Editing Plan for an Integral Clinical Trial

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 ==

=== General Criteria ===

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

#preliminary signs of efficacy in a human trial
#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 ===

*[[Acetyl L-carnitine (ALCAR)]] {{#pmid:23421600|beghi2013}} 
*[[TUDCA (tauroursodeoxycholic acid)]] {{#pmid:25664595|elia2015}}
*Lithium + valproate {{#pmid:24667005|Boll2014}}

=== Selection by Processes ===

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


{| class="wikitable"
! Process/Parameter || How common in ALS? || Effect of Manipulation || Candidate Substances
|-
| [[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 (TMGy)]], [[Vitamin D3]]
|-
| [[Mitochondrial dysfunction]] || ||  || [[Acetyl L-carnitine (ALCAR)]], [[European milk thistle extract]], [[MitoQ]], [[PQQ]], [[R Alpha Lipoic Acid (R-ALA)]], [[Ubiquinol]]
|-
| [[Glutamate|Glutamate toxicity]] ||  ||  || [[Acetyl L-carnitine (ALCAR)]], [[Alcohol]], [[Inosine]], [[Magnesium]], [[Methylcobalamin]], [[Pycnogenol]], [[R Alpha Lipoic Acid (R-ALA)]], Riluzole
|-
| [[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]]
|-
| Glutathione support ||  ||  || [[TUDCA (tauroursodeoxycholic acid)]], [[European milk thistle extract]], [[R Alpha Lipoic Acid (R-ALA)]], [[Selenium]], [[N-Acetyl-cysteine (NAC)]],[[Trimethylglycine (TMG)]]
|-
| [[Homocysteine]] ||  ||  || [[Methylcobalamin]], [[Folic acid]], [[Trimethylglycide (TMG)]], [[N-Acetyl-cysteine (NAC)]]

|}

== References ==
@@ Line 8: / Line 8: @@
 === General Criteria ===
-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:
+The substances to be included in the cocktail should either be available as over-tnhe-counter products or prescribing them off label should be straightforward. In addition, they need to fulfil at least one of the following criteria:
 #preliminary signs of efficacy in a human trial
@@ Line 27: / Line 27: @@
 ! Process/Parameter || How common in ALS? || Effect of Manipulation || Candidate Substances
 |-
-| [[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]]
+| [[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 (TMGy)]], [[Vitamin D3]]
 |-
 | [[Mitochondrial dysfunction]] || ||  || [[Acetyl L-carnitine (ALCAR)]], [[European milk thistle extract]], [[MitoQ]], [[PQQ]], [[R Alpha Lipoic Acid (R-ALA)]], [[Ubiquinol]]
-|-
-| [[Apoptosis|Anti apoptotic]] || ||  || [[Melatonin]], [[TUDCA (tauroursodeoxycholic acid)]], [[Methylcobalamin]]
 |-
 | [[Glutamate|Glutamate toxicity]] ||  ||  || [[Acetyl L-carnitine (ALCAR)]], [[Alcohol]], [[Inosine]], [[Magnesium]], [[Methylcobalamin]], [[Pycnogenol]], [[R Alpha Lipoic Acid (R-ALA)]], Riluzole
@@ Line 37: / Line 35: @@
 | [[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]]
 |-
-| Glutathione support ||  ||  || [[TUDCA (tauroursodeoxycholic acid)]], [[European milk thistle extract]], [[Glutathione]], [[R Alpha Lipoic Acid (R-ALA)]], [[Selenium]], [[N-Acetyl-cysteine (NAC)]],[[Trimethylglycine (TMG)]]
+| Glutathione support ||  ||  || [[TUDCA (tauroursodeoxycholic acid)]], [[European milk thistle extract]], [[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.{{#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)]]
+| [[Homocysteine]] ||  ||  || [[Methylcobalamin]], [[Folic acid]], [[Trimethylglycide (TMG)]], [[N-Acetyl-cysteine (NAC)]]
 |}
-== Selection of Substances from Candidates ==
-=== Glutathione Support ===
-Sublingual glutathione was found to be superior to oral glutathione or NAC in one comparative study.{{#pmid:26262996|schmitt2015}}
 == References ==