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Tetrahydrobiopterin double-blind, crossover trial in Machado-Joseph disease
JOURNAL
OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal of the Neurological Sciences 136(1996) 7 l-72
Tetrahydrobiopterin double-blind, crossover trial in Machado-Joseph disease Tetsuo S&ai a,*, Yasunobu Antoku a, Toyojiro Matsuishi b, Hiroshi Iwashita a ’ Deparhnent of Neurology, National Chikugo Hospital, 515 Kurakazu, Chikugo City, Fukuoka 833, Japan b Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan
Received 2 June 1995;revised 31 July 1995;accepted3 September 1995
Keywords: MachadeJoseph disease; Tetrahydrobiopterin; Therapy; Sulfamethoxazole-trimethoprim; Double-blind; Crossover trial
Machado-Joseph disease (MJD) is one of the most common types of dominantly inherited spinocerebellar degeneration (Sakai et al., 1983; Rosenberg, 1991) which is distributed worldwide and the causative gene maps to 14q ( Takiyama et al., 1993; Maruyama et al., 1995). Unfortunately, no specific therapy has been established.We previously reported that sulfamethoxazole-trimethoprim, an antimicrobial drug, ameliorated the neurologic deficits in eight patients with MJD, probably because trimethoprim increasesthe turnover rate of tetrahydrobiopterin (BH4) in the brains of MJD patients (Sakai et al., 1995). Here, we report the results of a double-blind, placebo-controlled, crossover trial of BH4 in MJD patients. This study included five men aged 40-56 who were diagnosed as having ‘clinically definite’ or ‘probable’ MJD according to our previously published criteria (Sakai and Oda, 1993). All of them were found to have abnormal CAG repeats(Maruyama et al., 1995). Four patients took prior medication, which regimen remained uninterrupted throughout the crossover trial. After all patients were hospitalized, they. gave informed consent which was approved by the hospital internal review board. Tetrahydrobiopterin, 1 mg/kg of body weight, was administered to four patients in the form of (6R)-5,6,7,8-Tetrahydro-L-biopterin dihydrochloride, and to the remaining patient in the form of (6R, S)-5, 6, 7, 8-Tetraydro-L-biopterin dihydrochloride (Dr. B. Schircks Laboratories, Jona, Switzerland). The BH4 powder and ascorbic acid were mixed and encapsulated. The BH4 and placebo (ascorbic acid) capsules were of similar color, size, and weight. All of the
l
Corresponding author. Tel.: 942-52-2195;Fax: 942-53-7053.
0022-510X/%/$15.00 0 19% Ekevier Science B.V. All rights reserved SSDI 0022-5 10X(95)00296-0
patients were treated with BH4 and placebo for 10 days each according to a randomized, double-blind, crossover study design with a washout period of 9 days between the first and second treatment periods. Patient assessmentwas performed daily by the administration of six questions regarding subjective feelings, neurologic examinations, and timed tests according to our previous method (Sakai et al., 1995). Statistical analyseswere performed using a paired t test; a p value less than 0.05 was considered significant (two-tailed). The results were as follows: No one complained of any adverse effects. (1) Questionnaire. Choking was mildly improved on the first BH4 treatment day, though not significant ( p < 0.10). (2) Neurologic examinations. Hyperreflexia of the knee jerks was mildly improved on the 10th day of BH4 treatment, but it was not significant ( p < 0.10). (3) Timed tests.Significant improvementswere seen on several timed tests. These results, though preliminary, implied that BH4 showed mild improvements of neurologic deficits. Since the dose used in this trial was too low (1 mg/kg of body weight) and the duration was short (10 days), we would like to advocate a multi-center trial, if possible, in a higher dose and in a longer term to determine whether BH4 is applicable in the alleviation of neurologic symptoms and signs in patients with MJD.
Acknowledgements
We thank Dr. Hideshi Kawakami, Third Department of Internal Medicine, Hiroshima University, Hiroshima for Investigation of the CAG repeatsof the patients.
