Studies have been done, both with injectables, as well as oral doses.The rates of seroconversion for hcv infection average over 40% in a myriad of studies, starting in 1998, for both hepatitis B & C. Both injectables as well as oral doses were effective. Dose range in the various studies were between 600mg and 900mg daily. Normalization of enzymes occurred in around 70% of hepatitis C patients. In studies of non-viral hepatitis an anti-fibrotic effect was found on repeat biopsy.

Not only is this a strong anti-viral, it also has a distinct liver protectant quality. This is a very versatile compound effective in diseases ranging from fungal and parasitic infections, cancer, arrhythmias, skin problems and others.Treatment time varied from 3 to 12 months in all the published studies. Also when the virus has been zeroed out, some recommend taking a 200 mg daily dose ongoing.

There are no serious side effects for the alkaloid oxymatrine reported. However, serious side effects have been described in children taking large quantities of the whole herb or closely related herbs. The main toxic effect was convulsions. Because of this we strongly advise not using this if pregnant or nursing as it may affect the nervous system of baby or fetus.

So far in very limited use we have seen no negative effects. Not only was it tolerated by patients with sensitive digestion, it actually strengthened digestion.I am very excited about this compound and would appreciate any feedback, including copies of blood tests.

These statements have not been reviewed by the FDA!

OXYMATRINE
Update on Clinical Effects and Safety
by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon

Oxymatrine is present in sophora roots along with matrine and small amounts of other tetracyclo-quinolizidine alkaloids (from Sophora flavescens: kushen; and Sophora subprostrata: shandougen), as described in a previous article (Matrine and Oxymatrine: Subjects of Research; START, August 2002). Sophora roots and the isolated or partially-isolated alkaloids have been used for several clinical applications, including viral hepatitis, cancer, heart arrhythmia (especially in viral myocarditis and fibrillation), and skin diseases. One of the areas of particular interest has been viral hepatitis, which is still not satisfactorily controlled by modern medicine, because some people don't tolerate the side effects of treatment and stop early, while others are not cured by the treatment even if pursued fully. Since 1998, ITM has made available tablets of sophora root extract that is rich in oxymatrine and matrine (20% total alkaloids, so that a 1-gram tablet provides 200 mg of total alkaloids). However, little is known of its effectiveness other than by implication from reports about the use of similar materials in China, which will be reviewed here.

VIRAL HEPATITIS

Among the earliest publications about clinical application of oxymatrine for viral hepatitis was a preliminary study by Li Jiqiang and colleagues, with patients having hepatitis C. Their report, in which positive results were claimed, appeared in Chinese in 1998 (1) and again in English in 1999 (2). They gave oxymatrine injection (600 mg once per day) to patients with hepatitis B, and observed that the viral load declined, indicating that oxymatrine served to inhibit viral replication; in addition it appeared to reduce liver fibrosis. The inhibitory effect of oxymatrine on hepatitis C virus was confirmed by Chen Yanxi and his colleagues at the Shanghai Second Medical University in cell culture tests (3) and a protective effect of oxymatrine against liver cell death was indicated in a pharmacology study with non-viral (immune-based) liver damage (4).

Chen's group then established a clinical trial, this time for hepatitis B, using injection of 400 mg/day oxymatrine for three months, with observed reduction in hepatitis B virus levels (5). Kang Junjie and Kang Suqiong, at the Treatment Center for Hepatic Diseases of the Amoy Municipal Hospital, used oxymatrine injection for 30 patients with hepatitis B for three months, given along with administration of oral Chinese herb formulas, which revealed inhibition of liver fibrosis (6). In laboratory animal studies carried out by Chen Weizhong and his colleagues at the Changzheng Hospital in Shanghai, matrine was shown to reduce the formation of liver fibrosis that was caused by chemical damage to the liver (7).

