Pharma Tips

Hepatoprotective Drugs and it’s Biological Screening

By: Mitul Shah | Views: 36620 | Date: 14-Jun-2010

Hepatoprotective drugs means the drugs that are prevent the liver disease. The liver is an organ that is located in the upper right hand side of the abdomen, mostly behind the rib cage.

1. Introduction:
Hepatoprotective drugs means the drugs that are prevent the liver disease. 
The liver is an organ that is located in the upper right hand side of the abdomen, mostly behind the rib cage.
2. Liver anatomy:
.  
The liver of an adult normally weighs close to three pounds and has many functuctions
• The liver produces and secretes bile into the intestine where the bile assists with the digestion of dietary fat.
• The liver helps purify the blood by changing potentially harmful chemicals into harmless ones. The sources of these chemicals can be outside the body (for example, medications or alcohol), or inside the body (for example, ammonia, which is produced from the break-up of proteins; or bilirubin, which is produced from the break-up of hemoglobin).
• The liver removes chemicals from the blood (usually changing them into harmless chemicals) and then either secretes them with the bile for elimination in the stool, or secretes them back into the blood where they then are removed by the kidneys and eliminated in the urine.
• The liver produces many important substances, especially proteins that are necessary for good health. For example, it produces albumin, the protein building-block of the body, as well as the proteins that cause blood to clot properly.

3. Liver disease

(3.1)Definition:
Liver disease is a term for a collection of conditions, diseases, and infections that affect the cells, tissues, structures, or functions of the liver. 
Also called: Hepatic disease 

Your liver is the largest organ inside your body. It is also one of the most important. The liver has many jobs, including changing food into energy and cleaning alcohol and poisons from the blood. Your liver also makes bile, a yellowish-green liquid that helps with digestion. 
The liver is an important organ located in the upper right quadrant of the abdomen. It is responsible for: 
• Filtering the blood 
• Making bile, a substance that helps digest fat and excrete certain fatty substances 
• Processing and hooking fats to carriers (including cholesterol), and storing sugars, helping the body transport and save energy. 
• Making important proteins, such as most of those involved in blood clotting 
• Metabolizing many medications, such as barbiturates, sedatives, and amphetamines 
• Storing iron, copper, vitamins A and D, and several of the B vitamins 
• Making important proteins like albumin that regulate fluid transport in the blood and kidneys. 
• Helping break down and recycle red blood cells


If the liver becomes inflamed or infected, its ability to perform these functions may be impaired. Liver disease and infections are caused by a variety of conditions including viral infections, bacterial invasion, and chemical or physical changes within the body. The most common cause of liver damage is malnutrition, especially that which occurs with alcoholism.


(3.2)Types of  liver disease:     
a) Necrosis
b) Cirrhosis
c) Hepatitis – may be viral, toxic or deficiency type.
d) Hepatic failure
e) Chemical / Drug induced Hepatotoxicity: Generally may be hepatitis, jaundice and carcinogenesis.
f) Liver disorders due to impaired metabolic function. Generally the disorders associated with fat (liposis) and bilirubin (Jaundice) metabolisms are very commonly seen.

1. Disorders associated with fat metabolism : Fatty Liver
2. Disorders associated with bilirubin metabolism – Jaundice or Icterus which may be of different types based open mechanisms of action and etiology.
• Hemolytic / prehapatic jaundice.
• Obstructive (Post – Hepatic / Cholestatic Jaundice).
• Hepatogenous jaundice
• Hereditary Jaundice: Syndrome or familial hyper bilirubinaemia, Dubin – Johnson syndrome and Crigler – Najjar syndrome etc, are some of the hereditary jaundice types usually observe. 

