Interferon and Chai Hu (Radix Bupleurum)

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Interferon and Chai Hu (Radix Bupleurum)

 

by Acupuncture/Herbalists Andrew Pacholyk, Jeanne Atkin, Ron Venke, MS, L.Ac.

 

Abstract

 

This research takes a look at the Chinese herb Chai Hu (Rx.Bupleurum) which

contains constituents known as saikosaponins that appear to account for much of

the medicinal activity of the plant. Test tube studies have shown that the

saikosaponins in Chai Hu can increase production of various chemicals known as

cytokines that immune cells use to signal one another. Test tube studies have

also found that saikosaponins can inhibit growth of liver cancer cells and are

anti- inflammatory. This research also takes a look at the combination of

Interferon and Chai Hu. When interferon was discovered in 1957, it was hailed as

a significant antiviral agent. In the late 1970s, interferon made a big splash

as a symbol of recombinant gene technology and the medical breakthroughs it

would bring. Fifteen years later, interferon is a symbol of something quite

different--the complexity of the biological processes of cancer and the value of

endurance and persistence in tackling this complexity. Our research takes a look

at the combination and their side effects.

 

Keywords Chai Hu, Interferon, Hepatitis, Cancer, Traditional ,

Western Medicine, Side effects, AST and ALT enzymes, Saikosaponins, Cirrhosis

 

Hepatitis C, also known as " The Silent Epidemic " is the most common blood born

pathogen in the world yet it was not even identified until 1989. It is known as

the silent epidemic due to it's slow progression, which occurs over many years.

Four out of five people with Hepatitis C have no signs or symptoms and are

completely unaware that they have the virus. A person infected with the virus

may not have symptoms for up to two decades after they are infected. One of the

most common causes of liver transplant in the United States is due to chronic

hepatitis C in the later stages of the disease. (1)

 

Previously referred to as non-A, non-B hepatitis or post transfusion hepatitis

it is a viral disease that causes inflammation of the Liver and has infected 3.9

million Americans. Each year there are estimated to be 35,000 new cases. HCV is

a small single strand RNA virus that penetrates a liver cell and replicates

outside of the cell's nucleus. It is an insidious disease that does not begin to

show symptoms until liver damage has already occurred. It can literally take

decades for the disease to create histological changes in the Liver leading to

cirrhosis or hepatocellular carcinoma. Due to it's insidious nature there are

thousands of people who are infected yet unaware. The number of people infected

with HCV are thought to be 170 million worldwide.

 

In the U.S. the numbers are surely underestimated because it is not mandatory to

report Hepatitis C to the Centers for Disease Control and Prevention. Among the

prison population alone there is a very high incidence of Hepatitis C, which is

not included in the estimates. Illegal drug use makes up 60% of HCV transmission

in the U.S. Risk of infection from occupational exposure through needle sticks

and splashes makes up less than 4% of reported cases. The mode of transmission

of HCV is through the blood. Therefore, the populations at highest risk are IV

drug users sharing needles, health care workers involved in needle stick

accidents and those who have received blood transfusions prior to 1992. Since

1992, the screening for HCV at blood banks has greatly reduced infection through

blood transfusions. There is the possibilty of transmission of the Hepatitis C

virus through sexual transmission or vertical transmission from mother to infant

but these cases are rare. (2) Retrieved July 1, 2003 from

http://www.pegasys.com/basics/what c.asp

 

Diagnosis of HCV infection is determined by review of patient history,

serological testing and liver biopsy. The first sign of a possible infection is

an increase in enzymes found in healthy liver cells. AST and ALT are the two

enzymes that indicate liver inflammation. ALT enzymes are produced by the

hepatocytes and are therfore more specific for liver disease than AST. When they

are damaged they will leak into the bloodstream and cause elevaated levels.

Because AST is also present in muscle and brain tissue as well as liver tissue

it is a less specific indicator of liver disease. For example, you will see high

levels of AST in the early stages of a myocardial infaction. Most people

infected with HCV don¹t know that they carry the virus because they have no

symptoms or very vague ones, which could be attributed to many other pathologies

related to a high stress lifestyle. Some of the most common symptoms are fatigue

and exhaustion, sometimes a fluike syndrome, muscle joint pain, nausea, stomach

pain, and lack of appetite.

