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The Vitamin A derivative etretinate improves skin sclerosis in patients with systemic sclerosis
Journal of Dermatological Science (2004) 34, 62—66
LETTER TO THE EDITOR
The Vitamin A derivative etretinate improves skin sclerosis in patients with systemic sclerosis Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular damage and fibrosis of the skin and various internal organs. The mechanisms responsible for the tissue changes remain unclear, but it is thought that key cytokines may induce the vascular damage and the accumulation of excessive extracellular matrix that the fibroblasts produce. The treatments for SSc are aimed at symptomatic relief, and it is often difficult to change the course of this disease. When systemic corticosteroids or immunosuppressants are used for the systemic involvement, we often observe that the skin sclerosis is also improved in many cases. However, there are few specific treatments for skin sclerosis caused by SSc. Therefore, we treated certain SSc patients with the Vitamin A derivative etretinate orally. It is typically used for psoriasis, pustulosis palmaris et plantaris, and other conditions to normalize the epidermal cell turnover time. The aim was to prospectively evaluate the advantages of etretinate for the treatment of skin sclerosis in patients with SSc compared with a control group using the modified Rodnan total skin thickness score. We enrolled 31 SSc cases whose sclerotic changes had been followed up from their first visit (Table 1). Twelve cases that gave their informed consent in writing to the institutional ethics committee or the old Nippon Roche K.K. (present CHUGAI PHARMACEUTICAL CO., LTD) were treated with etretinate orally (Groups 1 and 2 in Tables 1 and 2). One of these 12 cases was Barnet I, 5 were Barnet II, and 6 cases were Barnet III. Five were treated concurrently with other agents, such as systemic corticosteroids, immunosuppressants, d-penicillamine, methotrexate, bucillamine and/or UVA irradiation. Nineteen cases were not treated with etretinate (Groups 3 and 4 in Tables 1 and 2). Six of these cases 19 cases were Barnet I, five were Barnett II, and eight cases were Barnet ifi. Thirteen of the 19 cases were treated concurrently with other therapeutic agents. One of them was treated with systemic corticosteroids and UVA1 irradiation. Six cases did not receive etretinate or any other therapies except for vasodilators, ointments, etc. The initial oral dose
of etretinate was 0.5 mg/kg per day, and it was tapered after the skin sclerosis improved or when any side effects appeared. We used the modified Rodnan total skin thickhess score to assess the degree of skin sclerosis due to SSc [1]. In each case, a significant improvement was defined as when the score after the start of treatment with etretinate or other therapies and the sustained score was reduced to less than 75% of the score when the treatments was started. This definition was referred to the standard that Binks et al. defined [2]. In each group, the mean ± S.D. of the first scores and the sustained scores of all cases were compared using Student’s t test. P-values less than 0.01 were regarded as stafistically significant. The results of the one-way ANOVA test and Fisher’s PLSD test by Stat View 5.0 showed that there were no significant differences in disease duration among each group. As shown in Tables 1—3, significant improvements were obtained in 60% of the Group 2, and in 85.7% of Group 1. However, these improvements did not occur in the control cases that did not receive etretinate. Only one case from Group 4 had the improvement. Fig. 1 shows the changes in the scores from the significantly improved cases in Group 1. In all cases treated with etretinate, and in Group 1, the mean sustained scores decreased significantly compared with the scores when the first treatments were started (P < 0.01). In Group 2, the improvement was not statistically significant, but there was a trend for the scores to decrease. Hyperlipidemia, alopecia, chilitis, and