HERBALS IN LIVER DISORDERS - AN UPDATE

A

PROJECT REPORT

FOR ELECTIVE SUBJECT SUBMITTED TO THE

HEMCHANDRACHARYA NORTH GUJARAT UNIVERSITY,

PATAN.

IN PARTIAL FULFILLMENT OF

THE REQUIREMENT FOR THE DEGREE OF BACHELOR OF PHARMACY

SUBMITTED BY:

HITESH M. PATEL

TO

DEPARTMENT OF PHARMACOGNOSY

S.K. PATEL COLLEGE OF

PHARMACEUTICAL EDUCATION AND RESERCH.

GANPAT VIDYANAGAR

KHERVA, NORTH GUJARAT.

2006-2007

gnu.i

nflibn

et.ac

.in

CERTIFICATE

This is to certify that the project work for elective subject entitled

“ HERBALS IN LIVER DISORDERS- AN UPDATE” Represents the bonafide

work of Mr. HITESH PATEL carried out under my guidance and supervision in

the department of Pharmaceutics of S.K.Patel College of Pharmaceutical

Education and Research, Ganpat Vidyanagar, during the academic year

2006-2007. He has collected the literature sincerely and methodically. This work

is up to my satisfaction.

GUIDE H.O.D.

MR.KAPIL M. KHAMBHOLJA DR.R.K. PATEL

(M. pharm,PGDCRP) (M.pharm, Ph.D.)

Lecturer, Asst. professor.

Department of Pharmacognosy, Department of Pharmacognosy

S.K.Patel College of pharmacy, S.K.Patel College of pharmacy

Kherva. Kherva.

PRINCIPAL

Dr. M.M.PATEL

(M.Pharm, PhD, LLB FIC)

S.K.Patel College of

Pharmaceutical education &research

Ganpat Vidyanagar, Kherva.

DATE:

PLACE: KHERVA gnu.i

nflibn

et.ac

.in

gnu.i

nflibn

et.ac

.in

gnu.i

nflibn

et.ac

.in

gnu.i

nflibn

et.ac

.in

ACKNOWLEDGEMENT

First, I would like to express my salutation to god for giving me the strength, confidence

and moral boost to successful completion of this project.

“You want to do the right thing &

You want to do it for right reasons

But if you don’t have right guidance

You can never hit the right target.”

Numerous people have been instrumental in enabling me to give a concrete shape to my

thesis However; I must mention the names of few people who have made catalytic

impact on the development of this thesis.

First and foremost, I would like to acknowledge the continuous encouragement and help

extended to me by Mr. KAPIL M KHAMBHOLJA for preparing this thesis. He has been

my sole guide & philosopher throughout the period of my work. His extensive knowledge

of the subject and the way he imparted the same to me has enabled me to develop the

thesis in a cohesive manner and kindled within me a passion for the subject.

I also express my profound gratitude to Dr. M.M.PATEL our Principal, who has been a

constant source of inspiration to steer me forward throughout the four years of my study.

I take this opportunity to place on record my indent ness to Dr.R K PATEL, Mrs

NIKUNJANA R PATEL, and HARDIK PATEL for helping me when needed.

I also thankful to my parents who lead me from darkness to light, ignorance to enlighten,

confusion to clarity throughout my life

“Your sorrow get divided and

Yours happiness get multiplied

Only with your friends.”

gnu.i

nflibn

et.ac

.in

A friend is a person who understands your feeling, emotion, and helps you

to be what you to be. I am thankful to my friends Mehul, Ajit, Dixit, Dada,

Manku, Pako, Jalaram, Vishal, Mehta, Pintoo, Dhruv, DB and rest of the

Kherva giants and my class mates.

HITESH PATEL

gnu.i

nflibn

et.ac

.in

INDEX

Sr.no Subject

Page no

1 LIVER 1

1.1 ANATOMY OF LIVER 2

1.1 PHYSIOLOGY OF LIVER

2 LIVER DISORDERS 3

2.1 CAUGES OF LIVER DISEASE 4

2.2 DIAGNOSTIC TEST FOR LIVER 4

3 INFLUANCING LIVER DISEASE WITH DIET 5

3.1 VITAMINS SUGGESTED DURING COMBINATION

THERAPY.

7

4 HEPATOPROTECTIVE FACTORS IN DRUG INDUCE

LIVER DISEASE.

9

5 SIDE EFFECTS OF ALLOPATHIC DRUGS 12

6 HERBAL HEPATOLOGY 18

6.1 INTRODUCTION 18

6.2 HEPATOPROTECTIVE ACTIVITY 19

6.3 AYURVEDA AND LIVER 19

6.4 BOTENICALS AS HEPATOPROTECTIVE AGENTS 20

6.5 MEDITIONAL PLANTS WITH HEPATOPROTECTIVE

ACTIVITY

39

7 LIVER DISEASE AND TREATMENT 40

7.1 MILK THISTLE AND ITS EFFECT ON LIVER DISEASE 40

7.2 LIVER CIRROSIS AND TREATMENT 41

7.3SAMe, MAY IMPROVE SURVIVAL IN LIVER

CIRRHOSIS.

42

7.4 BCCAS IN LIVER ENCEPHALOPATHY 43

7.5 OPCS IN LIVER INTERNAL BLEEDING 43

7.6 OTHER NATURAL TREATMENT 43

7.7 HERBS USED ONLY WITH CAUTION 44

8 SCINTIFIC RESEARCH VARIOUS HEPATOPROTECTIVE

AGENTS

46

9 REFRENCES 50

gnu.i

nflibn

et.ac

.in

CHAPTER 1. LIVER (1)

1.1 ANATOMY OF LIVER.

The liver is organ associated with digestive tract. It is heaviest single organ in

body,weight is about 1.5 kg in adult.The liver is normally reddish brown in colour

and lies under the cover protection of lower ribes, on the right side of the upper

abdomen. gnu.i

nflibn

et.ac

.in

The liver has major two portion right lobes and left lobes which is separated by

falciform ligament. Liver is also joined to stomach and deodenum by folds of membrane

called gastrohepatic ligament.

1.2. PHYSIOLOGY OF LIVER (1)

The liver serves many metabolic functions.

It receives blood return from G.I. tract and it convert glucose molecule to

glycogen. It also metabolite sugar and protein. Liver cell also contain many

mitochondria.

A tiny chemical power house whose presence indicating very high metabolic

activity.

The liver destroy the toxic materials may be ingested along with food and water.

It may be alcohol. The liver makes and stores vitamin A which is essential for

the well being of the surface lining tissue.

It also store iron which is used in production of hemoglobin in the blood. Bile is

also produced in liver which is used in digestion of fat.liver also play an

important role in clotting of blood and control the level of prothrombin and

fibrinogen.

gnu.i

nflibn

et.ac

.in

CHAPTER 2. LIVER DISORDERS (2)

(1)Congestial bileduct atresia:-

It include the bile duct failing to develop and problems with enzyme responcible

for bile metabolism

(2) Hepatitis:-

Virus, bacteria, parasites and drug can cause it, alcohol etc.may leads to fever and

upper abdominal pain and yellowing of eye

(3) Cirrhosis:-

It involves the death of liver cell. It causes alcoholism or hemochromatosis etc.

and symptoms are breast enlargement and testicular wasting in men.

(4) Liver cancer:-

Cancer of liver may spread to another part of body such as breast, lung, pancrease and

stomach

2.1 Causes of Liver diseases.

1) Viral infection:

Examples are hepatitis A, B, C, D, and E.Here B&C may cause more severe

syndrome.

2) Alcoholism:

Ethanol is commonest causeas of cirrhosis in world. Prolonged and excessive

exposure to alcohol may cause inflammatory activity.

3) Immune disorders:

Primary biliary cirrhosis &its primary affect women between 40 to 60 years of

age.Primary sclerosis cholergitis occurs in young men of 20 to 40 years.

4) Infectious diseaes:

Infection caused by schizones, a major cause of mortality and morbidity.

5) Drugs and toxins:

6) Gilberts syndromes:

2.2 Diagnostic test for liver. gnu.i

nflibn

et.ac

.in

Investigation of liver disease often involves taking blood specimen to test for liver

enzyme, which are released from damaged liver cell.Removal of small specimen of liver

for examinationmay performed to investigate jaundice

1) Liver function blood test .

This test gives information to health of liverIt makes important protein such as

albumin &clotting factors.liver function blood test will reveal level of albumin in the

blood.

In severe liver disease, the albumin level decrease&fluid links into limbs (edema)

&reduction in clotting factor &leads to blood. Other abnormalitiesmay also be detected

such as enzyme level, liver cell.

2) Ultrasonography.

3) Computerized tonography.

4) Magnetic resonance imaging technique .

gnu.i

nflibn

et.ac

.in

CHAPTER 3.INFLUENCING LIVER DISEASE WITH DIET (3)

Everything we eat, breathe and otherwise absorb is processed by the liver. By

purifying and transforming our food into substances fueling our body, the liver is

dependant on what we feed ourselves. In the face of liver disease, where liver

function is impaired, proper nutrition takes on increasing importance.

A balanced diet containing sufficient calories and an appropriate ratio of

carbohydrates, proteins and fats can assist a damaged or struggling liver to regenerate

new, healthy liver cells. The common liver disease, cirrhosis, refers to the

replacement of damaged liver cells by fibrous scar tissue. Fibrous scar tissue inhibits

the liver from performing its many varied, critical functions. Individuals with

cirrhosis typically experience weight loss, which is associated with either a decreased

intake of food, or a decreased ability to process food.

Protein and the Liver.

Protein in our diet comes from foods such as meat, fish, eggs, cheese, nuts and

dairy. Proteins typically provide the building blocks for the body to repair damaged

tissue. However, in the case of a severely damaged liver, ingested proteins may not be

properly processed, leaving excessive toxic waste circulating in the body. With any type

of liver disease, it is paramount to work closely with a healthcare physician to design a

customized nutritional plan.

According to the American Liver Foundation, adults with cirrhosis require a

balanced diet rich in protein, allowing liver cells to regenerate. However, too much

protein can have the opposite effect. According to Melissa Palmer, MD, author of Dr.