This initial work culminated recently in two large multicenter, double-blind placebo-controlled clinical evaluations of oxymatrine given orally (in capsules) for treatment of viral hepatitis. Following a laboratory experiment demonstrating that oxymatrine inhibited the hepatitis B virus (8), a clinical study was set up that involved 216 patients with hepatitis B treated for 24 weeks (9). The patients received either oxymatrine injection, as had been used previously, or oxymatrine capsule; both were effective for reducing viral activity markers. These positive results led to the second, longer study, in which the researchers recruited 144 patients, with either hepatitis B or hepatitis C and randomized them into two groups: oxymatrine (group A) and placebo (group B). The patients took oxymatrine in capsules orally at 900 mg/day for 52 weeks. The authors of the study concluded that (10):

Oxymatrine could effectively treat chronic viral hepatitis and promote the serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) in chronic hepatitis B and C to convert to negative and reduce serum level of ALT….In present study, we found that the scores of hepatic fibrosis after therapy in group A were 4.72±5.63, much smaller than 6.76±6.67 before therapy, and the scores in group B after therapy increased significantly. There was an obvious difference between the two groups. The scores of histological inflammatory activity in group A decreased from 46.08±3.84 before treatment to 4.00±2.97 after therapy, and the scores in group B after therapy did not decrease obviously. There was an obvious difference between the two groups both in improvement of histopathology and in improvement of noninvasive indexes, such as clinical manifestations and serum markers of hepatic fibrosis. Associated indexes of liver function and imaging detection indicated that oxymatrine was an ideal drug of antihepatic fibrosis. It is valuable to pay more attention to the basic and clinical research of oxymatrine in order to explore the accurate mechanisms of its effect on antihepatic fibrosis.

To evaluate further the mechanisms of oxymatrine in hepatitis patients, a study was set-up to test several additional blood parameters as affected by injection and capsule forms of oxymatrine (11); it was shown the serum cholinesterase and liver function tests improved, while other serum parameters were unaffected (e.g., albumin, prothrombin activity). A laboratory investigation into the mechanism of oxymatrine suggested that there might also be an immune-based response to the virus involving the T-cells (12).

In yet another multicenter study, oxymatrine injection was compared with IFN-a and reported to have similar efficacy in seroconversion, yet oxymatrine didn't produce the adverse reactions commonly noted with interferon (13). The combination of interferon and lamivudine has been used to increase response of hepatic virus to treatment; a study compared using lamivudine with either interferon or oxymatrine, indicating similar results for both therapies (14). Considerable additional work is being done on oxymatrine and matrine, including development of enhanced delivery systems, such as liposome-encapsulated alkaloid (15).

SAFETY

The Chinese reports of using oxymatrine indicated little or no adverse reaction. For example, in the clinical trial reports, adverse reactions were limited to local reactions at the injection site for oxymatrine. Blood analysis and renal function tests did not show abnormalities.

However, some concern was raised in a summary report about possible neurotoxicity of high doses of herbs by Wang Xiaoping at the Laboratory of Neurodegenerative Diseases, University of Science and Technology of China. He described three young patients in China who consumed high dose sophora decoctions and then suffered serious neurological effects, apparently as a result (16). Since sophora is known in traditional medicine as a sedative, and since alkaloids frequently interact with the nervous system, such effects are certainly possible, especially when used in overdosage in children, as occurred in these cases. This report concluded with a note that:

The Chinese National Pharmacopoeia identifies the adult maximum dose of sophora root as 9 g/day and the adult toxic dosage as 30 g. But the 3 children had received 30-40 g. In 1976, the toxic effects of sophora root were investigated in rats by the Drugs Agency of Tianjin China; these studies showed that the neurodegenerative damage occurred in the striatum, forebrain and limbic system. Damage induced by sophora root was also observed in 7 other published Chinese case reports.

The toxic effects in children noted in the report involved various movement disorders, mainly convulsions, followed by other uncontrolled movement, attributed to possible action of the herbal constituents on the basal ganglia. Thus, for example, a 9-year-old boy was given the decoction of 40 grams of sophora root each day for three consecutive days for treatment of hepatitis B and suffered from these symptoms. An 11-year-old girl was treated with 40 grams of sophora root all in one dose, for sore throat and fever, and also suffered convulsions. A 12-year-old boy was given 30 grams of sophora per day for 7 days for treating a facial infection before he experienced these symptoms.

The absence of any such reports of movement disorders in the various clinical trials of oxymatrine, which included a relatively high dosage of the alkaloids either by injection or oral administration, compared to these adverse events could have several origins:

Materia Medica guides used as a primary resource by practitioners who prescribe Chinese herbs generally mention no toxicity of sophora roots, and this is true of most pharmacology texts describing the herb and its active constituents. Yet, a potential for negative effects at high dosage apparently has been suggested in China, at least by some. In the book Ten Lectures on the Use of Medicinals from the Personal Experience of Jiao Shude (17), with regard to kushen (sophora root) he notes: "The dosage is generally 6-9 grams; for skin diseases, one can sometimes use 15-30 grams….There is a saying that taken over extended periods or in numerous large doses, kushen may damage the kidney and cause pain or heaviness in the lumbar area. I mention this for your reference."

