Difference between revisions of "Plan for an Integral Clinical Trial"

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(Glutathione Support)
 
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=== General Criteria ===
 
=== General Criteria ===
  
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The substances to be included in the cocktail should either be available as over-the-counter products or prescribing them off label should be straightforward. In addition, they need to fulfil at least one of the following criteria:
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#preliminary signs of efficacy in a human trial
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#validated effect on a parameter or process that can be estimated to decelerate disease progression in a majority of ALS patients
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=== Selection by Trial Results ===
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*[[Acetyl L-carnitine (ALCAR)]] {{#pmid:23421600|beghi2013}}
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*[[TUDCA (tauroursodeoxycholic acid)]] {{#pmid:25664595|elia2015}}
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*Lithium + valproate {{#pmid:24667005|Boll2014}}
  
 
=== Selection by Processes ===
 
=== Selection by Processes ===
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The basis of this section is the page [[Supplements listed by their effects]]
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{| class="wikitable"
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! Process/Parameter || How common in ALS? || Effect of Manipulation || Candidate Substances
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|-
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| [[Neuroinflammation]] || General || Reduction is probably beneficial; M2 state of microglia should be promoted{{#pmid:28790913|geloso2017}}. || [[3nB]], [[Baicalin]], [[Curcumin]], [[Ibuprofen]], [[Luteolin]], [[Magnolia bark extract]], [[Peony root extract]], [[Spirulina]], [[Trimethylglycine (TMG)]], [[Vitamin D3]]
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|-
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| [[Mitochondrial dysfunction]] || ||  || [[Acetyl L-carnitine (ALCAR)]], [[European milk thistle extract]], [[MitoQ]], [[PQQ]], [[R Alpha Lipoic Acid (R-ALA)]], [[Ubiquinol]]
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|-
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| [[Apoptosis|Anti apoptotic]] || ||  || [[Melatonin]], [[TUDCA (tauroursodeoxycholic acid)]], [[Methylcobalamin]]
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|-
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| [[Glutamate|Glutamate toxicity]] ||  ||  || [[Acetyl L-carnitine (ALCAR)]], [[Alcohol]], [[Inosine]], [[Magnesium]], [[Methylcobalamin]], [[Pycnogenol]], [[R Alpha Lipoic Acid (R-ALA)]], Riluzole
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|-
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| [[HSF1|Heat shock protein inducers]] || Misfolded proteins are a fundamental hallmark of ALS. || Heat shock response assists in proper folding of the proteins and contributes to disaggregation{{#pmid:28724966|wang2017}} of misfolded ones. || [[Curcumin]], [[Peony root extract]]
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|-
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| Glutathione support ||  ||  || [[TUDCA (tauroursodeoxycholic acid)]], [[European milk thistle extract]], [[Glutathione]], [[R Alpha Lipoic Acid (R-ALA)]], [[Selenium]], [[N-Acetyl-cysteine (NAC)]],[[Trimethylglycine (TMG)]]
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|-
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| [[Nrf2]] activators ||  ||  || [[Sulforaphane]], [[Resveratrol]], [[Curcumin]]
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|-
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| [[MMP-9]] inhibitors ||  ||  || [[Sulforaphane]], [[TUDCA (tauroursodeoxycholic acid)]]
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|-
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| [[Homocysteine]] || Homocysteine level correlates with disease progression.{{#pmid:18195267|zoccolella2008}},{{#pmid:19551535|zoccolella2010}} The effect is possibly due to oxidative stress (via NMDA receptor stimulation {{#pmid:26500495|bukharaeva2015}}) and excitotoxicity. It also causes ER stress and inflammation through NF-kappaB activation.{{#pmid:18594946|curro2009}} || At least short-term reduction of Hcy with methylcobalamin improves compound ation potentials in ALS patients.{{#pmid:19551535|zoccolella2010}}  || [[Methylcobalamin]], [[Folic acid]], [[Taurine]], [[Trimethylglycide (TMG)]], [[N-Acetyl-cysteine (NAC)]]
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|}
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== Selection of Substances from Candidates ==
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=== Glutathione Support ===
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Sublingual glutathione was found to be superior to oral glutathione or NAC in one comparative study.{{#pmid:26262996|schmitt2015}}
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== References ==

Latest revision as of 14:00, 14 April 2018

A number of substances have been trialed individually for ALS, and some of them have shown preliminary results that warrant further studies. Even more of them have a plausible mechanism but no clinical results. Although ALS is a collection of diverse diseases, it is possible to recognize several characteristic parameters or processes, manipulation of which would probably be beneficial to majority of PALS.

The aim of this exercise is to propose a "cocktail" consisting of several substances that can be tested integrally in order to see if they have a combined measurable effect on ALS progression.


