Background
Human T lymphotropic virus type I (HTLV-I) infects approximately 10 to 20 million people worldwide, mainly in large endemic areas such as southern Japan, the Caribbean, Central and South America, the Middle East, Melanesia, and equatorial regions of Africa [
1,
2]. HTLV-I is a human retrovirus and the causative agent of adult Tcell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [
3,
4]. HAM/TSP is a chronic progressive myelopathy characterized by bilateral pyramidal tracts involved with sphincteric disturbances [
5]. Only a small proportion of HTLV-I-infected individuals develop HAM/TSP. However, the main neurological symptoms (for example, motor dysfunction of the lower extremities accompanied by urinary disturbance) are progressive and lead to a deterioration in the quality of life (QoL) of patients once the myelopathy develops. Therefore, novel and safe therapeutic regimens are needed for HAM/TSP patients to use as treatment, or to prevent disease progression.
The primary neuropathological feature of HAM/TSP is chronic inflammation in the spinal cord caused by high HTLV-I proviral load in peripheral blood. Immunomodulatory therapy such as corticosteroid hormones and interferon (IFN)α has been the main treatment administered to HAM/TSP patients to date [
6]. Although these treatments have produced good results in the short term, their overall efficacy is controversial [
6,
7]. In addition, it is not known if these treatments can be tolerated as a long-term or lifelong treatment against HAM/TSP, or whether they are necessary in the therapeutic strategy against HAM/TSP. When treating HAM/TSP, the optimal treatment is elimination of HTLV-I-infected cells from peripheral blood because HTLV-I-infected CD4
+ T cells are the first responders in the immunopathogenesis of HAM/TSP [
8].
(
N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-
N-[4-hydoxy-1-methyl-2-(propyldithio)-1-butenyl]-formamide) is known as prosultiamine and as Alinamin®. It is a product of Takeda Pharmaceutical Company Limited (Osaka, Japan). Prosultiamine is a homolog of allithiamine, which was originally synthesized from thiol-type vitamin B1 and allicin [
9]. For stability in the blood and efficient access of vitamin B1 to tissues, prosultiamine was developed after allyl disulfide derived from allicin was substituted with propyl disulfide in the structure of allithiamine [
10]. Importantly, prosultiamine is pharmacologically stable and is readily available for the treatment of Wernicke’s encephalopathy and polyneuropathy induced by deficiency of vitamin B1. Moreover, it has been shown to be safe for use in Japan. Therefore, this drug could be utilized immediately for conducting clinical trials in individuals with HAM/TSP.
Recently, we demonstrated that prosultiamine can induce the caspase-dependent apoptosis of HTLV-I-infected cells through disruption of intracellular redox reactions by a disulfide moiety in its structure [
11]. Based on these data, we undertook a clinical trial based on the intravenous administration of prosultiamine in HAM/TSP patients with the purpose of targeting HTLV-I-infected cells [
11]. We found that prosultiamine administration for 2 weeks was safe and induced clinical improvement. Examples of such improvement included a decrease in (i) spasticity of the lower extremities and (ii) levels of HTLV-I provirus in peripheral blood mononuclear cells (PBMCs) to 30% to 50% of pretreatment levels.
As mentioned above, we do not know if prosultiamine can be tolerated as a long-term treatment against HAM/TSP or indeed if it is necessary in the therapeutic strategy against HAM/TSP. Therefore, in the present study, we administered prosultiamine via the oral route for 12 weeks in subjects with HAM/TSP. We found that such treatment could result in (i) improved motor function in the lower extremities based on a decrease in spasticity, (ii) appreciable amelioration of associated urinary disturbance, and (iii) a decrease in the level of HTLV-I provirus in peripheral blood.
Discussion
Effective therapeutic regimens are needed urgently to treat such myelopathic symptoms of HAM/TSP as spasticity of lower extremities and urinary disturbance. To this end, we administered prosultiamine via the oral route for 12 weeks in subjects with HAM/TSP. This treatment improved (i) the motor ability of the lower extremities by decreasing spasticity, and (ii) urinary function. The mean duration of illness of the patients enrolled in this study was relatively long (approximately 21 years), so the efficacy of this treatment is promising. Indeed, these data suggest that the pathological processes in the spinal cord of HAM/TSP patients are partially reversible and treatable even if the tissues are damaged over a long period of time.
