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The effects of a herbal medicine (Mao-to) in patients with chronic hepatitis C after injection of IFN-[beta].

Summary

We found that a herbal medicine (Mao-to) relieves the side effects of interferon (IFN)-[beta] and the combination therapy improves the biochemical response rate. However, the exact mechanism by which Mao-to is effective remains to be established. We conducted a controlled trial to clarify the effects of Mao-to. The study was carried out in 18 patients with chronic hepatitis C, and we examined subjective symptoms, body temperature and cytokines such as interleukin (IL)-1[beta], IL-1receptor antagonist (ra), IL-6 and TNF-[alpha]. Each patient received 6 million units of IFN-[beta] intravenously. Mao-to was given orally just before, just after, and 1 hour after IFN administration. The control study was carried out 6 months after the combination therapy of Mao-to and IFN-[beta]. The scores for general malaise, arthralgia and discomfort were significantly lower in the combination group than in control group. Body temperature did not significantly differ between the two groups. Plasma IL-6 level and IL-1ra were significantly elevated in the combination group compared to control (P = 0.0057 and 0.0003, respectively). Mao-to did not affect plasma concentrations of IL-1[beta] and TNF-[alpha]. We considered the increment of IL-1ra caused by Mao-to is to be one of the key factors involved in reducing the flu-like symptoms accompanying IFN-[beta] and improving the biochemical response rate.

Key words: herbal medicine, Mao-to, IFN-[beta], IL-6, IL-1ra

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Introduction

Interferon (IFN) is now in worldwide use in the treatment of chronic hepatitis C, and it has been reported that IFN has been associated with a decreased incidence of hepatocellular carcinoma (Yoshida et al. 1999; Nishiguchi et al. 1995). Therefore, we consider that all patients with chronic HCV infection are, in principle, candidates for antiviral therapy. However, side effects are problematic, as IFN is poorly tolerated by some patients resulting in dose and/or duration restrictions of the therapy (Dusheiko et al. 1997).

The most common and predictable adverse events of IFN are flu-like symptoms such as fever, general malaise and discomfort. Those symptoms occur in almost all patients, and they can be controlled by the administration of nonsteroidal anti-inflammatory drugs. However, in some patients, these flu-like symptoms become severe and necessitate a reduction in dose or the complete cessation of treatment (Dusheiko et al. 1997; Soma et al. 2001; Shiratori et al. 2000). Accordingly, controlling the side effects of IFN is important, and in this respect we found that a herbal medicine (Mao-to) ameliorates these effects (Kainuma et al. 2002). Furthermore, we previously reported that combination therapy with Mao-to and IFN-[beta] increases the biochemical response rate in chronic hepatitis C, with a high viral load ([greater than or equal to]1 Meq/ml) of genotype 1b (Kainuma et al. 2002). However, the exact mechanism by which Mao-to is effective remains to be established. Therefore, we conducted a controlled trial to clarify the effect of Mao-to on subjective symptoms, body temperature and cytokines in patients treated with IFN-[beta].

Materials and Methods

Patients

Eighteen Japanese patients with chronic hepatitis C (6 males, 12 females; mean age 56.1 [+ or -] 9.6 years, range 38-69) were enrolled. In all patients the diagnosis of chronic hepatitis C was based on the following criteria: positivity for serum anti-HCV antibodies by second generation enzyme immunoassay (Orthro Diagnostic Systems, Raritan, NJ), presence of HCV-RNA in the serum by PCR, elevated serum levels of alanine aminotransferase (ALT) at least twice the upper limit of normal for more than 6 months before entry, and histological evidence of chronic hepatitis on liver biopsy. Patients with liver cirrhosis, lung fibrosis and emphysema were excluded from the study. All patients were seronegative for HBsAg and anti-HIVAb. None of the patients had been treated with IFN previously. The baseline characteristics of the patients prior to combination therapy with Mao-to and IFN-[beta] are shown in Table 1.

The study was approved by the Human Subjects Committee of Toyama Medical and Pharmaceutical University. All subjects gave written informed consent in accordance with the ethical guidelines set forth in the 1975 Declaration of Helsinki.