• Cirrhosis, which is a serious condition that causes tissues and cells in the liver to be replaced by scar tissue.
• Type I glycogen storage disease, which causes problems in controlling blood sugars when a person fasts
• Porphyria, a condition that causes a malfunction in how the body uses porphyrins.
• Porphyrins are important in making hemoglobin in red blood cells, to carry oxygen throughout the body.
• Hemochromatosis:, a condition which causes the body to absorb and store too much iron. The iron buildup causes damage to the liver and other organs.
• Primary sclerosing cholangitis, a condition that causes the bile ducts of the liver to narrow due to inflammation and scarring
• Sarcoidosis:, a disease that causes a buildup of lesions within the liver and other organs of the body
• Gallstones, which may block the bile duct
• Hepatitis:, an inflammation and infection of the liver caused by any of several viruses
• Cystic disease of the liver, which causes lesions and fluid-filled masses in the liver

►Liver diseases most likely to be seen in children include: 
• Galactosemia: an inherited disease in which the body can not tolerate certain sugars in milk. These sugars can build up, causing serious damage to the liver and other organs of the body. 
• Alagille's syndrome: a condition in which the bile ducts narrow and deteriorate, especially during the first year of life 
• Alpha 1- antitrypsin deficiency: a genetic liver disease in children that can lead to hepatitis and cirrhosis of the liver 
• Neonatal hepatitis: which is hepatitis that occurs in a newborn during the first few months of life 
• Tyrosinemia: a disorder that causes serious problems with liver metabolism 
• Hemorrhagic telangiectasia: a condition in which thin blood vessels allow frequent and easy bleeding of the skin and digestive tract 
• Reye's syndrome: a condition that causes a buildup of fat in the liver. This condition has been linked in some cases to use of aspirin, especially in conjunction with chickenpox, influenza, or other illnesses with fever. 
• Wilson's disease: an inherited condition that causes a buildup of the mineral copper in the liver 
• Tthalassemia: a group of hereditary anemias, or low red blood cell counts 
• Biliary atresia: a condition in which the bile ducts extending from the liver to the intestine are too small in diameter or are missing 
• Chronic active hepatitis: an inflammation of the liver that causes severe scarring and interference with liver function 
Like other parts of your body, cancer can affect the liver. You could also inherit a liver disease such as hemochromatosis. 

►Alcohol-related liver diseases include: 
• Fatty liver disease, which causes an enlarged liver 
• Alcoholic hepatitis 
• Alcoholic cirrhosis 

(3.3)Signs and symptoms of the liver disease:

Symptoms partly depend on the type and the extent of liver disease. In many cases, there may be no symptoms. Signs and symptoms that are common to a number of different types of liver disease include: 
• Jaundice, or yellowing of the skin 
• Darkened urine 
• Nausea 
• Loss of appetite 
• Unusual weight loss or weight gain 
• Vomiting 
• Diarrhea 
• Light-colored stools 
• Abdominal pain in the upper right part of the stomach 
• Malaise, or a vague feeling of illness 
• Generalized itching 
• Varicose veins (enlarged blood vessels) 
• Fatigue 
• hypoglycemia (low blood sugar) 
• Low grade fever 
• Muscle aches and pains 
• Loss of sex drive 
• Depression 

►A rare but severe form of the liver infection called acute fulminant hepatitis causes liver failure. Symptoms of liver failure include: 
• An enlarged and tender liver 
• Enlarged spleen 
• Susceptibility to bleeding 
• Encephalopathy, which is a disorder that affects how the brain functions 
• Changes in mental status or level of consciousness 
• Ascites, which is an accumulation of fluid inside the abdomen 
• Edema or swelling under the skin 
• Aplastic anemia, a condition in which the bone marrow cannot make blood cells


(3.4)Causes of liver disease:

Liver disease can be caused by a variety of factors. Causes include: 
• Congenital birth defects, or abnormalities of the liver present at birth 
• Metabolic disorders, or defects in basic body processes 
• Viral or bacterial infections 
• Alcohol or poisoning by toxins 
• Certain medications that are toxic to the liver 
• Nutritional deficiencies 
• Trauma, or injury

(3.5)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. 
• 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.


(3.6)Diagnosis:

A healthcare professional can determine whether a person's symptoms, medical history, and physical exam are consistent with liver disease. Hepatomegaly, an enlarged, firm liver, and other signs of liver disease may be found on examination.