The comment about the "kidney" may refer to the Chinese kidney system, which could indicate a knowledge of neurological effects, since the kidney system is said to relate to the brain. In toxicity evaluations, as relayed by Zhu Youping in his book Chinese Materia Medica: Chemistry, Pharmacology, and Applications (18) it is noted that: "Repeated intraperitoneal administration of 100-500 mg/kg of oxymatrine daily for 2-4 weeks caused no significant damage to the heart, spleen, and kidneys in mice." These laboratory test doses were close to the fatally toxic level (LD50), which by this route of administration was reported to be 521 mg/kg, but did not adversely affect the kidney (organ); further, adverse renal effects were not seen in the clinical trials. The toxicity of the total alkaloids of sophora by oral route in rats was rated at 1.2 g/kg (LD50). In the Advanced Textbook of Traditional Chinese Medicine and Pharmacology (19), under kushen, it is noted that "For its strong bitter taste and cold property, a large dosage should be avoided to prevent any possible damage to stomach function." This is not a specific reference to experience of adverse effects, but a rendition of the Chinese dogma that cold and bitter herbs inhibit the digestive system.

To be safe, children should not take high doses of sophora root or its extracts and should probably avoid this herb material entirely, in case there might be some unexpected high sensitivity in some young children. In addition, sophora and its alkaloids should be avoided during pregnancy, in the event that there is a sensitivity of the nervous system in the fetus. Adults should not exceed the amounts used in the clinical trials, which have been in the range of 600 mg by injection or 900 mg orally, and adults with renal disorders might avoid using this herb as a precaution even though the one comment relayed above does not seem to have clinical or laboratory support at this time. For the Oxymatrine tablets provided by ITM, with 200 mg of alkaloids per tablet, the recommended adult dosage is 1 tablet each time, three times daily (total 600 mg); but practitioners may advise taking 1 tablet up to four times daily (total, 800 mg). This tablet is not intended for use by children. It is prescribed by health professionals who specialize in Chinese herbs, such as acupuncturists.

Despite the positive results from Chinese laboratory and clinical studies, one should not consider that the effectiveness of oxymatrine in viral hepatitis and liver fibrosis is proven. Its use for adults-as long as it appears to be providing positive results-should be limited to one year, based on the maximum duration utilized in the clinical trials. The acute adverse effects suggested for sophora roots taken in high dose do not appear to occur with prolonged administration of the proper dosage of sophora or its sophora alkaloids.

MATRINE AND OXYMATRINE
Subjects Of Chinese Research
by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon

Matrine and oxymatrine are the two major alkaloid components found in sophora roots. They are obtained primarily from Sophora japonica (kushen), but also from Sophora subprostrata (shandougen), and from the above ground portion of Sophora alopecuroides. The matrines were first isolated and identified in 1958; they are unique tetracyclo-quinolizindine alkaloids (see Figure 1) found only in Sophora species thus far. An intensive investigation into the pharmacology and clinical applications of these alkaloids has gone on for the past decade and remains one of the focal points of Chinese medical research. The main clinical applications are treatment of people with cancer, viral hepatitis, cardiac diseases (such as viral myocarditis), and skin diseases (such as psoriasis and eczema).

The crude herb and crude hot-water extracts of sophora have been available in the West for more than 25 years. An alkaloid fraction of sophora roots containing a standardized level of oxymatrine and matrine (20%) was first introduced by the Institute for Traditional Medicine, and made available to practitioners in tablet form under the name Oxymatrine (White Tiger) in 1998. It has been used without reported side effects. In China, the alkaloids are often given by injection, but this method of administration is not acceptable in the West, so oral dosing is used here instead. When taken orally, much of the oxymatrine is converted to matrine; to get high blood levels of oxymatrine, it must be given by injection. However, it is unclear whether oxymatrine is clinically more effective than matrine. Chinese researchers have also used the alkaloids in capsule form, with results that appear similar to the injection. Sophora is also administered in complex formulas made as decoctions and taken orally.

Sophora japonica contains about a dozen alkaloids, with matrine and oxymatrine being by far the highest, together comprising about 2% of the dried root stock (most of it in the form of oxymatrine), followed by closely related alkaloids: mainly sophocarpine, but also minute amounts of sophoranol, sophoramine, sophoridine, allomatrine, isomatrine, and others (see Figure 2). These alkaloids were first reported as constituents of kushen in a series of publications from 1958-1978.

