Efficacy of prosultiamine treatment in patients with human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: results from an open-label clinical trial

BMC Medicine

Atsushi Kawakami²  Hideki Sakai⁷  Hitoshi Sasaki⁶  Katsuya Satoh³  Hideki Nakamura²  Tomoko Narita-Masuda²  Kunihiko Nagasato¹  Yoshihiro Nishiura¹  Toshio Matsuzaki⁴  Ikuo Kinoshita⁵  Kentaro Yamaguchi⁶  Shinji Yamato³  Taku Fukuda²  Tomohiro Matsuo⁷  Tatsufumi Nakamura³ 

[1] Neurology Section, Isahaya Health Insurance General Hospital, Nagasaki, Japan;Translational Medicine Unit, Department of Clinical Neuroscience and Neurology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan;Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan;Department of Neurology, Okatsu Hospital, Kagoshima, Japan;Neurology Section, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan;Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan;Department of Nephro-Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

关键词: Treatment;    Prosultiamine;    HTLV-I;    HAM/TSP;   

Others  :  856941
DOI  :  10.1186/1741-7015-11-182

 received in 2013-02-26, accepted in 2013-05-30,  发布年份 2013

【 摘 要 】

Background

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy characterized by motor dysfunction of the lower extremities and urinary disturbance. Immunomodulatory treatments are the main strategy for HAM/TSP, but several issues are associated with long-term treatment. We conducted a clinical trial with prosultiamine (which has apoptotic activity against HTLV-I-infected cells) as a novel therapy in HAM/TSP patients.

Methods

We enrolled 24 HAM/TSP patients in this open-label clinical trial. Prosultiamine (300 mg, orally) was administered once daily for 12 weeks. We monitored changes in the motor function of the lower extremities and urinary function as well as copy numbers of the HTLV-I provirus in peripheral blood mononuclear cells (PBMCs).

Results

Improvement in the motor function of the lower extremities based on a reduction in spasticity (for example, decrease in time required for walking and descending a flight of stairs) was observed. In an urodynamic study (UDS), bladder capacity and detrusor pressure and then maximum flow rate increased significantly. Detrusor overactivity and detrusor-sphincter dyssynergia improved in 68.8% and 45.5% of patients observed at pretreatment, respectively. Improvement in UDS corresponded with improvements in the score of nocturia-quality of life questionnaire. HTLV-I proviral copy numbers in PBMCs decreased significantly (approximately 15.4%) compared with pretreatment levels.

Conclusions

These data suggest that prosultiamine can safely improve motor dysfunction of the lower extremities and urinary disturbance as well as reduce HTLV-I provirus levels in peripheral blood. It therefore has potential as a new therapeutic tool for HAM/TSP patients.

Trial registration

University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number, UMIN000005969.

Please see related commentary: http://www.biomedcentral.com/1741-7015/11/183 webcite.

【 授权许可】

   
2013 Nakamura et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]De-Thé G, Bomford R: An HTLV-I vaccine: why, how, for whom? AIDS Res Hum Retroviruses 1993, 9:381-386.
• [2]Hollsberg P, Hafler DA: Pathogenesis of diseases induced by human T-lymphotropic virus type I infection. N Engl J Med 1993, 328:1173-1182.
• [3]Yoshida M: Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol 2001, 19:475-496.
• [4]Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A, Matsumoto M, Tara M: HTLV-I associated myelopathy, a new entity. Lancet 1986, 8488:1031-1032.
• [5]Osame M, Matsumoto M, Usuku K, Izumo S, Ijichi N, Amitani H, Tara M, Igata A: Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemia-like cells. Ann Neurol 1987, 21:117-122.
• [6]Nakamura T, Nishiura Y, Eguchi K: Therapeutic strategies in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cent Nerv Syst Agents Med Chem 2009, 9:137-149.
• [7]Kira J, Fujihara K, Itoyama Y, Goto I, Hasuo K: Leukoencephalopathy in HTLV-I-associated myelopathy/tropical spastic paraparesis: MRI analysis and a 2 year follow-up study after corticosteroid therapy. J Neurol Sci 1991, 106:41-49.
• [8]Nakamura T: HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP): the role of HTLV-I-infected Th1 cells in the pathogenesis, and therapeutic strategy. Folia Neuropathol 2009, 47:182-194.
• [9]Fujiwara M, Watanabe H, Matsui K: “Allithiamine” a newly found derivative of vitamine B1. I. discovery of allithiamine. J Biochem (Tokyo) 1954, 41:29-39.
• [10]Matsukawa T, Yurugi S: On the structure of allithiamine. Proc Japan Acad 1952, 28:146-149.
• [11]Nishiura Y, Nakamura T, Fukushima N, Nakamura H, Ida H, Aramaki T, Eguchi K: Disulfide-mediated apoptosis of human T-lymphotropic virus type-I (HTLV-I)-infected cells in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Antivir Ther 2009, 14:533-542.
• [12]Osame M: Review of WHO Kagoshima meeting and diagnostic guidelines for HAM/TSP. In Human Retrovirology: HTLV. Edited by Blattner WA. New York, NY: Raven; 1990:191-197.
• [13]Osame M, Igata A, Matsumoto M: HTLV-I-associated myelopathy (HAM) revisited. In HTLV-I and the Nervous System. Edited by Román GC, Vernant J-C, Osame M. New York, NY: Alan R, Liss, Inc; 1989:213-223.
• [14]Bohannon RW, Smith MB: Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther 1987, 67:206-207.
• [15]Abraham L, Hareendran A, Mills IW, Martin ML, Abrams P, Drake MJ, MacDonaqh RP, Noble JG: Development and validation of a quality-of-life measure for men with nocturia. Urology 2004, 63:481-486.
• [16]Yu HJ, Chen FY, Huang PC, Chen THH, Chie WC, Liu CY: Impact of nocturia on symptom-specific quality of life among community-dwelling adults aged 40 years and older. Urology 2006, 67:713-718.
• [17]Yoshida M, Ikeda S: Development of the Japanese version of the nocturia quality of life questionnaire (N-QOL) [in Japanese]. Jpn J Urol Surg 2010, 23:833-838.
• [18]Veldhuyzen Van Zanten SJO, Chiba N, Armstrong D, Barkun AN, Thomson ABR, Mann V, Escobedo S, Chakraborty B, Nevin K: Validation of a 7-point global overall symptom scale to measure the severity of dyspepsia symptoms in clinical trials. Aliment Pharmacol Ther 2006, 23:521-529.
• [19]Oliveira P, Castro NM, Carvalho EM: Urinary and sexual manifestations of patients infected by HTLV-1. Clinics 2007, 62:191-196.
• [20]Castro NM, Rodrigues W Jr, Freitas DM, Muniz A, Oliveira P, Carvalho EM: Urinary symptoms associated with human T-cell lymphotropic virus type I infection: evidence of urinary manifestations in large group of HTLV-I carriers. Urology 2007, 69:813-818.
• [21]Taylor GP, Goon P, Furukawa Y, Green H, Barfield A, Mosley A, Nose H, Babiker A, Rudge P, Usuku K, Osame M, Bangham CRM, Weber JN: Zidovudine plus lamivudine in human T-lymphotropic virus type-I-associated myelopathy: a randomized trial. Retrovirology 2006, 3:63.
• [22]Olindo S, Belrose G, Gillet N, Rodriguez S, Boxus M, Verlaeten O, Asquith B, Bangham C, Signaté A, Smadja D, Lezin A, Césaire R, Willems L: Safety of long-term treatment of HAM/TSP patients with valproic acid. Blood 2011, 118:6306-6309.