other side effects appeared as a result of etretinate treatment. However, they were not serious, and most of them disappeared when we tapered the dose of etretinate or added symptomatic treatments. Specifically useful treatments for the skin sclerosis due to SSc have not been established yet. Some systemic or topical treatments have been reported to be successful, such as dexamethasone pulse therapy, intravenous immunoglobulin therapy, cyclosporin A, methotrexate, d-penicillamine, bucillamine, etc. However, in most of these studies, the number of cases was not large and a control group was not included. In the case of retinoids, systemic or topical retinoids (etretinate, tretinoin,
0923-1811/$30.00 © 2003 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2003.11.007
Letter to the Editor
Table 1 Changes in the skin scores Duration till the score was reduced to less than 75% of the initial score in the definitely improved cases (months)
Score when the treatment with etretinate was started
Highest score after treatment with etretinate
Lowest score after treatment with etretinate
Sustained score
66 1 Unknown Unknown 60 1 47 72 54 Unknown 36 2 51 17
5 — 4 0.5 Unknown 0.75 7.25
15 5 6 8 31 29 17
15 5 6 8 31 29 19
3 5 3 1 17 17 8
4 5 4 1 17 18 8
I II III III
40 41 23 59
0.5 108 18 2
0.07 — 3.5 —
7 6 23 4
7 8 23 16
0 3 15 8
0 8 15 8
III
43
11
0.25
14
14
5
6
Group No. Etretinate Maximum doses of the other treatmentsa,b
Maximum Age at Barnet onset grade (years)
1
1 2 3 4 5 6 7
+ + + + + + +
− − − − − − −
II II II II III III III
2
8 9 10 11
+ + + +
12
+
PSL30 mga PSL10 mgb UVAb PSL pulseb CyA250 mgw MTX7.5 mgw BUC200 mgw MTX7.5 mga
Duration from onset to the treatment with etretinate (months)
PSL: prednisolone, MTX: methotrexate, CyA: cyclosporin A, BUC: bucillamine. b: an agent which was given before the treatment with etretinate was started, s: an agent which was given at the same time as when the treatment with etretinate was started, a: an agent which was given after the treatment with etretinate was started, w: an agent which was given after the treatment with etretinate was stopped. a Systemic corticosteroids, immunosuppressants, d-penicillamine, methotrexate, bucillamine, and/or UVA/UVA1 . b The dose of systemic corticosteroids is converted into prednisolone equivalents.
63
64
Table 2 Changes in the skin scores Maximum Barnet grade
Age at Duration from onset onset to the (years) treatment with etretinate (months)
Duration till the score was reduced to less than 75% of the initial score in the definitely improved cases (months)
Score when the treatment with etretinate was started
Highest score after treatment with etretinate
Lowest score after treatment with etretinate
Sustained score
3
I I II II III III I I I I
59 38 50 77 58 61 79 60 47 55
13 3 3 11 53 1 0 36 0 14
— — — — — — — — — —
6 3 5 9 13 6 4 3 4 2
9 3 8 9 13 7 7 6 4 3
9 3 3 9 13 7 7 6 4 3
9 3 5 9 13 7 7 6 4 3
II
41
65
—
3
7
3
3
II II
33 48
1 48
— —
11 5
11 5
11 5
11 5
III
51
11
—
11
15
10
15
III
61
8
—
17
19
19
19
III
54
3
—
19
22
12
22
III III
55 53
5 9
— 8
18 14
25 14
25 9
25 9
III
11
3
—
20
18
18
18
4
13 14 15 16 17 18 19 20 21 22
— — — — — — — — — —
23
—
24 25
— —
26
—
27
—
28
—
29 30
— —
31
—
− − − − − − PSL10 mg CyA150 mg PSL5 mg PSL15 mg + CyA150 mg PSL10 mg + BUC200 mg PSL30 mg BUC300 mg D-PC300 mg CyA150 mg PSL15 mg + CyA200 mg D-PC300 mg CyA75 mg PSL12.5 mg + CPA pulse D-PC200 mg PSL20 mg + BUC150 mg, CyA200 mg PSL10 mg + UVA1
PSL: prednisolone, MTX: methotrexate, CyA: cyclosporin A, BUC: bucillamine, d-PC: d-penicillamine, CPA: cyclophosphamide. a Systemic corticosteroids, immunosuppressants, d-penicillamine, methotrexate, bucillamine, and/or UVA/UVA1 . b The dose of systemic corticosteroids is converted into prednisolone equivalents.
T. Ikeda et al.
Group No. Etretinate Maximum doses of the other treatmentsa,b
Letter to the Editor
65
Table 3 Changes in the skin score of each group Group Etretinate Other Significantly treatmentsa improved casesb
Scores when first treatments were started (mean ± 1S.D.)