Crude drugs

The component drugs of Mao-to are shown in Table 2.

Management protocol

On the first day, each patient received 6 million units (MU) of IFN-[beta] (human fibroblast IFN, Feron, Toray Industries Inc., Tokyo, Japan) dissolved in 100 ml of saline and drip-infused iv for 30 min starting at 9 am. Mao-to was given orally just before, just after, and 1 hour after IFN administration. Combination therapy of Mao-to and IFN-[beta] was conducted continuously for 8 weeks. and after that, IFN was not given until the control study.

The control study was carried out as follows. After 6 months of combination therapy with Mao-to and IFN-[beta] by the above schedule, each patient received a dose of 6 MU of IFN-[beta] dissolved in 100 ml of saline and drip-infused iv for 30 min starting at 9 am (Fig. 1).

To analyze the levels of cytokines, venous blood was drawn from the brachial vein at 60, 90, 120, 150 and 180 min after the end of infusion. The severity of symptoms was classified into 4 categories (1: none, 2: very slight, 3: moderate, 4: serious) using self-reporting system consisting of 29 questions. Body temperature was measured in the axilla every hour after the infusion of IFN-[beta] for 3 hours.

Measurement of cytokines

Plasma cytokine levels of interleukin (IL)-1[beta], IL-6, IL-1receptor antagonist (IL-1ra), and tumor necrosis factor-[alpha] (TNF-[alpha]) were measured by sensitive enzymelinked immunosorbent assay (ELISA) using commercially available kits (IL-1[beta], IL-6, IL-1ra: R & D Systems Inc., Minneapolis, MN; TNF-[alpha]: Amersham International plac, Buckinghamshire, England). The cytokine ELISA kits had sensitivities of 0.13 pg/ml, 0.38 pg/ml, 85 pg/ml and 0.3 pg/ml for IL-1[beta], IL-6, IL-1ra and TNF-[alpha], respectively.

Statistical analysis

The results of the symptom score are expressed as mean [+ or -] S.D. and body temperature and cytokines are expressed as mean [+ or -] S.E. Repeated measure ANOVA (Analysis of variance), Mann-Whitneys' U test, and Students' t test were used for comparison, with a P-value of <0.05 being considered significant.

Results

Effect of Mao-to on flu-like symptoms induced by IFN-[beta]

We compared subjective symptoms in patients treated with IFN-[beta] + Mao-to (combination group) to those of patients treated with IFN-[beta] alone (control group) (Table 3). At one hour after the administration of IFN-[beta], the scores of general malaise, arthralgia and discomfort were significantly lower in the combination group than in the control group (general malaise: 1.8 [+ or -] 0.9 vs 2.6 [+ or -] 1.0, p < 0.05; arthralgia: 1.6 [+ or -] 1.0 vs 2.2 [+ or -] 1.1, p < 0.05; discomfort: 1.4 [+ or -] 0.8 vs 2.2 [+ or -] 1.2, p < 0.05). Two hours after the administration of IFN-[beta], the same symptoms were lower in the combination group than in the control group (general malaise: 1.9 [+ or -] 0.8 vs 2.9 [+ or -] 1.1, p < 0.01; arthralgia: 1.8 [+ or -] 1.1 vs 2.6 [+ or -] 1.1, p < 0.05; discomfort: 1.4 [+ or -] 0.9 vs 2.4 [+ or -] 1.3, p < 0.05). Moreover, the scores for general malaise and discomfort were significantly lower in the combination group than in the control group 3 hours after the administration of IFN-[beta] (general malaise: 1.8 [+ or -] 0.8 vs 2.9 [+ or -] 1.1, p < 0.01; discomfort: 1.4 [+ or -] 0.9 vs 2.2 [+ or -] 1.1, p < 0.05).

[FIGURE 1 OMITTED]

All patients in combination group were perspirating from 2 hours after the end of IFN-[beta] administration, on the other hand, perspiration was almost absent in the control group at the same time point.