Selection of Substances[edit]

General Criteria[edit]

The substances to be included in the cocktail should either be available as over-the-counter products or prescribing them off label should be straightforward. In addition, they need to fulfil at least one of the following criteria:

  1. preliminary signs of efficacy in a human trial
  2. validated effect on a parameter or process that can be estimated to decelerate disease progression in a majority of ALS patients

Selection by Trial Results[edit]

Selection by Processes[edit]

The basis of this section is the page Supplements listed by their effects


Process/Parameter How common in ALS? Effect of Manipulation Candidate Substances
Neuroinflammation General Reduction is probably beneficial; M2 state of microglia should be promoted[4]. 3nB, Baicalin, Curcumin, Ibuprofen, Luteolin, Magnolia bark extract, Peony root extract, Spirulina, Trimethylglycine (TMG), Vitamin D3
Mitochondrial dysfunction Acetyl L-carnitine (ALCAR), European milk thistle extract, MitoQ, PQQ, R Alpha Lipoic Acid (R-ALA), Ubiquinol
Anti apoptotic Melatonin, TUDCA (tauroursodeoxycholic acid), Methylcobalamin
Glutamate toxicity Acetyl L-carnitine (ALCAR), Alcohol, Inosine, Magnesium, Methylcobalamin, Pycnogenol, R Alpha Lipoic Acid (R-ALA), Riluzole
Heat shock protein inducers Misfolded proteins are a fundamental hallmark of ALS. Heat shock response assists in proper folding of the proteins and contributes to disaggregation[5] of misfolded ones. Curcumin, Peony root extract
Glutathione support TUDCA (tauroursodeoxycholic acid), European milk thistle extract, Glutathione, R Alpha Lipoic Acid (R-ALA), Selenium, N-Acetyl-cysteine (NAC),Trimethylglycine (TMG)
Nrf2 activators Sulforaphane, Resveratrol, Curcumin
MMP-9 inhibitors Sulforaphane, TUDCA (tauroursodeoxycholic acid)
Homocysteine Homocysteine level correlates with disease progression.[6],[7] The effect is possibly due to oxidative stress (via NMDA receptor stimulation [8]) and excitotoxicity. It also causes ER stress and inflammation through NF-kappaB activation.[9] At least short-term reduction of Hcy with methylcobalamin improves compound ation potentials in ALS patients.[7] Methylcobalamin, Folic acid, Taurine, Trimethylglycide (TMG), N-Acetyl-cysteine (NAC)


Selection of Substances from Candidates[edit]

Glutathione Support[edit]

Sublingual glutathione was found to be superior to oral glutathione or NAC in one comparative study.[10]

References[edit]