72
T. Sakai et al,/Journal
of the Neurological
References Maruyama, H., S. Nakamura, Z. Matsuyama, T. Sakai, M. Doyu, G. Sobue, M. Seto. M. Tsujihata, N. Ooi, T. Nishio, R. Takahashi, M. Hayashi, 1. Nishino, T. Ohtake, T. Oda, M. Nishimura, T. Saida, H. Matsumoto, M. Baba, Y. Kawaguchi, A. Kakizuka and H. Kawakami ( 1995) Molecular featuresof the CAG repeats and clinical manifestation of Machado-Josephdisease.Hum. Mol. Genet. 4: 807-812. Rosenberg, R.N. (1991) Joseph disease: an autosomal dominant motor system degeneration. In: J.N. de Jong (Ed.), Handbook of Clinical Neurology, revised series. Hereditary Neuropathies and Spinocerebellar Atrophies, Vol. 16(60). Elsevier, New York, pp. 467-478. Sakai, T., M. Ohta and H. Ishino (1983) Joseph disease in a nonPortuguesefamily. Neurology 33: 74-80.
Sciences 136 (1996) 71-72
Sakai, T. and K. Oda ( 1993) Abundant reinnervation in peripheral nerves in Josephdisease.Neurology 43: 428-430. Sakai. T., T. Matsuishi, S. Yamada. H. Komori and H. Iwashita (1995) Sulfamethoxazole-trimethoprim double-blind, placebo-controlled, crossover trial in Machado-Josephdisease. J. Neural Transm. [Gen Sect] 102: 159-172. Takiyama, Y., M. Nishizawa, H. Tanaka, S. Kawashima, H. Sakamoto, Y. Karube, H. Shimazaki, M. Soutome, K. Endo. S. Ohta, Y. Kagawa, I. Kanazawa, Y. Mizuno, M. Yoshida, T. Yuasa, Y. Horikawa, K. Oyanagi, H. Nagai, T. Kondo, T. Inuzuka, 0. Or&era and S. Tsuji (1993) The gene for Machado-Josephdisease maps to human chromosome14q. Nature Genet. 4: 300-304.
OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal of the Neurological Sciences 136(1996) 7 l-72
Tetrahydrobiopterin double-blind, crossover trial in Machado-Joseph disease Tetsuo S&ai a,*, Yasunobu Antoku a, Toyojiro Matsuishi b, Hiroshi Iwashita a ’ Deparhnent of Neurology, National Chikugo Hospital, 515 Kurakazu, Chikugo City, Fukuoka 833, Japan b Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan
Received 2 June 1995;revised 31 July 1995;accepted3 September 1995
Keywords: MachadeJoseph disease; Tetrahydrobiopterin; Therapy; Sulfamethoxazole-trimethoprim; Double-blind; Crossover trial
Machado-Joseph disease (MJD) is one of the most common types of dominantly inherited spinocerebellar degeneration (Sakai et al., 1983; Rosenberg, 1991) which is distributed worldwide and the causative gene maps to 14q ( Takiyama et al., 1993; Maruyama et al., 1995). Unfortunately, no specific therapy has been established.We previously reported that sulfamethoxazole-trimethoprim, an antimicrobial drug, ameliorated the neurologic deficits in eight patients with MJD, probably because trimethoprim increasesthe turnover rate of tetrahydrobiopterin (BH4) in the brains of MJD patients (Sakai et al., 1995). Here, we report the results of a double-blind, placebo-controlled, crossover trial of BH4 in MJD patients. This study included five men aged 40-56 who were diagnosed as having ‘clinically definite’ or ‘probable’ MJD according to our previously published criteria (Sakai and Oda, 1993). All of them were found to have abnormal CAG repeats(Maruyama et al., 1995). Four patients took prior medication, which regimen remained uninterrupted throughout the crossover trial. After all patients were hospitalized, they. gave informed consent which was approved by the hospital internal review board. Tetrahydrobiopterin, 1 mg/kg of body weight, was administered to four patients in the form of (6R)-5,6,7,8-Tetrahydro-L-biopterin dihydrochloride, and to the remaining patient in the form of (6R, S)-5, 6, 7, 8-Tetraydro-L-biopterin dihydrochloride (Dr. B. Schircks Laboratories, Jona, Switzerland). The BH4 powder and ascorbic acid were mixed and encapsulated. The BH4 and placebo (ascorbic acid) capsules were of similar color, size, and weight. All of the
l
Corresponding author. Tel.: 942-52-2195;Fax: 942-53-7053.