Effect of Mao-to on body temperature change after IFN-[beta] injection

During the pretreatment period, there was no significant difference between the combination and control groups in terms of body temperature. After IFN-[beta] injection, it elevated gradually, reaching the maximum at 3 hours. There was no significant difference between the two groups (Fig. 2).

Effect of Mao-to on plasma cytokine levels

Plasma IL-6 and IL-1ra levels were not significantly different between the combination and control groups during the pretreatment period. Thereafter, the plasma IL-6 levels gradually increased in both groups, with the highest levels being observed 120 min after the end of IFN administration, and they gradually decreased. But the combination group showed significantly higher IL-6 levels than the control group (P = 0.0057), especially, at 60, 120 and 180 min (Fig. 3). On the other hand, plasma IL-1 ra showed a gradual increase, with the highest levels being observed 180 min after the end of IFN administration. The combination group showed a significantly higher IL-1ra than the control (P = 0.0003), especially, at 90, 120, 150 and 180 min (Fig. 4). Plasma concentration of IL-1[beta] and TNF-[alpha] were below the assay sensitivity on most occasions.

Discussion

We recently reported that the scores of fever, general malaise and discomfort on the first day are significantly lower in the IFN + Mao-to group than in the IFN-alone group (Kainuma et al. 2002). However, the study was not conducted in a randomized controlled manner. In this study, we conducted a self-controlled trial. General malaise and discomfort were reduced significantly in the combination group in comparison with the control group during the observation periods. From these results, it became apparent that Mao-to is effective in reducing flu-like symptoms, and especially those of general malaise and discomfort. Furthermore, an interesting finding was that, although maximum body temperature did not differ in the two groups 3 hours after IFN-[beta] administration, the patients experienced less general malaise and discomfort in the combination group. Because we have already experienced that flu-like symptoms were relieved by perspiration after body temperature were elevated in combination therapy of Mao-to and IFN-[beta], we have thought that perspiration would be important to relieve flu-like symptoms. In this study, all combination group patients were perspirating from 2 hours after the end of IFN-[beta] administration, but the perspiration was almost absent in the control group at the same time point. We considered that the effect of Mao-to in reducing flu-like symptoms such as general malaise and discomfort could be attributed to perspiration, despite maximum body temperature was not significant different between two groups.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

It has been reported that IL-6 is a key factor in symptom formation in influenza virus infection (Hayden et al. 1998), and IL-6 may have a role in mediating the expression of symptoms and signs during influenza virus A infection (Skoner et al. 1999). In addition, it was reported that IL-6 was at least partly involved in the production of fever and flu-like symptoms in treatment with a deoxycytidine analogue (Masuda et al. 1998). Refering to these facts, we examined the plasma IL-6 level in this study, and we found that it was significantly increased after IFN-[beta] administration in both groups, but that the level in the combination group was significantly higher than that in the control. Contrary to previous reports, the formation and severity of flu-like symptoms and the plasma IL-6 level were not correlated in this study. Additionally, an interesting observation was that general malaise and discomfort were significantly relieved in the combination group despite a significant increment in IL-6, because a low dose of IL-6 (0.5 [micro]g/kg body wt.) is associated with an increased level of fatigue, inactivity and concentration difficulties in humans (Spath-Schwalbe et al. 1998).

Another finding in this study was that the plasma IL-1ra concentration was also significantly increased after IFN-[beta] administration in both groups. Recently, Ohno et al. reported that plasma IL-6 and IL-1ra levels significantly increased after IFN-[beta] injection (Ohno et al. 1998), and our results are compatible with their findings. In this regard, a particularly important findings is that plasma IL-1ra was significantly increased in the combination group compared to that in the control group, and this may be interpreted to indicate that this significant IL-1ra increment is one of the key factors in reducing flu-like symptoms. However, as flu-like symptoms were relieved in the combination group in comparison to those in the control despite the fact that plasma IL-1ra did not significantly differ between the two groups at one hour post IFN-[beta] administration, it must be assumed that other factors were also induced by the ingestion of Mao-to. This latter point remains to be proven. We hypothesized that suppression of IL-1 production is one of the mechanism by which Mao-to reduced flu-like symptoms. Kakkon-to, which is used for the improvement of symptoms in acute phase of influenza infection was reported to suppress IL-1[alpha] production responsive to IFN (Kurokawa et al. 1996). Mao-to is also used for this purpose, and Ephedra herba, Cinnamomi Cortex and Glycyrrhizae Radix are common composition between Mao-to and Kakkon-to. However, IL-1 was not detected from plasma in almost all patients, further studies are needed to prove our hypothesis.