Melissa Palmer’s Guide to Hepatitis and Liver Disease, “If too much protein is

consumed and not enough carbohydrates, the liver will be forced to use protein as an

energy source. This is an unwise and inefficient use of protein, as protein will be diverted

from its primary job of building cells and tissues. Furthermore, this will put undo stress

on the liver, as it is more taxing for the liver to convert protein into energy than it is to

convert carbohydrates into energy.”

The Atkins diet is a popular weight-loss plan encouraging consumption of very

high amounts of protein and very low amounts of carbohydrates. Critics of the Atkins

diet emphasize the danger that a diet centered on protein can have on the body. High gn

u.infl

ibnet.

ac.in

protein intake can change the pH of the blood, making it very acidic. When the blood is

too acidic, the body goes into a state of ketosis, a life-threatening metabolic condition that

can seriously damage the liver. Because of the possible repercussions, a knowledgeable

physician must determine the amount of protein consumed by someone with impaired

liver function. Whether concerned with helping the liver regenerate healthy cells, or

preventing the dangerous condition of ketosis, those with liver disease should not leave

their protein consumption to chance.

Carbohydrates and the Liver.

Carbohydrates come from starch and sugar and are found in food such as bread,

potatoes, rice, pasta, cereals, fruit and sweets. The body breaks down carbohydrates into

glucose, and stores it in the liver as glycogen. Glycogen is essential for a steady supply of

energy, as it is released between meals when blood sugar levels drop. Therefore,

glycogen is the link connecting the liver with blood sugar regulation. According to

Palmer, “People with liver disease should strive for a diet consisting of approximately 60

to 70 percent carbohydrates, with complex carbohydrates predominating. For such

people, a well-balanced diet will include at least 400 grams of carbohydrates.” Most

experts agree that for optimal nutritional value, carbohydrates should be the main source

of calories for individuals with liver disease.

Fats and the Liver.

Fats in our diet come from many sources including butter, lard, and cream,

cooking oils, cheese, animal fats and many prepared foods. According to Palmer,

“Ideally, a person should aim for something in the neighborhood of 10 to 20 percent.

People who are overweight should aim for 10 percent. While it is important to eat as little

fat as possible, eating a small amount of the more healthy fats does have some benefit …

essential fatty acids, perform (as the name suggests) a variety of duties that are essential

to the proper functioning of the body.”Some people with liver disease have problems

digesting and absorbing fat. Individuals with this issue likely need to decrease their fat

intake and will be instructed by their physician to consume a certain type of fat more

easily absorbed by the body.

Conclusion. gnu.i

nflibn

et.ac

.in

Although liver disease is so prevalent in today‟s society, most people are unaware

of how influential food can be to our liver‟s health. While most authorities agree that

carbohydrates should be the most predominant part of a liver supportive diet, balanced

amounts of protein and fat are also crucial. Choosing the right balance of foods with your

physician will take your specific metabolism needs and liver health status into

consideration. When individuals with liver disease follow their advised nutritional

program, the support offered to their liver is unmatched by any modern medical

intervention.

3.1 Vitamins Suggested During Combination Therapy.(4)

A Japanese research study demonstrates benefits of Vitamin E and C supplementation

during combination therapy. These vitamins appear to protect cells from damage

typically incurred from conventional Hepatitis C therapy.In a study involving 30

patients with chronic hepatitis C who were receiving interferon-alpha-2b (IFN-alpha-

2b) and ribavirin combination therapy, daily supplementation with vitamin E (500

mg/day) and vitamin C (750 mg/day) was found to improve the fatty acid

composition of mononuclear cells. At baseline, all study subjects were found to have

a lower level of EPA (eicosapentaenoic acid) and a higher level of the molar ratio of

arachidonic acid to EPA in mononuclear cells, as well as a significant correlation

between the molar ratio and the level of serum alanine aminotransferase, as compared

with healthy volunteers. After intervention, subjects who did not receive nutritional

supplementation (the “non-vitamin group” - 16 subjects) experienced a significant

decrease in the EPA levels of mononuclear cells at 4 and 8 weeks into treatment,

while subjects who received vitamins E and C daily (the “vitamin group” - 14

subjects) maintained the EPA level of mononuclear cells. Both groups experienced a

significant decrease in serum levels of alanine aminotransferase two weeks into the

treatment. In addition, the “vitamin group” was found to have increased levels of

plasma and red blood cell alpha-tocopherol and plasma ascorbic acid levels. These

results suggest that patients with hepatitis C who are undergoing IFN-alpha-2b and

ribavirin therapy may benefit from supplementation with the antioxidant vitamins, E

and C, through their effect on maintaining the level of EPA in mononuclear cell

phospholipids. The authors hypothesize that the efficacy of IFN-alpha-2b and

ribavirin therapy might be further improved through oral supplementation with EPA..

gnu.i

nflibn

et.ac

.in

CHAPTER 4. HEPATOPROTECTIVE FACTORS IN DRUG-

INDUCED LIVER DISEASE(5)

Drug Induced liver disease (DILD) is a common cause of life-threatening, acute

liver failure and is a major reason drugs are removed from clinical development

and widespread use. Because of its idiosyncratic nature, accurate prediction of

which new drugs will cause DILD and who will be at risk for the development of

this disease is difficult. Likewise, the pathogenesis of DILD is complex and

appears to involve the formation of reactive drug metabolites that affect critical

biochemical functions or elicit an immune response. Recent studies, however,

have demonstrated that a deficiency of key protective factors in the liver – such

as anti-inflammatory cytokines and others – can lead to increased tissue

susceptibility to DILD, often through unchecked protoxicant activities. In this

regard, scientists tested the hypothesis that IL-13, an anti-inflammatory cytokine,

is another such factor. Administration of an IL-13 neutralizing antibody (NAb)

two hours before acetaminophen (APAP) treatment in wild-type (WT) mice

attenuated serum IL-13 concentration and significantly exacerbated liver injury

up to 24 hours after APAP administration. While the qualitative nature of the

resulting centrilobular lesions was similar, morphometric analysis revealed that

IL-13 NAb pretreatment significantly increased lesion area.

Moreover, APAP administration to IL-13 knockout (KO) mice confirmed the

protective role of IL-13 in APAP-induced liver injury. Serum TNF-?

Concentration was significantly elevated in APAP-treated IL-13 KO mice and in

WT mice co-administered with IL-13 NAb and then APAP. In contrast, no

differences were observed in protein adduct formation or detoxifying liver

glutathione levels between APAP-treated IL-13 deficient and WT mice. Taken

together, these results suggest that IL-13 is a critical hepatoprotective factor,

modulating the expression of protoxicant mediators but not APAP metabolism.

Further elucidation of the hepatoprotective role of IL-13 will be useful in better

understanding the mechanism and in facilitating the prediction of DILD gnu.i

nflibn

et.ac

.in

susceptibility, thereby preventing the removal of otherwise beneficial drugs from

the market.

Hepatotoxicity caused by drug-induced liver injury (DILI) is a dangerous and

increasing problem. It has become the leading cause of acute liver failure in the

United States, exceeding all other causes combined, including viral infections

and alcoholic liver disease. It is also a principal reason for withdrawing approved

drugs from the market. As toxicologists scientists work to prevent this by

detecting liver injury in animals during the pre-clinical and non-clinical phases of

new drug development. Yet those efforts sometimes fail.

It is a problem of the numbers that causes much difficulty. Serious DILI is

relatively uncommon or rare, thanks to your diligent work in excluding the really

toxic drugs. But it still occurs in some people, and when hundreds of thousands

or millions are exposed to a drug, even a few hundred cases of acute liver failure

may be unacceptable. Another problem of the numbers is that the rare,

idiosyncratically susceptible person may not be found in a controlled clinical

study even of several hundred patients (it takes about three times the inverse of

the incidence to have a 95% chance of finding at least one such person, i.e., if the

true incidence of the problem is 1 per 1,000 then 3,000 must be studied). Even

more numerical problems arise when we consider how to detect the liver injury

when it does happen. For rare events, a very sensitive test is not good enough,

and extraordinarily specific tests are needed to avoid being inundated with false-

positive results in those who do not have significant DILI.

Monitoring for detecting liver injury is usually not done as recommended, may

be unable to prevent serious damage even if done, and false positive test results

create excessive costs with little proved benefit. Even when liver injury is

detected, too often not enough information is gathered or reported to make

possible the exclusion of non-drug-related cause of the abnormalities seen, and

only a small fraction of the actual cases are reported at all to our adverse event

reporting system.

A drug-induced liver injury network of six medical centers has been established

and funded by the Liver Section of the National Institute for Diabetes and gnu.i

nflibn

et.ac

.in

Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health to

begin to address these problems.two things are needed to sharpen our methods

for detecting DILI, making accurate differential diagnosis and correct attribution

of causality as indeed drug-induced, and then to find ways to fund and carry

prospective safety studies to define true incidence of DILI in people exposed,

identify risk factors that make certain individuals more susceptible, and focus on

learning about the mechanisms by which injury occurs. We then can initiate

rational risk management procedures, and demonstrate their value by showing

quantitative reduction or elimination of the problems.

The hepatoprotective effect of a biflavonoid complex, kolaviron, and its fractions

from Garcinia kola seeds, together with the possible mechanisms involved was

investigated in mice intoxicated with a single dose of D-galactosamine (GalNH2).

Likewise, the ability of vitamin E to attenuate the toxicity was examined.

Kolaviron was separated by thin-layer chromatographic technique into three

fractions; Fraction I, Fraction II and Fraction III with RF values of 0.48, 0.71 and

0.76, respectively. Pretreatment with kolaviron, fraction I and fraction II at a dose

of 100 mg/kg for seven consecutive days before challenge with a single dose of

GalNH2 (800 mg/ kg) significantly (P<0.05) decreased serum alanine (ALT) and

aspartate (AST) aminotransferases by 67%, 70%, 71% and 39%, 35%, 46%,

respectively over GalNH2-only intoxicated mice.

gnu.i

nflibn

et.ac

.in

CHAPTER 5. HEPATIC SIDE EFFECTS OF ALLOPATHIC

DRUGS(6,7)

Dose Study of Acetaminophen -induced Hepatotoxicity (First Experiment)

In Figure 1and 2, the concentrations of circulating liver enzymes (AST and ALT)

over the course of one week following an oral challenge with varying acute doses of

acetaminophen. The doses at 0.5 and 1.0 g/kg produced no noticeable effects in

circulating enzyme concentrations. However, the 2.0 g/kg dose caused an immediate

significant elevation of both AST and ALT 24 h after injection. Although both enzymes

were still elevated compared to baseline 3 days after oral ingestion of acetaminophen, the

values did not attain statistical significance. At seven days, the values between the control

and test groups were essentially the same.