An overview of recent research on the pharmacology and clinical applications of the sophora alkaloids is presented below. In general, the dosage of the sophora alkaloids administered clinically is in the range of 400-600 mg per day.

VIRAL HEPATITIS

As described by Chen Yanxi and his colleagues at the Shanghai Second Medical University (1):

In recent years, oxymatrine has been recommended for treating chronic hepatitis B and chronic hepatitis C and has been shown effective in clinical practice. It has been utilized for these applications broadly, but the factors affecting its efficacy have not yet been determined.

Chen and his group gave oxymatrine injection to patients with hepatitis B. He confirmed that the viral load declined by this treatment, suggesting that oxymatrine served to inhibit the viral replication, not just reduce liver damage, which is the primary and more limited effect of many herbs used for hepatitis. Antiviral activity, for hepatitis C virus, was confirmed by the same group in cell culture tests (2). Clinical effectiveness for patients with hepatitis C had been reported earlier, including reduction of viral load (3). Oxymatrine may reduce death of liver cells damaged by means other than by inhibiting viral activity, as indicated in a pharmacology study of liver protective effects in immune-based liver damage (4).

Kang Junjie and Kang Suqiong, at the Treatment Center for Hepatic Diseases of the Amoy Municipal Hospital, reported that oxymatrine injection did not cause side effects other than rare local reactions at the injection site (5). They used this injection along with oral administration of complex Chinese herb formulas designed to match symptom-sign complexes and claimed that the effects were comparable to those attained with interferon therapy, except that adverse reactions were avoided. In particular, they claimed that the use of oxymatrine and Chinese herb formulas inhibited liver fibrosis (for further information on Chinese herbs for this purpose, see: Treatment and prevention of liver fibrosis). The inhibition of fibrosis appears to be a separate for additional function of sophora alkaloids beyond inhibiting viral activity. In laboratory animal studies carried out by Chen Weizhong and his colleagues at the Changzheng Hospital in Shanghai, matrine was shown to reduce the formation of liver fibrosis that was caused by chemical damage to the liver (6).

Thus, in relation to viral hepatitis, the sophora alkaloids appear to inhibit the viral replication, reduce destruction of liver cells, and protect against fibrosis. It has also been suggested that the alkaloids promote the flow of bile.

CANCER

Sophora subprostrata has long been regarded an anticancer herb in China. According to cancer specialist Chang Minyi (7), "Sophora subprostrata works through stimulating the anticancer immune mechanism of the patient and reinforcing his resistance against the growth of the tumor." In 1998, Xu Xiangru and Jiang Jikai, working at the Congqing University of Medical Sciences, published a review of anticancer activity of sophora alkaloids (8). They relayed pharmacology studies indicating the alkaloids could inhibit growth of tumor cells directly, and could also affect immune functions. In clinical work, they described the use of sophora alkaloids for treating the side effect of leukopenia caused by cancer chemotherapy or radiation therapy and for treating certain cancers, notably uterine cervical cancer and leukemia. The herb is also considered an important ingredient in treatment of esophageal and laryngeal cancer. In a recent pharmacology study, it was reported that matrine could help leukemia cells differentiate into mature and normal white blood cells (9). Nonetheless, sophora alkaloids should not be relied upon as a sole treatment for cancer, but as an adjunct therapy, as there is no proof that the herb or these compounds are curative.

CARDIAC DISEASES

Sophora and its alkaloids are commonly used in China for treatment of heart arrhythmias (10). A possible mechanism of action is to help block sodium and calcium channels, a mechanism relied on by several antiarrhythmic pharmaceuticals. In a review of sophora alkaloid effects on the heart, Li Yan and He Liren, at the Affiliated Yueyang Hospital of Shanghai University of TCM, reported that:

Li and He also relayed a clinical report from the Third Clinical Medical College of Beijing Medical University, about treatment of 167 patients with fast arrhythmia. The patients received each day 3-10 sophora root tablets (extract of 2 grams crude herb/tablet). The results indicated positive effects on various kinds of arrhythmia, such as premature systole, paroxysmal ventricular tachycardia, atrial fibrillation, and sinus tachycardia; the efficacy for premature systole appeared to be the best. This Beijing study and others were described also by Niu Kuizhi in his review (12) of clinical applications of sophora (kushen).