 

Cirrhosis may develop in 10-20% of HCV infected people but will take decades to

develop. However, most people infected will not develop severe liver disease.

Currently, Interferon is the only method of treatment for Hepatits C. The first

trial of Interferon was reported in 1986. It reported that although Interferon

was effective at low doses and was successful in reducing serum ALT levels it

was associated with relapse when treatment was stopped which indicated that the

virus was not eradicated. Only 15-20 % of patients sustained persistently normal

ALT levels but there was still detectable viremia. It appears that Interferon

therapy only cures infection in a small porportion of patients. This being so,

the goal of Interferon therapy is to suppress infection in order to minimize,

not eradicat liver disease. (3) July 1, 2003

http://cpmcnet.columbia.edu/dept/gi/ribavirin.html

 

Hepatitis- TCM Perspective

 

With chronic persistent Hepatitis you will see mild increases in ALT, AST and

the virus won't develop cirrhosis With chronic active Hepatitis there will often

be exacerbation with jaundice, increased levels of AST & AST, fibrosis of the

Liver, nodules leading to shrunken Liver, cirrhosis and the increased

possibility of Liver cancer

 

There are three stages to Chronic Active Hepatitis:

Stage 1- Liver becomes swollen

Stage 2- Cirrhosis - fibrosis occurs and Liver shrinks (now the liver, spleen

and portal vein are involved)

Stage 3- Hyper portal hypertension Splenomegaly occurs as a result of the blood

not moving from the Spleen. This creates ascites due to the improper flow of

blood. (The portal vein connects the Liver and Spleen).

 

 

The Spleen sends the blood to the Liver, the Liver rinses and cleans the blood.

In Chronic Active Hepatitis where there are nodules and fibrosis the blood from

the Spleen has nowhere to go and this is what creates ³Hyper portal

Hypertension². The liver cannot create the protein albumin due to the lack of

blood and then the lymphatic system shuts down. The overflow in the Spleen leads

to Ascites

 

TCM treats HCV according to the s/s at the time of diagnosis- since there are

several different stages to the disease it must be treated according to which

stage the patient is in. If the disease is diagnosed in the early stages it does

not have to progress toward further deterioration if treated with acupuncture

and herbs.

 

Early stage s/s:

fever, common cold, GI tract sx¹s with decreased appetite, abdominal bloating,

epigastric/ hypochondriac pain, diarrhea, jaundice, severe fatigue.

 

In the early stages you may see jaundice and will definitely see increased

levels of AST

 

With chronic HCV there does not have to be jaundice or can have dark, dull

jaundice...in the early stages there will probably be hypochondriac pain and

constant fatigue will occur when the virus has become chronic.

 

With hypochondria pain there are several different patterns:

- Liver qi stagnation- (hyperactive or depressed: emotions) moving pain and

distension aggravated by the emotions

- Liver blood stasis consistent pain worse with pressure & fixed location, pain

may be worse at night

- Phlegm/damp accumulation

- Food stasis

 

- Liver deficiency

 

 

You must identify whether the pathology of the hypochondriac pain is interior/

exterior:

- Exterior is damp/ heat

- Interior can be Liver Qi stagnation, Blood stasis, Liver yin deficiency

- You must identify whether the disease is in the acute or chronic stage

-You must identify excess/ deficiency:

Excess - Acute or short exacerbation, pain with pressure, forceful pulse

Deficiency - Chronic or long exacerbation, dull pain better with pressure,

severe fatigue

 

 

Jaundice (Yang Huang/ Yin Huang) there are several patterns:

When the red blood cells break down hemoglobin is exposed and this creates

jaundice. Hemoglobin produces bilirubin which is what produces the color of

urine, stool and skin. When the Spleen is enlarged it is in hyperfunction and

kills an excess amount of red blood cells which in turn increases the production

of bilirubin. This is why you will see an excessive yellow coloration of the

skin and sclera and lighter colored stools.