  1. Beghi et al.: Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:397-405. PMID: 23421600. DOI. Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40-70 years of age, duration 6-24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9%) patients receiving ALC and 39 (97.5%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.
  2. Elia et al.: Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur. J. Neurol. 2016;23:45-52. PMID: 25664595. DOI. BACKGROUND AND PURPOSE: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). METHODS: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. RESULTS: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). CONCLUSIONS: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.
  3. Boll et al.: Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis. J. Neurol. Sci. 2014;340:103-8. PMID: 24667005. DOI. The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1 month, and every 4 months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9 months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p=0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21 months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.
  4. Geloso et al.: The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches. Front Aging Neurosci 2017;9:242. PMID: 28790913. DOI. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a non-cell autonomous motor neuron loss. While it is generally believed that the disease onset takes place inside motor neurons, different cell types mediating neuroinflammatory processes are considered deeply involved in the progression of the disease. On these grounds, many treatments have been tested on ALS animals with the aim of inhibiting or reducing the pro-inflammatory action of microglia and astrocytes and counteract the progression of the disease. Unfortunately, these anti-inflammatory therapies have been only modestly successful. The non-univocal role played by microglia during stress and injuries might explain this failure. Indeed, it is now well recognized that, during ALS, microglia displays different phenotypes, from surveillant in early stages, to activated states, M1 and M2, characterized by the expression of respectively harmful and protective genes in later phases of the disease. Consistently, the inhibition of microglial function seems to be a valid strategy only if the different stages of microglia polarization are taken into account, interfering with the reactivity of microglia specifically targeting only the harmful pathways and/or potentiating the trophic ones. In this review article, we will analyze the features and timing of microglia activation in the light of M1/M2 phenotypes in the main mice models of ALS. Moreover, we will also revise the results obtained by different anti-inflammatory therapies aimed to unbalance the M1/M2 ratio, shifting it towards a protective outcome.
  5. Wang et al.: Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program. Nat Commun 2017;8:82. PMID: 28724966. DOI. TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein.
  6. Zoccolella et al.: Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis. Neurology 2008;70:222-5. PMID: 18195267. DOI. BACKGROUND: Both in vitro and in vivo studies indicate that homocysteine (Hcy) may be directly involved in the damage of motor neurons and in several pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis. OBJECTIVE: To determine whether plasma Hcy levels were higher in ALS patients than healthy controls and to examine the relationship between Hcy levels and clinical ALS phenotypes. METHODS: In a cross-sectional study, we compared Hcy, B(12), and folate levels in 62 patients with ALS and 88 age- and sex-matched controls recruited as outpatients in a tertiary clinical center. RESULTS: Patients with ALS had higher median plasma Hcy levels (11.2 [range 5.8 to 46] vs 9.7 [range 4.5 to 15.9] micromol/L; p = 0.0004) and lower folate levels (4.4 [range 1.7 to 22.1] vs 5.8 [range 2.3 to 21.1] ng/mL; p = 0.0003), compared with controls. Multivariate logistic regression revealed a strong direct association between plasma Hcy levels and presence of ALS (odds ratios adjusted for age, sex, and B-vitamin levels comparing the top tertile [Hcy levels >or= 11.6 micromol/L] with the bottom tertile [Hcy levels < 9.2 micromol/L]: 6.4; 95% CI 2.2 to 19.1; p for trend = 0.0008). We also found a trend for higher Hcy levels in patients with shorter interval from symptom onset to diagnosis (ODI; <14 months), compared with patients with longer ODI (>14 months; median Hcy levels 11.8 [range 5.8 to 46] vs 10.1 [range 7.2 to 17.6] micromol/L; p = 0.09). In a multivariate model, Hcy levels strongly correlated with shorter interval onset diagnosis (r(2) = 0.18; p = 0.01). CONCLUSIONS: Plasma homocysteine (Hcy) levels were significantly increased in patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. ALS cases with shorter time to diagnosis presented higher Hcy levels, suggesting that higher Hcy may be linked to faster progression of the disease.
  7. 7.0 7.1 Zoccolella et al.: Homocysteine levels and amyotrophic lateral sclerosis: A possible link. Amyotroph Lateral Scler 2010;11:140-7. PMID: 19551535. DOI. Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have also been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). We reviewed the published evidence to assess possible correlations between Hcy and ALS. A Medline literature search was performed to identify all studies on Hcy and ALS or motor neurons published from 1 January 1966 through 28 February 2009. Twelve studies (one in vitro, eight in vivo, and three studies on human subjects) were reviewed. The in vitro and in vivo animal studies showed that Hcy can damage motor neurons by inducing oxidative stress and stimulating excitotoxic receptors. In preliminary studies on human subjects, ALS subjects had higher median Hcy levels compared to age- and sex-matched controls. Higher Hcy levels were also correlated with a possible marker of disease progression. Finally, a short-term treatment with a high dose of methylcobalamin, which reduces Hcy levels, was effective in improving compound motor action potentials in patients with ALS. In conclusion, several types of evidence show that accumulation of Hcy may increase the risk and progression of motoneuronal degeneration. If this is confirmed, early interventions to decrease Hcy levels may be useful to modify ALS progression and possibly onset.
  8. Bukharaeva et al.: Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia. Front Cell Neurosci 2015;9:391. PMID: 26500495. DOI. Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D-aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS.
  9. Currò et al.: Homocysteine-induced toxicity increases TG2 expression in Neuro2a cells. Amino Acids 2009;36:725-30. PMID: 18594946. DOI. High levels of homocysteine promote cell damage mainly through induction of oxidative stress, endoplasmic reticulum (ER) stress, and activation of pro-inflammatory factors. The effects of homocysteine were here examined in the continuously dividing neuroblastoma cell line Neuro2a. Cell treatment with homocysteine (100-500 microM) for 4 h increased ROS production while reducing cell viability in a dose-dependent manner. Cell exposure to 250 microM homocysteine was able to induce transglutaminase 2 up-regulation and increased in situ transglutaminase activity. These effects were prevented by the incubation with the transglutaminase activity inhibitor cystamine. Homocysteine also induced NF-kappaB activation that seemed associated with transglutaminase 2 up-regulation since the specific NF-kappaB inhibition by SN50 was able to reduce transglutaminase expression and activity levels. In the light of these observations, it may be postulated that TG2 up-regulation is involved in cell response to homocysteine-induced stress, in which NF-kappaB activation plays also a pivotal role.
  10. Schmitt et al.: Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biol 2015;6:198-205. PMID: 26262996. DOI. Glutathione (GSH) is critical to fight against oxidative stress. Its very low bioavailability limits the interest of a supplementation. The purpose of this study was to compare the bioavailability, the effect on oxidative stress markers and the safety of a new sublingual form of GSH with two commonly used dietary supplements, N-acetylcysteine (NAC) and oral GSH. The study was a three-week randomized crossover trial. 20 Volunteers with metabolic syndrome were enrolled. GSH levels and several oxidative stress markers were determined at different times during each 21-days period. Compared to oral GSH group, an increase of total and reduced GSH levels in plasma and a higher GSH/GSSG ratio (p=0.003) was observed in sublingual GSH group. After 3 weeks of administration, there was a significant increase of vitamin E level in plasma only in sublingual GSH group (0.83 µmol/g; p=0.04). Our results demonstrate the superiority of a new sublingual form of GSH over the oral GSH form and NAC in terms of GSH supplementation.