1 2 3 4
13.75 ± 9.53 15.86 10.80 9.11 ± 6.11 7.00 10.08
+ + − −
− + − +
6/7 (85.7%) 3/5 (60%) 0/6 (0%) 1/13 (7.7%)
± ± ± ±
10.65 7.79 3.52 6.90
Sustained scores (mean ± 1S.D.) 7.83 ± 5.94c 10.16 ± 6.74
8.14 7.4 7.67 11.3
± ± ± ±
6.72c 5.37 3.50 7.65
a
Systemic corticosteroids, immunosuppressants, d-penicillamine, methotrexate, bucillamine, and/or UVA/UVA1 . A significantly improvement was comfirmed when the score after the start of treatment with etretinate or other therapies and the sustained score after the start of treatments were reduced to less than 75% of the initial score. c Significantly decreased compared with the mean score when the first treatments were started (P < 0.01). b
isotretinoin, etc.) have been reported to be successful for the treatment of the skin sclerosis due to SSc [3,4]. Malcellus et al. suggested that treatment with etretinate orally for scierodermatous chronic graft-versus-host disease may present a new therapeutic option [5]. Retinoids decrease collagen production in an animal model, the tight skin mouse [6], and also in SSc human skin fibroblasts in vitro [7]. In this report, which had a small number of subjects, the mean sustained scores in all cases treated with etretinate decreased significantly compared with the mean scores when the first treatments were started. However, improvements were barely noticeable in all of the cases that did not receive etretinate. The cases from Groups 1 and 2 were the most successfully treated with etretinate, received it on
Fig. 1
their first visit. In contrast, it is well known that systemic corticosteroids and immunosuppressants are often used for the systemic involvements or rapidly progressing skin sclerosis. It is thought that etretinate should be used during the early stages of SSc, and could be administered specifically on the first visit for the skin involvements of SSc. The duration from the start of treatment to a definite improvement ranged from 0.5 to 7.25 months in Group 1 and from 2 days to 3.5 months in Group 2. Marcellus mentioned that 20 of the 27 sclerodermatous graft-versus-host disease patients also showed the improvements of the skin involvements after 3 months of treatment with etretinate [5]. It is thought that a period of time might be required till the effects of treatment with etretinate begin to appeare.
Changes in the scores of the significantly improved cases of Group 1.
66 These results suggest that etretinate is a specific and useful treatment for the sclerotic skin due to SSc.
References [1] Brennan P, Silman A, Black C, Bernstein R, Coppock J, Maddison P, Sheeran T, Stevens C, Woliheim F. Reliability of skin involvement measures in scleroderma. The UK Scleroderma Study Group. Br J Rheumatol 1993;31:457—60. [2] Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis 2001;60:577—84. [3] Bahmer FA, Zaun H. Isotretinain therapy for progressive systemic sclerosis. Arch Dermatol 1985;121:308. [4] Mizutani H, Yoshida T, Nouchi N, Hamanaka H, Shimizu M. Topical tocoretinate improved hypertropic scar, skin sclerosis in systemic sclerosis and morphea. J Dermatol 1999;26:11—7. [5] Marcellus DC, Altomonte VL, Farmer ER, Horn TD, Freemer CS, Grant J, et al. Etretinate therapy for refractory scierodermatous chronic graft-versus-host disease. Blood 1999;93:66—70. [6] Delany AM, Brinckerhoff CE. The synthetic retinoid (4-hydroxyphenyl)retinamide decreases collagen expression
T. Ikeda et al. in vitro and in the tight-skin mouse. Arthritis Rheum 1993;36:983—93. [7] Ohta A, Uitto J. Procollagen gene expression by scleroderma fibroblasts in culture. Inhibition of collagen production and reduction of pro alpha 1 (I) and pro alpha 1(III) collagen messenger RNA steady-state levels by retinoids. Arthritis Rheum 1987;30:404—11.