It was reported that adrenaline infusion increases the plasma concentration of IL-6 (Sondergaard et al. 2000). HPLC analysis demonstrated that ephedrine is a major component of Mao-to, and the daily dose of Mao-to extract contained 23.8 [+ or -] 2.7 mg of ephedrine (Kainuma et al. 2002). There are close similarities between the pharmacological effects of adrenaline and ephedrine, as both of them act as adrenergic agents. Therefore, we considered that Mao-to could increase endogenous adrenaline, and thereby increase the plasma IL-6 level.

The administration of IL-6 in humans is reported to cause the induction of circulating IL-1ra (Tilg et al. 1994), and it has been reported that the concentration of IL-1ra increased following an increase in the concentration of IL-6 after adrenaline infusion (Sondergaard et al. 2000). Our data is in accord with these previous reports, as increased plasma IL-6 levels were followed by increased plasma IL-1ra levels. IL-1ra is a member of the IL-1 family that antagonizes the effects of both IL-1[alpha] and IL-1[beta] by blocking the binding of IL-1 to cell surface receptors (Arend, 1991; Dinarell et al. 1991). Therefore, our data suggested that the biological activity of IL-1 was more reduced in the combination group than in control. IL-1 is presumed to be a mediator of hepatitis (Kishihara et al. 1996; Itoh et al. 1995), and an increase in IL-1ra possibly suppresses liver inflammation through a reduction in IL-1 activity.

Furthermore, IL-6 has been shown to have an anti-inflammatory effect via synthesis of IL-1ra (Tilg et al. 1994; Jordan et al. 1995). Based on our findings, it is suggested that an increase in IL-1ra following an increment of IL-6 could reduce the serum ALT level and lead to an increase in biochemical responders, which was supported by our clinical evidence that combination therapy with Mao-to and IFN-[beta] might increase the biochemical response rate in chronic hepatitis C with a high viral load ([greater than or equal to]1 Meq/ml) of genotype 1b (Kainuma et al. 2002). Moreover, in this study, 9 of the eighteen patients (50%) have become biochemical responders (data not shown).

In summary, we demonstrated in this study that the flu-like symptoms induced by IFN-[beta] were reduced by ingesting Mao-to, and that Mao-to elevated the plasma IL-6 and IL-1ra levels. Moreover, it is suggested that the increment of IL-1ra induced by the intake of Mao-to is one of the key factors in reducing the flu-like symptoms accompanying IFN-[beta] and improving the biochemical response rate. Nevertheless, the mechanisms of Mao-to remain unclear, and further studies are required.
Table 1. Characteristics of 18 patients enrolled in this study.

Age Range (years) 38-69
 Mean [+ or -] SD 56.1 [+ or -] 9.6
Sex (M/F) 6/12
ALT (IU/I) Range 40-277
 Mean [+ or -] SD 105.8 [+ or -] 56.9
HCV-RNA (KIU/ml)* Range 39-780
 Mean [+ or -] SD 443.2 [+ or -] 239.7
Histological stage of Liver fibrosis (F1/F2/F3) 6/8/4

* Serum HCV RNA levels were tested by commercial PCR (Amplicore HCV
v2.0)

Table 2. Constituent list of Mao-to.

Ephedrae Herba 6.0 g
Armenicae Cortex 6.0 g
Cinnamomi Cortex 4.0 g
Glycyrrhizae Radix 2.0 g

Mao-to was decocted with 600 ml water in an earthen teapot on an
electric heater (Toshiba; HP-634 600 W) for 40 minutes until the volume
of extractant was reduced to about 300 ml.

