whole plant

Sarothamnus scoparius

Papilionaceae

Root

Silibum marianum

Asteraceae

Seeds

Solanum nigrum

Solanaceae

Leaves

Taraxacum officinale

Asteraceae

Root

Terminalia chebula

Combretaceae

Fruits

Tinospora cordifolia

Menispermaceae

Fresh stem

Trigonella foenum graecum

Papilionaceae

Leaves and seeds

Viola odorata

Violaceae

Whole plant

Zingiber officinale

Zingiberaceae

Rhizome.

A list of plants with hypolipidaemic activity is given in table 3

Table 3. Plants with hypolipidaemic activity

Sl.No

Name of Plant

Family

Common/ Indian vernacular names

Plant parts

1

Aegle marmelos

Rutaceae

Beal fruit, bilwa

Fruits

2

Agave Veracruz

Amaryllidaceae

American aloe, barakhawar

Roots, leaves,

gum

3

Allium cepa

Lilliaceae

Onion, piyaj, palandu

Bulbs

4

Aloe barbadensis

Lilliaceae

Ghee kumar, gwarpatha

Leaves

5

Bambusa arundunacea

Graminae

Bamboo vamsha

Leaves

6

Bosswellia serrata

Burserraceae

Salai guggal

Gum

7

Brassicavercapitata

Cruciferae

Cabbage

Oil

8

Cajanus cajan

Fabaceae

Red gram

Seeds

9

Capparis decidua

Capparaceae

Karli, tint

Leaves, fruits

and stems

10

Capsicum frutescens

Solanaceae

Chillies

Fruits

11

Carum capaticum

Umbelliferae

Jowan, ajowan

Fruits, roots

12

Celastrus paniculatus

Celastraceae

Khunjri, kusur

Seed oil, barks,

roots and fruits

13

Curcuma amada

Zingiberaceae

Mango ginger, haridra

Rhizomes

14

Cyamopsis tetragonoloba

Leguminosae

Guar, gwar

Seeds

15

Emblica officinalis

Euphorbiaceae

Amla, amlki

Dried fruits,

Seeds, leaves

16

Eugenia cumini

Myrtaceae

Jamun

Seeds

17

Inula racemosa

Compositae

Puskarmul

Roots

18

Juglans regia

Juglandaceae

Walnut, akhrot

Kernel, oil

19

Medicago sativum

Papilionaceae

Alfalfa

Seeds

20

Momordica charantia

Cucurbitaceae

Bitterground,

Fruits

21

Musa saspientum

Musaceae

Banana, kela

Roots, Stems, Flowers, Fruits

22

Nepeta hindostana

Labiatae

Billiola, badranj boya

Whole plant

23

Phaseolus aureus

Fabaceae

Green gram

Seeds

24

Phaseolus mungo

Fabaceae

Black gram

Seeds

25

Picrohiza kurroa

Scrophulariaceae

Kulki, kataki

Roots

26

Piper nigrum

Piperaceae

Golmirch, kalimich

Leaves

27

Pisum sativum

Papilionaceae

Gardenpea, matar

Seeds

28

Pterocarpus marsupium

Papilionaceae

Indian malabarkino

Gum and leaves

29

Saussuraea lappa

Asteraceae

Kustha, Kut

Roots

30

Terminalia arjuna

Combretaceae

Arjun

Barks

A brief review on some plant such as Eclipta alba, Andrographis paniculata, Picrorhiza kurroa, Commiphora mukul, Curcuma longa and Camellia sinensis are given below.

Eclipta alba

It is reported that the plant is anthelmintic, good for complexion, hair, eyes, and teeth; cures inflammations, hernias, eye diseases, bronchitis, asthma, leucoderma, anemia, diseases of heart and skin, itching, night blindness, syphilis; used to prevent abortion and miscarriage, and for uterine pains after delivery. It is principally used as tonic and deobstruent in hepatic and splenic enlargements and in various chronic skin diseases. There is a popular beleif that the herb taken internally and applied externally will turn the hair black20.

Bhandary and Chandrasekar21 have reported that the plant is used in jaundice, eye and ear infections and also as antifungal. Bhatt and coworkers22 have reported that the juice of fresh leaves of the plant is given in fever and jaundice. Jamir23 has reported that the leaf juice of the plant is applied as hair-tonic on the scalp.

Govindachari and coworkers24 have reported the isolation of a coumestan derivative, wedelolactone from the plant. Wagner and coworkers25 have reported the coumestan derivatives, wedelolactone and demethyl wedelolactone, which exhibits antiheptatotoxic activities in CCl4, galactosamine and phelloidin induced liver damage in rats.

Singh and coworkers26 have reported chemical constituents such as ecliptal, a thiophene derivative, eclabosaponins, common sterols, hentriacontenol and 14-heptacosanol. Sarg and coworkers27 have reported leuteolin-7-O- glucoside, alkaloids and polypeptides.

Saxena and coworkers28 have reported that the alcoholic extract of the plant shows protective effect on experimental liver damage in rats and mice.