Takaharu Ikeda∗ Koji Uede Fukumi Furukawa Department of Dermatology Wakayama Medical Universityr 811-1 Kimiidera, Wakayama 641-0012, Japan Hideo Hashizume Department of Dermatology Hamamatsu University School of Medicine Hamamatsu, Japan ∗ Corresponding
author Tel.: +81-73-441-0661; fax: +81-73-448-1908 E-mail address: [email protected] (T. Ikeda) 13 November 2003
LETTER TO THE EDITOR
The Vitamin A derivative etretinate improves skin sclerosis in patients with systemic sclerosis Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular damage and fibrosis of the skin and various internal organs. The mechanisms responsible for the tissue changes remain unclear, but it is thought that key cytokines may induce the vascular damage and the accumulation of excessive extracellular matrix that the fibroblasts produce. The treatments for SSc are aimed at symptomatic relief, and it is often difficult to change the course of this disease. When systemic corticosteroids or immunosuppressants are used for the systemic involvement, we often observe that the skin sclerosis is also improved in many cases. However, there are few specific treatments for skin sclerosis caused by SSc. Therefore, we treated certain SSc patients with the Vitamin A derivative etretinate orally. It is typically used for psoriasis, pustulosis palmaris et plantaris, and other conditions to normalize the epidermal cell turnover time. The aim was to prospectively evaluate the advantages of etretinate for the treatment of skin sclerosis in patients with SSc compared with a control group using the modified Rodnan total skin thickness score. We enrolled 31 SSc cases whose sclerotic changes had been followed up from their first visit (Table 1). Twelve cases that gave their informed consent in writing to the institutional ethics committee or the old Nippon Roche K.K. (present CHUGAI PHARMACEUTICAL CO., LTD) were treated with etretinate orally (Groups 1 and 2 in Tables 1 and 2). One of these 12 cases was Barnet I, 5 were Barnet II, and 6 cases were Barnet III. Five were treated concurrently with other agents, such as systemic corticosteroids, immunosuppressants, d-penicillamine, methotrexate, bucillamine and/or UVA irradiation. Nineteen cases were not treated with etretinate (Groups 3 and 4 in Tables 1 and 2). Six of these cases 19 cases were Barnet I, five were Barnett II, and eight cases were Barnet ifi. Thirteen of the 19 cases were treated concurrently with other therapeutic agents. One of them was treated with systemic corticosteroids and UVA1 irradiation. Six cases did not receive etretinate or any other therapies except for vasodilators, ointments, etc. The initial oral dose
of etretinate was 0.5 mg/kg per day, and it was tapered after the skin sclerosis improved or when any side effects appeared. We used the modified Rodnan total skin thickhess score to assess the degree of skin sclerosis due to SSc [1]. In each case, a significant improvement was defined as when the score after the start of treatment with etretinate or other therapies and the sustained score was reduced to less than 75% of the score when the treatments was started. This definition was referred to the standard that Binks et al. defined [2]. In each group, the mean ± S.D. of the first scores and the sustained scores of all cases were compared using Student’s t test. P-values less than 0.01 were regarded as stafistically significant. The results of the one-way ANOVA test and Fisher’s PLSD test by Stat View 5.0 showed that there were no significant differences in disease duration among each group. As shown in Tables 1—3, significant improvements were obtained in 60% of the Group 2, and in 85.7% of Group 1. However, these improvements did not occur in the control cases that did not receive etretinate. Only one case from Group 4 had the improvement. Fig. 1 shows the changes in the scores from the significantly improved cases in Group 1. In all cases treated with etretinate, and in Group 1, the mean sustained scores decreased significantly compared with the scores when the first treatments were started (P < 0.01). In Group 2, the improvement was not statistically