 

In the case of jaundice one cannot determine which type it is without doing

blood tests There are two types of jaundice:

Conjugated = Liver and Gallbladder are involved

Unconjugated = Hemalytic jaundice

 

 

In TCM Jaundice is broken down into Yin huang/ Yang huang jaundice:

Yin huang = Chronic, slow development, damp with cold (Spleen qi or yang

xu-damp-damp cold

Yang huang = Acute/ short duration damp with heat (Stomach heat=damp=dampheat)

damp heat w/damp predominance or damp heat with heat predominance.

 

 

One must determine whether the pattern is exterior/ interior or a combination of

both

External = Usually damp turbidity heat

Internal = Spleen/ Stomach dysfunction with Liver/ Gallbladder dysfunction (damp

turbidity obstruction the middle jiao)

 

 

Ascites = Abdominal Swelling = Gu Zhang * One of the most difficult cases to

treat

 

Splenomegaly occurs when the Spleen is hyperactive and kills too many red blood

cells - Liver doesn¹t receive enough blood and becomes fibrosis- albumin is

decreased - lymphatic system shuts down= fluid stays in abdominal cavity=

Ascites

 

Acupuncture is not a practical treatment during the ascites stage as the Spleen

is enlarged which makes the fat layer much thinner and the possibility of

puncturing the organ is heightened.

 

- Main s/s: abdominal swelling, foot edema when standing, distension, yellowish

skin, anemia, caput medusae, spider nevi

 

The three basic patterns of Ascites are:

1- Qi stagnation

2- Blood Stasis

3- Phlegm Rheum

 

 

Early stages = Patient will have excess pattern with Liver qi stagnation

(branch)and Spleen qi deficiency (root)

 

Later stage = Heat accumulation caused by pathogenic products of qi/ blood/

water Spleen/ Liver/ Kidney damage

 

Must identify if the Ascites (Gu Zhong) is :

Acute/ chronic, excess/ deficient

Excess: Use purgatives (Qi stagnation, damp accumulation)

Deficient: Yin Pattern (Spleen/ Kidney yang deficiency or Liver/ Kidney yin

deficiency

 

 

Gu Zhang Excess Pattern:

Air (Qi stagnation/ Damp accumulation) = Swelling with even drum like shape,

shiny skin, loud sound upon percussion

Water (Cold damp accumulation / Damp heat accumulation) = Abdominal swelling

like a frog, palpates like leather pouch

Blood = Blood stasis of Liver / Spleen) Abdominal swelling with concretions,

caput medusae and spider nevi

 

 

Gu Zhang Deficiency Pattern:

Spleen / Kidney yang deficiency: abdominal swelling with sever distention

(frog), better in morning/worst at night

Liver/ Kidney yin deficiency : * Most common pattern in chronic hepatitis*

abdominal swelling and distention with Caput medusae

 

 

Gu Zhang Complications:

Bleeding due to Ascites: varicosities in portal veins, gum or nose bleeding

(mild), abrupt onset of bleeding from vomit or defecation (severe), dark tarry

stool

Coma due to Ascites: (Heat leading to wind) = coma in late stages, high fever,

vexation with delirious speech, angry eyes, corpse breath, dark scanty urine,

constipation

 

 

Interferons are a group of proteins whose main role is to inhibit viral

infections and stimulate the immune system to fight off disease. They are also

known to regulate many different kinds of cell functions. They are able to

promote or halt the ability of certain cells to differentiate and can also

inhibit cell division. Initially these Interferon was considered potential cure

alls for many viral diseases and cancers but after extended research it has been

shown that they have a much more limited capability. The protein Interferon

derived it's name from it's function which is to interfere with infection.

 

When a cell is infected with a virus the protein Interferon is secreted and

stimulates other cells both infected and noninfected to prevent viruses from

replicating. Twenty different types of Interferon-alpha's have been identified

as well as one beta and one gamma. They belong to a larger class of proteins

called cytokines, which are proteins that carry signals between cells. Type I

Interferons are produced by almost every cell in the body and type II is

produced by specialized cells in the immune system known as T lymphocytes and

natural killer cells. When a disease is released into the blood stream (such as

HCV), Interferon binds to cell receptors and are drawn inside the cell¹s

cytoplasm causing a number of reactions which produce other proteins that fight

off the disease. There are over 30 disease fighting proteins identified today

which are produced by Interferon. (4) July 1, 2003

http://galenet.galegroup.com/servlet/HWRC

 

Side Effects of Interferon Therapy

 

Side effects of interferon therapy include flu-like symptoms, psychiatric

symptoms (such as irritability, depression, , suicidal ideation and/or

development of new or worsening of pre-existing psychiatric disorders, including

psychosis), thyroid dysfunction, and bone marrow suppression. In addition,

pulmonary problems including pneumonitis and sarcoidosis have been reported.