SKIN DISEASES

Sophora is frequently used in treatment of skin diseases, applied topically and consumed orally. One of the primary uses for topical therapy is treatment of vaginitis, particularly that due to candida infection (13). Recently, a topical liniment was developed combining sophora's matrine with the anti-inflammatory flavonoid baicalin from scute (huangqin) for treatment of eczema, neurodermatitis, and psoriasis (14). This treatment was reported to be highly effective, especially for eczema, though the number of cases was small, so that further research must be done. The use of sophora for psoriasis is a promising new area (15). Zhang Junling and his colleagues at the Department of Dermatology, Tianjin Changzheng Hospital, studied the mechanism by which sophora alkaloids reduce psoriasis patches (16). They found that the alkaloids could inhibit keratinocytes, the cells that reproduce continuously to produce the characteristic scales.

Figure 1: Matrine (left) and oxymatrine (right).

Figure 2: Allomatrine (left), isomatrine (middle) and sophoranol (right).

TREATMENT AND PREVENTION OF LIVER FIBROSIS
by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon

Liver fibrosis is one of the processes that occurs when the liver is damaged. Such damage may be the result of:

Fibrosis is both a sign of liver damage and a potential contributor to liver failure via progressive cirrhosis of the liver. In China, liver fibrosis due to viral hepatitis is the major concern because the level of hepatitis B (and, to a lesser extent, C) viral infection is very high. Detection of the underlying liver disease is often delayed and effective medical treatment for viral hepatitis (e.g. interferon, which has a limited success rate) may not be readily available; thus, many people in China have moderate to advanced cirrhosis when they first seek treatment.

In a recent issue (June 2002, English language version) of the Chinese Journal of Integrated Traditional and Western Medicine, 10 articles were devoted to the subject of liver diseases, with 5 original research articles (1-5) plus one review (6) about liver fibrosis specifically. The current article summarizes what was presented about liver fibrosis therapy in that issue of the journal and adds commentaries to aid in interpreting the results. In addition, another review article about liver fibrosis (7) appeared a year earlier in the Journal of Traditional Chinese Medicine (June 2001); it provided few details of the treatments, mainly focusing on possible mechanisms of action for herbal therapies. The introduction to that article, written by Du Bin of the Nanjing University of TCM and Pharmacy, succinctly describes the process of liver fibrosis and is reproduced here:

Liver fibrosis is a gradual process of increased secretion and decreased degradation of extracellular materials. Most authors hold that the process is initiated by the damage of hepatic cells, which leads to activation and secretion of multiple cellular factors from Kupffer cells [macrophages which line the liver sinusoids]. These factors-along with the cellular factors secreted by damaged hepatic cells, thrombocytes, and endothelial cells of the hepatic sinusoid, and some chemical mediators-are activators of hepatic stellate cells. Being activated, the hepatic stellate cells differentiate into myofibroblasts, and, via self-secretion and parasecretion, proliferate and synthesize a massive amount of extracellular materials, which gradually accumulate and lead to formation of liver fibrosis. Since fibrosis is a common development in a variety of chronic liver diseases, prevention against its formation is of great importance.

Essentially, damaged liver cells activate stellate cells that dump materials (e.g., collagens) into the matrix outside the cells; the materials accumulate and form fibrous masses.

BRIEF SUMMARY OF THE ORIGINAL RESEARCH ARTICLES

Chinese research publications frequently display flaws in research design and reporting that make it difficult to interpret the results. In his review article on liver fibrosis (6), Nie Guang commented: "It is worth pointing out that the level of recent studies is low, with many concrete tasks waiting to be done." Almost all published reports from China about traditional Chinese medicine therapies are positive ones. In the following outlines of the journal articles, the basic nature of the study is presented, but the details of the results are left out. Instead, a quotation from the study author(s) reflecting on their interpretation is provided, edited as necessary for clarity.

Study 1: Treatment of Liver Fibrosis with Qinggan Capsule (1)

In traditional Chinese medical therapy, attempts are often made to address several aspects of a disease rather than only one of its manifestations. The Qinggan Capsule is an example of a broad formulation to treat hepatitis symptoms with a focus on the accompanying hepatic fibrosis in patients with chronic hepatitis B. In this study, 63 out-patients were treated with a preparation of B vitamins with glucurone as the control substance, while some patients additionally received Qinggan Capsules, containing 16 herbs: astragalus, salvia, white peony, capillaris, polygonatum, licorice, codonopsis, rehmannia, shen-chu, tang-kuei, curcuma, crataegus, alisma, dioscorea, isatis root, and chin-chiu. The dosing of the herbs was three capsules each time (made from 2.75 grams of crude herbs), three times daily. A therapeutic course was 6 months.

