ISR over-activation may play an important role in ALS pathogenesis, as supported by data from pre-clinical models and PALS. Several different ISR inhibitors have been tried in ALS models or inPALS with mixed results; but given the differents pecific actions of these, it is not possible to generalize across the whole class. ISRIB can attenuate parts of the ISR and has shown benefits in cell models of familial ALS. A group of PALS in Spain who are taking ISRIB report subjective improvements in some ALS-related symptoms, but objective evidence is lacking. Reported side effects are minimal, but no published trials of ISRIB exist,leaving questions about safety and tolerability unanswered. In addition, concerns remain about its solubility and human bioavailability. Currently,there is not enough information to support the regular use of ISRIB for treating ALS. Furthers tudies are required to evaluate its pharmacokinetics, safety, and efficacy in PALS.
Patient case reports
Alpha Lipoic Acid
ALA has several plausible mechanisms for slowing ALS progression, including enhancing energy production, reducing oxidative stress as a potent antioxidant and anti inflammation. Preclinical studies demonstrated better motor function and improved survival. One open label study suggested improved QOL and fatigue when administered as a palladium lipoic acid complex, but motor function was not assessed. Several PALS in the ALS online community reported improved muscle strength when taking ALA as part of extensive supplement regimens, but most did not. Therefore, it is unclear whether the reported improvement was directly related to ALA. Although one clinical trial was completed in PALS, the result has not been published. ALA was safe and well-tolerated based on self report from PALS and in clinical trials for other disease conditions at 600 mg daily. Given the above, we cannot endorse ALA as an effective therapy for PALS. We support more research on the efficacy of ALA in slowing ALS progression.
Light Therapy
Light therapy has not yet been convincingly shown to help people with ALS. However, at specific wavelengths and energy densities, LT appears safe and has theoretically plausible mechanisms. There is a single case report suggesting benefits for light therapy in ALS, but it contains in sufficient detail to independently confirm diagnosis or treatment benefit. Further studies are needed to determine whether LT is useful for people with ALS, and via what specific protocols.
Vinpocetine
Vinpocetine has several plausible mechanisms by which it could slow ALS progression. There are two PALS online who reported improved motor functions on supplement cocktails containing Vinpocetine, but many other PALS have had no
benefits. Serious side effects from Vinpocetine are rare and it is inexpensive. We support further study of Vinpocetine in ALS, but our group was split on what the next step should be; some were in favor of a study in a pre-clinical ALS model and others were in favor of a small human trial to confirm its benefit on cramps (7) and to explore whether it is safe, tolerable and might slow disease progression.
Anti-fungals
It is unknown if fungi exist in the brain of PALS. If they do exist, it is unknown if they have any pathogenic effect, and unknown if antifungal drugs would modify ALS disease progression. There are no pre-clinical ALS model studies, verified ALS cases, or ALS clinical trials to suggest that antifungals would be of any significant benefit to PALS, and these medications can cause harm. At this time, we strongly discourage PALS from taking antifungal drugs for their ALS disease. We hope in the future that independent laboratories will look for fungi in the CNS of PALS using more appropriate experimental methods.
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Perampanel
Perampanel is a drug currently used to treat seizures which has a mechanism of action that theoretically could be useful in treating patients with ALS. A single flawed study in a mouse model of ALS showed some benefits of perampanel, but data from humans with ALS is quite limited. Due to the lack of data in PALS, the failure of the closely related drug talampanel in ALS clinical trials, and several serious safety concerns, including an increased fall risk and serious psychiatric adverse effects, we cannot recommend off-label use of perampanel for ALS at this time. We look forward to the results of the on-going clinical trials of perampanel in ALS and we will update our TOE grades accordingly when these results become available.
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RT001
RT001 has a novel mechanism for reducing oxidative stress that could theoretically work better than more traditional antioxidants. In the small trial of patients with Friedreich’s ataxia, it seems to be safe and well-tolerated at lower dosages but can cause nausea and diarrhea at higher doses. At the time of this writing, there is very little efficacy or safety data in PALS. An expanded access program is underway which allows PALS at certain clinics to try this compound free of charge. Data resulting from this expanded access program will help the planning of a possible future clinical trial.
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Penicillin G/Hydrocortisone
In our opinion, there is no convincing evidence that GABA overload plays a role in ALS progression. PNG/HC has other theoretical mechanisms by which it could slow ALS progression, but previous human trials involving steroids and a trial of a b lactam with more potent effects on glutamate did not help. We have not been able to confirm the diagnoses, nor the improvements described in the case series of 3 PALS taking PNG/HC; however, even if these treatment effects were real, these improvements were transient and quickly became unresponsive to treatment. Unless the ongoing placebo-controlled trial shows objective and sustained clinical improvements, we do not recommend that PALS take this expensive and risky combination of penicillin G and hydrocortisone.
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