Many further tests may also be used to support the diagnosis. These include blood tests, such as: 
• Liver function tests, which are blood tests that check a wide variety of liver enzymes and byproducts 
• A complete blood count (CBC), which looks at the type and number of blood cells in the body 
• Abdominal X-rays 
• Ultrasounds, to show size of abdominal organs and the presence of masses 
• An upper GI study, which can detect abnormalities in the esophagus caused by liver disease 
• Liver scans with radiotagged substances to show changes in the liver structure 
• ERCP, or endoscopic retrograde cholangiopancreatography. A thin tube called an endoscope is used to view various structures in and around the liver. 
• Abdominal CT scan or abdominal MRI, which provide more information about the liver structure and function 


In some cases, the only way to definitively diagnose the presence of certain liver diseases is by a liver biopsy. This procedure involves the removal of a tiny piece of liver tissue for examination under a microscope. Liver biopsies may have to be done repeatedly to see how the disease is progressing or responding to treatment.


(3.7) Long term effects of the disease:

Long- term effects depend on the type of liver disease present. For example, chronic hepatitis can lead to: 
• Cirrhosis of the liver 
• Liver failure 
• Illnesses in other parts of the body, such as kidney damage or low blood counts
►Other long-term effects of liver disease may include: 
• Gastrointestinal bleeding. This includes bleeding esophageal varices, which are abnormally enlarged veins in the esophagus and/or the stomach. 
• Encephalopathy, which is deteriorating brain function that may progress to a coma 
• Peptic ulcers, which erode the stomach lining 
• Liver cancer


4. Treatment
Treatment for  liver disease include allopathic and herbal drug treatment: 

4.1 Hepatoprotective allopathic treatment:

A) DRUGS:
Specific drugs used in the management of liver disease:

1) Ursodeoxycholic acid (Ursodiol):
Mechanism of action: 
Ursodeoxycholic acid decreases intestinal absorption and suppresses hepatic synthesis and storage of cholesterol. This is believed to reduce cholesterol saturation of bile and thereby allowing solubilization of cholesterol-containing gall stones. It has little effect on calcified gallstones or on radiolucent bile pigment stones and therapy is only successful in patients with a functional gall bladder. Ursodeoxycholic acid, a relatively hydrophilic bile acid, is also believed to protect the liver from the damaging effects of hydrophobic bile acids, which are retained in cholestatic disorders. The hepatoprotective effect may however, be less in cats and dogs than in humans as the major circulating bile acid in dogs and cats is taurocholate. This is more hydrophilic and less hepatotoxic than the major circulating bile acids in humans. The immunomodulatory effects of ursodeoxycholic acid are believed to involve decreased immunoglobulin production by B lymphocytes, decreased interleukin-1 and interleukin-2 production by T lymphocytes, decreased expression of hepatocyte cell surface membrane HLA class I molecules and possibly stimulation of the hepatocyte glucocorticoid receptor.
Clinical applications:
ursodeoxycholic acid has been used in the management of chronic hepatic diseases in humans such as primary biliary cirrhosis, biliary disease secondary to cystic fibrosis, nonalcoholic steatohepatitis, idiopathic chronic hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, and alcoholic hepatitis. However, its therapeutic efficacy in some of these disorders has not been firmly established. 

Dose rate:
Dogs and cats: 10–15 mg/kg q24h or divided and given q12h. It is recommended that ursodeoxycholic acid be administered for 3–4 months after which the patient should be reassessed for improvement in biochemical markers of hepatocellular pathology. If there has been improvement, treatment is continued, but if there has been no improvement or progression, either treatment should be terminated or additional therapies such as glucocorticoids or colchicine added.
Adverse effects:
• Ursodeoxycholic acid appears to be well tolerated by dogs and cats; vomiting and diarrhoea are reported rarely. There is some concern in human patients that taurine depletion may be potentiated by chronic treatment with ursodeoxycholic acid.
• This may be important in cats that are obligate taurine conjugators. This potential for taurine depletion may be exacerbated in some cats with hepatobiliary disease that have increased urinary excretion of taurine-conjugated bile acids. 
• Dogs are less likely to become taurine depleted by this mechanism as they can shift to glycine conjugation. Ursodeoxycholic acid should not be used in patients with extra-hepatic biliary obstruction, biliary fistulas, cholecystitis or pancreatitis.
2) Penicillamine:
Penicillamine is a degradation product of penicillin but has no antimicrobial activity. It was first isolated in 1953 from the urine of a patient with liver disease who was receiving penicillin
Mechanism of action:
Penicillamine chelates several metals including copper, lead, iron, and mercury, forming stable water soluble complexes that are renally excreted. It also combines chemically with cystine to form a stable, soluble, readily excreted complex. Although it usually takes months to years for hepatic copper levels to decrease, clinical improvement is often seen in Bedlington Terriers after only a few weeks suggesting the drug has other beneficial effects other than copper depletion. Penicillamine induces hepatic metallothionein, which may bind and sequester copper in a nontoxic form. It may also have antifibrotic effects as it inhibits lysyl oxidase, an enzyme necessary for collagen synthesis and directly binds to collagen fibrils, preventing cross-linking into stable collagen fibres. However, its efficacy as an antifibrotic agent in humans is doubtful and it has not been evaluated in veterinary medicine. Penicillamine may have immunomodulatory effects and has been demonstrated to reduce IgM rheumatoid factor in humans with rheumatoid arthritis. However, its mechanism of action in this disease remains uncertain.

