The home of Cell Danger Response and
Anti-Purinergic Therapy
Purinergic signaling is an important regulatory mechanism in a wide range of inflammatory diseases. Shifting the balance between purinergic P1 and P2 signaling is an emerging therapeutic concept that aims to dampen inflammation and promote healing. This has some similarity with shifting the balance between th1, th2 and th17 in the immune response.
Purinergic signaling plays a role in the nervous system, the immune system and the endocrine system, all implicated in autism. It is one way that microglia in the brain can be activated, which is a common feature of autism.
Robert Naviaux
Robert Naviaux, an autism researcher, believes that
the purinergic signaling complex of a cell, sometimes known as the purinome, lies behind some types of autism. He is researching the use of an old anti-parasite drug called Suramin to treat autism. Having started on mouse models of autism he has moved on to humans and has been encouraged by his initial findings.
Naviaux promotes his idea of the Cell Danger Response (CDR) a metabolic response to a threat, which encompasses inflammation, innate immunity, oxidative stress, and the ER (Endoplasmic Reticulum) stress response.
My conclusion is that Naviaux may well be proven correct, but for now his ideas are still outside the mainstream.
The CDR is maintained by purinergic signaling and it seems that in some types of disease this signaling remains active. Inhibiting purigenic signaling is put forward as a therapy for some chronic disorders.
Naviaux proposes his Anti-Purinergic Therapy (APT) to correct multiple metabolic anomalies that were produced by an over- activated Cell Danger Response (CDR). In his mouse experiments his therapy did indeed correct multiple metabolic anomalies.
When researching Anti-PurinergicTherapy (APT) and Cell Danger Response (CDR) it is hard to find anything written by anyone other than Naviaux and his team. This is not necessarily a bad thing, but given all Naviaux’s papers it does look odd.My conclusion is that Naviaux may well be proven correct, but for now his ideas are still outside the mainstream.
Naviaux’s initial idea seems to have been to prove that APT works in autism using an existing drug (Suramin) and then afterwards develop a new, safer drug. Over time the view has shifted towards thinking that the existing drug, suramin, is safe enough.
Suramin
Suramin has existed as a drug for a hundred years. It is used to treat used to treat African sleeping sickness and river blindness, which are caused by parasites.
In parasites Suramin is effective by inhibiting their energy metabolism and thus killing them.
A drawback with Suramin is that it has to been injected intravenously and, as with many anti-parasitic drugs, it cannot be taken often. In people with a parasite infection there can be toxicity, but in people without such an infection, the drug is now considered safe below the level of 200 μM. It reacts very little with other drugs.
Fortunately Suramin has a long half-life, usually found to be about two months, but Naviaux found it to be just two weeks in his human trial. The longer the half-life the less often you would have to take Suramin. I wonder if his very small initial dose has affected the half-life, which should not be the case; but there must be a reason.
Naviaux’s antipurinergic therapy research history
1. Maternal immune activation mouse model of autism (2013)
2. Fragile X mouse model (2014/5)
3. Human stage 1 trial with single dose Suramin (2015/17)
Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders.
Objectives and Methods
We used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice.
Results
We found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities.
Conclusions
Hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.
Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1knockout) mouse model
Background
This study was designed to test a new approach to drug treatment of autism spectrum disorders (ASDs) in the Fragile X (Fmr1) knockout mouse model.
Methods
We used behavioral analysis, mass spectrometry, metabolomics, electron microscopy, and western analysis to test the hypothesis that the disturbances in social behavior, novelty preference, metabolism, and synapse structure are treatable with antipurinergic therapy (APT).
Results
Weekly treatment with the purinergic antagonist suramin (20 mg/kg intraperitoneally), started at 9 weeks of age, restored normal social behavior, and improved metabolism, and brain synaptosomal structure. Abnormalities in synaptosomal glutamate, endocannabinoid, purinergic, and IP3 receptor expression, complement C1q, TDP43, and amyloid β precursor protein (APP) were corrected. Comprehensive metabolomic analysis identified 20 biochemical pathways associated with symptom improvements. Seventeen pathways were shared with human ASD, and 11 were shared with the maternal immune activation (MIA) model of ASD. These metabolic pathways were previously identified as functionally related mediators of the evolutionarily conserved cell danger response (CDR).
Conclusions
The data show that antipurinergic therapy improves the multisystem, ASD-like features of both the environmental MIA, and the genetic Fragile X models. These abnormalities appeared to be traceable to mitochondria and regulated by purinergic signaling.
Researchers at the University of California, San Diego School of Medicine have launched a clinical trial to investigate the safety and efficacy of an unprecedented drug therapy for autism.
The phase 1 clinical trial, which is recruiting 20 qualifying participants, will evaluate suramin – a century-old drug still used for African sleeping sickness – as a novel treatment for children with a diagnosis of Autism Spectrum Disorder (ASD). Previous published research by Robert K. Naviaux, MD, PhD, professor of medicine, pediatrics and pathology at UC San Diego School of Medicine, and colleagues reported that a single injection of suramin reversed symptoms of ASD in mouse models.
This trial is the first to test suramin in children with ASD.