The most striking effect in this clinical trial was the amelioration of urinary disturbance in HAM/TSP patients. The common urodynamic findings in HAM/TSP patients are DO, DSD and detrusor hypoactivity [
19]. However, as evaluated by UDS, prosultiamine treatment resulted in a significant increase in detrusor pressure and bladder capacity followed by an increase in maximum flow rate with improved DO. DSD also improved in 45.5% (5 of 11 patients observed at pretreatment) (
P = 0.0736). Although this value did not reach statistical significance, it showed a tendency of improvement. This is the first time that the therapeutic effect for urinary dysfunction in HAM/TSP patients was evaluated in detail by UDS. With respect to the effect of urinary conditions on the QoL of HAM/TSP patients, nocturia, urgency, increased frequency of urination and dysuria have been reported to be the main problems [
20]. Therefore, we evaluated the change in QoL of patients using N-QoL questionnaires during treatment. The improved UDS corresponded with improvements in the score of N-QoL questionnaires. Concomitant pharmacological therapies for the neurogenic bladder were continued during the present study. However, the efficacy of prosultiamine treatment, even in patients who were not having concomitant therapies (cases 5, 6, 11, 13, 23, and 24), strongly suggested that urological improvement was dependent solely upon prosultiamine treatment (Table
1). Overall, these data suggest that prosultiamine treatment can reverse bladder dysfunction in HAM/TSP patients.
Recently, two reports have focused on targeting HTLV-I in therapeutic trials against HAM/TSP. One study used reverse transcriptase (RT) inhibitors, whereas the other used a histone deacetylase enzyme inhibitor for treatment [
21,
22]. In the former, the results of combination therapy (zidovudine + lamivudine) in a randomized, double-blind, placebo-controlled study suggested that RT inhibitors were not effective for targeting HTLV-I for the treatment of HAM/TSP. In the latter study, long-term treatment using valproic acid did not reduce the number of HTLV-I-infected cells in peripheral blood [
22]. A decrease in the HTLV-I provirus in PBMCs was one of the primary endpoints in our recent report [
11]. Indeed, oral administration of prosultiamine induced a significant decrease in HTLV-I proviral copy numbers in PBMCs, However, the rate of reduction was not as high as we had expected. This finding might suggest a limitation of the protocol used in the present study. Thus, the remarkable improvement of motor dysfunction and urinary function in the present study cannot be attributed solely to a decrease in HTLV-I proviral copy numbers in PBMCs. The exact mechanism is not known. Prosultiamine was originally developed for efficient access of vitamin B1 to nervous tissues [
10]. Although this drug is reduced to a part thiamine and propyl disulfide by the intracellular reducing system after penetration to the cells [
10], it is suspected that the disruption of intracellular redox system is induced during reduction of disulfide bond leading to the apoptosis of HTLV-I-infected cells [
11]. Therefore, it might be conceivable that, as one of the mechanisms, this drug functions to induce the apoptosis of HTLV-I-infected cells in the spinal cord even if the extent of reduction of the number of HTLV-I-infected cells in PBMCs is relatively small. Further investigations including analysis of cerebrospinal fluid are needed to elucidate the exact mechanism of action of prosultiamine.
Conclusions
In the present work we have demonstrated that oral administration of prosultiamine can safely promote improvement of motor function of the lower extremities based on a reduction of spasticity along with appreciable amelioration of urinary disturbance associated with a decrease in the amount of HTLV-I provirus in peripheral blood. Our results suggest that prosultiamine could be a promising therapeutic tool for HAM/TSP patients. Therefore, further studies are warranted, such as the evaluation of prosultiamine treatment against HAM/TSP in a large-scale, randomized, controlled study.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
TN designed the study, assessed the neurological findings, analyzed data, and wrote the paper. TMatsuo designed the study, analyzed data, and contributed to the urological studies. HSakai contributed to the urological studies. TF and TN-M assessed the neurological findings. TN, TF and SY managed the blood supply and laboratory studies. KY and HSasaki handled the prosultiamine and enclosed it in capsules. IK, TMatsuzaki, YN, KN, HN, KS, and AK were involved in managing the patients. All authors contributed to the manuscript and approved the final version of the report.