[Minocycline for the treatment of amyotrophic lateral sclerosis: neuroprotector or neurotoxin? Reflections on another failure of translational medicine].
A recent publication of the results of a clinical trial of minocycline in 412 ALS patient has aroused considerable controversy in the ALS scientific community. As on previous occasions, the results obtained in the laboratory are not reproduced in clinical practice. The reasons for this new disappointment in translational medicine are analysed by applying the successes obtained in the experimental animal model for ALS to humans. The most frequently suggested causes for explaining these continuous failures are unawareness of the correct dosage to be used, the ideal duration of the clinical trial in phase III, sample size, the search for a primary outcome for measurement other than survival, the need for biomarkers giving information on the progression of the disease and whether this is modified by the introduction of the drug for study. Debate focuses on whether the transgenic mouse model of ALS which expresses SOD1 mutations which we have been using for more than a decade is an exact reflection of the clinical profile and the physiopathogenic mechanisms present in patients with spo- radic ALS. There is the possibility that depending on the dose administered, minocycline can be a neuroprotector or a neurotoxin. In other words, at a dose of 200 mg/day, this drug behaves like <<Dr. Jekyll>> and like <<Mr. Hyde>> at doses of 400 mg. For the authors of the trial, this possibility does not seem to be the cause of the disappointing results obtained. However, they acknowledge that one of the limitations of their study was that it was impossible to compare the effects of minocycline in the patient after receiving 200 or 400 mg. For many other researchers running ongoing clinical trials in both ALS and other neurological diseases, the dose of 200 mg/day is chosen as ideal for testing the effectiveness of minocycline in patients. The strategy of administering the maximum dose of a drug to be tested may give rise to misleading results. We agree with the opinion of other authors, who say that minocycline should be given a second chance.
Gámez
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D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009498:Neurotoxins / Q000627:therapeutic use; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D018696:Neuroprotective Agents; D009498:Neurotoxins; D008911:Minocycline