In the trial, suramin will be given as a single dose through an intravenous line. Half of the participating children will receive suramin; half will receive a placebo (saline infusion). Behavioral and medical tests will be conducted before and after treatment, and include some blood and urine analyses.
The trial is the first clinical investigation of a novel theory, advanced by Naviaux, that posits autism may be a consequence of abnormal cell communication resulting from abnormal activation of the cell danger response.
Cells threatened or damaged by microbes, such as viruses or bacteria, or by physical forces or by chemicals, such as pollutants, react defensively, a part of the normal immune response, Naviaux said. Their membranes stiffen. Internal metabolic processes are altered – most notably mitochondria, the cells’ critical “power plants” – resulting in activation of the cell danger response and reduced communications between cells.
Naviaux said the cell danger response theory does not contradict other research regarding the causes of autism. Rather, it offers another perspective and, perhaps, a new therapeutic target.
Because suramin treatment for autism is unprecedented, Naviaux emphasized it is not known whether the drug will produce any beneficial effect in humans. He noted that suramin, as currently constituted, cannot be used for more than a few months without a risk of toxicity in humans and that it is not available as an ongoing treatment.
NEWSLETTER—The UCSD Suramin Autism Study
The 2017 Clinical Trial
I think the interviews with parents and press release from the University are actually a better read than the clinical trial and gives a different impression.
Interviews with Parents (click)
Press Release:-
Researchers Studying Century-Old Drug in Potential New Approach to Autism
Five of the 10 boys received a single, intravenous infusion of suramin, a drug originally developed in 1916 to treat trypanosomiasis (sleeping sickness) and river blindness, both caused by parasites. The other five boys received a placebo. The trial followed earlier testing in a mouse model of autism in which a single dose of suramin temporarily reversed symptoms of the neurological disorder.
Participating families also reported benefits among the children who received suramin. “We saw improvements in our son after suramin that we have never seen before,” said the parent of a 14-year-old who had not spoken a complete sentence in 12 years.
“Within an hour after the infusion, he started to make more eye contact with the doctor and nurses in the room. There was a new calmness at times, but also more emotion at other times. He started to show an interest in playing hide-and-seek with his 16-year-old brother. He started practicing making new sounds around the house. He started seeking out his dad more.
“We have tried every new treatment out there for over 10 years. Nothing has come close to all the changes in language and social interaction and new interests that we saw after suramin. We saw our son advance almost three years in development in just six weeks.”
“We had four non-verbal children in the study,” said Naviaux, “two 6-year-olds and two 14-year-olds. The six-year-old and the 14-year-old who received suramin said the first sentences of their lives about one week after the single suramin infusion. This did not happen in any of the children given the placebo.”
Additionally, Naviaux said, “that during the time the children were on suramin, benefit from all their usual therapies and enrichment programs increased dramatically. Once suramin removed the roadblocks to development, the benefit from speech therapy, occupational therapy, applied behavioral analysis and even from playing games with other children during recess at school skyrocketed. Suramin was synergistic with their other therapies.”
Naviaux and colleagues do not believe CDR is the cause of ASD, but rather a fundamental driver that combines with other factors, such as genetics or environmental toxins. And suramin, at this stage, is not the ultimate answer.
But the therapeutic benefit of suramin was temporary: Improvements in the treated boys’ cognitive functions and behaviors peaked and then gradually faded after several weeks as the single dose of suramin wore off.
The primary import of the trial’s findings, said Naviaux, is that it points a way forward, that suramin should be tested in larger, more diverse cohorts of persons with ASD. (Naviaux said his research has been limited by costs; his lab is primarily supported through philanthropy.)
“This work is new and this type of clinical trial is expensive,” he said. “We did not have enough funding to do a larger study. And even with the funding we were able to raise, we had to go $500,000 in debt to complete the trial.”
But “even if suramin itself is not the best antipurinergic drug for autism, our studies have helped blaze the trail for the development of new antipurinergic drugs that might be even better,” said Naviaux. “Before our work, no one knew that purinergic signaling abnormalities were a part of autism. Now we do, and new drugs can be developed rationally and systematically.”
Levitt at USC agreed: “The suramin pilot study is too small from which to draw specific conclusions about the treatment, but there is no doubt that the pilot study reports positive outcomes for all five children who received the medication. The findings provide a strong rationale for developing a larger study that can probe functional improvements in children in greater depth.”
The potential financial cost of ASD treatment using suramin cannot yet be determined for several reasons, the study authors said. First, additional trials are required to determine the effective dosage and frequency for different types of patients. Suramin is used much differently for treating sleeping sickness, but the cost for a one month course of treatment is modest: approximately $27.
The 2017 Clinical Trial
I think the interviews with parents and press release from the University are actually a better read than the clinical trial and gives a different impression.
Interviews with Parents (click)
Press Release:-
Researchers Studying Century-Old Drug in Potential New Approach to Autism
Five of the 10 boys received a single, intravenous infusion of suramin, a drug originally developed in 1916 to treat trypanosomiasis (sleeping sickness) and river blindness, both caused by parasites. The other five boys received a placebo. The trial followed earlier testing in a mouse model of autism in which a single dose of suramin temporarily reversed symptoms of the neurological disorder.