The plant extract was tested on rabbits to study the effect on liver damaged by administering CCl4. The extract was given in a dose of 90 mg/kg body weight. The laboratory and histopathological investigation showed that the extract is capable in normalizing the liver function29.

Dixit and coworkers30 tested the herb powder clinically in 50 children suffering from jaundice and found that the serum bilirubin levels and alkaline phosphatase levels were normalized when the drug was given for 2 to 3 weeks.

Andrographis paniculata

The juice of the leaves of the plant together with certain spices, such as cardamom, clove, cinnamon, dried in the sun and made into little globules, are prescribed for infants to relieve griping, irregular stools and loss of appetite. The plant is highly useful in general debility, dysentery and certain forms of dyspepsia. The roots and leaves are febrifuge, stomachic, tonic, alterative and anthelmintic31.

Aminuddin and Girach32 have reported that the plant paste is applied on scalp to kill hair lice. Saiprasad and Pullaiah33 have reported that the leaves mixed with pepper and garlic and made into juice were given orally to cure epilepsy. Mishra and coworkers34 have reported that the whole plant is crushed and used for stomach pain and acidity.

Handa and Sharma35 have isolated andrographolide (0.78%) from the plant. They have also reported on the antihepatotoxic activity of andrographolide against CCl4 intoxicated rats.

Andrograpanin, oxyoxoandrographolide, glycosides, oroxylin neoandrographolide, andrographiside, wogonin, andrographidienes A, B, C, D, E and F have been reported from this plant36.

Binduja and coworkers37 have investigated the choleretic effect of andrographolide in rats and guinea pigs and found that andrographolide produces a significant dose dependant choleretic effect. The action was found to be more potent than silymarin.

Trivedi and Rawal38 have reported that water extract of Andrographis paniculata prevents BHC induced increase in the activities of enzymes glutamyl transpeptidase, glutathione S transferase and lipid peroxidation. They have also reported that the plant shows protective effects in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase as well as the level of glutathione indicating the antioxidant and hepatoprotective activity of the plant. Antihepatotoxic activity of this plant was reported by several researchers with various animal and experimental models39-47 .

Picrorhiza kurroa

The root is said to possess cooling, stomachic, cardiotonic, antipyretic, anthelmintic and laxative properties. It also promotes appetite and useful in biliousness, bilious fevers, urinary discharges, asthma, hiccough, blood troubles, burning sensations, leucoderma and jaundice. In China and Malaya, the rhizome is a favorite remedy for bilious dyspepsia accompanied by fever48.

The plant is reported to contain, iridoid glycosides, picroside I, kutkoside, picroside III, veronicoside, minecoside, phenol glycosides, picein, androsin, cucurbitacin glycosides and 4-hydroxy-3-methoxy-acetophenone49.

Ansari and coworkers50 have reported that the ethanol extract of the plant has protective property against CCl4 induced liver damage in rats. Rastogi and coworkers51 have reported that picroliv protects against alcohol induced chronic hepatotoxicity. Dwivedi and coworkers52 have reported that picroliv offers protection against thioacetamide induced hepatic damage in rats.

Anandan and coworkers53 have reported on the protective effect of the plant extract on D-galactosamine induced hepatitis in rats. Atal and coworkers54 have reported that the plant is a potent immunostimulant of both cell mediated and humoral immunity.

Commiphora mukul

Oleo gum resin exudates of Commiphora mukul commonly known as guggul belonging to the family Burseraceae has been well recognized as valuable drugs in Ayurveda55,56.It is used in the treatment of neurological and urinary disorders obesity and arthritis.It has been reported that resin contains gugulsterones E and Z, guggulosterols I to V, cembrene, mukulol and a-camphorone57.

It has been reported by several researchers that guggul and guggulipid (the standardized product of the extraction of the oleo gum resin by ethyl acetate) lowers blood cholesterol and lipids in animal models58-65.

Dwarkanath and Satyawati66 have conducted clinical studies on guggul in patients with hypercholesterolemia with associated obesity, ischaemic heart disease, hypertension, diabetes etc. The study showed a fall in total serum cholesterol and serum lipids in all cases treated with guggul. The body weight also revealed a significant decline in patients of obesity.

Kuppurajan and coworkers67 have reported the antihyperlipidemic effect of guggulu in hypercholesterolemic and hyperlipidemic cases.

Kotiyal and coworkers68 have reported that guggul significantly reduces the total serum cholesterol, total lipids and triglycerides levels in patients of hyperlipidemia and allied disorders.

Asthana and coworkers69 have reported that when guggulipid is administered in the dose of 1.5 gm per day for 12 weeks, it brought down the levels of cholesterol by 16.9% and triglycerides by 27%.

Upadhyaya and coworkers70 have studied the effect of guggulu powder in patients of ischaemic heart disease for a duration of 12 weeks. Complete improvement in precordial pain was noted in 75% patients. Reduction in body weight was found to be 1 kg/month. Biochemical investigations revealed reduction in serum cholesterol (27%) serum triglycerides (36%) phospholipids (20%) and free fatty acids (37%).