significant, but there was a trend for the scores to decrease. Hyperlipidemia, alopecia, chilitis, and other side effects appeared as a result of etretinate treatment. However, they were not serious, and most of them disappeared when we tapered the dose of etretinate or added symptomatic treatments. Specifically useful treatments for the skin sclerosis due to SSc have not been established yet. Some systemic or topical treatments have been reported to be successful, such as dexamethasone pulse therapy, intravenous immunoglobulin therapy, cyclosporin A, methotrexate, d-penicillamine, bucillamine, etc. However, in most of these studies, the number of cases was not large and a control group was not included. In the case of retinoids, systemic or topical retinoids (etretinate, tretinoin,
0923-1811/$30.00 © 2003 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2003.11.007
Letter to the Editor
Table 1 Changes in the skin scores Duration till the score was reduced to less than 75% of the initial score in the definitely improved cases (months)
Score when the treatment with etretinate was started
Highest score after treatment with etretinate
Lowest score after treatment with etretinate
Sustained score
66 1 Unknown Unknown 60 1 47 72 54 Unknown 36 2 51 17
5 — 4 0.5 Unknown 0.75 7.25
15 5 6 8 31 29 17
15 5 6 8 31 29 19
3 5 3 1 17 17 8
4 5 4 1 17 18 8
I II III III
40 41 23 59
0.5 108 18 2
0.07 — 3.5 —
7 6 23 4
7 8 23 16
0 3 15 8
0 8 15 8
III
43
11
0.25
14
14
5
6
Group No. Etretinate Maximum doses of the other treatmentsa,b
Maximum Age at Barnet onset grade (years)
1
1 2 3 4 5 6 7
+ + + + + + +
− − − − − − −
II II II II III III III
2
8 9 10 11
+ + + +
12
+
PSL30 mga PSL10 mgb UVAb PSL pulseb CyA250 mgw MTX7.5 mgw BUC200 mgw MTX7.5 mga
Duration from onset to the treatment with etretinate (months)
PSL: prednisolone, MTX: methotrexate, CyA: cyclosporin A, BUC: bucillamine. b: an agent which was given before the treatment with etretinate was started, s: an agent which was given at the same time as when the treatment with etretinate was started, a: an agent which was given after the treatment with etretinate was started, w: an agent which was given after the treatment with etretinate was stopped. a Systemic corticosteroids, immunosuppressants, d-penicillamine, methotrexate, bucillamine, and/or UVA/UVA1 . b The dose of systemic corticosteroids is converted into prednisolone equivalents.
63
64
Table 2 Changes in the skin scores Maximum Barnet grade
Age at Duration from onset onset to the (years) treatment with etretinate (months)
Duration till the score was reduced to less than 75% of the initial score in the definitely improved cases (months)
Score when the treatment with etretinate was started
Highest score after treatment with etretinate
Lowest score after treatment with etretinate
Sustained score
3
I I II II III III I I I I
59 38 50 77 58 61 79 60 47 55
13 3 3 11 53 1 0 36 0 14
— — — — — — — — — —
6 3 5 9 13 6 4 3 4 2
9 3 8 9 13 7 7 6 4 3
9 3 3 9 13 7 7 6 4 3
9 3 5 9 13 7 7 6 4 3
II
41
65
—
3
7
3
3
II II
33 48
1 48
— —
11 5
11 5
11 5
11 5
III
51
11
—
11
15
10
15
III
61
8
—
17
19
19
19
III
54
3
—
19
22
12
22
III III
55 53
5 9
— 8
18 14
25 14
25 9
25 9
III
11
3
—
20
18
18
18
4
13 14 15 16 17 18 19 20 21 22
— — — — — — — — — —
23
—
24 25
— —
26
—
27
—
28
—
29 30
— —
31
—
− − − − − − PSL10 mg CyA150 mg PSL5 mg PSL15 mg + CyA150 mg PSL10 mg + BUC200 mg PSL30 mg BUC300 mg D-PC300 mg CyA150 mg PSL15 mg + CyA200 mg D-PC300 mg CyA75 mg PSL12.5 mg + CPA pulse D-PC200 mg PSL20 mg + BUC150 mg, CyA200 mg PSL10 mg + UVA1
PSL: prednisolone, MTX: methotrexate, CyA: cyclosporin A, BUC: bucillamine, d-PC: d-penicillamine, CPA: cyclophosphamide. a Systemic corticosteroids, immunosuppressants, d-penicillamine, methotrexate, bucillamine, and/or UVA/UVA1 . b The dose of systemic corticosteroids is converted into prednisolone equivalents.
T. Ikeda et al.
Group No. Etretinate Maximum doses of the other treatmentsa,b
Letter to the Editor
65
Table 3 Changes in the skin score of each group Group Etretinate Other Significantly treatmentsa improved casesb
Scores when first treatments were started (mean ± 1S.D.)