Participating families also reported benefits among the children who received suramin. “We saw improvements in our son after suramin that we have never seen before,” said the parent of a 14-year-old who had not spoken a complete sentence in 12 years.
“Within an hour after the infusion, he started to make more eye contact with the doctor and nurses in the room. There was a new calmness at times, but also more emotion at other times. He started to show an interest in playing hide-and-seek with his 16-year-old brother. He started practicing making new sounds around the house. He started seeking out his dad more.
“We have tried every new treatment out there for over 10 years. Nothing has come close to all the changes in language and social interaction and new interests that we saw after suramin. We saw our son advance almost three years in development in just six weeks.”
Additionally, Naviaux said, “that during the time the children were on suramin, benefit from all their usual therapies and enrichment programs increased dramatically. Once suramin removed the roadblocks to development, the benefit from speech therapy, occupational therapy, applied behavioral analysis and even from playing games with other children during recess at school skyrocketed. Suramin was synergistic with their other therapies.”
Naviaux and colleagues do not believe CDR is the cause of ASD, but rather a fundamental driver that combines with other factors, such as genetics or environmental toxins. And suramin, at this stage, is not the ultimate answer.
But the therapeutic benefit of suramin was temporary: Improvements in the treated boys’ cognitive functions and behaviors peaked and then gradually faded after several weeks as the single dose of suramin wore off.
The primary import of the trial’s findings, said Naviaux, is that it points a way forward, that suramin should be tested in larger, more diverse cohorts of persons with ASD. (Naviaux said his research has been limited by costs; his lab is primarily supported through philanthropy.)
“This work is new and this type of clinical trial is expensive,” he said. “We did not have enough funding to do a larger study. And even with the funding we were able to raise, we had to go $500,000 in debt to complete the trial.”
But “even if suramin itself is not the best antipurinergic drug for autism, our studies have helped blaze the trail for the development of new antipurinergic drugs that might be even better,” said Naviaux. “Before our work, no one knew that purinergic signaling abnormalities were a part of autism. Now we do, and new drugs can be developed rationally and systematically.”
Levitt at USC agreed: “The suramin pilot study is too small from which to draw specific conclusions about the treatment, but there is no doubt that the pilot study reports positive outcomes for all five children who received the medication. The findings provide a strong rationale for developing a larger study that can probe functional improvements in children in greater depth.”
The potential financial cost of ASD treatment using suramin cannot yet be determined for several reasons, the study authors said. First, additional trials are required to determine the effective dosage and frequency for different types of patients. Suramin is used much differently for treating sleeping sickness, but the cost for a one month course of treatment is modest: approximately $27.
Study:-
Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial
Objective: No drug is yet approved to treat the core symptoms of autism spectrum
disorder (ASD). Low-dose suramin was effective in the maternal immune
activation and Fragile X mouse models of ASD. The Suramin Autism Treatment-
1 (SAT-1) trial was a double-blind, placebo-controlled, translational pilot
study to examine the safety and activity of low-dose suramin in children with
ASD. Methods: Ten male subjects with ASD, ages 5–14 years, were matched by
age, IQ, and autism severity into five pairs, then randomized to receive a single,
intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes
were ADOS-2 comparison scores and Expressive One-Word Picture Vocabulary
Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist,
autism treatment evaluation checklist, repetitive behavior questionnaire, and
clinical global impression questionnaire. Results: Blood levels of suramin were
12 1.5 lmol/L (mean SD) at 2 days and 1.5 0.5 lmol/L after 6 weeks.
The terminal half-life was 14.7 0.7 days. A self-limited, asymptomatic rash
was seen, but there were no serious adverse events. ADOS-2 comparison scores
improved by 1.6 0.55 points (n = 5; 95% CI = 2.3 to 0.9; Cohen’s
d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo
group. EOWPVT scores did not change. Secondary outcomes also showed
improvements in language, social interaction, and decreased restricted or repetitive
behaviors. Interpretation: The safety and activity of low-dose suramin
showed promise as a novel approach to treatment of ASD in this small study.
Reviews of the trial published in 2017
Unfortunately the sample is just too small; only 5 people received the single dose treatment. I am sure they would have had no shortage of volunteers and the study would have had far more value with 50 people receiving the drug.
They will tell you the trial cost many hundreds of thousands of dollars. How much more to include a few more participants?
Since all autism trials use different methods to measure the severity of autism we cannot compare the potency of its effect to say the last bumetanide trial.
Researchers should be told by the FDA/EMA to use at least one rating scale in common with other studies.
The big surprise for me was the short half-life of just 14 days. The drug is usually quoted as having a half life three times longer.
The next stage will hopefully have more participants and compare the effect of multiple doses of increasing amount.
Please Dr Naviaux, use CARS (Childhood Autism Rating Scale), include children with epilepsy, GI problems, asthma etc. Have a balance between early onset autism, regressive autism and of course severity of autism.
Parental reporting of improvements, while important, is hugely open to bias. All the kids that received Suramin developed a rash on their body and none of the placebo group did, so I guess the parents who saw the rash would have built up their hopes.