Effects of an Herb Formula on Acetaminophen-induced Hepatotoxicity In figure

3and 4, the enzymes AST and ALT were followed in a minimum of 10 rats in a control

and test group over 7 days after they had been given a dose of 2.0 mg/kg of

acetaminophen. Similar to the previous studies, rats receiving the single acute dose of

actaminophen showed a statistically significant elevation of the two enzymes. Those

receiving herb for one week prior and after the acetaminophen challenge showed little

change in AST concentrations. Consistent with the AST findings, elevations in ALT

levels were much less in the herb takers than the rats in the control group not taking herb.

Thus, the group of rats receiving the combination of herbs prior to and post

acetaminophen challenge showed a statistically significant lowering of the two enzymes

at both 24 and 72 h compared to the group receiving only the acetaminophen.Effects of

an Herb Formula on Alcohol-induced Hepatotoxicity Alone and Combined with

Acetaminophen.

In the fourth and last experiment, depicted in Figures 5 and 6, the group of 10 rats

receiving ethanol for one week compared to those gavaged with the same volume of

water in a similar manner showed a statistically significant elevation of both AST and

ALT. These alcohol-induced elevations in both enzymes were negated in alcoholic rats

concomitantly receiving the combinations of herbs (Fig. 5 and 6). In this same study, the

renal parameters, circulating blood urea nitrogen and creatinine, were also followed. No gnu.i

nflibn

et.ac

.in

statistically significant differences were seen among the three groups: the control group,

the group receiving alcohol alone, or those given the alcohol and receiving the herb

combination. The two groups of rats gavaged with alcohol for one week, both the

controls and those receiving the herbal combination, were also given acetaminophen (2.0

g/kg). Twenty-four hours later, the respective readings of AST and ALT in the rats given

only acetaminophen was 205 + 42 (SEM) and 92 + 19.1 (SEM) compared to the rats

given both acetaminophen and herbal combination, 114 + 20.8 (SEM) (P<0.05) and 69 +

11.9 (SEM). These values connoting injury from acetaminophen in the presence of oral

alcohol ingestion were somewhat less than seen in the previous studies.

Phytochemical products have been used for centuries to promote liver health. Although

the exact mechanisms behind this protection are uncertain, many theories have been

proposed. Oxidative stress plays a central role in most hepatocellular diseases and

hepatotoxicities. Many of the protective effects on the liver behind green tea and grape

seed extract are based on their antioxidant abilities. In studies involving the ability of

silibinin, a major constituent of silymarin, to scavenge reactive oxygen species, this

antioxidant was also shown to enhance intracellular levels of glutathione, thus enhancing

it ability to combat reactive oxygen species in liver. Additionally, a growing body of

evidence suggests that many non-nutrient phytochemicals exhibit biological activities

that are relevant to liver health and include properties in addition to antioxidant of

choleretic and cancer prevention, anti inflammation, as well as induction of enzymes

exhibiting detoxifying activity. Studies in rats indicate that silymarin increased biliary

excretion and, at the same time, increased the endogenous pool of bile salts (B-

muricholate and ursodeoxycholate)]. Both factors being potentially hepatoprotective.

gnu.i

nflibn

et.ac

.in

FIGURE 1:

Dose-dependent changes in AST (units/Liter) during the period of the experiment over 0-

7 days. Each data point represents average + S.E.M. See Materials and Methods section

for details.

Figure 2

Dose-dependent changes in ALT (units/Liter) during the period of the experiment

over 0-7days. Each data point represents average + S.E.M. See Materials and Methods

section for details.

gnu.i

nflibn

et.ac

.in

Figure 3 :

Changes in AST (units/Liter) in control and combination groups during the period

of the experiment over 0-7 days. Each data point represents average + S.E.M.

Figure 4

Changes in ALT (units/Liter) in control and combination groups during the period

of the experiment over 0-7 days. Each data point represents average + S.E.M.

gnu.i

nflibn

et.ac

.in

Figure 5

Estimate of AST (units/Liter) in control, alcohol, and alcohol plus drug treated

animals. Each data point represents average + S.E.M. See

Figure 6

Estimate of ALT (units/Liter) in control, alcohol, and alcohol plus drug treated animals.

Each data point represents average + S.E.M.

gnu.i

nflibn

et.ac

.in

CHAPTER 6. HERBALS IN HEPATOLOGY(8)

Medicinal herbs 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. A drug having

beneficial affect on the liver is known as hepatoprotective drug. On the other hand, drugs

having toxic affect on the liver are better known as hepatotoxic drugs. Clinical research

has also shown that herbals have genuine utility in the treatment of liver diseases.

6.1 Introduction

The liver performs number of important functions, including Bile production and

excretion, excretion of bilirubin (bile pigment), cholesterol (a form of fat), hormones, and

drugs. metabolism of fats, proteins, and carbohydrates, enzyme activation, storage of

glycogen (stored form of glucose), vitamins, and minerals, synthesis of plasma proteins,

such as albumin and globulin, and clotting factors and blood detoxification and

purification.

Some functions are not affected by any medicinal preparation to be much of therapeutic

value. Hepato-biliary drugs are used for increasing biliary secretions. These groups of

drugs are also known as cholagouges which are believed to increase the secretion of bile.

Precisely speaking, cholagouges help in better emptying out of the biliary tract rather

then increasing bile formation and emptying.

The main function of bile is stimulation of normal bile flow (also known as

choleresis). For achieving this affect, drugs derived from plant source are frequently used

and are popularly known as choleretics. Cholagouges hasten the gall-bladder emptying

whereas choleretics act specifically on liver. Bile is hurried down before it finds time to

be altered in the gut. This is affected by group of drugs known as cholagouge purgatives.

Silymarin is a potent hepatoprotecive drug having established place in hepatology

practice. Silymarin is a flavonol-lignan mixture obtained from seeds of Silybum

marianum. Silymarin is a mixture of silybin, isosilybin, silychristin and silydianin.

Research on Indian medicinal herbs like Picrorhiza kurroa (Kutki) and Andrographis

paniculata (kalmegh) has thrown light on hepatoptotective activity and it is more

promising than silymarin. gnu.i

nflibn

et.ac

.in

6.2 The hepatoprotective activity of the drug is said to be based on two

mechanisms(7)

1. The drug alters the structure of the outer membrane of the hepatocytes in such a way as

to prevent penetration of the liver toxin into the interior of the cell.

2. The drug stimulate the action of nucleolar polymerase A, resulting in ribosomal protein synthesis and, thus stimulates the

regenerative ability of the liver and formation of new hepatocytes.

6.3 Ayurveda and Liver.

Ayurveda is the oldest healthcare system. As far as diagnosis and treatment of

liver diseases is concerned, Ayurveda has its own concept. The three biological humors

(vata, pitta and kapha) are considered to play major role in pathogenesis as well as

treatment of all diseases. In Ayurveda, liver is known as ykritta. It has been described as

one of the chief organ of the human body. The major disease described in Ayurvedic

texts is Kamla, which is compared with jaundice.

According to Charka Samhita, Pandu (anemia) and kamla are related to each

other. In fact if a patient suffering from pandu keeps on consuming pitta aggravating

foods, the already disturbed pitta further affects blood and skin resulting in kamla. The

eyes, skin, mucus membrane and nails are yellow coloured. In addition the patient has

general debility, indigestion and anorexia.

Ayurvedic texts have described three types of kamla.

Kostha-ashrita: Kostha refers to the abdomen. Kamla confined to abdominal

cavity is known as kostha-ashrita kamla.

Shakha-ashrita: Shakha refers to arms and legs. Kamla appearing in extremities is

known as shakha-ashrita kamla.

Ubhya-ashrita: When kamla is found both in abdomen and extremities it is known

as ubhya-ashrita kamla.

Although the Ayurvedic texts have not described liver diseases in detail but still

number of formulations have been mentioned which have been used successfully by gnu.i

nflibn

et.ac

.in

practitioners of Ayurveda. These formulations are of diverse origin and may be derived

from plant source alone or herbs in combination with minerals. In following pages we

discussion on popular Ayurvedic medicinal herbs used in the treatment of liver diseases.

6.4.HERBALS/BOTANICALS AS HEPATOPROTECTIVE AGENTS(9-23)

Eclipta Alba

Eclipta Alba is popularly known as trailing eclipta. Eclipta Alba grows

wild in moist places or on the sides on the sides of water channels.

It contains resin, alkaloid (eclipticine), and Wedelolactone (C15H10O7).

Another alkaloid, 25-ß-hydroxyverazine has been reported from alcoholic

extract of the Eclipta

Saxena, Singh and Anand (1993) studied the hepatoprotective effect of

ethanol/ water (1:1) extract of Eclipta Alba in rats against carbon

tetrachloride induced hepatotoxicity. The researchers concluded that

Eclipta Alba prevented carbon tetrachloride induced hepatotoxicity by

regulating the levels of hepatic microsomal drug metabolizing enzymes.

Singh, Chandan, Agarwal and Anand (2001) studied in vivo

hepatoprotective activity of active fractions from ethanolic extract of

Eclipta Alba leaves.

The extract was further fractionized and agent with potent

hepatoprotecvtive activity was looked for. One fraction was containing

wedelolactone and other fraction was containing apigenin, 4-

hydroxybenzoic acid and protocatcheuic acid. The second fraction was

found to be more active hepatoprotective. Dixit and Achara studied the

hepatoprotective activity of Eclipta Alba in guinea pigs against carbon

tetrachloride induced hepatotoxicity. It was concluded that Eclipta Alba

has significant hepatoprotective activity against carbon tetrachloride

induced hepatotoxicity.

Picrorhiza kurroa Royle (Kutki)

Picrorhiza kurroa is a distinguished medicinal herb of Ayurveda. It has

been described under the group of bitter drugs. It is an established herbal gnu.i

nflibn

et.ac

.in

remedy for variety of disease ranging from indigestion to hepatitis.