[11, 12, 13, 14]

 

A blood count is obtained at weeks 1, 2, and 4 after therapy is started and

monthly thereafter. Interferon therapy is contraindicated in patients with

decompensated cirrhosis, profound cytopenias, psychiatric disorders, and

autoimmune diseases. Patients taking interferon must be monitored for hemolysis,

and, because of teratogenic effects in animals, men and women taking the drug

must practice strict contraception until 6 months after conclusion of therapy.

Ribavirin which is often combined with interferon in the treatment of hepatitis

should be avoided in persons over age 65 and in others in whom hemolysis could

pose a risk of angina or stroke. Rash, itching, headache, cough, and shortness

of breath also occur with the drug. [11]

 

For people with chronic hepatitis C the recommended standard treatment lasts for

twelve (12) months if a person is responding. The doctor will know by the eighth

week of treatment if it is working. If it is not, the treatment is stopped. For

people with chronic hepatitis B the recommended standard treatment consists of

four (4) months. For people with acute hepatitis C the treatment consists of

four (4) months. [15]

 

Each person responds very differently to the treatment. The first needle of the

medication usually produces the most severe side effects of the whole treatment.

People get flu-like symptoms: fever, chills, muscle aches. This lasts between

four (4) to eight (8) hours. The flu-like symptoms disappear as the body gets

used to the extra interferon. [15]

 

For people with chronic hepatitis C treatment is considered to be working if

liver enzymes have decreased. Ideally, the liver enzymes should be within normal

limits by week eight (8) of treatment. A sustained response is defined as liver

enzymes remaining within normal limits six (6) months after finishing treatment.

For people with chronic hepatitis B it may take up to a year or more after the

treatment is finished to know whether the treatment was successful. The reason

for this is that the measure in the blood that indicates successful treatment

can take up to a year to change. For people with acute hepatitis C the treatment

is considered successful if at the end of treatment the hepatitis C virus was no

longer detectable. [15]

 

Interferon therapy appears to eradicate or cure infection in only a small

proportion of patients. Thus, cure is an unrealistic goal of current interferon

regimens. Interferon is suppressive to the hepatitis C virus. The goal of

therapy should be to suppress infection to a degree that liver disease is

minimized. [16]

 

The results of several published clinical studies demonstrate that about 50% to

70% of patients with chronic hepatitis C respond to treatment with interferon

alfa-2b as documented by reductions in the serum aminotransferase activities to

near normal. Several studies have also shown that about 70% of patients have a

decrease in liver inflammation on follow-up liver biopsy. Unfortunately, most

patients relapse and have recurrent liver inflammation after treatment is

discontinued. [16]

 

Several studies have tested a combination of interferon alfa-2b and ribavirin.

This drug combination was approved by the United States Food and Drug

Administation in June, 1998 for patients with chronic hepatitis C who have been

treated previously with interferon alone and " relapsed " after treatment was

discontinued. It may also be useful in patients never treated previously or in

those who did not respond at all to previous interferon treatment. Study results

suggest that a combination of interferon alpha-2b and ribavirin induce a

sustained response in more patients than treatment with interferon alpha-2b

alone. [16]

 

For about 30% of patients, various psychic disorders are noticed: personality

disorders, mood disorders, anxiety states, suicidal tendencies, manic and

psychotic symptoms. Psychiatric side-effects may require dose reduction or

premature discontinuation of interferon therapy in chronic hepatitis C. [16]

 

Many studies have evaluated the psychiatric side-effects of interferon. [20] One

study assessed the incidence and predictive factors of anxiety and depression

symptoms during and after treatment with interferon in a group of 71 patients.