Nonetheless the trial did show a short term benefit from Suramin. But is it a NAC type of benefit, or a bumetanide scale of benefit?
Reviews of Naviaux
When researching Anti-PurinergicTherapy (APT) and his Cell Danger Response (CDR) it is hard to find anything written by anyone other than Naviaux.
There is this review of his findings:-
Naviaux is also an expert in mitochondrial disease.
Anti-purinergic Therapy and Chronic Fatigue Syndrome
One problem with neurological conditions like fibromyalgia, Chronic Fatigue Syndrome and sometimes even MS (Multiple Sclerosis) is that people do not think they are real conditions, or that sufferers exaggerate their symptoms.
Many alternative practitioners who aim to treat these conditions also treat people with autism.
Naviaux suggests that Chronic Fatigue Syndrome is an objective metabolic disorder that could also respond to antipurinergic therapy.
Naviaux may indeed be correct, but I am not sure it helps establish the credibility of his therapy for autism.
The chemical signature that we discovered is evidence that CFS is an objective metabolic disorder that affects mitochondrial energy metabolism, immune function, GI function, the microbiome, the autonomic nervous system, neuroendocrine, and other brain functions. These 7 systems are all connected in a network that is in constant communication using the language of chemistry and metabolism.
All animals have ways of responding to changes in environmental conditions that threaten survival. We discovered that there is a remarkable uniformity to this cellular response regardless of the many triggers that can produce it. We have used the term, the cell danger response (CDR) to describe the chemical features that underlie this response. Historical changes in the seasonal availability of calories, microbial pathogens, water stress, and other environmental stresses have ensured that we all have inherited hundreds to thousands of genes that our ancestors used to survive all of these conditions.
The body responds differently to the absence of resources (eg, caloric restriction or famine) than to the presence of pathogens and toxins. We can classify two responses: a single-step response to the absence of resources, and a two-step process in response to the presence of a threat. Both responses are completed by a return to normal.
When resources are severely curtailed or absent, metabolism is decreased to conserve limited resources in an effort to “outlive” the famine. This is often called a caloric restriction response. On the other hand, when the cell is faced with an active viral, bacterial, or fungal attack, or certain kinds of parasitic infection, or severe physical trauma this activates the two-step response. The first step is to acutely activate the CDR. Innate immunity and inflammation are regulated by the metabolic features of the CDR. Activation of the CDR sets in motion a powerful sequence of reactions that are tightly choreographed to fight the threat. These are tailored to defend the cell against either intracellular or extracellular pathogens, kill and remove the pathogen, circumscribe and repair the damage, remember the encounter by metabolic and immunologic memory, shut down the CDR, and to heal.
In most cases, this strategy is effective and normal metabolism is restored after a few days or weeks of illness, and recovery is complete after a few weeks or months.
However, if the CDR remains chronically active in either state, many kinds of chronic complex, chronic diseases can occur. In the case of CFS, when the CDR gets stuck, or is unable to overcome a danger, the body enters into a kind of siege metabolism that further diverts resources away from mitochondria and sequesters or jettisons key metabolites and cofactors to make them unavailable to an invading pathogen. This has the effect of further consolidating the hypometabolic state. When the hypometabolic response to threat persists for more than 6 months, it can cause CFS and lead to chronic pain and disability. Metabolomics now gives us a way to characterize this response objectively, and a way to follow the chemical response to new treatments in systematic clinical trials.
Suramin Pharmacology
Suramin has a broad effect blocking receptors both P2X and P2Y, it does not have an effect on the third type of purinergic receptors called P1.
If you believe in the idea of balancing P1 and P2 signaling, you might consider increasing the effect of the P1 receptors to counteract excessive signaling from P2. I am not sure I agree with this because P1 agonists would make asthma worse, not better. Unless the idea is to counter excess P2 signaling, by reducing P1 signaling. P1 antagonists (that reduce P1 signaling) include theophylline which I did suggest for other reasons might help some autism.
If you want to be an early adopter of the Dr Naviaux, you need a P2 antagonist.
Suramin is not expensive, but rarely used in developed countries.
Conclusion
I think that Suramin is an interesting therapy, even if not everybody is convinced at the proposed mode of action. It does help both in mouse models of autism and in a very small human trial. We now need a large trial that includes a better behavioral assessment of the result, so we can actually judge it properly.
Will it help everybody with an autism diagnosis? I doubt it, but then I do not think any single drug ever will.
The question is more are there any biomarkers for who might respond and Naviaux does mention the “fever effect”.
I think the more people consider the broader metabolic symptoms, the easier it will become to put people into sub-groups of autism and assign them effective therapies.
As with Bumetanide, which is effective in a something like 40% of autism, I expect Suramin will be partially effective and will need other therapies to be added.
A very important point is the cost of clinical trials and indeed drug approval in the US. If just the overspend on this trial was $500,000, a trial on 10 kids with a single infusion of the trial drug, it is time to move the research to India or Eastern Europe.
North Korea will develop a ballistic missile with nuclear warheads for less money than it costs to develop a drug in the US.
Why do you think Bumetanide is not being developed as an autism therapy in the US? It costs too much.