Modern clinical studies have confirmed the efficacy and safety of

Picrorhiza kurroa for the treatment of liver disease. The roots and

rhizomes are used in medicinally important parts. Powder, decoction,

infusion, confection, and alcoholic extract of the drug are prescribed in

Ayurveda and Homeopathy.

The chemistry of Picrorhiza kurroa is complex. The active constituent is

known kutkin, a mixture of kutkoside and picroside.

Picrosides are iridoid glycosides and have been further divided

into picrosides I, II, and III. Other constituents are apocynin, andorsin, and

cucurbitacin glycosides. Pharmacologically, Kutkin (Picrosides and

kutkosides) has hepatoproptective activity. Apocynin is a potent NADPH

oxidase inhibitor and has anti-oxidant and anti-inflammatory activity.

Some herbalists have described Picrorhiza kurroa as liver herb. Today we

have estimated active constituents of the drug, which may be responsible

for the hepatoprotective activity of the drug. Most of the studies have

shown Picrorhiza kurroa extract (standardized to kutkin content) has

potential hepatoprotective activity as compared to placebo.

Kutkin from Picrorhiza kurroa has shown significant curative activity in

vitro in primary cultured rat hepatocytes against toxicity induced by

thioacetamide, galactosamine, and carbon tetrachloride. Liver injury was

induced in 16 mice by thrice-a-week injection of carbon tetrachloride for

nine weeks. Eight of them were given daily feeding of Picrorhiza kurroa

extract (12 mg/Kg) 10 days prior to carbon tetrachloride injection. Control

mice (n = 6) were injected with olive oil for the same period. Serum

markers of liver injury and histology of liver tissues were studied. Hepatic

glutathione, total thiol, glucose 6-phosphate dehydrogenase, catalase, lipid

peroxidation and plasma membrane-bound Na+/K+ ATPase were also

determined.

The extract of Picrorhiza kurroa appears to offer significant protection

against liver damage by carbon tetrachloride. In another study, the active gnu.i

nflibn

et.ac

.in

constituent of Picrorhiza kurroa showed a dose dependent

hepatoprotective activity against oxytetracycline induced hepatic damage

in rats.

Phyllanthus niruri Linn (Bhumyamla)

Phyllanthus niruri is well-known Ayurvedic pant used for its beneficial

effect in liver diseases. It is folk remedy for asthma, bronchitis, anemia,

jaundice and tuberculosis. Whole plant is used in medicine.

It contains lignans (phyllanthin and hyophyllanthin). Syamasundar,

Singh, Thakur, Huasin, Kiso and Hikino (1985) studied the

Hepatoprotective constituents of Phyllanthus niruri. They isolated

phyllanthin, hypophyllanthin and tricontanal from hexane extract of

Phyllanthus niruri.

All the three constituents demonstrated hepatoprotecvtive activity.

Phyllanthin and hypophyllanthin were active against carbon tetrachloride

and galactosamine induced hepatotoxicity whereas tricontanal was active

only against galactosamine induced hepatotoxicity.

Taraxacum officinale Wigg.

Taraxacum officinale is commonly known as dandelion, loin‟s teeth and

fairy clock. In Ayurveda, the plant is known as dugdhpheni as it abounds

in milky juice. The root of the medicinal plant is reputed remedy for liver

and gall bladder diseases in various systems of alternative medicine.

The medicinal plant contains rich amount of bitter principles including

taraxacin, taraxacerin and lactupicrin. It also contains triterpenoids

(taraxasterol and taraxerol), flavonoids and tetrahydrodetin B.

Animal research has given indication that Taraxacum officinale has no

effect on bile flow. According to European Scientific Cooperation of

Phytotherapy T. officinale has demonstrated cholretic effect in dogs and

rats. However human trials indicating definite use of the drug in liver

diseases are missing.

Cichorium intybus Linn gnu.i

nflibn

et.ac

.in

Cichorium intybus, member of family Compositae and leaves of the plants

are used as salad.

It contains bitter principles (Cichorin, lactucin and intybin). In addition it

contains inulin. Kalanatri and Rastmanesh from Ahwaz University of

Medical Science, Iran studied the hepatoprotective potential of crude

extract of Cichorium intybus.

The extract was administered at doses of 25mg/kg, 50mg/kg, 75 mg/kg, 100

mg/kg, 125 mg/kg and 150 mg/kg orally to the mice. The extract

demonstrated hepatoprotective effect at a dose of 75mg/kg and carbon

tetrachloride elevated liver enzymes were significantly reduced as

compared to control group. The drug also showed liver tissue regenerating

capacity.

Tephrosia purpurea Pers

Tephrosia purpurea is commonly known as Wild Indigo. In Ayurveda, it

is known as Sharpunkha, as the tip of the leaves are pointed. In Ayurveda,

the drug is especially indicated in the treatment of enlarged spleen but

animal research has demonstrated Tephrosia purpurea to be

hepatoprotective. Root and alkali preparation (Sharpunkha-kshara) are

used in medicine.

It contains bioflavonoids including rutin, rotenoid and tephrosin.

Ramamurthy and Srinivisan (1993) studied the hepatoprotective effect of

Tephrosia purpurea against galactosamine and carbon tetrachloride

induced liver damage in experimental animals. Powder of aerial parts was

administered orally at a dose of 500 mg/kg. Tephrosia purpurea inhibited

the rise of SGOT, SGPT and bilirubin. The drug also demonstrated liver

tissue regenerating capacity as evident by histopatahological changes.

Thus the authors concluded the drug to be effective in acute and chronic

hepatotoxicity and the action may be due to membrane stabilizing effect

on liver cells.

Solanum nigrum Linn gnu.i

nflibn

et.ac

.in

In Ayurveda the plant is known as Kakamachi. Solanum nigrum is a small

herb growing in waste and shady places. Whole plant and berries are used

in medicine.

The fruit contains four glyco-alklaoids including Solamargine, solasonine

or solanine and solanigrine. Solamargine and solasonine are present in

leaves also.

Sultana, Perwaiz, Iqbal and Athar (1995) demonstrated the antioxidant

activity of crude extract of Solanum nigrum and Cichorium intybus. The

drugs inhibited the free radical mediated DNA damage. According to

Authors, free radical scavenging activity of Solanum nigrum and

Cichorium intybus may account for there hepatoprotective activity.

Raju, Anbuganpathi, Gokulakrishan, Rajkapoor, Jayakar and Manian

(2003) studied the hepatoprotective effect of ethnaolic extract of Solanum

nigrum against carbon tetrachloride induced hepatotoxicity. They

evaluated the effect by studying biochemical and histopatalogical

parameters. According to authors the extract demonstrated significant

hepatoprotective effect.

Andrographis paniculata Nees

Andrographis paniculata is well known medicinal plant for its usefulness

in liver diseases. In Ayurveda it is known as Bhunimba or Kalmegha. It is

used as bitter tonic and febrifuge. Because of bitter taste it is popularly

known king of bitters.

It contains diterpene lactones (Andrographolide, neoandrographolide and

kalmeghin).

Shukla, Visen, Patnaik and Dhawan (1992) studied the cholretic activity of

Androgrpaholide. The diterpene lactone produced dose dependent

chloretic effect evidenced by increase in bile flow, bile salt and bile acids

in animal models. The cholretic effect of Andrographis paniculata was

found to be better than silymarin. According to Trivedi and Rawal (2001),

alcoholic extract of Andrographis paniculata demonstrated significant

hepatoprotective activity against carbon tetrachloride induced gnu.i

nflibn

et.ac

.in

hepatotoxicity. The fact was further supported at morphological,

biochemical and functional parameters.

Boerhaavia diffusa Linn.

In Ayurveda it is known as Punarnava and commonly known as spreading

hogweed.

It is found throughout India. In India the roots of the plant find

application in Ayurvedic prescriptions for liver and gall bladder dieses.

However its specific use in Ayurveda is as diuretic.

It contains an alkaloid punarnavine. Chandan, Sharma and Anand (1991)

reported hepatoprotective activity of alcoholic extract of B. diffusa against

carbon tetrachloride induced hepatotoxicity in animal models.

The extract demonstrated significant cholretic activity. Rawat, Mehrotra,

Tripathi and Shome (1997) studied the hepatoprotective activity of roots

and aqueous extract in thioacetamide intoxicated rats. The aqueous extract

demonstrated significant hepatoprotective activity as compared to root

powder.

Curcuma longa Linn.

Curcuma longa commonly known as turmeric is another plant which has

got scientists attention as novel hepatoprotective agent. Dried rhizomes are

used in medicine. It is cultivated throughout India. In Ayurveda, paste of

the drug is applied over the right hypochondriac region for the treatment

of enlarged liver. Above all the use of drug in the treatment of jaundice is

mentioned.

It contains yellow coloured coloring matter called curcumin.

Curcuminoids have shown to be antioxidant and anti-inflammatory

activities. Hepatoprotective activity can be ascribed to antioxidant activity.

Glychyrrhiza glabra Linn.

Glychyrrhiza glabra is popularly known as licorice. In Ayurveda, it is

known as Yastimadhu which signifies sweet taste of the drug. The roots

are used in medicine. gnu.i

nflibn

et.ac

.in

It contains glycosides including glychyrrhizin, glycyramarin, isoliquiritin

and isoliquiritin. Glychyrrhizin is the sweet principle of licorice and is

fifty times sweeter than sugar. Other components include asparagine, resin

and estrogen steroid.Glychyrrhizin is anti viral, anti-inflammatory and

anti-allergic. Recent work in Japan has thrown light on hepatoprotective

activity of licorice. Glycyrrhizin has demonstrated hepatoprotective

activity in animal models against carbon tetrachloride induced toxicity. It

reduces alanine transaminase and aspartate transaminase values in serum.

The exact mode of action is not clear but it has been proposed that

glycyrrhizin has inhibitory effect on immune mediated cytotoxicity against

hepatocytes and on nuclear factor (NF)-kappa B, which activates genes

encoding inflammatory cytokines in the liver.

Berberis aristata DC

Berberis aristata, commonly known as Indian Barberry is important

medicinal plant of Ayurveda and Western herbal medicine. In Ayurveda it

is known as Daruharidra. Rasaut is semisolid watery extract obtained from

Berberis aristata. The plant is used as hepatic stimulant and chalogouge.

Chemically it contains alkaloids (berberine, berbamine and oxycanthine),

tannins, gum and resin.