Clinical applications:

Penicillamine is a monothiol chelating agent which is used in veterinary medicine in the treatment of copper-storage hepatopathy (e.g., Bedlington Terriers), lead toxicity, and cystine urolithiasis. It has also been used in the management of rheumatoid arthritis in humans. Wilson’disease is treated by trientine or penicillamine.

Dosage and formulations:
For management of copper-associated hepatopathy, a dose of 10–15 mg/kg q12h PO is given on an empty stomach. However, if GIT adverse effects are experienced, these may be reduced if it is given with food, although absorption may be reduced. Alternatively, reduce dose and gradually build up to full dos
Adverse effects:
• GIT adverse effects are common resulting in nausea and vomiting. Smaller doses on a more frequent basis may alleviate adverse effects. Alternatively, the drug can be given with food although this will reduce absorp
• Other adverse effects observed infrequently or rarely include:
Fever.
Lymphadenopathy.
Skin hypersensitivity reactions.
Immune-complex glomerulonephropathy.

Other drugs include:
Liver disease treatment will depend on the type and the extent of disease. For example, treating hepatitis B, hepatitis C, and hepatitis D may involve the use of medications such as the antiviral medication alpha interferon. Other medications used to treat liver disease may include ribavirin, lamivudine, steroids, and antibiotics.Wilson’disease is treated by trientine or penicillamine.
Other drugs are: 
Alphamethyldopa, halothane, INH (isoniazid), rifampicin, pyrazinamide,phenylbutazone allopurinol, chlorpromazine, methyltestosterone, erythromycin, glibenclamide.




B) SIDE EFFECTS:

It will depend on the treatments used for the liver disease. Antibiotics may cause stomach upset or allergic reactions. Side effects of interferon include a flu-like illness with fever, and body aches.

A liver transplant can cause many complications, including failure or rejection of the new liver. After a liver transplant, a person will need to take powerful anti-rejection medications for the rest of his or her life. Because these medications interfere with normal immunes system functioning, they increase the person's risk for infections and certain types of cancer. 

A person with hepatitis B, hepatitis C, or hepatitis D needs to be monitored for side effects and benefits during and after interferon treatment. Alpha interferon treatment might be repeated if the disease flares up again. A person who has received a liver transplant is checked for further disease, as well as for function of the new liver. 

Cirrhosis can lead to a number of complications, including liver cancer. In some people, the symptoms of cirrhosis may be the first signs of liver disease.


4.2 Herbal tratment:

4.2. A) CLASSIFICATION:
These are generally classified into 3 categories without any strict delineation amongst them. 

1.  Anti hepatotoxic agents:
These generally antagonise the effects of any hepatotoxin causing hepatitis or any liver disorder or disease.

2.  Hepatotropic agents:
These generally support or promote the healing process of the liver. In practice these two activities can not be easily distinguished from each other.

3.  Hepatoprotective agents:
These generally prevent various types of liver affections prophilactically.
In general any hepatoprotective agent can act as an antihepatotoxic or hepatotropic agent but the vice versa is always not true.

