Jon Baker

ALS untangled no. 20: The Deanna protocol

ISSN 2167-8421 print/ISSN 2167-9223 online

ALSUntangled: Introducing the table of evidence

We found no precedent for grading the types of evidence we review, so we used a ‘ crowd sourcing ’ approach to create the TOE. One ALSUntangled reviewer (RB) constructed a fi rst draft. The rest of the review team then suggested edits via emails over two months. Finally a subset of reviewers met in person and validated the utility of the TOE by attempting to convert the evidence from all 26 prior ALSUntangled reviews into this.

ALS untangled no. 17: "When ALS Is Lyme"

ISSN 1748-2968 print/ISSN 1471-180X online

ALSUntangled No. 16: Cannabis

ISSN 1748-2968 print/ISSN 1471-180X online

ALS untangled 15: Coconut oil

ISSN 1748-2968 print/ISSN 1471-180X online

ALSUntangled No. 37: Inosine*

Urate (sometimes referred to as uric acid) is a naturally occurring antioxidant (5,6). Interest in urate as a possible neuroprotective agent began when researchers noted that high urate levels are associated with lower risk of developing Parkinson’s disease (7–9) and Alzheimer’s disease (10). Naturally occurring high levels of urate are also associated with slower disease progression in Parkinson’s disease (11–13). The biological mechanisms that cause ALS are not completely understood, but they are likely to include damage to the motor neurons from oxidative stress, as supported by both autopsy and laboratory studies (14). It follows that antioxidants such as urate (or agents that increase levels of these such as inosine) might theoretically be neuroprotective in ALS. Some (15–18) but not all (19–22) studies find that high urate is associated with prolonged survival in PALS. Further database analyses and clinical trials are underway to try and clarify this. Beyond just neuroprotection via urate elevation, recent work suggests that inosine can stimulate the growth of axons in culture, promote collateral sprouting in the corticospinal tract, and even enhance motor recovery after traumatic brain injury (23). These observations suggest that inosine might be able to enhance reinnervation in ALS. ALSUntangled assigns a TOE ‘Mechanism’ grade of C based on this information (Table I).

ALSUntangled No. 36: Accilion

Accilion is a topical mineral cream advertised by Advanced Mineral Compounds, LLC (AMC, 2). It is one of several products with different names and websites (Table I) that trace their origin to a botanist named John Wayne Kennedy (20) and his patent entitled ‘Bioavailable minerals for plant health’ (19). Three of these products are topical mineral creams while a fourth is a mineral supplement marketed to be sprayed on agricultural crops to promote disease resistance and improve growth. These products appear to have similar ingredients and similar proposed mechanisms, and nearly identical description by which they claim to distinguish themselves from other mineral compounds (Table I). A representative from AMC has told us that these products are different in important ways including ‘‘zinc/copper ratios’’ and ‘‘redox’’, that there is a legal dispute underway between the current owners, and that ‘‘efforts to have these compounds independently assessed and thoroughly verified are now routinely obstructed’’ (21). Interestingly, the same cancer-patient testimonials appear for three of these products and the same ALS-patient testimonial appears for two of them (Table I).

ALSUntangled No. 35: Hyperbaric Oxygen Therapy*

HBOT involves treating patients with 100% oxygen at pressures several times higher than atmospheric pressure. This is accomplished by placing patients in a sealed, pressurized chamber (2). HBOT was initially used to treat decompression sickness after diving. There are currently 14 approved, evidencebased indications for HBOT including treatment of air embolism, carbon monoxide poisoning, nonhealing wounds (such as diabetic wounds), burns, gangrene, brain abscess, and radiation injury (3). Numerous websites advertise off-label HBOT for a wide variety of other conditions including multiple sclerosis, dementia, stroke and ALS (4,5). Metaanalyses conclude that there is insufficient evidence to support the use of HBOT in multiple sclerosis (6), dementia (7) and stroke (8). The FDA has warned patients against such off-label use (9).

ALSUntangled No. 34: GM604

Genervon makes several claims on its website (3) regarding possible mechanisms of GM604 without any supporting data or references. Multiple members of ALSUntangled contacted Genervon by phone and emails in the hope of establishing a dialogue that would allow us to eventually better understand this and several other issues described below; unfortunately, our requests were either never answered (4) or were answered along with the following statement, which prevents us from sharing: ‘This email is sent on behalf of Genervon Biopharmaceuticals, LLC. It may be privileged and contains confidential information intended only for the use of the recipient(s) named above. Use by anyone else is strictly prohibited’ (5). PubMed searches of GM6 and GM604 identified only a single possibly relevant publication (2). In this study, GM604 or vehicle were administered to mice following an experimentally induced stroke and reperfusion. Treatment with GM604 was associated with lower markers of inflammation and apoptosis, reduced stroke size, and improved behavioral outcomes relative to treatment with vehicle. It is not clear that recovery from stroke bears any similarity to neuroprotection in ALS, so this paper cannot be relied upon to provide foundation for a relevant ALS mechanism. This study was funded by Genervon, and one of the authors of this paper is a member of the Genervon leadership team (6), which creates a potential conflict of interest. There may be other unpublished mechanistic data on GM604. The paper on GM604 (2) states ‘Studies with the synthesized GM6 also demonstrated similar trophic effects in a transected femoral nerve rat model. In a zebrafish bioassay, GM6 protected the organism from L-2-hydroxyglutaric acid (LGA), induced oxidative stress and apoptosis in the CNS, and reduced apoptosis by 85% in the midbrain’. However, the only references we can find to support this work are patent applications. Based on all this, ALSUntangled assigns a TOE ‘Mechanism’ grade of D. It should be noted here that various other neurotrophic factors have been tested in ALS, including IGF1 (7), CNTF (8) and BDNF (9)

ALSUntangled No. 29: MitoQ

ISSN 2167-8421 print/ISSN 2167-9223 online