Sida rhombifolia Linn

Sida rhombifolia (Atibala) is one of the five plants described under „Bala‟

drug of Ayurveda. It is commonly known as Alkali Traditionally it used as

antirheumatic, astringent and demulcent. It is reported to contain an

alkaloid (ephedrine) and mucilage.

Rao and Mishra (1997) studied the hepatoprotective and anti-

inflammatory activity of various parts and aqueous extract of Sida gnu.i

nflibn

et.ac

.in

rhombifolia. The animals were rendered hepatotoxic by treatment with

carbon tetrachloride, paracetamol and rifampicin. Inflammation was

induced by carrageenan. The aerial parts and there aqueous extract

demonstrated significant hepatoprotective activity whereas methanolic

extract of aerial parts demonstrated significant anti-inflammatory activity.

It was concluded that hepatoprotevtive activity of the drug can de due to

free radical scavenging activity.

Swertia chirata Ham.

Swertia chirata is known as Kiratatikta in Ayurveda. The infusion was

once a time a popular remedy for convalescence from a severe illness. It is

also used in the treatment of loss of appetite. Whole plant is used in

medicine.

It contains bitter glycosides including amarogentin and gentiopicrin and

xanthones. Mukherjee, Sur and Maiti (1997) reported hepatoprotective

activity of Swertia chirata in rats.

Emblica officinalis Gaertn

Emblica officinalis, commonly known as Indian Gooseberry or Emblic

myrobalan. It is important ingredient of Triphala, famous Ayurvedic

remedy for constipation.

Fruits are used in medicine. Emblica officinalis is considered to the best

source of Ascorbic acid (vitamin C). In addition, it contains gallic acid,

tannic acid, albumin and calcium. The bark contains leukodelphinidin and

procyanidin. The fruit contains alkaloids phyllantidine and phyllanthine.

Aqueous extract of Emblica officinalis has significant antioxidant and

hepatoprotective activity. The extract was found to be potent inhibitor of

lipid peroxide formation of scavenger of hydroxyl and super oxide

radicals.

Spirulina platensis

Spirulina is a blue green alga growing in fresh water. Spirulina is widely

prescribed in anemia. It has curative effect on inflammatory disease of

liver and pancreas. gnu.i

nflibn

et.ac

.in

It contains vitamins A, C, E and B-complex, β-carotene and

polyunsaturated fatty acids. Vadiraja, Gaikwad and Madyastha (1998)

studied the effect of C-phycocyanin on carbon tetrachloride and R-(+) -

pulegone induced liver damage.

Intraperitoneal administration of single dose of phycocyanin in a dose of

200mg/kg one to three hours prior to carbon tetrachloride and R-(+) -

pulegone, demonstrated significant hepatoprotective activity.

Eucalyptus terelicomis

Ursolic acid isolated from leaves of Eucalyptus terelicomis demonstrated

hepatoprotective effect against thiacetamide, galactosamine and carbon

tetrachloride in rats. Pretreatment with ursolic acid increased the viability

of liver cells. In large doses, ursolic acid demonstrated choleretic effect.

Further the authors concluded that hepatoprotective activity of ursolic

acid was comparable to silymarin. In Ayurveda it is used in the treatment

of enlarged spleen, hence the name plihaghana (pliha = spleen). It is also

prescribed in liver diseases. Rohitkarishta is formulation based on the

plant.

Achyranthes aspera Linn

Achyranthes aspera is small herb which grows all over India. In

Ayurveda, it is also own as Apamarga. In English it is known as Prickly

chaff flower.

In traditional medicine, it is popular remedy for bronchitis and asthma.

Decoction of the herb is said to be diuretic. Whole herb and alkali

prepared from the herb (Apamargakshara) are used in enlarged liver.

Taraxacum officinale

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 roots of the plant have the

most activity regarding the liver and gallbladder. Oral administration of gnu.i

nflibn

et.ac

.in

extracts from the roots of Taraxacum officinale has been shown to act as a

cholagogue, increasing the flow of bile.

Bitter constituents like taraxecerin and taraxcin are active constituents of

the medicinal herb.

Cichorium intybus

Cichorium intybus is a popular Ayurvedic remedy 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.9 In preclinical studies an alcoholic extract of the

Cichorium intybus was found to be effective against chlorpromazine-

induced hepatic damage in adult albino rats.

A bitter glucoside, Cichorin (C32H34O19) has been reported to be the

active constituent of the herb.

Solanum nigrum

In Ayurveda, the drug is known as kakamachi. 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.

Glychyrrhiza glabra

Glychyrrhiza glabra, commonly known as licorice contains triterpene

saponin, known as glycyrrhizin, which has potential hepatotprotective

activity.

It belongs to a group of compounds known as sulfated polysaccharides.

Several studies carried out by Japanese researchers have shown

glycyrrhizin to be for anti-viral and 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 gnu.i

nflibn

et.ac

.in

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 have been studied on free

radical generation and lipid peroxidation in primary cultured rat

hepatocytes.

Wilkstroemia indica

W. indica is a Chinese herb and has been evaluated in patients suffering from

hepatitis B.

A dicoumarin, daphnoretin is the active constituent of the herb. The drug has

shown to suppress HbsAG in Hep3B cells. It is said to activator of protein kinase

C.

Curcuma longa

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, and

paracetamol. Diarylhepatonoids including Curcumin is the active constituent of

the plant.

Tephrosia purpurea

In Ayurveda, the plant is known as sharpunkha. 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.

The roots, leaves and seeds contain tephrosin, deguelin and quercetin. The

hepatotprotective constituent of the drug is still to be proved.

gnu.i

nflibn

et.ac

.in

6.5. MEDICINAL PLANTS WITH HEPATOPROTECTIVE PROPERTISE(24)

Plant name Parts used Chemical

constituent

Pharmacological

Activity

Acacia

catechu

(mimosacea

e)

Katha

Heart wood

of 20-

30years old

plants

Cyanidanol(+)has

been isolated from

the plant

Hepatoprotective

activity against ccl4

induced hepatic injury

was found.

Andrograph

is

Paniculata(a

canthaceae)

Leaves Andrographin,panicol

in,apigenin,neoandro

grapholide

Andrographolide &

neoandrographolide

possess

hepatoprotective

activity

Allium

sativum

(liliaceae)

Garlic,lasan

Bulbs Allin &

cyanidanol(+)has

been isolated from

the plant

Hepatoprotective

activity against ccl4

induced hepatic injury

was found.

Boerhaavia

diffusa(nyct

aginacea)pu

narnava,hog

weed

Roots and

aerial parts

Retinoid,steroid,flavo

ne,punarnavin,ursolic

acid

Chloroform and

methanolic extracts of

root showes

Hepatoprotective

activity against ccl4

induced hepatic injury

was found.

Baccharies Phalloidin,a The active compound gnu.i

nflibn

et.ac

.in

trimera

(asteraceae)

flavonoid compound

has been isolated

phalloidin possess

hepatoprotective

activity

Artemisia

capillaries

(astereceae)

Bulbs Capparism,axcapillin,

quercetin

Cytotoxicity in primary

cultured hepatosides

Boerhavia

repanda

(nyctaginac

eae)

Roots By the hydrolysis

produce

glucose,xylose,arabin

ose and glucoprotein

In rats

galactosamine,paraceta

mol,chloroform shows

Hepatoprotective

activity against ccl4

induced hepatic injury

was found.

Butea

monosperm

a(kuntze)

Fresh juice

and gum

from stem

Isobutrin,butrin,paloa

onin,coreopsin,jalaric

ester ,α-amyrin,β-

sitostrerol

Hepatoprotective effect

has been reported in

isobutrin,butrin and

two flavonoids isolated

from flowers,(s)-

ginsenoside,(r)-

ginsenoside used

against ccl4 induced

cytotoxity

Calotropis

gigantean(as

clepiadacea

e)madar

Flowers Latex,caoutchoue,coa

gulam,resins,α-

calotropeol

The ethanolic extract

shows

Hepatoprotective

activity against ccl4

induced hepatic injury

was found.

Canscora

decussate(g

Whole

plants

Mangiferin,xanthone,

canscoradione,sitoste

Mangiferin shows

Hepatoprotective gnu.i

nflibn

et.ac

.in

entianaceae)

shankpushpi

rol,campesterol activity against ccl4

induced hepatic injury

was found.

Dianthus

superbus

(caryophylla

ceae)

Whole

plants

D-lanoside,‟H‟,

‟F‟,‟E‟,‟D‟ isolated

from the plant

D-lanoside,‟H‟,

‟F‟,‟E‟,‟D‟ isolated

shows

Hepatoprotective

activity

Cichorium

intybus(aste

raceae)kasa

ni

Root Quercitrin,apigenim,h

yperin,decaffeoylter

acid

Dried root is used in

homoeopathy for liver

diseases

Curcuma

domestica

(zingiberace

ae)turmeric

Rhizo mes. Butrin,isobutrin,jalari

c ester 1.2%

Ethanolic extract of

rhizomes shows

Hepatoprotective

activity against ccl4

induced hepatic injury

was found.

Euphorbia

nematocyph

a(euphorbia

ceae)

Whole plant Brevifolium

hyperin,ellagic

acid,di-methyl ellagic

acid

Hepatoprotective

activity of this

compound has been

ascribed to their

antioxidative effect.

Cynara

scolymus

(asteraceae)

hathichak

Whole plant Cymarine,cynaropicri

n,grosheimin,acrylic

acid,taraxasterol,cyna

rogenin,cynarin

Hepatoprotective

activity against ccl4

and gal=N induced

hepatic injury was

found.

gnu.i

nflibn

et.ac

.in

Emblica

officinalis(e

uphorbiacea

)

Fruits Phyllembin obtain

from fruit. Seed fat

contained linolic

acid(64.8%) and

closely resembled

linseed oil from

fruits.

Aqueous extract of fruit

can prevent toxic effect

of lead nitrate and

alluminium sulphate on

liver parenchyma cells

Fructus

schizandrac

Fruits Lignans belonging to

dibenzocyloctno

group isolated from

the alcoholic extract

of kernels of the

plant.

Hepatoprotective

activity of this

compound has been

reported from the

kernels of the plant

Garcinia

kola

(clusiaceae)

Whole

plants

Kolaviron,a mixure

of bioflavonoids and

kolaflavanone,β-

sitosterol,stearic,palm

itic,myristic and oleic

acid.

