Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis

Abstract

ObjectivesCeftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing.MethodsIn Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug.ResultsStage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy.ConclusionsThe goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed.Trial RegistrationClinicalTrials.gov NCT00349622.

Anti-Depressant Effect of Ceftriaxone in Forced Swimming Test and in Tail Suspension Test in Mice

“…These studies showed that ceftriaxone decreased glutamate-mediated excitetoxicity and reduced SOD (superoxide dismutase) induced neurotoxicity [8]. Ceftriaxone also underwent trials for the possible treatment of ALS (amyotrophic lateral sclerosis) [9][10][11][12]. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by loss of cortical, brainstem and spinal motor neurons [9].…”

Цефалоспорин-Асоційований Біліарний Псевдолітіаз У Дітей

“…В рандомизированном двойном слепом плацебо-контролируемом ис-следовании безопасности применения цефтри-аксона для лечения латерального амиотрофи-ческого склероза показано, что использование препарата в низких (2 г/сут) и высоких (4 г/сут) дозах в течение 20 недель сопровождается раз-витием псевдолитиаза приблизительно у 70 % пациентов без существенных различий между группами, но количество симптомных форм хо-лелитиаза больше среди пациентов, получавших высокие дозы антибиотика [7].…”

“…продемонстрировали, что урсодезоксихолевая кислота позволяет сократить длительность и ускорить разрешение цефтриаксон-индуцированного псевдолитиаза, что дает основа-ния рекомендовать включение урсодезоксихолевой кислоты в качестве сопровождения антибактери-альной терапии для профилактики развития холе-литиаза [7]. Пролонгированное исследование эф-фективности использования урсодезоксихолевой кислоты в дозе 300 мг/сутки подтвердило достовер-ность снижения частоты гепатобилиарных побоч-ных эффектов [13].…”

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“…Recent findings have shown that antibiotics of the -Lactam family increase the expression of EAAT2 and lead to delayed disease progression and increased survival in mouse models [53]. Unfortunately, the clinical trial of these antibiotics in ALS patients was stopped at Phase III due to inability to reach the specified efficacy criteria [54]. Although a disappointing result, hope remains that increasing glutamate transporter expression within astrocytes may be a potential treatment option.…”