The results confirmed the great incidence of depression and anxiety not only

during interferon alpha therapy but also after treatment is discontinued. [19].

Another study of 104 patients found the cumulative frequency of clinically

relevant emotional distress (depression, anxiety, or anger/hostility) during

interferon alfa therapy was 57.7%, as compared with 22.5% before therapy.

Interferon alfa therapy had to be stopped prematurely because of untreatable

psychiatric symptoms in 8.3% of patients. [18]

 

In another study fifty-five patients with chronic hepatitis C were prospectively

followed for 24 weeks and assessed with seven neuropsychiatric symptom measures

and one quality of life scale. Of 42 patients treated with INF-alpha and

ribavirin, 11 (26%) were receiving psychiatric treatment at baseline. They

scored higher on all rating scales at baseline and became more symptomatic

during treatment. Of the 31 patients (74%) not in psychiatric care at baseline,

15 (48%) required treatment for neuropsychiatric symptoms, and seven (23%) met

criteria for major depression during INF-alpha therapy. [22]

 

A case of a 26-year-old man who was diagnosed with active chronic hepatitis B

began treatment with IFN-alpha was reported. Five months after initiation of

therapy, he developed acute psychosis with prominent persecutory delusions and

auditory hallucinations. Despite discontinuation of IFN-alpha therapy and

addition of antipsychotic drug treatment, only partial recovery from psychosis

was observed after 4 months of hospitalization. [21]

 

Although the most commonly encountered side effects of interferon therapy

include nonspecific constitutional symptoms, pulmonary involvement is rare. Two

cases of sarcoidosis appearing in patients receiving interferon therapy for

hepatitis C infection, were reported. [13] The case of a 36-year-old woman with

chronic hepatitis C who developed sarcoidosis within 10 weeks of treatment with

recombinant interferon-alpha2a and ribavirin is described and all seven similar

cases published in English from 1989 to 2001 are. [12]

 

In another paper, four patients are described who all developed respiratory

disorders while being treated with IFN-alpha for hematological malignancies. In

three patients the pulmonary disorder apparently was caused by a cell-mediated

immunological side effect in the form of interstitial pneumonitis. In one

patient the symptoms were most likely caused by an autoimmunologic reaction,

primarily engaging the vascular system, initially in the lungs. [14]

 

Traditional has been considering the effects of liver damage

for many years. In the 1980s China developed its own hepatitis B epidemic. The

doctors there have for the last 20 years been refining Chinese herbal medicine

to lessen the damage of both hepatitis B and C. They have found that Chinese

herb formulas can help to protect the liver against long-term damage of the

hepatitis virus. Chinese formulas can be modified to work with patients with or

without interferon.

 

Bupleurum contains constituents known as saikosaponins that appear to account

for much of the medicinal activity of the plant. Test tube studies have shown

that the saikosaponins can increase production of various chemicals known as

cytokines that immune cells use to signal one another. Test tube studies have

also found that saikosaponins can inhibit growth of liver cancer cells,[1] and

are anti-inflammatory. [2,3]

 

The Traditional Chinese Herbal symptoms of Chai Hu are referred to as: Qi

constraint with excess - feeling stressed, unrest, chest pain and tightness,

menstrual pain, headache, painful digestion with bloating, allergies.

 

Translated into Western terms Chai Hu is an analgesic, anti- inflammatory and

has anti-spasmotic properties. The Western indications include nervousness with

restlessness and pain, headache, dysmenorrhea, intercostal neuralgia, myalgia,

dyspepsia, peptic ulcer, biliary and intestinal colic, IBS, spasmodic coughing

and deafness.

 

Human trials, only one double-blind, have shown that the bupleurum- containing

formula with saikosaponins may help reduce symptoms and blood liver enzyme

levels in children and adults with chronic active viral hepatitis.[4,5,6,7] Most

of these studies were in people with hepatitis B infection, though one

preliminary human trial has also shown a benefit in people with hepatitis C.11

saikosaponins were also found, in a large, preliminary (but not double-blind),

study to decrease the risk of people with chronic viral hepatitis developing

liver cancer.[8].

