The objective of this study was to evaluate the effectiveness of traditional herbal medicines (Kampo) on the symptoms of Yusho. Yusho is a mass food poisoning that was caused by ingestion of rice oil contaminated with dioxins and related organochlorines in 1968. Patients with Yusho suffer from skin symptoms (acneform eruptions, liability to suppuration and pigmentation), respiratory symptoms (cough and expectoration of sputum), neurological symptoms (numbness and paresthesia of extremities), arthralgia and general fatigue, and no effective treatment has yet been developed. In this clinical trial, four Kampo formulae (Bakumondo-to, Keigai-rengyo-to, Gosha-jinki-gan and Hochu-ekki-to) were administered to four representative Yusho symptoms (respiratory, skin, neurological symptoms and general fatigue), respectively. Twenty-seven Yusho patients were enrolled and two formulae were administered to each patient for half-a-year each. The effectiveness of Kampo formulae was estimated by changes in the intensity of symptoms measured by a visual analogue scale (VAS) of 100 mm recorded at baseline and after administration of each formula. The influence of Kampo formulae on patients’ quality of life (QOL) was also assessed by the SF-36 (NBS). Twenty-five patients completed the treatment. Bakumondo-to significantly improved respiratory symptoms as well as patients’ QOL in the context of vitality, compared with other formulae. In contrast, Hochu-ekki-to impaired patients’ QOL in the context of physical functioning and vitality, compared with other formulae. This study demonstrated for the first time that a Kampo formula Bakumondo-to is useful for treating respiratory symptoms caused by dioxins.
A mass food poisoning involving at least 1900 individuals occurred in western Japan in 1968, which was later referred to as Yusho oil disease because it was caused by the ingestion of rice bran oil contaminated with dioxins, polychlorinated biphenyls (PCBs) and other related organochlorine compounds [
Kampo is a traditional herbal medicine that originated in China, and has been developed into a unique form in Japan. Each Kampo formula comprises several herbal extracts intended to increase the treatment effects and to diminish the adverse reactions of each herb, and is selected according to the pharmacological features and constitution of each patient [
Patients aged
Each Kampo formula was manufactured as a spray-dried powder of hot water extracts obtained from several medicinal plants. The daily dose of each formula was 7.5 g, except Bakumondo-to (9 g), and was administered orally three times a day before each meal. Nine grams of Bakumondo-to contained 6 g of extracts from 10 g enlarged part of the root of
The primary endpoint was the intensity of symptoms measured on a visual analogue scale (VAS) of 100 mm. The target symptoms were general fatigue for Hochu-ekki-to, skin symptoms (acneform eruptions, liability to suppuration and pigmentation) for Keigai-rengyo-to, neurological symptoms (numbness and paresthesia of extremities) for Gosha-jinki-gan, and respiratory symptoms (cough and expectoration of sputum) for Bakumondo-to. Secondary endpoints were the intensity of other symptoms for which each Kampo formula was not specifically targeted, patients’ QOL evaluated by the SF-36 (NBS) [
Primary and secondary endpoints were measured at baseline and after each treatment. Laboratory tests were additionally conducted when possible side effects were observed, or optionally with any other reasons. The VAS and SF-36 were measured by trained nurses who had experience in communicating with Yusho patients. A VAS was a horizontal line, 100 mm in length, and the left-hand end (0 mm) represented no symptom, whereas the right-hand end (100 mm) represented the severest symptom. At baseline and after each treatment, patients received a questionnaire having four lines of VAS for four symptoms. Trained nurses then asked patients to mark the point on the line which they represented their current state of their symptoms. Nurses determined the VAS score by measuring in millimeters from the left-hand end to the point that patients had marked. Blood samples were collected by the medical doctors and measured by a contracted research company. Blood concentrations of dioxins, PCBs and PCQ were measured by Fukuoka Institute of Health and Environmental Sciences, Fukuoka, Japan. The detailed method to measure the organochlorine compounds is described by Todaka et al. [
Due to the limited number of Yusho patients, two formulae were administered to each patient for half-a-year each. Sample size could not be statistically defined, because no background information was available on the VAS for the symptoms in Yusho patients. The maximum number of eligible patients was estimated to be 100, considering the location of residence and the health condition of patients. The prevalence of general fatigue, skin symptoms, neurological symptoms and respiratory symptoms was estimated to be 60, 30, 50 and 60%, respectively, by annual medical health check-ups from 2001 to 2003 for Yusho patients [
When a candidate was recruited, the minimum information sufficient for the allocation was sent to one of the authors (S. Tokunaga). If the patient complained of more than two symptoms, two symptoms were selected according to severity of the symptoms, request of the patients and evenness of the number of formulae to be allocated. The order of the symptoms for which the Kampo formulae were prescribed was allocated by the minimization method stratified by age (
Analysis of the primary endpoint, the effectiveness of the Kampo formulae measured by the changes in VAS from the baseline value, was evaluated by the Student's
The flowchart of patients through the study is shown in Figure
Flow of patient through the study.