A very important point is the cost of clinical trials and indeed drug approval in the US. If just the overspend on this trial was $500,000, a trial on 10 kids with a single infusion of the trial drug, it is time to move the research to India or Eastern Europe.
North Korea will develop a ballistic missile with nuclear warheads for less money than it costs to develop a drug in the US.
Why do you think Bumetanide is not being developed as an autism therapy in the US? It costs too much.
Peter,
ReplyDeleteI hope this study does not end with a whimper after starting off with a bang or was it my ears playing tricks. You do make it seem like a damp squib. At phoenix rising site, things look much more optimistic...there are observations from parents of the test group.
I think the apprehension mainly revolves around small sample size. I also feel that analysing biological changes in detail is not that bad as it validates his biological theory behind autistic behaviours which might pave way for better drug therapies. In case of bumetsnide, we only have a hypothesis. A balanced mix of behavioral as well as biological measures will make an autism study truly remarkable. Right now the only thing remarkable seems to be your blog. And your suggestion about shifting autism research to India.
Peter does raise a good point about research being excessively expensive in the United States and the reasons are many. For one, the USA is very corrupt in the white collar professions. Doctors, lawyers and other professionals all do whatever they can to interject themselves into everything whether they are needed or not so that they always get a cut. Doctors like lawyers are a piece work profession these days so they get paid for every minute they spend on something regardless of whether they do a good job or not. A 15 minute visit is 200 dollars billed to someone or an insurance company that in sum adds up to why 20% of the USA economy is spent on healthcare for worse service than you find in many less wealthy parts of the world. On your bill you will have incomprehensible charges that really are just line items for all the corruption involved as if the entire USA health care system is run by mobsters. When it comes to human research there is no escaping these costs. If you don't make sure everyone gets paid off, your research just won't get done.
ReplyDeleteNevertheless, there is hope. The Hollywood film industry has operated with similar corruption for many decades and it is now being squashed by competition from around the globe where production costs are much lower for the same quality or at least about the same quality of work you get from the professionals in Hollywood.
So while the USA has for decades been the leader in research around the world, I think a confluence of factors will force more research to be done in nations which don't have as much red tape. That is not to say nations with even worse corruption problems than the USA such as Russia and China or even India will suddenly become research powerhouses, rather politically neutral nations on the geopolitical stage such as those in eastern Europe or south America may be a wiser place to spend private research dollars to get the answers needed for patrons who want the best return on their scientific investment.
Agreed. Just spoke with someone from Honduras about this, he would rather go to Mexico for healthcare than use for profit insurance medical care here in the U.S. He watched his co-worker have his leg amputated in the U.S.- His view: They see what kind of inurance you have and how much they can make by doing xyz. They convince you to do things that you might not need that might put you at risk. So then you get a surgery that you could have lived without and then you get an infection- sepsis and then by by leg. Not ok. I get you can get an infection anywhere but where do we draw the line to what is absolutely necessary with benefit/risk.
DeleteTwo things worth noting about purinergic receptors and suramin's and possible modes of action:
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pubmed/22948816
Mast cells are known effector cells in allergic and inflammatory diseases, but their precise roles in intestinal inflammation remain unknown. Here we show that activation of mast cells in intestinal inflammation is mediated by ATP-reactive P2X7 purinoceptors.
Secondly, suramin is a potent antiretroviral/RT inhibitor
http://m.pnas.org/content/82/22/7733.abstract
Almost all 5 parents in the active arm of the study report striking positive mood changes within hours of their child receiving the infusion:
http://www.sandiegouniontribune.com/business/biotech/sd-me-autism-parents-20170525-story.html
thanks, Nat, for this. I have never been as interested in a doctor's research as Naviaux's.. Four years ago my son's doctor told me to keep an eye on Naviaux. This makes the most sense for me - for my son's form of autism.
DeleteYour comments about his research into CFS not helping the credibility of his research into autism are prejudicial and callous in regards to the real needs of people with CFS. If the science stands up what is the issue?
ReplyDeleteAs I suggested there is widespread belief in the medical community that these are not genuine conditions and that people who treat them are by association not serious. This is not my personal opinion, but that is clearly what many doctors believe. They do not believe the conditions are genuine and nothing I write will change that.
DeleteAutism, when severe, is a massive disability, meaning people have no real life. It is often more disabling than Down Syndrome, because most people with DS are actually very happy people. Many lay people still regard autism as a made up condition.
I want autism to be treated by mainstream medicine, and not be seen as a money making opportunity by unqualified people.
If Naviaux wants milions of dollars of funding he needs to be taken seriously. He struggled to raise funds for a study to treat five people.
I think he is very clever, but you have to wonder how a chiropractor raises $40 million to develop CM-AT and yet the much more qualified scientist struggles.
Post Wakefield, autism research related to GI issues was unfundable for many years. Being taken seriously is very important.
Your out of date. The doctor's believe in CFS. They just don't know how to treat it so they ignore it. The researchers such as Naviaux, Davis, the people at Columbia Uni, Fluge and Mella, Scheinenbogen in Berlin and Staines in Australia are all getting results indicating cellular hypometabolism. What if research into CFS also ended up helping autism? No need to pander to prejudices despite what you have heard about grant processes. Grant money for CFS has been increasing too.