Kolaviron to produce

hepatoprotective effect

against ccl4 induced

liver injury.

Garcinia

mangostana

(clusiaceae)

Fruits Three new xanthones

gartanin,8-

deoxygartamin and

normangostin were

isolated from fruits.

Fruits are used in

chronic diarrhea and

dysentery. It has

possesses

hepatoprotective

activity.

Gymnospori

a

Montana(rot

h)

Leaves Tingenone,3-O acetyl

oleanoliic acid,

Hexacosane,betulin,β

-sitosterol isolated

from steam bark,root

bark and leaves.

Methanolic extract of

leaf of plant produced

significant reversal of

majority of the altered

biochemical parameters

studied and gnu.i

nflibn

et.ac

.in

histopathological

studies confirmed the

presence of significant

hepatoprotective

activity.

Liquidamba

r

formaosana(

hamamelida

ceae)

Fruits Betulinic acid has

been isolated from

fruit of plant

hepatoprotective

activity has been

reported in betulonic

acid.

Hypoestes

triflora(acan

thaceae)

Leaves Benzoic acid. Duration of barbiturate

sleep indication

presence of

hepatoprotective

activity. This activity is

reported to benzoic

acid. It prevented ccl4

induced elevation in

transaminase activity in

mice.

Indigofera

tinctoria(fab

aceae)

Aerial plant Analysis of the leaves

give the following

values:

nitrogen(5.11%),phos

phoric

acid(0.18%),potash(1

.67%)and lime

(5.35%)

The extract was found

to afford significant

protection to mice. Rats

and rabbits against ccl4

induced hepatic injury.

It was also found to

increase liver weight

and bile flow in rats

indicating microsomal

enzyme induction.

Lawsonia Barks Two new xanthones- hepatoprotective gnu.i

nflibn

et.ac

.in

alba

(lythraceae)

laxanthones 1 and 2

isolated characterized

as 1,3dihydroxy 6,7

dimethoxy-xanthone

and 1-hydroxy-3,6-

diacetoxy-7-methoxy

xanthone

respectively.

activity has been

reported in ethanol

water extract of the

bark against CCL4

induced liver toxicity .

Nymphaea

stellata

(nymphaeac

eae)

Whole plant Proteins (14.56 %);

carbohydrates

(67.4%)

Petroleum ether extract

was found to promote

parenchyma tissue

regeneration.

Ocimum

sanctum

(lamiaceae)

Leaves Ursolic acid,

apigenin, luteolin,

apigenin-7-O-

glucuronide,

Extract protected rats

against CCL4 induced

liver injury.

Picrorrhiza

kurroa

(scrophulari

aceae)

Roots Picrolin is mixture of

picroside 1 and

kutliside in the ratio

of 1:1.5 has been

obtain from root of

plant. Picroside 2

isolated and

characterized as 6‟-

(4-hydroxy-3-

methoxy cinnamoyl

catalpol)

hepatoprotective

activity in picroline, a

standardized fraction of

root containing 60% of

mixture of picroside 1

and kutkoside in which

shows action against

toxicity of CCL4

Tinospora

cordifolia(m

enispermace

ae)

Dry stems

with barks

Two bitter

substances,substance

A(C22H34O10,

5H2O)substances B.

Biochemical,morpholo

gical and

histopathological

parameters have been gnu.i

nflibn

et.ac

.in

giloin,gilenin were

isolated.

evaluated from the

decoction of the plant

and hepatoprotective

activity.

gnu.i

nflibn

et.ac

.in

CHAPTER 7. LIVER DISORDERS AND TREATMENTS.

7.1 Milk Thistle Extract and Its Effect on Liver Fibrosis(25)

Regardless of its cause, the progression of liver disease is typically measured by the

suppleness, and in turn, the functionality of the liver. Recent studies demonstrate the

ability of the milk thistle extract, Silybin Phytosome®, to inhibit the hardening of

liver tissue.

Some types of liver disease respond well to prescribed therapy, while others take

on a chronic status. In addition to addressing the underlying cause of dysfunction, these

chronic liver diseases require vigilance to support liver tissue health. While each disease

has a preferred conventional treatment standard, an increasing number of clinicians are

predominantly concerned with fibrosis prevention.

According to the Merck Manual, Fibrosis is an accumulation of fibrous tissue in

the liver resulting from an imbalance between production and degradation of the

extracellular matrix, and accentuated by the collapse and condensation of preexisting

fibers. In more general terms, fibrosis is the hardening of liver tissue, occurring when the

liver is impaired and thus, unable to break down fibrous material.

The liver is touted as the most dynamic organ in the body. This title is not only a

result of the numerous functions for which it is responsible, but also for its self-

restorative capability. The liver is the only organ capable of regenerating parts of it to

repair any sustained damage.

Helping maintain the liver‟s texture is akin to supporting this organ‟s health. To

prevent or inhibit fibrosis, all individuals with liver disease would benefit from an

accelerated regeneration of damaged liver tissue.

Milk thistle is a flower, a member of the aster family. Its seeds and roots have

been used for an assortment of medical purposes for thousands of years. Three

biochemicals have been isolated from the milk thistle: silychristine, silydianin, and

silybin. The mixture of these three substances is called “silymarin.”

Silymarin traditionally has been used in the treatment of liver disease and, while it

has recently been advocated for use in pets, most of the information available about it

concerns human use. The biological mechanism of action of milk thistle is unknown. The

National Institutes of Health have a keen interest in studying the potential benefits of gnu.i

nflibn

et.ac

.in

silymarin on the liver. In the article that follows, published in the July 2005 issue of

Hepatology, J H Hoofnagle, MD, of the Institute of Diabetes and Digestive and Kidney

Diseases (NIDDK) writes about the NIH-initiated effort to conduct the first

scientifically rigorous study of silymarin.

Milk thistle has been used for centuries to treat acute and chronic liver diseases

and, even today, is one of the most widely used herbal medications. Its active ingredients

appear to be several closely related flavinoids, collectively known as silymarin. Most

silymarin preparations have at least a dozen molecular components and their isomers,

including silybin, isosilybin, cis-silybin, silydianin, and silychristine. It is not clear

whether one, several, or all of these components are the active ingredient(s), and most

commercial preparations represent rough extracts of the milk thistle plant (Silybum

Marianum) rather than a purified subcomponent.

Results of studies in experimental animal models suggest that silymarin has a

broad spectrum of hepatoprotective effects. Thus, silymarin can protect experimental

animals against injury from several toxins, including amanita phalloides, carbon

tetrachloride, ethanol, and galactosamine. Silymarin is partially protective even when

given after exposure.

7.2 Liver Cirrhosis and treatment (26,27)

The liver is a marvelously sophisticated chemical laboratory, capable of carrying

out thousands of chemical transformations on which the body depends. The liver

produces important chemicals from scratch, modifies others to allow the body to use

them better, and neutralizes an enormous range of toxins. Without a functioning liver,

you can't live for very long.

Unfortunately, a number of influences can severely damage the liver. Alcoholism

is the most common. Alcohol is a powerful liver toxin that harms the liver in three stages:

alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Although the first two

stages of injury are usually reversible, alcoholic cirrhosis is not. Generally, more than 10

years of heavy alcohol abuse is required to cause liver cirrhosis. Other causes include

hepatitis C infection, primary biliary cirrhosis, and liver damage caused by occupational

drugs.

7.3 SAMe:may improve survival in liver cirrhosis (28,29)

gnu.i

nflibn

et.ac

.in

Individuals with liver cirrhosis have difficulty synthesizing the substance SAMe

(S-adenosylmethionine) from the amino acid methionine. For this reason, supplemental

SAMe (best known as a treatment for depression and osteoarthritis) has been tried as a

treatment for cirrhosis. However, as yet the evidence that it works is not strong.

A 2-year, double-blind, placebo-controlled trial followed 117 people with

alcoholic liver cirrhosis. Overall, those given SAMe didn't do significantly better than

those given placebo. However, when the results were reevaluated to eliminate individuals

with severe liver cirrhosis, a significant reduction in mortality and liver transplantation

was seen with SAMe.

SAMe has also shown a bit of promise for primary biliary cirrhosis, though evidence is

not consistent.

7.4 BCAAs: Might Be Helpful for Hepatic Encephalopathy(30)

In advanced liver cirrhosis, individuals experience severe mental confusion and

may slip into a coma. This condition is called hepatic encephalopathy. One of the primary

causes of hepatic encephalopathy is excessive ammonia levels in the body.

There is some reason to believe that special amino acids called BCAAs

(branched-chain amino acids) might be helpful for individuals with hepatic

encephalopathy, based on how they are metabolized in the body. However, the evidence

that BCAAs actually help is not yet conclusive. Furthermore, individuals with cirrhosis of

the liver should not increase amino acid or protein intake except under physician

supervision.

7.5 OPCs: Might Help Prevent Internal Bleeding(31)

Individuals with cirrhosis are susceptible to internal bleeding. Highly preliminary

evidence suggests that OPCs (oligomeric proanthocyanidins) might help prevent this

problem.

OPCs are best documented as a treatment for venous insufficiency (closely related

to varicose veins), where they are thought to work in part by stabilizing blood vessels.

7.6 Other Natural Treatments That Might Help (32,33,34)

One small study suggests that the supplement carnitine might be helpful for

people with hepatic encephalopathy.The amino acid taurine might help reduce muscle

cramps in individuals with cirrhosis. (However, see warning in the BCAA section.) gnu.i

nflibn

et.ac

.in

One study suggests that protein from vegetable sources might be preferable to

protein from animal sources for people with liver cirrhosis, presumably due to differences

in amino acid content.

Preliminary evidence from animal studies suggests that the supplement

phosphatidylcholine might help prevent alcoholic liver cirrhosis. The supplement

ornithine alpha-ketoglutarate (OKG) has shown promise for treating hepatic

encephalopathy, a life-threatening complication of cirrhosis.Vitamin K has shown a bit of

promise for helping prevent liver cancer in people with cirrhosis of the liver.

An Ayurvedic herbal combination has been studied for the treatment of cirrhosis,

but current evidence supporting its use remains incomplete and

contradictory.Antioxidants have been proposed for the treatment of primary biliary

cirrhosis, based on the theory that free radicals play a role in the disease process.

