作者: Shiide, Youichi ; Shimizu, Hidetoshi ; Yoshino, Hiide ; Akimoto, Makoto ; Kano, Osamu ; Mizutani, Tomohiko ; Sekino, Hisakuni ; Nishimura, Yukiko ; Kanai, Kazuaki ; Hirai, Manabu ; Ito, Kimiko ; Yashiro, Makiko ; Kimura, Hideki ; Ueda, Masaki

PURPOSEEdaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration.METHODSTwo single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated.FINDINGSAfter reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported.IMPLICATIONSIn patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS.CLINICAL TRIAL REGISTRATIONClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www.CLINICALTRIALSgov.

2020-05-01·Journal of Neurology2区 · 医学

Cognitive and behavioral status in Japanese ALS patients: a multicenter study

2区 · 医学

Article

作者: Adachi, Yoshiki ; Aoki, Tetsuya ; Hanajima, Ritsuko ; Raaphorst, Joost ; Yokota, Osamu ; Watanabe, Hirohisa ; Atsuta, Naoki ; Shimizu, Toshio ; Yoshino, Hiide ; Yabe, Hayato ; Arai, Kimihito ; Takigawa, Hiroshi ; Kimura, Hideki ; Kusumi, Kimiyoshi ; Watanabe, Yasuhiro ; Oda, Masaya ; Kanba, Makoto ; Nakashima, Kenji ; Hiroe, Yu ; Masuda, Michihito ; Ogino, Mieko ; Beeldman, Emma ; Aiba, Ikuko ; Nomoto, Masahiro ; Ichikawa, Hiroo ; Adachi, Tadashi ; Ito, Satoru ; Isose, Sagiri ; Nishiyama, Kazutoshi ; Izumi, Yuishin ; Hasegawa, Kazuko ; Sobue, Gen

OBJECTIVESAmyotrophic lateral sclerosis (ALS) patients may present with cognitive and behavioral abnormalities similar to frontotemporal dementia (FTD). In this multicenter study we examined Japanese ALS patients with and without FTD in order to characterize the full extent of cognitive and behavioral abnormalities, including associations with functional motor status, anxiety and depression.METHODSPatients were evaluated using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Hospital Anxiety and Depression Scale, ALS Functional Rating Scale-Revised, spirometry, and verbal fluency tests. Caregivers were asked to complete the ALS-FTD-Questionnaire (ALS-FTD-Q), a behavioral screen. We defined severe cognitive impairment (MoCA < 21 or FAB < 11), mild impairment (11 ≤ MoCA ≤ 25 or 11 ≤ FAB ≤ 15), and normal cognition (MoCA > 25 or FAB > 15). Severe and mild behavioral impairments and normal behavior were defined by the ALS-FTD-Q scores.RESULTSIn 145 ALS patients, better cognitive scores were correlated with earlier age at onset, whereas a worse behavioral score was associated with a longer disease duration and higher level of anxiety and depression. Around seventy percent of all ALS patients showed mild (40-45%) or severe cognitive impairment with cognitive impairment outnumbering behavioral impairment fivefold. Cognitive functions were more impaired in patients with age of onset over 65 years, while behavioral scores were not related to age.CONCLUSIONSConsidering the high prevalence of in particular cognitive impairment, and the diversity of impairments, the cognitive and behavioral aspects of Japanese ALS patients should be given more attention clinically.

2019-03-04·Expert Review of Neurotherapeutics3区 · 医学

Edaravone for the treatment of amyotrophic lateral sclerosis

3区 · 医学

Review

作者: Yoshino, Hiide

INTRODUCTIONAmyotrophic lateral sclerosis (ALS) is a progressive fatal disorder that affects all skeletal muscles, leading to death, mostly within 2-4 years from onset. To date, the anti-glutamatergic drug riluzole is the only drug that has been approved for the treatment of this disease; however, its efficacy is modest. Oxidative stress is considered to be involved in the pathology of ALS, and in this regard, the free radical scavenger edaravone, which was originally developed for the treatment of acute ischemic stroke, has also been developed for the treatment of ALS. Areas covered: This review describes the pharmacological properties of edaravone and the progress of clinical trials conducted to evaluate the efficacy of this drug in the treatment of ALS. Expert commentary: Edaravone is the first drug to show effective inhibition of the motor function deterioration experienced by ALS patients with early-stage probable and definite types. In order to effectively prolong the quality of motor function, edaravone treatment should be initiated as soon as the diagnosis has been confirmed; however, the respiratory function should be carefully monitored when a deterioration in breathing capacity is detected.

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