4.2. B) INTRODUCTION:
Herbal Medicine is defined as branch of science in which plant based formulations are used to alleviate the diseases. It is also known as botanical medicine or phytomedicine. Lately phytotherapy has been introduced as more accurate synonym of herbal or botanical medicine. Recently, treatment of diseases with herbal medicine has been addressed as phytopharmacotherapy. Moreover, herbal medicinal products have been included lately in dietary supplements. 

Early in the twenty century herbal medicine was a prime healthcare system as antibiotics or analgesics were not available. With the development of allopathic systems of medicine, herbal medicine gradually lost its popularity among people and it was based on the fast therapeutic actions of synthetic drugs.  Almost a century has passed and we have witnessed limitations of allopathic systems of medicine. Lately herbal medicine has gained momentum and it is evident from the fact that certain herbal remedies peaked at par with synthetic drugs. 

It can be concluded that knowledge of Alternative and Complementary Systems of Medicines like Ayurveda, botany, pharmacognosy and phytochemistry, biochemistry, ethno pharmacology and toxicology is integral part of herbal medicine. 

Recently we have witnessed explosive growth of herbal drug industry. Data and meta-analysis have shown that more and more people are consulting herbal practitioners. Its cheering that the World Health Organization has also identified importance of herbal medicine. According to a study from U.S., 60-70% patients living in rural areas are dependent on herbal medicine for their day to day diseases.

Several authors have reported favorable results with herbal drugs (mostly in form of extracts) either in animal or in human studies. Ginkgo biloba L., Echinacea purpurea L., Hypericum perforatum L. and Cimcifuga racemosa (L.) Nutt., were subjected to clinical trials.  

Silybum marianum L., the reputed hepatoprotective, has remained a golden standard in the treated of liver ailments. Several years have passed but status of this herbal drug remains unquestioned. In India, a study reported that Picrorrhiza kurroa Royle., is more potent than Silybum marianum as hepatoprotective agent (however, this study is not complete in all aspects). If the results of the study were true, then more clinical trials were warranted with Picrorrhiza kurroa.   

Herbal drugs are significant source of hepatoprotective drugs. Mono and poly-herbal preparations have been used in various liver disorders. According to one estimate, more than 700 mono and poly-herbal preparations in the form of decoction, tincture, tablets and capsules from more than 100 plants are in clinical use. Surprisingly, several studies have appeared in journals addressing hepatotoxic potential of herbal drugs. These studies suggest that the drugs that were claimed to be hepatoprotective, are actually hepatotoxic. 
In India, several steps have been taken to improve quality of Ayurvedic medicines. Good manufacturing practice (GMP) guidelines have been introduced so as to ensure quality control. Medicinal plant boards have been constituted at state and center level to inspire people, particularly the farmers for adopting cultivation of medicinal plants. Herbal gardens have been developed to make the common man conversant with the rich heritage of Indian system of medicine. Various institutes like NIPER, NBRI, CIMAP and CDRI are playing pivotal role in laying down standards for Ayurvedic system of medicine. 

To conclude it may be said that herbal drugs have provided us with potent weapons like atropine, codeine, taxol, vincristine and vinblastine. In the modern scenario, diseases are becoming drug-resistant and scientists are studying possible roles of plant based drugs for screening life saving drugs. The herbal system of medicine is a full fledged system of medicine and it can not be ruled out as quackery. Backing up this system is the fact that ancient findings and documentation have through the centuries provided us with leads on the development of life-saving drugs. 