The authors stated:

So far, there is no proof that Qinggan Capsule has an inhibitory effect on the hepatitis B virus itself; therefore, the effects of Qinggan Capsule in improving pathological changes in the liver, particularly the antifibrosis effect, may be through mechanisms other than antiviral action....Liver fibrosis is the pathological process of fibrous connective tissue development secondary to inflammatory necrosis of liver cells. Once it happens, fibrosis could further accelerate the inflammatory necrosis process by way of cytokines or by affecting the intrahepatic microcirculation. Hans Popper [a famous hepatologist in the U.S. during the 20th century] has pointed out that "anyone who can stop or delay liver fibrosis would be able to cure most chronic liver diseases." Hence, in treating chronic hepatitis B, attention should be paid to both stopping liver fibrosis and killing the virus. Qinggan Capsule consists of 16 Chinese herbal drugs. Some components, such as salvia, tang-kuei, and astragalus, have been proven to have antifibrosis action.

Study 2: Treatment of Liver Fibrosis with Ginkgo Leaf (2)

Gingko leaf (see: Ginkgo) is a blood vitalizing herb that has flavonoids and glycosides as active components. In this study, 86 out-patients with chronic hepatitis B were treated either with ginkgo tablets that each contained 2.4 mg ginkgolide and 9.6 mg flavones or with Yiganling Tablet (for which the main active component was silymarin, extract of milk thistle, 35 mg/tablet). The dosing was 10 tablets each time of the ginkgo and 3 tablets each time of the silymarin (silybin), three times daily. In addition, all patients received appropriate medical care that did not include other agents known to have anti-fibrosis activity or immune effects. Treatment time was three months. To determine effect on liver fibrosis, measurements were made of blood content of hyaluronic acid, collagen type IV, laminin, pro-collagen peptide type III, and platelet activating factor (PAF). In addition, some patients underwent liver biopsy.

The authors commented:

It was found in this study that the serum level of PAF was elevated in patients with chronic hepatic cirrhosis, and in those after anti-fibrosis treatment [the gingko tablets], it could be lowered along with improving of the liver fibrosis in a positively correlated manner, suggesting that PAF participates in the genesis and development of liver fibrosis in chronic hepatitis.

Ginkgo glycoside ß, one of the chief components of ginkgo leaf, is a strong PAF receptor antagonist....It was reported that good effect was obtained by using composite ginkgo leaf granule, containing ginkgo leaf and 9 other Chinese herbs to treat early stage liver fibrosis, with evident improvement in blood level of superoxide dismutase [SOD, a well known antioxidant] and malondialdehyde [MDA, an indicator of lipid peroxidation activity]. It illustrated that the ginkgo preparation has anti-lipid peroxidation effects and can reduce the injury by oxygen free radicals on liver cells. Similar therapeutic effect has also been obtained by the authors by applying the ginkgo preparation in treating acute hepatitis with severe jaundice.

Results in this study showed that, after treatment for three months, the clinical effect of ginkgo preparation was markedly superior to that of Yiganling Tablet (silybin)....These results indicate that ginkgo leaf has obvious effects of liver protection, anti-inflammation, and anti-fibrosis, and may even reverse liver fibrosis.

Study 3: Treatment of Liver Fibrosis with Ruangan Granules (3)

Preparations of astragalus and salvia are frequently used to vitalize blood circulation and treat chronic diseases involving blood stasis. In this study 120, out-patients with chronic hepatitis B were treated with either Ruangan Granules, consisting of several herbs including astragalus, salvia, prunella, turtle shell, red peony, bupleurum, atractylodes, zedoaria, notoginseng, and cordyceps, or Biejia Ruangan Tablets (undefined contents). The Ruangan Granules contained the extract of 2.63 grams of crude herb materials in each gram of granules, and was administered 20 grams each time, three times daily (hence, the equivalent of about 158 grams of crude herbs per day). In addition, some patients in each of the groups received an IV drip of glycyrrhizin (the main active component of licorice, shown to have antiviral action), along with cysteine and glycine (the combination of these two amino acids is said to prevent some of the sodium/potassium imbalance that can arise with high dose licorice treatments). To monitor liver fibrosis, the researchers measured serum levels of fibronectin, laminin, and hyaluronic acid. Ultrasound tests were conducted to monitor the morphology of the liver. Treatment time was three months.