 

Bupleurum has also been used to reduce symptoms of and possibly decrease the

severity of liver cirrhosis though clinical studies on this condition are

generally lacking. One randomized trial (it was unclear if this trial was

double-blind) found that saikosaponins could reduce the rate of liver cancer in

people with liver cirrhosis. [9]. There have been numerous reports of both

synthetic interferon and Bupleurum-containing herbal formulas contributing to

the occurrence of acute pneumonitis or interstitial pneumonia. The particular

form of lung damage involved is more likely to occur when interferon and herbal

treatment are combined, especially in an uncoordinated approach or unsupervised

setting. [10].

 

Research indicates that the inflammation may be due to allergic- immunological

mechanisms in which interferon causes neutrophils to accumulate in the lung,

rather than toxicity, and that the herbal formula alone may not injure lung

tissue, but more likely increases the effect of interferon. [11].

 

Five cases of drug-induced pneumonitis due to Sho-saiko-to (Japanese formula) or

interferon-alpha or both were studied. In all 5 cases the underlying disease was

chronic hepatitis or liver cirrhosis caused by hepatitis C virus.

 

Interferon-alpha alone was administered in one case, Sho-saiko-to alone was

administered in two cases, and both were administered in two cases.

Bronchoalveolar lavage was done in 4 cases. In three cases, lymphocytosis and

abnormally low CD4/8 ratios were found on examination of bronchoalveolar lavage

fluid. In the only case in which interferon-alpha alone was given the percentage

of neutrophils in bronchoalveolar lavage fluid was abnormally high, and the

adult respiratory distress syndrome developed. Lymphocyte stimulation tests were

done in four cases, and in all four cases the only positive results were against

Sho-saiko-to or against interferon-alpha.

 

The frequency of drug-induced pneumonitis among patients with chronic hepatitis

or liver cirrhosis was 0.7% in those given only Sho-saiko- to, 0.5% in those

given only interferon-alpha, and 4.0% in those given both interferon-alpha and

Sho-saiko-to. Therefore, pneumonitis due to Sho-saiko-to and to interferon-alpha

is more likely to occur if these two drugs are given simultaneously.[12].

 

Medicinal Side Effects

 

There have been numerous reports of both synthetic interferon and

Bupleurum-containing herbal formulas contributing to the occurrence of acute

pneumonitis or interstitial pneumonia. The particular form of lung damage

involved is more likely to occur when interferon and herbal treatment are

combined, especially in an uncoordinated approach or unsupervised setting.

 

Shosaikoto – a Japanese preparation used for improving hepatic dysfunction in

chronic hepatitis. Its Chinese name is Xiao Chai Hu Tang. It may trigger

interstitial pneumonia in people with chronic HCV who also are taking

interferon, according to Precaution from the Pharmaceutical Affairs Bureau.

 

In the only case in which interferon-alpha alone was given the percentage of

neutrophils in bronchoalveolar lavage fluid was abnormally high, and the adult

respiratory distress syndrome developed. Lymphocyte stimulation tests were done

in four cases, and in all four cases the only positive results were against

Sho-saiko-to or against interferon-alpha.

 

In Conclusion

 

Interferons are a group of proteins whose main role is to inhibit viral

infections and stimulate the immune system to fight off disease. They are also

known to regulate many different kinds of cell functions. They are able to

promote or halt the ability of certain cells to differentiate and can also

inhibit cell division. Bupleurum has also been used to reduce symptoms of and

possibly decrease the severity of liver cirrhosis though clinical studies on

this condition are generally lacking. There have been numerous reports of both

synthetic interferon and Bupleurum-containing herbal formulas contributing to

the occurrence of acute pneumonitis or interstitial pneumonia.

 

In human trials, only one double-blind, have shown that the bupleurum-

containing formula with saikosaponins may help reduce symptoms and blood liver

enzyme levels in children and adults with chronic active viral hepatitis. Most

of these studies were in people with hepatitis B infection, though one

preliminary human trial has also shown a benefit in people with hepatitis C.

