The Lancet Neurology (Impact Factor: 21.9). 04/2013; 12(4):339-45. DOI: 10.1016/s1474-4422(13)70037-1
BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank chi(2) on 1 df=1.64; p=0.20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0.71 (95% CI 0.40-1.24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.
[Show abstract][Hide abstract] ABSTRACT: Fragestellung: Bewirkt die Gabe von Lithium eine Reduktion der Krankheitsprogression der amyotrophen Lateralsklerose (ALS)?Hintergrund: Zwei unabhängige Gruppen haben neuroprotektive Effekte von Lithium in zellulären Modellen gesehen; in einer weiteren Studie wurden In-vivo-Effekte beim Tier und beim Menschen berichtet .Patienten und Methodik: 214 Patienten mit ALS wurden Gruppen zugeordnet, die entweder Lithium oder Placebo erhielten. Die Studie war als multizentrische, randomisierte, doppelblinde placebokontrollierte Phase-III-Studie geplant. Primärer Endpunkt war das Überleben nach 18 Monaten.Ergebnisse: 59% der Patienten in der Placebo- und 50% der Lithium-Gruppe überlebten 18 Monate. Der negative Effekt der Medikation war nicht statistisch signifikant. Die Nebenwirkungsraten waren in beiden Gruppen vergleichbar.Schlussfolgerungen: Wie bereits in drei vorherigen Studien gezeigt, hat Lithium keinen Effekt auf die Progression bei der ALS [2–4].Kommentar von Albert Ludolph, Ulm ...
[Show abstract][Hide abstract] ABSTRACT: Autophagy is an intracellular degradation pathway essential for cellular and energy homoeostasis. It functions in the clearance of misfolded proteins and damaged organelles, as well as recycling of cytosolic components during starvation to compensate for nutrient deprivation. This process is regulated by mTOR (mammalian target of rapamycin)-dependent and mTOR-independent pathways that are amenable to chemical perturbations. Several small molecules modulating autophagy have been identified that have potential therapeutic application in diverse human diseases, including neurodegeneration. Neurodegeneration-associated aggregation-prone proteins are predominantly degraded by autophagy and therefore stimulating this process with chemical inducers is beneficial in a wide range of transgenic disease models. Emerging evidence indicates that compromised autophagy contributes to the aetiology of various neurodegenerative diseases related to protein conformational disorders by causing the accumulation of mutant proteins and cellular toxicity. Combining the knowledge of autophagy dysfunction and the mechanism of drug action may thus be rational for designing targeted therapy. The present review describes the cellular signalling pathways regulating mammalian autophagy and highlights the potential therapeutic application of autophagy inducers in neurodegenerative disorders.
Biochemical Society Transactions 10/2013; 41(5):1103-30. DOI:10.1042/BST20130134 · 3.19 Impact Factor
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