Table 3. Subjective symptom after IFN-[beta] administration.

 1 hour 2 hour
 control combination control

general
 malaise 2.6 [+ or -] 1.0 1.8 [+ or -] 0.9* 2.9 [+ or -] 1.1
arthralgia 2.2 [+ or -] 1.1 1.6 [+ or -] 1.0* 2.6 [+ or -] 1.1
discomfort 2.2 [+ or -] 1.2 1.4 [+ or -] 0.8* 2.4 [+ or -] 1.3
appetite loss 1.3 [+ or -] 0.5 1.6 [+ or -] 0.9 1.7 [+ or -] 1.0
vomiting 1.4 [+ or -] 0.9 1.2 [+ or -] 0.5 1.7 [+ or -] 1.1
headache 2.1 [+ or -] 1.1 1.7 [+ or -] 0.8 2.1 [+ or -] 1.1
thirst 2.0 [+ or -] 1.1 1.6 [+ or -] 1.0 2.0 [+ or -] 1.1
chest
 oppression 1.6 [+ or -] 0.9 1.1 [+ or -] 0.3 1.6 [+ or -] 1.0
chills 1.4 [+ or -] 0.7 1.3 [+ or -] 0.8 1.7 [+ or -] 0.9

 2 hour 3 hour
 combination control combination

general
 malaise 1.9 [+ or -] 0.8** 2.9 [+ or -] 1.1 1.8 [+ or -] 0.8**
arthralgia 1.8 [+ or -] 1.1* 2.3 [+ or -] 1.0 1.9 [+ or -] 1.1
discomfort 1.4 [+ or -] 0.9* 2.2 [+ or -] 1.1 1.4 [+ or -] 0.9*
appetite loss 1.7 [+ or -] 0.8 2.1 [+ or -] 1.2 1.9 [+ or -] 1.0
vomiting 1.3 [+ or -] 0.7 1.7 [+ or -] 1.1 1.5 [+ or -] 0.9
headache 1.9 [+ or -] 0.9 2.1 [+ or -] 1.0 2.1 [+ or -] 1.1
thirst 1.8 [+ or -] 1.1 2.3 [+ or -] 1.1 1.9 [+ or -] 1.1
chest
 oppression 1.2 [+ or -] 0.4 1.5 [+ or -] 0.9 1.1 [+ or -] 0.3
chills 1.3 [+ or -] 0.6 1.3 [+ or -] 0.5 1.2 [+ or -] 0.4

Scoring: none, 1 point; very slight, 2 points; moderate, 3 points;
severe, 4 points
Note; data are mean [+ or -] S.D. * p < 0.05, ** p < 0.01


Acknowledgements

The authors wish to thank N. Kuribayashi for excellent assistance.

Abbreviations: HCV -- hepatitis C virus; IFN -- interferon; ALT -- alanine aminotransferase; IL -- interleukin; TNF -- tumor necrosis factor; IL-1ra -- interleukin-1 receptor antagonist

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M. Kainuma (1), S. Sakai (1), N. Sekiya (1), N. Mantani (2), N. Ogata (3), Y. Shimada (1), and K. Terasawa (1)

(1) Department of Japanese Oriental Medicine, Toyama Medical and Pharmaceutical University, Japan

(2) Department of Integrated Japanese Oriental Medicine, Faculty of Medicine, Gunma University School of Medicine, Japan

(3) Department of Clinical and Laboratory Medicine, Toyama Medical and Pharmaceutical University, Japan

Address

M. Kainuma, Department of Japanese Oriental Medicine, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan

Tel.: ++81-76-434-7393; Fax: ++81-76-434-0366; e-mail: Kainuma@ms.toyama-mpu.ac.jp
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Author:Kainuma, M.; Sakai, S.; Sekiya, N.; Mantani, N.; Ogata, N.; Shimada, Y.; Terasawa, K.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:9JAPA
Date:Jan 1, 2004
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