The authors commented:

We consider that liver fibrosis is caused by evil damp-heat left behind by chronic hepatitis, and by the combination of liver stagnancy, spleen deficiency, and blood stasis resulting from the long-term course of the disease. In the early stage of liver disease, a TCM syndrome of pathogenic excess, such as qi stagnation and dampness accumulation, is manifested along with spleen qi deficiency. The syndrome of insufficient essence [yin deficiency] would occur with the further development of the disease. Therefore, for patients with liver fibrosis, qi deficiency with yin deficiency is the root syndrome and blood stasis impeding the collaterals is the branch. The appropriate therapy involves nourishing yin, supplementing qi, activating blood circulation, and softening the hard mass to dissolve accumulation.

Studies in recent years showed that the pathogenesis of liver fibrosis is directly related to the activation and metabolism of the extra-cellular matrix of the liver, liver stellate cells, and cytokines; the non-collagen glycoproteins also play a key role in liver fibrosis formation. Fibronectin and laminin have an effect on the extra-cellular matrix, and they also regulate the cellular function. Large amounts of hyaluronic acid deposited in the liver blood sinus is the key basis of liver fibrosis and portal hypertension formation. This study showed that beside the effect of improving liver function, Ruanguan Granules could regulate the serum levels of fibronectin, laminin, and hyaluronic acid and reduce the size of the spleen and width of the portal vein, indicating that it has definite effects in reverting the formation of liver fibrosis in the course of chronic hepatitis.

Study 4: Pharmacology Study of Benefit Liver Granules (4)

The Benefit Liver Granules (Yigan Tang or Yigan Chongji) is a formulation based on the use of astragalus and salvia as a treatment for chronic liver diseases. Its ingredients, for a one day dose in clinical application, are derived from: 45 grams salvia, 30 grams isatis root, 12 grams each of white atractylodes and white peony, 10 grams each of tang-kuei tails and curcuma, 8 grams each of astragalus, gallus (chicken gizzard lining), and magnolia bark, and 6 grams each of hoelen and citrus. The researchers tested this formulation, as well as the decoction of just salvia and astragalus, in rats which were induced to have liver fibrosis via treatment with liver toxic chemicals, namely carbon tetrachloride initial treatment followed by alcohol regular treatment.

The authors stated:

TCM holds that hepatic fibrosis is mainly caused by blood stasis, which manifests chiefly by symptoms such as hepatomegaly, splenomegaly, expanded venation on the abdominal wall, blood nevi [skin patches of red color, also called spider moles, similar to congenital moles], liver palm [palmar erythema; palms redden and feel hot], and wiry, unsmooth pulse. Medicines which promote blood circulation to remove blood stasis are effective in treating these disorders and have been applied widely. Studies have illustrated that Chinese herbal medicines for promoting blood circulation, removing blood stasis, dredging the channels, and nourishing the liver have the effect of anti-liver fibrosis. For example, research conducted by Wang Baoen, et al., proved that the Composite 861, consisting of salvia, astragalus, spatholobus [jixueteng], etc., could prevent liver fibrosis formation and block its development, even reversing the pathological progress.

Benefit Liver Granules is an effective drug for treatment of chronic hepatopathy prepared by professor Yao Xixian and his colleagues, consisting of high doses of Chinese herbal medicines for promoting blood circulation to remove stasis, such as salvia and tang-kuei. It possesses the effects of improving symptoms of chronic hepatopathy, lowering transaminase, subsiding jaundice, softening the liver, and shrinking the spleen. The essential elements of Benefit Liver Granules, such as salvia and tang-kuei, could lower the portal venous pressure in dogs with liver cirrhosis. Salvia has a good effect of anti-hepatic fibrosis, raises the superoxide dismutase activity [SOD, a well known antioxidant] in the liver, and reduces the content of liver malondialdehyde [MDA, an indicator of lipid peroxidation activity] significantly. It was demonstrated that anti-lipid peroxidation action may be an important mechanism of its anti-hepatic fibrosis effect. In another article of the study, the concentrated decoction of Benefit Liver Granules showed significant effect in abating hepatic fibrosis and pathological ultrastructural changes of the liver in rats, and in reducing the deposition of collagens in liver tissue. Further, the effects could be enhanced by prolonging the therapeutic course.