DeleteThe problem for his credibility is not that he mentions CFS, but that its easy to link CDR with immune system "stressors", and THIS is a big no no.
DeleteJane, I see what you are saying. ;) But he does have the maternal immune activation model, so can they just push the usual blame it all on the mothers theory to get around that taboo? ha! Actually, I am one of those maternal immune activation models - was sick with flu/pneumonia during my first trimester.
DeleteTanya, I agree. Blame us but keep working please ;)
DeleteI think for my kid MIA (severe asthma during pregnancy + other complications) was the first hit, then RAMD as per Dr. Kelley's (with very convincing lab works). So you see why I'm interested in Naviaux's work.
Unfortunately science is not immune (pun intended) to politics and economics... but one can always hope :)
Jane.
Hi everyone,
ReplyDeleteFirst, Peter - thank you for the very timely article!
Here are my 1.5 cents (Canadian currency conversion not so hot right now):
1. I take this trial result as very positive. Yes, its a small sample size, but the results themselves are very positive. This seems to indicate that many of our kids can be treated at any age, assuming they are having a CDR issue as the cause / contributor to their symptoms. What I like about Naviaux's hypothesis is that it can help explain why so many systems seem perturbed in ASD kids.
2. Financially, the fact that Naviaux was $500K in the hole to do this trial is truly sad.
I look at someone like Sean Parker who put $500 million into cancer research - give him tons of credit. He saw that he can do a lot of good for a lot of people, and put his money into something that will actually impact people.
Wish that ASD had a billionaire who would do for ASD research what Parker has done for Cancer. We need to find wealthy champions (or many parents like us) who would crowdfund good research.
If Naviaux came out tomorrow and said that he needed $1 million to run a study on a drug that does what Suramin does but is far more effective, orally bioavailable, fewer off target reactions, etc., could we not find 1,000 parents who would crowdfund $1,000 each to fund the trial? If I was asked to put $1k or more towards funding a really good trial / research into ASD, I would do it.
3. When I first heard of Naviaux's research I delved into looking into natural anti-purinergic treatments. Would the community agree to all work together to create a table that identifies inhibitors and antagonists for each P2X and P2Y receptor in a matrix much like the ones Peter has in his article? I'm going to start, and will share it with the community but if others also want to share in the effort, please do. I know Berberine, Naringin, Amentoflavone, and Emodin were a few of the ones I had found that I believe hi at least P2X7, but if we can create a list for each P2X and P2Y receptor, we can create a list of options to try to hit as many of these receptors simultaneously to come as close as we can to Suramin. Just a thought.
Thanks everyone!
AJ
AJ, autism does have a billionaire, Jim Simons. His funding goes to many leading autism researchers. I wonder why his foundation did not fund Naviaux. Maybe they will next time.
DeleteSuramin is made in Germany by a huge company called Bayer. They are in the process of buying Monsanto. You would think they might be interested in new applications of their off-patent drug.
Suramin is much more potent than other substances, but why not look for alternatives.
AJ,
DeleteI think Natasha's comment on mode of action of suramin is extremely important. Antiretroviral properties and regulating mast cell induced intestinal inflammation.
CDR seems to be a highly plausible cause behind many autisms and it might also explain why so many therapies addressing mitochondrial issues work for many autistic kids.
If you look at the kids he selected for the trial, I think three or four out of five had regressions suggestive of mitochondrial dysfunction. The ones with infantile autism were not severely incapacitated. So it was not a heterogeneous autistic sample.
Still, as you said, his hypothesis might suggest why so many systems seem perturbed in autism and as a parent I would be willing to donate when and if requirements arise. I have an intuition that this was no ordinary research and there is more to come. I just pray it happens fast. You know what the dear scientist said ...'if suramin works as a treatment protocol for autism, it might end'.
Kritika, Naviaux is a specialist in mitochondrial disease. Perhaps this is why his sample is skewed towards regressive autism.
DeleteWe now need some Polish psychiatrists, who seem happy to inject off-label substances (cerebrolysin), to take an interest. It would be very easy to find the most effective dose and response rate, with such an approach. There already is research into what dose is free of side effects.
The slow route will likely take 15 years and cost $50 million, since in the US Suramin is not an approved drug.
Peter,
DeleteIf Dr. Naviaux sets up a clinic there will be a stampede..cdr treatment for kids and cfs for their parents.
But in all seriousness, I find the hypothesis pretty convincing and it does touch upon so many issues that you have discussed. But it seems you are not impressed. Why?
Naviaux is probably among the cleverest 10 researchers mentioned in this blog. So I had high expectations that we would have more answers from this hard to fund study.
DeleteWe have most of the questions still unanswered. To answer those questions will need a study at least 10 times as big and using gradually increasing doses over a period of months. So even in the ideal scenario it will take some years.
The same issue was faced by Prof Catterall and his low dose clonazepam. He showed it worked in two mouse models. Then he said you either trial it off-label, or spend millions on an FDA approved trail. He actually did neither. In this blog we have done the off-label trial and found the effective dose, all for zero dollars.
