HERBALS IN LIVER DISORDERS - AN UPDATEgnu.inflibnet.ac.in/bitstream/123456789/2472/1/36-Hitesh...
Transcript of HERBALS IN LIVER DISORDERS - AN UPDATEgnu.inflibnet.ac.in/bitstream/123456789/2472/1/36-Hitesh...
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
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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
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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.”
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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
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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
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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
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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.
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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:
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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 .
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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
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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.
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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..
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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
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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
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.in
giloin,gilenin were
isolated.
evaluated from the
decoction of the plant
and hepatoprotective
activity.
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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
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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)
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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
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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
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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.
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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
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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
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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
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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.
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CHAPTER 9. REFERENCE:
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