However, despite apparent promise seen in open trials, a double-blind, placebo-controlled

study of 61 subjects failed to find that combination of vitamins A, C and E, selenium,

methionine and CoQ10 produced any benefit in terms of fatigue or other liver related

symptoms.

The bones of individuals with biliary cirrhosis often become thin. Taking calcium

and vitamin D supplements might help. Antioxidants such as vitamin C, vitamin E, and

lipoic acid have been tried for biliary cirrhosis, with promising results in very preliminary

trials.

7.7 Herbs and Supplements to Use Only with Caution (35,36)

Many natural products have the capacity to harm the liver. Furthermore, because

of the generally inadequate regulation of dietary supplements that exists at the time of

this writing, there are real risks that herbal products, at the least, may contain liver-toxic

contaminants even if the actual herbs listed on the label are safe. For this reason, it is

recommended that people with liver disease do not use any medicinal herbs except under

the supervision of a physician.

Vitamin A and beta-carotene supplements might cause alcoholic liver disease to

develop more rapidly. gnu.i

nflibn

et.ac

.in

All forms of vitamin B3 may damage the liver when taken in high doses, including niacin,

niacinamide (nicotinamide), and inositol hexaniacinate. (Nutritional supplementation at

the standard daily requirement level should not cause a problem.

A great many herbs and supplements have known or suspected liver-toxic

properties, including but not limited to barberry, borage, chaparral, coltsfoot, comfrey,

germander, germanium (a mineral), greater celandine, certain green tea extracts, kava,

kombucha, mistletoe, pennyroyal, poke root, sassafras, and various herbs and minerals

used in traditional Chinese herbal medicine. In addition, herbs that are not liver-toxic in

themselves are sometimes adulterated with other herbs of similar appearance that are

accidentally harvested in a misapprehension of their identity (for example, germander

found in skullcap products). Furthermore, blue-green algae species such as spirulina may

at times be contaminated with liver-toxic substances called microcystins, for which no

highest safe level is known. Some articles claim that the herb echinacea is potentially

liver-toxic, but this concern appears to have been based on a misunderstanding of its

constituents. Echinacea contains substances in the pyrrolizidine alkaloid family.

However, while many pyrrolizidine alkaloids are liver-toxic, those found in echifnacea

are not believed to have that property.

Whole valerian contains liver-toxic substances called valepotriates; however,

valepotriates are thought to be absent from most commercial valerian products, and case

reports suggest that even very high doses of valerian do not harm the liver.

gnu.i

nflibn

et.ac

.in

CHAPTER 8. SCINTIFIC RESEARCH OF VARIOUSE

HEPATOPROTECTIVE DRUGS.

(1)The hepatoprotective effect of calcium channel blockers (37)

The aim of this study was to investigate the effects of calcium channel blockers

on tertbutyl hydroperoxide (TBH) induced liver injury using isolated perfused rat

hepatocytes. Rat hepatocytes were immobilized in agarose threads and perfused with

Williams E medium. Hepatocyte injury was induced by the addition of tertbutyl

hydroperoxide (1 mM) to the perfusion medium 30 min after the addition of either

verapamil or diltiazim. Hepatocyte injury was observed by monitoring the functional and

metabolic competence of hepatocytes or by ultrastructural morphological examination of

hepatocytes. Verapamil (0.5 mM) reduced lactate dehydrogenase leakage in TBH-injured

hepatocytes as compared to the controls (154± 11 % vs. 247± 30 %). Lipid peroxides

production was reduced after verapamil pretreatment as compared to the controls and

oxygen consumption was increased by pretreatment of hepatocytes with verapamil.

Verapamil pretreatment increased the protein synthesis activity at both levels of granular

endoplasmic reticulum and free polysomes in cytoplasm and decreased ATPase activity.

Diltiazem was qualitatively effective as verapamil. It is concluded that in hepatocyte

oxidative injury, calcium channel blockers exhibited hepatoprotective properties. The

hepatoprotective effect of calcium channel blockers was accompanied by a decrease in

ATPase activity, which may implicate a normalization of Ca2+

i after TBH intoxication.

(2) Picrorhiza kurroa (38,39)

Picrorhiza kurroa (Pk), a known hepatoprotective plant, was studied in

experimental and clinical situtations. The standardization of active principles--Picroside 1

and 2 was done with High Performance Liquid Chromatography. Picroside 1 ranged from

2.72 to 2.88 mg/capsule and picroside 2 from 5.50 to 6.00 mg/capsule. In the

galactosamine-induced liver injury in rats, Pk at a dose of 200 mg/kg p.o. showed a

significant reduction (p < 0.05) in liver lipid content, GOT and GPT. In a randomised,

double-blind placebo controlled trial in patients diagnosed to have acute viral hepatitis

(HBsAg negative), Pk root powder 375 mg three times a day was given for 2 weeks (n =

15) or a matching placebo (n = 18) was given. Difference in values of bilirubin, SGOT

and SGPT was significant between placebo and Pk groups. The time in days required for gnu.i

nflibn

et.ac

.in

total serum bilirubin to drop to average value of 2.5 mg% was 75.9 days in placebo as

against 27.44 days in Pk group. The present study has shown a biological plausability of

efficacy of Pk as supported by clinical trial in viral hepatitis, hepatoprotection in animal

model and an approach for standardizing extracts based on picroside content

(3) Silymarin (40,41)

Silymarin, a compound in milk thistle (Silybum marianum), reduces the cellular

absorption of xenobiotics; inhibits leukotriene B4 formation, thus acting as an

hepatoprotective agent; has antioxidant and free radical–scavenging properties; increases

the expression of superoxide dismutase by lymphocytes; exerts anticarcinogenic and anti-

inflammatory effects by inhibiting the activation of nuclear factor kappa B; and reduces

the injury to kidney cells induced by paracetamol, cisplatin, or vincristine in vitro. At

high concentrations it also reduces the cytotoxicity of methotrexate that is enhanced by

concomitant ethanol or acetaminophen administration. In patients with alcohol-induced

liver disease, silymarin decreased levels of the hepatic enzymes alanine amino

transferase.

(4) Curcuma longa (42)

Curcuma longa, or turmeric, has been shown to be hepatoprotective in animal and

in vitro studies. It contains several antioxidant compounds, the most potent of which is

curcumin. Turmeric increases levels of superoxide dismutase, catalase, and glutathione

peroxidase; it also increases the activity of glutathione S-transferase, promoting

detoxification. By inhibiting production of arachidonic acid, it has anti-inflammatory

activity; it has been found to be as effective when taken orally as cortisone or

phenylbutazone in acute inflammation. Despite this finding, absorption of curcumin when

taken by mouth is poor, but is improved when curcumin is taken with piperine,

Camellia sinensis, or green tea, contains hepatoprotective polyphenols, the bioflavonoids

classified as catechins, which are powerful antioxidants that inhibit lipid peroxidation

induced by various toxins, including singlet oxygen. They also help maintain intracellular

protein thiol levels, which in turn maintain intracellular reduction-oxidation balance.

Green tea enhances phase 2 liver detoxification, increasing glucuronidation by 100% in

one animal study. The most active compound in green tea is epigallocatechin gallate. gnu.i

nflibn

et.ac

.in

Glycyrrhiza glabra, or licorice, exerts its hepatoprotective effect by decreasing lipid

peroxidation. It increases both cytochrome P450 activity and

(5) Hepatoprotection by "Dangqui-Long-Hwei-Wan" in Male Mice (43)

Abstract: Dangqui-Long-Hwei -Wan (D.L.H.W.) is a traditional Chinese

prescription for treatment of hepatitis. The hepatoprotective effects of D.L.H.W. and its

constituents were investigated on carbon tetrachloride-induced liver damage mice. The

hepatoprotective effect is more prominent for aqueous extracts of the complete formula

of D.L.H.W., especially the one cited in the Chinese medical book Hsuan-Ming-Lun

(H.M.L.). Our results are in accordance with those described in the Chinese medical

literature and the indications suggested in clinical treatment (Wang, 1982). The results

further indicate that Scutellariae Radix plays an important role in the hepatoprotective

activity. Moschus could be omitted from D.L.H.W. with no significant influence on its

effect. The underlying mechanism for the hepatoprotective effect of D.L.H.W. possibly

results from the inhibition of the formation of [multiplied by] C[Cl.sub.3] and the

enhancement of immunity of hepatitis-carrying patients.

The therapeutic effects of Chinese herbs and prescriptions are different from most

synthetic drugs due to their moderate activity and low toxicity. Chinese herbal formulas

generally are composed of 2 or more different herbs. Therefore, the pharmacological

effects of herbal combinations on the human body become very complex. Three types of

interactions may take place: between individual herbs, between the constituents of

individual herbs, and between the constituents of different herbs. The addition or

omission of herbs in the prescription will result in different effects. The pharmacological

properties of Chinese herbal combinations are still poorly understood at present.

Dangqui-Long-Hwei-Wan (D.L.H.W.), a traditional Chinese prescription, has

been used for treatment of patients with symptoms of constipation, swollen ears, blood in

the urine, gonorrhea, swelling and itching in the genital areas, yellow-coated tongue,

strong pulse, and redness in the mouth, tongue, and eyes. It relieves the internal heat of

the liver and gallbladder (Wui, 1994). D.L.H.W. is one of the most frequently prescribed

antihepatitis drugs in traditional Chinese medicine. Three different kinds of prescriptions

cited in classical medical texts, Hsuan-Ming-Lun (I) (Wang, 1982), Wan-Ping-Hui-Chun

(II) and Jen-Ee-Fan (III) (Shieh, 1921) respectively, are all referred to as D.L.H.W.. They gnu.i

nflibn

et.ac

.in

are composed of either 11 or 12 herbs in their formulas (Table 1), but with different

weight fractions. The basic formula is represented by Huang-Lien-Chieh-Tu-Tang

(H.L.C.T.T.) (Table 2, IA).

(6) Emblica officinalis (44)

Hepatoprotective activity of Emblica officinalis (EO) and Chyavanaprash (CHY)

extracts were studied using carbon tetrachloride (CCl4) induced liver injury model in rats.