Registration of patients followed by the first treatment occurred from October 26, 2005 to October 12, 2006. During the first treatment, the number of patients prescribed with Hochu-ekki-to, Keigai-rengyo-to, Gosha-jinki-gan and Bakumondo-to, was 5, 8, 8 and 6, respectively. One patient prescribed with Hochu-ekki-to and one with Gosha-jinki-gan withdrew from the trial after the first administration.
The second treatment started on April 12, 2006 and ended on March 29, 2007. During the second treatment, Hochu-ekki-to, Kaigai-rengyo-to, Gosha-jinki-gan and Bakumondo-to were administered to 9, 5, 5 and 6 patients, respectively. The second treatment ended between September 28, 2006 and October 18, 2007. In total, Hochu-ekki-to, Kaigai-rengyo-to, Gosha-jinki-gan and Bakumondo-to were administered to 14, 13, 13 and 12 patients, respectively. Details of the combination of formulae administered to each patient were shown in Table
Combination of Kampo formulae administered to each patient.
Second formula | ||||||
---|---|---|---|---|---|---|
Hochu-ekki-to | Keigai-rengyo-to | Gosha-jinki-gan | Bakumondo-to | (Withdrew) | Total | |
First formula | ||||||
Hochu-ekki-to | — | 1 | 3 | 0 | 1 | 5 |
Keigai-rengyo-to | 4 | — | 1 | 3 | 0 | 8 |
Gosha-jinki-gan | 4 | 0 | — | 3 | 1 | 8 |
Bakumondo-to | 1 | 4 | 1 | — | 0 | 6 |
Total | 9 | 5 | 5 | 6 | 2 | 27 |
Of the 27 patients aged 51–86 years (mean = 69.4, standard deviation (SD) = 7.9) who participated in this trial, 16 were men (59.3%) and 11 were women (40.7%). They were from Fukuoka (10 patients), Nagasaki (8 patients) and Hiroshima (9 patients) prefectures. The geometric mean blood concentrations (pg/g lipid) (5 to 95 percentiles) of dioxins and PCBs were 11.8 (9.3, 16.3) for 1,2,3,7,8-penta-CDD, 2.8 (2.3, 3.7) for 1,2,3,4,7,8-hexa-CDD, 46.0 (31.1, 76.8) for 1,2,3,6,7,8-hexa-CDD, 3.6 (2.9, 5.5) for 1,2,3,7,8,9-hexa-CDD, 43.3 (29.6, 54.5) for 1,2,3,4,6,7,8-hepta-CDD, 702.2 (456.8, 987.9) for octa-CDD, 1.7 (1.3, 3.1) for 2,3,7,8-tetra-CDF, 132.9 (78.5, 385.1) for 2,3,4,7,8-penta-CDF, 29.5 (15.2, 54.2) for 1,2,3,4,7,8-hexa-CDF, 15.3 (8.1, 20.8) for 1,2,3,6,7,8-hexa-CDF, 101.4 (68.2, 172.8) for 3,3′,4,4′,5-penta-CB (#126) and 198.9 (160.7, 261.5) for 3,3′,4,4′,5,5′-hexa-CB (#169). The geometric mean (5 to 95 percentile) blood concentration for PCQ was 0.6 (0.0, 4.4) ng/g.
Changes in the intensity of symptoms measured by VAS from baseline to the end of administration of formulae in each patient were presented in Figure
Changes in the intensity of symptoms by Kampo formulae in each patient. The intensity of symptoms was measured by VAS at the baseline and after treatment of 6 months. The values of the same patient were connected by the solid line if the symptom was targeted by the formula, or by the dashed line otherwise.
