Interferon and Chai Hu (Radix Bupleurum)- a Research

Related Posts

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. 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 Chinese Medicine 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-containin g 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-containin g 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-containin g 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 clinical trial of sho-saiko-to in chronic active hepatitis. Gastroent Jap 1989;24:715–9.

Related Posts :