1 2 3 4
13.75 ± 9.53 15.86 10.80 9.11 ± 6.11 7.00 10.08
+ + − −
− + − +
6/7 (85.7%) 3/5 (60%) 0/6 (0%) 1/13 (7.7%)
± ± ± ±
10.65 7.79 3.52 6.90
Sustained scores (mean ± 1S.D.) 7.83 ± 5.94c 10.16 ± 6.74
8.14 7.4 7.67 11.3
± ± ± ±
6.72c 5.37 3.50 7.65
a
Systemic corticosteroids, immunosuppressants, d-penicillamine, methotrexate, bucillamine, and/or UVA/UVA1 . A significantly improvement was comfirmed when the score after the start of treatment with etretinate or other therapies and the sustained score after the start of treatments were reduced to less than 75% of the initial score. c Significantly decreased compared with the mean score when the first treatments were started (P < 0.01). b
isotretinoin, etc.) have been reported to be successful for the treatment of the skin sclerosis due to SSc [3,4]. Malcellus et al. suggested that treatment with etretinate orally for scierodermatous chronic graft-versus-host disease may present a new therapeutic option [5]. Retinoids decrease collagen production in an animal model, the tight skin mouse [6], and also in SSc human skin fibroblasts in vitro [7]. In this report, which had a small number of subjects, the mean sustained scores in all cases treated with etretinate decreased significantly compared with the mean scores when the first treatments were started. However, improvements were barely noticeable in all of the cases that did not receive etretinate. The cases from Groups 1 and 2 were the most successfully treated with etretinate, received it on
Fig. 1
their first visit. In contrast, it is well known that systemic corticosteroids and immunosuppressants are often used for the systemic involvements or rapidly progressing skin sclerosis. It is thought that etretinate should be used during the early stages of SSc, and could be administered specifically on the first visit for the skin involvements of SSc. The duration from the start of treatment to a definite improvement ranged from 0.5 to 7.25 months in Group 1 and from 2 days to 3.5 months in Group 2. Marcellus mentioned that 20 of the 27 sclerodermatous graft-versus-host disease patients also showed the improvements of the skin involvements after 3 months of treatment with etretinate [5]. It is thought that a period of time might be required till the effects of treatment with etretinate begin to appeare.
Changes in the scores of the significantly improved cases of Group 1.
66 These results suggest that etretinate is a specific and useful treatment for the sclerotic skin due to SSc.
References [1] Brennan P, Silman A, Black C, Bernstein R, Coppock J, Maddison P, Sheeran T, Stevens C, Woliheim F. Reliability of skin involvement measures in scleroderma. The UK Scleroderma Study Group. Br J Rheumatol 1993;31:457—60. [2] Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis 2001;60:577—84. [3] Bahmer FA, Zaun H. Isotretinain therapy for progressive systemic sclerosis. Arch Dermatol 1985;121:308. [4] Mizutani H, Yoshida T, Nouchi N, Hamanaka H, Shimizu M. Topical tocoretinate improved hypertropic scar, skin sclerosis in systemic sclerosis and morphea. J Dermatol 1999;26:11—7. [5] Marcellus DC, Altomonte VL, Farmer ER, Horn TD, Freemer CS, Grant J, et al. Etretinate therapy for refractory scierodermatous chronic graft-versus-host disease. Blood 1999;93:66—70. [6] Delany AM, Brinckerhoff CE. The synthetic retinoid (4-hydroxyphenyl)retinamide decreases collagen expression
T. Ikeda et al. in vitro and in the tight-skin mouse. Arthritis Rheum 1993;36:983—93. [7] Ohta A, Uitto J. Procollagen gene expression by scleroderma fibroblasts in culture. Inhibition of collagen production and reduction of pro alpha 1 (I) and pro alpha 1(III) collagen messenger RNA steady-state levels by retinoids. Arthritis Rheum 1987;30:404—11.
Takaharu Ikeda∗ Koji Uede Fukumi Furukawa Department of Dermatology Wakayama Medical Universityr 811-1 Kimiidera, Wakayama 641-0012, Japan Hideo Hashizume Department of Dermatology Hamamatsu University School of Medicine Hamamatsu, Japan ∗ Corresponding
author Tel.: +81-73-441-0661; fax: +81-73-448-1908 E-mail address: [email protected] (T. Ikeda) 13 November 2003