Singh and coworkers71 have reported on the hypolipidemic and antioxidant activity of the plant in patients with hypercholesterolemia. They have also found that guggulipid decrease, total cholesterol level by 11.7%, LDL level by 12.5% and triglyceride by 12.0%. The lipid peroxide declined 33.3%. Gum guggul has been found to be hypocholesterolemic and hypolipidemic agent in experimental animals like pigs, chicks, rabbits and rats72.

Curcuma longa

Curcumin is the yellow colour substance present in the rhizomes of Curcuma longa, L (Family-Zingiberaceae). Curcuma longa rhizomes are commonly known as turmeric, used traditionally in India for biliary disorders, anorexia, coryza, cough, diabetic wounds, hepatic disorders, rheumatism and sinusitis73.

Vogel and Pelletier74,75 have isolated Curcumin in 1815 and the chemical structure was determined by Roughley and Whiting in 1973. Curcumin comprises curcumin I (diferuloylmethane) curcumin II (demethoxy curcumin) and curcumin III (bisdemethoxy curcumin).

Curcumin has been shown to have variety of activities such as antiinflammatory, antiplatelet, hypolipidemic, antioxidant, antimicrobial and antitumour activities76.

Rao and coworkers77 have reported that curcumin and ether extract of Curcumalonga have hypolipidemic action in rats. It was also reported that curcumin increase faecal excretion of bile acids and cholesterol in both the normal and hypercholesterolemic rats. The findings suggest that turmeric might raise the ratio of HDL cholesterol to total cholesterol.

Sharma78 has reported the antioxidant activities of curcumin. It has also been reported that curcumin inhibits lipid peroxidation in brain tissue. Free radical scavenging activity was also reported by Subramanian and coworkers79.

Joe and Lokesh80 have reported that curcumin can significantly inhibit the generation of reactive oxygen species like superoxide anions, H2O2 and nitrite radical generation by activated macrophages, which play an important role in inflammation. They have also reported that curcumin also lowers the production of reactive oxygen species in vivo.

Srivastava and coworkers81 have reported that curcumin inhibit ADP, collagen and epinephrine induced platelet aggregation in vitro and ex vivo. It was also reported that curcumin selectively inhibits thromboxane production.

Shalini and Srivastava82 have reported that curcumin is effective as the antioxidant BHA in inhibiting lipid peroxidation. Srinivasan and coworkers83 have reported that turmeric extract and curcumin counteract the increase in liver cholesterol in rats induced by cholesterol feeding.

Sreejayan and Rao84 have reported that curcumin reduce experimentally generated nitrite in vitro. This nitric oxide scavenging activity was also exhibited by other curcuminoids.

Reddy and Lokesh85 have reported that oral administration of curcumin reduces iron induced hepatic damage in rats by lowering lipid peroxidation. It has also been reported that turmeric extract lowers plasma cholesterol levels by 49mg/dl and triglycerides by 62mg/dl in an uncontrolled clinical trial on patients in China86. Antihyperlipidemic activity of curcumin has been reported by several researchers in various experimental models87-90.

Song and coworkers91 have reported that demethoxy curcumin and bisdemethoxy curcumin have antioxidant activity. Curcumin is believed to be extremely nontoxic.

Camellia sinensis

The leaves of Camellia sinensis are directly heat treated, rolled and dried to get green tea. The heat treatment consists of either pan firing or steaming to inactivate oxidising enzymes92. The plant belongs to the family Theaceae. Its leaf has numerous medicinal benefits mainly due to its antioxidant properties. Green tea contains tannins, polyphenols, catechins, epigallocatechin gallate and theaflavins. Polyphenols are the most important constituents which participate in tea fermentation and determine the liquor characteristics of tea.

Lin and coworkers93 have reported the hypolipidemic effect of green tea in rats fed with green tea for 27 and 63 weeks. The results also suggest that long term feeding is non toxic to liver and kidney.

Wang and Wang94 have isolated a water soluble polysaccharide from tea leaves and reported on its antihyperlipidemic effect.

Liu and coworkers95 have reported the antioxidative effect of polyphenolic compounds such as (-) epicatechin, (-) epigallocatechin, (-) epicatechin gallate, (-) epigallocatechin gallate and gallic acid against free radical initiated peroxidation of human low density lipoprotein.

Yang and Koo96 have reported that green tea lowers serum and liver cholesterol levels in diet induced hypercholesterolemic rats. They have also reported that green tea lowers plasma cholesterol by increasing fecal bile acids and cholesterol excretion.

Green tea tannins have been reported to have antiseptic, antioxidant effect and also used as detoxifying agent97. It was reported that green tea epicatechins partially protect DNA from peroxide radical induced strand breaks and base damage through fast chemical repair of DNA radicals98.

Dalluge and coworkers99 have developed a system for the measurement of six biologically active catechins in aqueous infusion of green tea.

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  100. About Authors:

    Nanjaian Mahadevan

    Dr.Nanjaian Mahadevan

    Address for correspondence
    Professor & Head, Department of Pharmacognosy, I.S.F. College of Pharmacy, Moga 142 001; Punjab.
    M: +91-9915939996; E mail: nnmahadevan@rediffmail.com

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