EO and CHY extracts were found to inhibit the hepatotoxicity produced by acute and

chronic CCl4 administration as seen from the decreased levels of serum and liver lipid

peroxides (LPO), glutamate-pyruvate transaminase (GPT), and alkaline phosphatase

(ALP). Chronic CCl4 administration was also found to produce liver fibrosis as seen from

the increased levels of collagen-hydroxyproline and pathological analysis. EO and CHY

extracts were found to reduce these elevated levels significantly, indicating that the

extract could inhibit the induction of fibrosis in rats.

gnu.i

nflibn

et.ac

.in

CHAPTER 9. REFERENCE:

1 Dr.Goyal R.K., Dr.Mehta Anita., Dr.Balaraman R.; Drasari and gandhi‟s elements of

Anatomy Physiology and health education.

2 Goodman and Gilman‟s the basis of therapeutics tenth edition.medical publicing

devision,tenth edition.

3 Ganong, William F., MD, Review of Medical Physiology, Prentice Hall, 1991.

Palmer, Melissa, MD, Dr. Melissa Palmer‟s Guide to Hepatitis and Liver Disease,

Penguin Putnam, 2004.

http://www.liverfoundation.org/, Diet and Your Liver, American Liver Foundation, 2003.

http://www.newsday.com/, Weighing the risks of Atkins diet, Delthia Ricks, 3/18/06.

http://www.nlm.nih.gov/, Diet – liver disease, Medline Plus, 9/22/05.

4 Nagai A, Murakati Y vitamin E and C supplementation prevents decrease of

eicosapentaenoic acid in mononuclear cells in chronic hepatitis C patients during

combination therapy of interferon alpha-2b and ribavirin,” -22.

5 Cupp MJ. Herbal remedies:hepatoprotective factor and drug interactions. Is Fam P19.

Fan," Apocynins A-D: new phenyl propanoid substituted flavan - 3 - ols isolated from

leaves of apocynum venetum “Chemical & pharmaceutical bulletin 2000, v. 47(7), p.

1049-1050, through MAPA 2000-01-0190

6 Ganong, William F., MD, Review of Medical Physiology, Prentice Hall, 1991.Palmer,

Melissa, MD, Dr. Melissa Palmer‟s Guide to dose related hepatic side eeffectser Disease,

Penguin Putnam, 2004

7. Cupp MJ. Herbal remedies: adverse effects and drug interactions. Is Fam Physician

1999: 59: 1239 – 44

8. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL.

Unconventional medicine in the United States – Prevalence, costs and patterns of use.

NEJM 1993,328-246-252.

9. De Smet PAGM, Keller K, Hansel R, Chandler RF, eds Adverse effects of

herbal drugs. Berlin, Germany: Springer – Verlag, 1997. gnu.i

nflibn

et.ac

.in

10. Samir Malhotra, Amritpal Singh, G.Munjal. Hepatotoxic potential of commonly

used herbal products. Gastroenterology Today 2001: 5: 110-111.Vol.V

No.2.ISSN 0971-8222.

11. Bisset NG, ed. Herbal drugs and phytopharmaceuticals. A handbook for

practice on a specific basis. Stuttgart: Medpharm Scientific, 1994: 326-8.

12 Vogel G. Natural substances with effects on the liver. In: Wagner H, Wolff P,

eds. New Natural Products and Plant Drugs with Pharmacological, Biological or

Therapeutic Activity. Heidelberg: Springer-Verlag; 1977.

13. Cordatos E. Taraxacum officinale. In: Murray M, Pizzorno J, eds. A Textbook

of Natural Medicine. Seattle: Bastyr University Press; 1992.

14.H. Kalantari PhD, M. Rastmanesh Pharm D. Protective Property of Cichorium

Intybus in CCL4 Induced Liver Damage in mice. School of Pharmacy, Ahwaz

University of Medical Sciences, Ahwaz, Iran.

15. Sanwa Kagaku Kenkyusha Co. Ltd.: Marmen Pharmaceutical Co. Ltd. -

Japanese patent. Chem Abst. 102: 32261 b (1985).

16. Zhao, M. Q. et al.: Acta Pharm. Sin. IS: 325 (1983).

17. Numazaki, K., et al. Effect of glycyrrhizin in children with liver dysfunction

associated with cytomegalovirus infection. Tohoku J Exp Med. 1994 Feb; 172(2):

147-53.

18. Chen HC, Chou CK, Kuo YH, Yeh SF. Identification of a protein kinase C

(PKC) activator, dephnoretin, that suppresses hepatitis B virus gene expression

in human hepatoma cells. Biochem Pharmacol 1996; 52:1025-1032. gnu.i

nflibn

et.ac

.in

19. Duke JA (1985) Die amphocholeretische Wirkung der Fumaria officinalis .Z

Allg Med 34:1819.

20. Srinivas L, Shalini VK. DNA damage by smoke: Protection by turmeric and

other inhibitors of ROS. Free Radical Biol Med 1991; 11:277-283.

21. Selvam R, Subramanian L, Gayathri R, et al. The anti-oxidant activity of

turmeric (Curcuma longa). J Ethnopharmacol 1995; 47:59-67.

21. M.Sree Rama Murthy, M.Srinivasan, R&D Department, TTK Pharma

Limited. Hepatotprotective Effect of Tephrosia pupurea in experimental animals.

Indian Journal of Pharmacology 1993; 25:34-36.

22. Adzet T, Camarasa J, Laguna JC. Hepatoprotective activity of polyphenolic

compounds from Cynara scolymus against CCl4 toxicity in isolated rat

hepatocytes. Departamento de Farmacognosia y Farmacodinamia, Facultad de

Farmacia, Nucleo Universitario de Pedralbes, Barcelona, Spain. J Nat Prod 1987

Jul-Aug; 50(4): 612-7.

23. Datta S, Sinha S, Bhattacharyya P. Hepatoprotective activity of a herbal

protein CI-1, purified from Cajanus indicus against beta-galactosamine HCl

toxicity in isolated rat hepatocytes. Department of Chemistry, Bose Institute,

93/1, A.P.C. Road, Calcutta 700009, India. Phytother Res 1999 Sep; 13(6): 508-

12.

24 .qadry j s.,Prof . shah C S ;Shah and qadry‟Pharmacognosy,twelth edition.

25. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin

treatment in patients with cirrhosis of the liver. J Hepatol. 1989;9:105–113. gnu.i

nflibn

et.ac

.in

26. Benda L, Dittrich H, Ferenzi P, et al. The effectiveness of silymarin therapy on the

survival rate of patients with liver cirrhosis [translated from German]. Wien Klin

Wochenschr. 1980;92:678–683.

27. Pares A, Planas R, Torres M, et al. Effects of silymarin in alcoholic patients with

cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial.

J Hepatol. 1998;28:615–621.

28. Mato JM, Camara J, Fernandez de Paz J, et al. S-adenosylmethionine in alcoholic liver

cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J

Hepatol. 1999;30:1081–1089.\

29. Avezov SA, Mansurov FKh. Efficacy of combined administration of ursodeoxycholic

acid and hepthral in the treatment of primary biliary cirrhosis] Klin Med (Mosk).

2004;82:46-9, 55-8.

30. Marchesini G, Bianchi G, Rossi B, et al. Nutritional treatment with branched-chain

amino acids in advanced liver cirrhosis. J Gastroenterol. 2000;35(suppl):7–12.

31. Lesbere FX. Effect of endotelon on the capillary fragility index in a specific group:

cirrhotic subjects [in French; English abstract]. Gaz Med Fr. 1983;90:332–337.

32. Matsuzaki Y, Tanaka N, Osuga T. Is taurine effective for treatment of painful muscle

cramps in liver cirrhosis? [letter]. Am J Gastroenterol. 1993;88:1466–1467.

33. Okita M, Watanabe A, Nagashima H. A vegetable protein-rich diet for the treatment of

liver cirrhosis. Acta Med Okayama. 1985;39:59–65.

34. Lieber CS, Robins SJ, Li J, et al. Phosphatidylcholine protects against fibrosis and

cirrhosis in the baboon. Gastroenterology. 1994;106:152–159.

35. Chan TY, Tang CH, Critchley JA. Poisoning due to an over-the-counter hypnotic,

Sleep-Qik (hyoscine, cyproheptadine, valerian). Postgrad Med J. 1995;71:227–228. gnu.i

nflibn

et.ac

.in

36. Chan TY. An assessment of the delayed effects associated with valerian

overdose [letter]. Int J Clin Pharmacol Ther. 1998;36:569.

37. Anandan, “Hepatoprotective effects of calcium channel blockers” . Current science

1999:V.76 (12); P. 1543-1545 through MAPA 9905-3015.Phsin 1999: 59: 1239 – 44?

38 .hakta, "Evaluation of hepatoprotective activity of cassia fistula leap extract” Journal of

etimopharmacology. 2000, v. 66(3) , P. 277-282 , through MAPA 2000-02-0850 effect of

picrarhiza kurroa on mitochondrial glutathione antioxidant system in D-galactosamine

induced hepatitis in rats.” Phytotherapy research 1999:V.12 (8); P.557-561 through MAPA

9904

39. Mandal "Hepatoprotective activity of picrorhiza kurroa extract on liver damage caused

by ccl4 in rats: Indian drugs. 2000, v. 36(7), P.470-473, through MAPA 2000- 01-0231

40. .Lucena MI, Andrade RJ, de la Cruz JP, et al. Effects of silymarin MZ-80 on oxidative

stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-

controlled clinical study. Int J Clin Pharmacol Ther. 2002;40:2–8

41. Pares A, Planas R, Torres M, et al. Effects of silymarin in alcoholic patients with

cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter

trial. J Hepatol. 1998;28:615–621.

42. Arteel “Antihepatotexic activity of curcuma longa on Paracetamol and galactosamine

induced hepatotoxicity in rats”, Plantes Medico.. 1999, V. 57(2), P.

37 - 39, through MAPA 9906 – 3735.

43. Ying yen,Ling ling yan,Journal of the Chinese Medical Association (J. Chin. Med.

Assoc.) ISSN 1726-4901 .2006, vol. 69, no2, pp. 86-88

44. Jeena K. Jose, Ramadasan Kuttan,Amala Cancer Research Centre.emblica officinalis as

hepatoprotective agents.

gnu.i

nflibn

et.ac

.in

gnu.i

nflibn

et.ac

.in