The effectiveness of Kampo formulae on the target symptom; the primary endpoint. The target symptoms were general fatigue for Hochu-ekki-to, skin symptoms for Keigai-rengyo-to, neurological symptoms for Gosha-jinki-gan and respiratory symptoms for Bakumondo-to. The effectiveness of the Kampo formulae was evaluated by changes in intensity of the symptoms from baseline to the end of administration, which was measured by VAS. Differences in effectiveness between the formulae administered for the target symptom and other formulae for the same symptom are shown. Data are means (dots) and 95% confidence intervals (bars). Bakumondo-to significantly improved respiratory symptoms compared with other formulae.
The effectiveness of Kampo formulae on symptoms other than the target; the secondary endpoints. The effectiveness of the Kampo formulae was evaluated by changes in intensity of the symptoms from baseline to the end of administration, which measured by VAS. Differences in effectiveness between the formulae for symptoms other than the target symptom are shown. Data are means (dots) and 95% confidence intervals (bars). The effectiveness of the formulae was not statistically significant, except for Keigai-rengyo-to, which worsened general fatigue by a marginal significance (
The baseline scores on the SF-36 (mean (SD)) were 36.9 (14.3) for physical functioning, 34.9 (10.8) for role physical, 38.0 (10.2) for bodily pain, 38.3 (9.8) for general health, 41.8 (9.5) for vitality, 39.3 (10.4) for social functioning, 35.5 (12.5) for role emotional, and 42.4 (9.3) for mental health. The comparison of changes in patients’ QOL from baseline after administration of Kampo formulae is shown in Figure
Changes in SF-36 from baseline values after administration of Kampo formulae. The influence of the Kampo formulae on patients’ QOL was evaluated by changes in SF-36 from baseline to the end of administration. Differences in influence on the scores of SF-36 between the formulae are shown. Data are means (dots) and 95% confidence intervals (bars). Bakumondo-to significantly improved patients’ QOL in the context of vitality, whereas Hochu-ekki-to significantly impaired patients’ QOL in the context of physical functioning and vitality, compared with other formulae.
The comparison of changes in blood concentrations of dioxins, PCBs and PCQ did not show any statistically significant differences between the Kampo formulae, except for 1,2,3,6,7,8-hexa-CDF, which was not a causative toxic compound for Yusho (data not shown). The concentration of 1,2,3,6,7,8-hexa-CDF decreased by 22% compared to other formulae (
In the present study, Bakumondo-to significantly improved respiratory symptoms (cough and expectoration of sputum) of Yusho compared with other formulae. Bakumondo-to also improved patients’ QOL in the context of vitality. On the other hand, Keigai-rengyo-to did not improve skin symptoms of Yusho, but marginally worsened general fatigue compared with other formulae. Hochu-ekki-to did not reduce general fatigue in Yusho patients, but impaired patients’ QOL in the context of physical functioning and vitality compared with other formulae, suggesting that it may not be appropriate to prescribe Keigai-rengyo-to and Hochu-ekki-to for Yusho patients. Gosha-jinki-gan did not demonstrate any influence on the symptoms of Yusho. In this study, patients were administered two Kampo formulae for half-a-year each. Although we did not observe any unusual effects by any combination of formulae, and Bakumondo-to constantly improved respiratory symptoms irrespective of combinations, contaminations of other formulae to the effectiveness on the target symptom would not be excluded completely, because statistical analyses were not available due to very limited number of patients in each combination. Additionally, none of the Kampo formulae produced serious adverse effects, and blood concentrations of dioxins and related compounds were little affected by the Kampo formulae. Although 40 years have passed since the outbreak of Yusho, and most patients still suffer from various symptoms [
Another alternative treatment for Yusho would be antagonistic compounds against the aryl hydrocarbon receptor (AhR), which is well known as a receptor for dioxins and other polycyclic aromatic hydrocarbons [
The intensity of respiratory symptoms, such as cough and expectoration of sputum, were shown to be significantly correlated with blood concentrations of dioxins in Yusho patients [
Hypothetical diagrams of the effect of Bakumondo-to. (a) After ligation of dioxins to the AhR, the receptor translocates from the cytosol to the nucleus, binds to DRE
In conclusion, we have demonstrated for the first time that a Kampo formula, Bakumondo-to, significantly improved respiratory symptoms (cough and expectoration of sputum) of Yusho compared with other formulae. This formula may be effective for the treatment of respiratory symptoms of patients intoxicated with other dioxins, such as 2,3,7,8-tetra-CDD.
The authors thank Yasue Iio, Sachiyo Tadakuma and Mikiko Yamane for their technical assistance. Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, Japan. H. Uchi and S. Tokunaga contributed equally to this work.