Update on Clinical Effects and Safety
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.
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).
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.