Study 5: Applying Salvia Active Component to Hepatic Stellate Cells (5)

Salvia (see: Salvia and the history of microcirculation research in China) is one of the most commonly used agents for treating fibrosis. One of the proposed mechanisms is to inhibit the hepatic stellate cells that proliferate and contribute substances to the hepatic extracellular matrix, forming the fibrotic mass. An active fraction of salvia, labeled IH764-3, was applied to cultured hepatic stellate cells. The authors stated:

Recent studies showed that to inhibit hepatic stellate cell (HSC) proliferation and promote HSC apoptosis would be helpful in reverting liver fibrosis. The effect of IH764-3 in different concentrations on HSC proliferation was observed in this study....The results showed that IH764-3 is effective in obviously inhibiting HSC proliferation....The apoptotic rate of HSC as revealed with brown staining in the IH764-3 group was significantly higher than that in the blank control group....It is held in TCM that the chief function of salvia is activating blood circulation and removing blood stasis. By modern pharmaco-chemical studies, the active fraction was found to consist chiefly of tanshinone, salviol, and tanshiol, etc.... The mechanism of salvia in treating liver fibrosis may be multisided and very complex, and the mechanism of salvia in inducing HSC apoptosis remains for further study.

Some further study has been conducted, indicating that a particular protein (caspase-3) is expressed in HSC exposed to this salvia component, which may contribute to apoptosis of the cells (8).

BRIEF OUTLINE OF THE REVIEW ARTICLE
ON TREATMENTS FOR LIVER FIBROSIS (6)

The review article in the Journal of Integrated Traditional and Western Medicine relays information from articles published from 1992-2001. It concisely mentions test methods and results with some complex formulas, single herbs, and active components. Here are the therapies reported:

SUMMARY AND ANALYSIS

The reports mentioned here include laboratory studies (both cell cultures and animal tests) and clinical trials. The principle of vitalizing blood circulation is the dominant therapy claimed to be of some benefit, and key herbs are salvia, tang-kuei, persica, notoginseng, curcuma, and red peony. A few other herbs commonly used to treat liver diseases are sometimes used as well, including bupleurum and white peony. Tonic herbs are mentioned in some cases, the main ones being astragalus and atractylodes. Licorice, which is classed with the qi tonics, is the only herb included in these studies for which a possible viral inhibitory action has been proposed; all the other herbs are thought to primarily impact the process by which a virus (or chemical assault) induces fibrosis.

There are several mechanisms by which the herbs can inhibit liver fibrosis, including: inhibition of hepatic stellate cells; reduced production and deposition of fibrotic materials (e.g., collagen); regulation of cytokines; reduction in oxidation reactions; and possible degradation and reabsorption of fibrotic materials. These, and other possible mechanisms, may be triggered by a single herb with multiple actions (as proposed, for example, with salvia). Alternatively, several mechanisms that ultimately serve to reduce fibrosis may be stimulated by properly combining herbs, each of which impacts one or two of the mechanisms.

The laboratory studies described here are especially relevant to acute processes of liver damage, but don't readily address the problem of chronic liver disease. The clinical studies involved patients with advanced hepatitis B disease, the most common chronic hepatovirus infection that occurs in the Chinese population. There is no reason to believe that the effects would be any different with hepatitis C.

Treatment times for clinical evaluations ranged from a minimum of three months up to a maximum of three years. Unless the underlying cause of liver fibrosis is removed, the treatment may need to be continued indefinitely, or, at the least, repeated from time to time. Some herbal materials have been proposed as viral inhibitors, such as oxymatrine (from sophora root) and glycyrrhizin (from licorice root). However, it is unclear whether these herbs or isolated active components can completely remove the virus, as opposed to only reducing its activity while the substances are administered.

Imperfections in the research methodology and reporting limit the interest that can be generated among researchers outside China to pursue the Chinese herb treatment of liver fibrosis in greater detail. However, Chinese researchers have already provided adequate data on the effects of salvia to justify further expenditure on research in this area. Salvia has the advantages of being non-toxic, inexpensive, readily available, well-defined chemically, and already subjected to numerous pharmacology studies revealing mechanism of action (5, 8, 9, 10, 11, 12, 13) and clinical trials suggesting positive effects (1, 3, 14, 15). It is possible that results superior to using salvia alone might be attained by utilizing a small herb formula in which salvia is a key ingredient, but further confirmation of salvia's effects-or that of its active components-would be essential in order to form the basis for future study of a more complex therapy.