AJ, would be nice to know if the families in the study know about the alternatives. Would be interesting to see if a jump start with suramin allows the alternatives t be even the slightest bit effective. I love your crowd fund idea - I would eagerly donate a nice amount. I'm not sure why there was trouble with raising the money. MY son's DAN doctor from 4 years ago was very intrigued and eager for his work. And it was even covered on National Public Radio about a year ago.
DeleteI do hope the possibility of a monthly dose of a medication for around 40% of the ASD population (the more severe and/or those who regressed) stirs the business interest of someone(s).
DeleteMeanwhile, here is a short film with parents and Naviaux himself, talking about the study:
https://www.youtube.com/watch?v=iWWF5nN7fUA
Svi bi solidarno pomogli,podrazumrva se, prepreka je neostatak jasne šeme i dostupnosti tretmana.
DeleteAJ, I did contribute with the first trial (a tiny bit mind, not 1k) :)
DeleteBut those who want to fund Naviaux's research can already do it through some existing channels:
http://naviauxlab.ucsd.edu/support/
http://www.nofone.org/how-to-help
How I wish Simons Foundation or other big one would see it as positively as we do...
Cheers!
AJ, John Rodakis of N of 1 is doing the funding...... I forgot about this since I got off facebook and not keeping up with the page. Will sign up for updates via his site.
DeletePeter, AJ, The only P2 antagonist I was able to find is PPADS tetrasodium salt.
ReplyDeletePPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) is a selective purinergic P2X antagonist.[2] It is able to block contractions of rabbit vas deferens induced by ATP or α,β,methylene-ATP. It appears to be relatively selective for P2X receptors, having no appreciable activity at α adrenergic, muscarinic M and M, histamine H, and adenosine A receptors.[3]
References
PPADS tetrasodium salt, Santa Cruz Biotechnology
Ziganshin, AU (December 1993). "PPADS selectively antagonizes P2X-purinoceptor-mediated responses in the rabbit urinary bladder.". British Journal of Pharmacology. 110 (4): 1491–95. doi:10.1111/j.1476-5381.1993.tb13990.x. PMC 2175839 Freely accessible. PMID 8306091.
Lambrecht, G. (1992). "PPADS, a novel functionally selective antagonist of P2 purinoreceptor mediated responses". European Journal of Pharmacology. 217: 217–19. doi:10.1016/0014-2999(92)90877-7. PMID 1330591.
I have no idea if it can be used in humans. If you can find details, please let me know.
I am posting as Anonymous, but if Dr Naviaux reads this, he would know who is posting. I live in San Diego and have an autistic 8yo son. I was referred to Dr. Naviuax by a mutual friend 2 years ago, before the Suramin study started. At that time, I didn't even know about Suramin, and was referred to Dr. Naviaux because I was looking for a geneticist to interpret my son's genetic mutations. He agreed to see me, but outright said that genetics don't matter and that it is all about metabolic pathways messed up by external factors such as pollution, household chemicals (fire retardant in mattresses was mentioned, BPA), pesticides, etc. We talked for an hour and I was impressed by him. At the end, he offered to run a blood test on my son to check his metabolic markers, the test that only his lab had as he claimed. He collected the blood test from my son (my son was screaming). In a month or so, I contacted him and asked for the blood test results. He said that he was very busy and gave me a new date. That continued for about 9 months until he angrily wrote to me that he is running out of money and is looking for $10k donation from me. I was very upset that the donation wasn't mentioned at our first visit when he voluntarily offered to run his metabolic blood test on my son and tortured him with the blood draw procedure. I told him that I don't have that kind of money, and I never heard from Dr. Naviaux again.
ReplyDeleteAbout Suramin. I am not sure why you are so excited about it. It doesn't address the core cause for activated CDR. It is like a headache medicine. You take it, you feel a relief, more functional, but when it wears off, you back to having the headache. If CRD is caused by toxins or hidden viruses in the body, you should fight those. I bet that steroids would have had a similar effect on the study subjects as Suramin. It would be interesting to know if any of the subjects had been given corticosteroids in the past.
Thanks, it is good to keep things in perspective and not get carried away. This is also why larger studies in multiple centers are needed, to validate the impact.
DeleteIf you read earlier papers and interviews of Dr. Naviaux before the Suramin study, he claimed back then that Suramin can cure autism by turning OFF the CRD permanently. But then he changed his view, and has been claiming that Suramin works for only 5 weeks or so. So, I am not sure what larger studies would prove.
DeleteMr. Anonymous
DeleteYour statement above 'if CRD is caused by hidden toxins or vurus, fight those' is a big revelation...a revelation about how disinterested you are in understanding the entire research. Please try harder.
"I am posting as Anonymous, but if Dr Naviaux reads this, he would know who is posting."
DeleteTranslation: He has a court order against me cause I'm a nutter.
"He collected the blood test from my son (my son was screaming)."
Translation: I had no idea how blood was collected. Apparently they use a sharp needle. Who knew???
"About Suramin. I am not sure why you are so excited about it."
Translation: My personal hate for Naviaux has completely clouded my judgment
"It doesn't address the core cause for activated CDR. It is like a headache medicine. You take it, you feel a relief, more functional, but when it wears off, you back to having the headache."