Saikosaponins were also found, in a large, preliminary (but not double-blind),

study to decrease the risk of people with chronic viral hepatitis developing

liver cancer. The particular form of lung damage involved is more likely to

occur when interferon and herbal treatment are combined, especially in an

uncoordinated approach or unsupervised setting. Shosaikoto – a Japanese

preparation used for improving hepatic dysfunction in chronic hepatitis or Xiao

Chai Hu Tang in Chinese, may trigger interstitial pneumonia in people with

chronic HCV who also are taking interferon, according to Precaution from the

Pharmaceutical Affairs Bureau.

 

References

 

1. Motoo Y, Sawabu N. Antitumor effects of saikosaponins, baicalin and baicalein

on human hepatoma cell lines. Cancer Lett 1994;86:91–5.

 

2. Yamamoto M, Kumagai A, Yamamura Y. Structure and actions of saikosaponins

isolated from Bupleurum falcatum L. I. Anti- inflammatory action of

saikosaponins. Arzneim Forsch 1975;25:1021–3.

 

3. Utrilla MP, Zarzuelo A, Risco S, et al. Isolation of a saikosaponin

responsible for the antiinflammatory activity of Bupleurum gibralticum Lam root

extract. Phytother Res 1991;5:43–5.

 

4. Hirayama C, Okumura M, Tanikawa K, et al. A multicenter randomized controlled

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1989;24:715–9.

 

5. Fujiwara K, Ohta Y, Ogata I, et al. Treatment trial of traditional Oriental

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6. Tajiri H, Kozaiwa K, Osaki Y, et al. The study of the effect of sho-saiko-to

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7. Gibo Y, Nakamura Y, Takahashi N, et al. Clinical study of sho- saiko-to

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8. Oka H, Yamamoto S, Kuroki T, et al. Prospective study of chemoprevention of

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9. Yamamoto S, Oka H, Kanno T, et al. Controlled prospective trial to evaluate

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10. Ishizaki T, Sasaki F, Ameshima S, Shiozaki K, Takahashi H, Abe Y, Ito S,

Kuriyama M, Nakai T, Kitagawa M. Pneumonitis during interferon and/or herbal

drug therapy in patients with chronic active hepatitis. Eur Respir J 1996

Dec;9(12):2691-2696.

 

11. Kakumu S, et al. Effects of TJ-9 Sho-saiko-to (kampo medicine) on interferon

gamma and antibody production specific for hepatitis B virus antigen in patients

with type B chronic hepatitis. Int J Immunopharmacol. 1991; 13(2-3): 141-146.

 

12. Nakagawa A, Yamaguchi T, Takao T, Amano H. [Five cases of drug- induced

pneumonitis due to Sho-saiko-to or interferon-alpha or both]. Nihon Kyobu

Shikkan Gakkai Zasshi 1995 Dec;33(12):1361-1366. 11. Tierney Jr., Lawrence M.,

McPhee, Stephen J., and Maxine A. Papadakis, eds (2003), 2003 Current Medical

Diagnosis & Treatment, 42'nd ed. New York: Lange Medical Books/McGraw-Hill

 

12. Tahan V, Ozseker F, Guneylioglu D, Baran A, Ozaras R, Mert A, Ucisik AC,

Cagatay T, Yilmazbayhan D, Senturk H., Sarcoidosis after use of interferon for

chronic hepatitis C: report of a case and review o. f the literature. Dig Dis

Sci. 2003 Jan;48(1):169-73. Review.

 

13. Rubinowitz AN, Naidich DP, Alinsonorin C., Interferon-induced sarcoidosis. J

Comput Assist Tomogr. 2003 Mar-Apr;27(2):279-83

 

14. Anderson P, Hoglund M, Rodjer S. Pulmonary side effects of interferon-alpha

therapy in patients with hematological malignancies. Am J Hematol. 2003

May;73(1):54-8.

 

15. Vera Simon, R.N., M.Sc.N., Hepatitis Information Network, hepnet.com

 

16. Gary L. Davis, M.D, University of Florida, hepcsolutions.com, American Liver

Foundation

 

17. Debien C, De Chouly De Lenclave MB, Foutrein P, Bailly D. [Alpha- interferon

and mental disorders], Encephale. 2001 Jul-Aug;27(4):308-17

 

18. Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M., Psychiatric symptoms in

patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin

Psychiatry. 2003 Jun;64(6):708-14.

 

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