Treatment options for common liver diseases such as cirrhosis, fatty liver, and chronic hepatitis are problematic. The effectiveness of treatments such as interferon, colchicine, penicillamine, and corticosteroids are inconsistent at best and the incidence of side-effects profound. All too often the treatment is worse than the disease. Conservative physicians often counsel watchful waiting for many of their patients, waiting in fact for the time when the disease has progressed to the point that warrants the use of heroic measures. Physicians and patients are in need of effective therapeutic agents with a low incidence of side-effects. Plants potentially constitute such a group.
Several hundred plants have been examined for use in a wide variety of liver disorders. Just a handful have been fairly well researched. The latter category of plants include: Silybum marianum (milk thistle), Picrorhiza kurroa (kutkin), Curcuma longa (turmeric), Camellia sinensis (green tea), Chelidonium majus (greater celandine), Glycyrrhiza glabra (licorice), and Allium sativa (garlic). This review will be divided into two parts. Silybum marianum and Picrorhiza kurroa, will be reviewed in Part One. Curcuma longa, Camellia sinensis, Chelidonium majus, Glycyrrhiza glabra, and Allium sativa
There are number of phytoconstituents from plants which have exhibited antihepatotoxic activity
A number of recent reviews have focused on the adverse effects of herbal products.In the current review, we will highlight on herbs known to be hepatoprotective, mechanisms of hepatoprotectivity, and clinical documentation.In fact some herbal products claiming to be hepatoprotective may actually be having some components with hepatotoxic potential.

Silybum marianum, Picrrorhiza kurroa, Andrographis paniculata, Phyllanthus niruri, and Eclipta alba are proven hepatoprotective medicinal herbs, which have shown genuine utility in liver disorders. These plants are used widely in hepatotprotective preparations and extensive studies have been done on them. Their discussion is beyond the scope of the article.
4.1.C) PLANTS USED IN THE TREATMENTT 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).

►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)
• Acetylbergenin (Lim et al.,2000)
• Kolaviron (Oluwatosin and Edward, 2006) 


1). Silybum 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
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  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 michanism 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. 


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.
• 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.

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.

4). Solanum nigrum:
Synonyms: Black nightshade.
Ayurvedic name: Kakamachi.
Family: Solanaceae. 
Chemical constituents: 
• Main active constituents are solamargine, andsolasonine.

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 a emollient, diuretic, antiseptic, and laxative properties.
• Antimicrobial, antioxidants, cytotoxic properties.
• It is also have antiulcerogenic activity and hepatoprotective activity.

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.

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.

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.

7). Curcuma longa:
Synonyms: Curucuma, turmeric, Indian saffron
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.

8). Tephrosia purpurea:
Synonyms: basterd indigo, hoary pea.
Ayurvedicname:  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). Fumaria officinalis:
Synonyms: Fumatory
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


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.

11). Chionanthus virginicus:
Synonyms: Fringe tree, old man’s beard.
Family: Oleaceae
Parts used:Dried root bark
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.


12). Andrograhis paniculata:
Synonyms: Kalmeg. 
Family: Acanthaceae. 
Parta 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.
•  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.

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.

14). Phyllanthus niruri/amarus:
Synonyms: Phyllanthus emblica, jonesiansoca.
Family: Euphorbiaceae
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. 


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.


4.1 D)  SOME OF HERBAL FORMULATIONS USED IN LIVER DISORDER:

1) Liv-52: It is non-toxic hepatoprotective substance from The Himalaya Drug Co. Liv.52 can improve the subjective condition and clinical parameters in patients with liver damage, in particular in alcoholic liver damage.

2) LIMARIN®: Capsules and Suspension : It has a potent hepatoprotective and free radical scavenging (antioxidant) action. LIMARIN® is developed from the active extract of the fruit of silybum marianum, or the milk thistle. Basically a European herbal product.

3) Cirrhitin: Cirrhitin is a natural medicine formulated specifically to treat Cirrhosis of the liver. Marketed by CCNOW.   Some other polyherbal preparations such as Livex, HD-03, Hepatomed, Live 100 and Hepatoguard with proven efficacy are also use in different types of liver disorders.


5. Evaluation of Hepatoprotective Activity:
►Investigation of Liver Function:
The liver function tests are employed for accurate diagnosis, to assess the severity of the
damage, to judge the prognosis and to evaluate the therapy.  The routinely performed liver function tests (LFTS) are as follows :

A. ABNORMALITIES OF BILE PIGMENTS AND BILE SALTS EXCRETION TESTS 
• Serum total direct and indirect bilirubin.
• Urine bile salts, bile pigments and urobilinogen.