0022-510X/%/$15.00 0 19% Ekevier Science B.V. All rights reserved SSDI 0022-5 10X(95)00296-0
patients were treated with BH4 and placebo for 10 days each according to a randomized, double-blind, crossover study design with a washout period of 9 days between the first and second treatment periods. Patient assessmentwas performed daily by the administration of six questions regarding subjective feelings, neurologic examinations, and timed tests according to our previous method (Sakai et al., 1995). Statistical analyseswere performed using a paired t test; a p value less than 0.05 was considered significant (two-tailed). The results were as follows: No one complained of any adverse effects. (1) Questionnaire. Choking was mildly improved on the first BH4 treatment day, though not significant ( p < 0.10). (2) Neurologic examinations. Hyperreflexia of the knee jerks was mildly improved on the 10th day of BH4 treatment, but it was not significant ( p < 0.10). (3) Timed tests.Significant improvementswere seen on several timed tests. These results, though preliminary, implied that BH4 showed mild improvements of neurologic deficits. Since the dose used in this trial was too low (1 mg/kg of body weight) and the duration was short (10 days), we would like to advocate a multi-center trial, if possible, in a higher dose and in a longer term to determine whether BH4 is applicable in the alleviation of neurologic symptoms and signs in patients with MJD.
Acknowledgements
We thank Dr. Hideshi Kawakami, Third Department of Internal Medicine, Hiroshima University, Hiroshima for Investigation of the CAG repeatsof the patients.
72
T. Sakai et al,/Journal
of the Neurological
References Maruyama, H., S. Nakamura, Z. Matsuyama, T. Sakai, M. Doyu, G. Sobue, M. Seto. M. Tsujihata, N. Ooi, T. Nishio, R. Takahashi, M. Hayashi, 1. Nishino, T. Ohtake, T. Oda, M. Nishimura, T. Saida, H. Matsumoto, M. Baba, Y. Kawaguchi, A. Kakizuka and H. Kawakami ( 1995) Molecular featuresof the CAG repeats and clinical manifestation of Machado-Josephdisease.Hum. Mol. Genet. 4: 807-812. Rosenberg, R.N. (1991) Joseph disease: an autosomal dominant motor system degeneration. In: J.N. de Jong (Ed.), Handbook of Clinical Neurology, revised series. Hereditary Neuropathies and Spinocerebellar Atrophies, Vol. 16(60). Elsevier, New York, pp. 467-478. Sakai, T., M. Ohta and H. Ishino (1983) Joseph disease in a nonPortuguesefamily. Neurology 33: 74-80.
Sciences 136 (1996) 71-72
Sakai, T. and K. Oda ( 1993) Abundant reinnervation in peripheral nerves in Josephdisease.Neurology 43: 428-430. Sakai. T., T. Matsuishi, S. Yamada. H. Komori and H. Iwashita (1995) Sulfamethoxazole-trimethoprim double-blind, placebo-controlled, crossover trial in Machado-Josephdisease. J. Neural Transm. [Gen Sect] 102: 159-172. Takiyama, Y., M. Nishizawa, H. Tanaka, S. Kawashima, H. Sakamoto, Y. Karube, H. Shimazaki, M. Soutome, K. Endo. S. Ohta, Y. Kagawa, I. Kanazawa, Y. Mizuno, M. Yoshida, T. Yuasa, Y. Horikawa, K. Oyanagi, H. Nagai, T. Kondo, T. Inuzuka, 0. Or&era and S. Tsuji (1993) The gene for Machado-Josephdisease maps to human chromosome14q. Nature Genet. 4: 300-304.