B. SERUM ENZYMES ASSYAS 
• SGOT (AST )
• SGPT  (AST )
• Alkaline phosphatase (ALP) and if necessary
• γ – Glutamyl transpeptidase (γ-GT) 
• Other enzymes 

C.  CHANGES IN PLASMA PROTEIN TESTS
• Thymol turbidity test.
• Determination of total proteins, albumin globulins.

►Generally direct toxins injure many tissues including liver (eg. CCl4), an indirect affects particular metabolic pathway of the liver (eg. galactosamine). Thus the hepatotoxins affect the liver in a number of ways as: 

1. Interference with hepatic bilirubin uptake, conjugation and excretion eg. Rifampicin.
2. Dose and time dependant reactions.
• Acute toxic hepatitis eg. Paracetamol
• Fatty liver eg. Tetracyclin
3. Dose independent reaction.
• Diffuse hepatocellular damage eg. Isoniazid
• Cholastatic hepatitis eg. Chlorpromazine
• Granulomatous infiltration eg. Phenytoin, Chlorpropamide.
►Hepatoprotective activity can be most easily evaluated / screened with the aid of several model systems of liver damage in experimental animals. In all test model systems conditions for liver damage are implemented and an attempt is made to counteract this toxicosis with the substance / preparation under test. The magnitude of the protective effect can be measured by estimating the enzymes and the rate of survival and can be verified histologically. The available methods are invivo, exvivo & invitro methods. 

A. IN VITRO METHOD: 

• Hepatocytes are isolated by using in-situ under aseptic condition and placed in chilled HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulphonic acid).

• These isolated hepatocytes than exposed to test samples and toxins like CCl4, thioacetamide, ethanol and paracetamol etc. 

• After a specified time period the degree of toxicity or protection is assessed by viability tests (Trypan blue dye exclusion method) and enzyme levels such as SGOT and SGPT. 


Advantages of in vitro models:

• More rapid and requires small quantities of test substances and fewer animals, where as in vivo studies require a large number of animals (six per group), 
• In Vivo study need up to 3-7 days of drug administration for a significant effect to produced and thus requires large quantities of drugs but In vitro method require 3 days study and less quantities of drugs. 
• Ability to dispose numerous samples at a time. 
• Low cost with a small size 
• Little variation and reproducibility of results. 
• The major disadvantage is that sometimes it may not reflect the events which occur in animals.

B. EX VIVO METHOD:

• In this method after completion of preselected in vivo test protocol hepatocytes are isolated and the percentage of viable cells and biochemical parameters are determined as liver function tests. 
• These methods are somewhat better correlated to clinical models than in vitro or in vivo methods.


C. IN VIVO METHOD:

These are of two types.     

1) Based on bile parameters: 

• The compounds having hepatoprotective claims are evaluated in general for their choleretic or anticholeretic activity in order to know whether the liver disorder is due to an abnormality of bilirubin metabolism or not. 

2) Based on serum parameters:

• Hepatotoxicity is produced in experimental animals by the administration of known dose of hepatotoxin like carbon tetrachloride, paracetamol, D-galactosamine, thioacetamide, ethyl alcohol etc., which produce marked measurable effects, the magnitude of which can be measured by carrying out various liver function tests. 
• It is very convenient laboratory method, reproducibility of results is rather poor.



5.1.  Experimental models for Hepatoprotective screening:
►Several chemical reagents and drugs which induce liposis, necrosis, cirrhosis, carcinogenesis and hepatobiliary dysfunctions in experimental animals are classified as hepatotoxins. The most important ones used are carbon tetrachloride (CCl4), thioacetamide (TAA). D-galactosamine, Paracetamol, chloroform, ethyl alcohol and Pyridine. The following are some of the experimental rat models employing these hepatotoxins:



1. CCl4 model :
A number of CCl4 models are devised depending upon its dosage through different routes of administration.

A.  ACUTE HEPATIC DAMAGE:
Acute liver damage, characterized by ischemia, hydropic degeneration and central necrosis is caused by oral or subcutaneous administration of CCl4 (1.25ml / kg). The biochemical parameters elevated are found to be maximum after 24 hours of CCl4 administration. Normally administered as 50 % V/V solution in liquid paraffin or olive oil.


B. CHRONIC REVERSIBLE HEPATIC DAMAGE:
Administration of CCl4 (1ml/kg s.c) twice weekly for 8 weeks produces chronic, reversible liver damage.


C. CHRONIC, IRREVERSIBLE HEPATIC DAMAGE:
Administration of CCl4 (1ml/kg s.c) twice weekly for 12 weeks simulates chronic, irreversible liver damage.

2. Thioacetamide model :
Thioacetamide (100 mg / kg s.c) induces acute hepatic damage after 48 hrs of administration by causing sinusoidal congestion and hydropic swelling with increased mitosis.

3. D-Galactosamine model :
D-galactosamine 800 mg /kg i.p induces acute hepatotoxicity after 48 hrs of administration with diffused necrosis and steatosis.

4. Paracetamol model :
Paracetamol induces acute hepatotoxicity depending upon its dosage through different routes of administration, such as-

A. Paracetamol 800 mg/kg i.p. induces centrilobular necrosis without steatosis.
B. Paracetamol at a dose of 3 g/kg p.o stimulates acute hepatic damage.

5. Chloroform model: 
It produces hepatotoxicity with extensive central necrosis, fatty metamorphosis, hepatic cell degeneration and necrosis either by inhalation (for 1hrin atmosphere) or by subcutaneous administration. (0.4-0.5 ml/kg). 

6. Ethanol model :
Ethanol induces liposis to a different degree depending upon its dose, route and period of administration as follows-
A. A single dose of ethanol 1 ml/kg induces fatty degeneration.

B. Administration of 40 % (v/v) ethanol 2 ml/100g/day p.o for 21 days produces fatty liver.
C. Administration of country made liquor 3ml/100g/day p.o for 21 days produces liposis.

5.2 Mechanism of Action of Some selected Hepatotoxins.

1. Carbon tetrachloride (CCl4):
The hepatotoxicity of CCl4 is due to the metabolic formation of the highly reactive trichloromethyl free radical which attacks the polyunsaturated fatty acids of the membrane of the endoplasmic reticulum and initiates a chain reaction. It is enhanced by induction of hepatic microsomal enzyme systems and vice versa by antioxidants which mop up the free radicals. The first cells to be damaged are those in the centrilobular region where microsomal enzyme activity is the greatest. The initial damage produced is highly localised in the endoplasmic reticulum which results in loss of cytocrome p450 leading to its functional failure with a decrease in protein synthesis and accumulation of triglycerides leading to fatty liver, a characteristic of CCl4 poisoning. If the damage is severe, it leads to disturbances in the water and electrolyte balance of hepatocytes leading to an abnormal increase in liver enzymes in plasma, there by impairing mitochondrial functions, followed by hepatocellular necrosis.

2. Paracetamol:
Paracetamol an analgesic and antipyretic is assumed to be safe in recommended doses, overdoses however taken with suicidal intent, produce hepatic necrosis- small doses are eliminated by conjugation followed by excretion, but when the conjugation enzymes are saturated the drug is diverted to an alternative metabolic pathway, resulting in the formation of a hydroxylamine derivative by cytochrome P450 enzyme. The hydroxylamine derivative, a reactive electrophillic agent, reacts non-enzymatically with glutathione and detoxifies. When the hepatic reserves of glutathione depletes, the hydroxylamine reacts with macromolecules and disrupts their structure and function. Extensive liver damage by paracetamol it self decreases its rate of metabolism and other substrates for hepatic microsomal enzymes.

3.  Thioacetamide:
Thioacetamide, a substitute for H2S with less toxicity and obnoxious smell, on repeated exposure produces cirrhosis by inhibiting the respiratory metabolism of the liver due to the uncontrolled entry of Ca+2 ions into hepatocytes; resulting in inhibition of oxidative phosphorylation. Early metabolic disturbances increase the RNA and protein content of the nuclear fraction of hepatocytes leading to varying graded liver damage including nodular cirrhosis, live cell proliferation, production of pseudolobules and parenchymal cell necrosis. The serum levels of glutamic dehydrogenase are also found to increase, indicative of mitochondrial injury, which plays an important role in thioacetamide induced hepatotoxicity. 


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vivek.D  |  12-Jul-2012 14:15:15 IST
A very good literature of reference.Thanks for the effort.
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