Translation: Apparently, I have no idea that millions of people take headache medicine for relief. I live under a rock
"If CRD is caused by toxins or hidden viruses in the body, you should fight those"
Translation: This is the one hour per day I have access to a computer. The rest of the day, the nurses keep me in a white jacket with my arms wrapped around my back.
"It would be interesting to know if any of the subjects had been given corticosteroids in the past."
Translation: I have no apparent knowledge of biology, and just pulling stuff out of thin air to attack Naviaux because I have become obsessed with him.
Anonymouse
I think this comment is directed at Dr. Naviaux because he is the one who believes that CRD is triggered by infections and toxins. He said so in the conversation with me. It is also published. Here is the interview with Dr. Naviaux:
Deletehttp://naviauxlab.ucsd.edu/wp-content/uploads/2016/09/Metabolomics-QA-for-CFS-v12.pdf
... when the cell is faced with an active viral, bacterial, or fungal attack, or certain kinds of parasitic infection, exposure to certain toxins, or severe physical trauma, this activates the two-step response. The first step is to acutely activate the CDR...
Dear K, in addition to my previous post, I would like to justify my comparison of Suramin to pain medication or anti-inflammatory steroids.
Deletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749528/
... ATP released from damaged or infected cells causes inflammation by release of inflammatory cytokines via P2X7 receptors and acts as a danger signal by occupying upregulated P2X receptors on immune cells to increase immune responses.
https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-016-0240-4
Persistent pain varies according to its causes, often resulting from local tissue damage or inflammation... To date, evidence suggests the involvement of ion channels, including adenosine triphosphate (ATP)-gated cation channel P2X receptors, in central nervous system pain transmission and persistent modulation upon and following the occurrence of neuropathic pain. Several P2X receptor subtypes, including P2X2, P2X3, P2X4, and P2X7, have been shown to play diverse roles in the pathogenesis of central pain including the mediation of fast transmission in the peripheral nervous system and modulation of neuronal activity in the central nervous system...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265705/
It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states.
: It appears that multiple things can activate ATP-gated P2X/P2Y receptors and the associated pain: infections, toxins, traumas, etc. Suramin, being a non-selective antagonist of P22X/P2Y receptors, does not resolve the issue that caused ATP release and its activation of P2X/P2Y receptors (so called CDR). For example, if ischemia caused activation of P2X/P2Y, giving Suramin will not resolve it. Nor will it kill a virus, or remove a pathogen or a toxin. It is like giving Ibuprofen during flu hoping that it will cure you from the flu. Corticosteroids, which are also very effective in regressive autism cases, also modulate P2X receptors and reduce inflammation, and just like in Suramin case, the results are temporary or last as long as the treatment.
"I think this comment is directed at Dr. Naviaux because he is the one who believes that CRD is triggered by infections and toxins."
DeleteDeflect! Deflect!
"He said so in the conversation with me"
...even though I apparently harassed him for 9 months without a response from him. Hmmm. Better get my stories straight.
"I would like to justify my comparison of Suramin to pain medication or anti-inflammatory steroids."
Since it made no sense the first time, and was completely illogical, I'm going to double down!
"It is like giving Ibuprofen during flu hoping that it will cure you from the flu"
Which has been done by no one ... ever.
"and just like in Suramin case, the results are temporary or last as long as the treatment."
Like practically every other drug on the market ... but since I'm trying to attack Naviaux, let's all pretend that all medications are one and done cures.
Anonymouse
Dear Anonymous,
DeleteYou make a valid point but research into biochemical therapies for autism is currently at a stage where even the smartest pediatricians do not know of any basic tests which they would like to recommend for a young child under their care.
Dr. Naviaux's work is interesting not because suramin temporarily resolved some of the autistic symptoms but because he offers a plausible explanation, potentially treatable, at least partially, behind some autisms. Worth getting excited about..not really but it does make you want to sit up and take notice.
As a parent to a five year old with autism, the improvements and the dramatic episodes that parents whose kids got suramin infusion reported, do not look really dramatic to me. They are a part of our life...periods of heightened awareness, reciprocity, cognition and then back. Metabolonomics, genomics, proteomics...whatever.. it does not matter to me. But any potential therapy which recognizes that autistic behaviours might not be permanent and might be treatable will make me sit up and take notice. And if corticosteroids or pain medications jump start development, or even temporarily ameliorate 'autistic symptoms', its worth sitting up and taking notice.
Keep giving your perspective.
Dear AnonyMOUSE,
DeleteI appreciate your posts. They show how strongly you feel about this issue and how strongly you believe in Dr Naviaux research and its practical value. We, as parents of autistic children, need hope. And I am glad that you found one in his work. I am sorry that my posts upset you so much.
Dear K,
DeleteI am like you - will not give up hope of curing my son. There are so many possible reasons for autism, that a single treatments will not work for everyone. Over the years, I read many parent reports and articles about autism. I divide autism cases into the following:
1. Brain damage at birth (birth asphyxia) or from an injury later in life (e.g. falling and hitting head) or from seizures (they leave brain lesions). HBOT is the right treatment in these cases.
2. Poor oxygen delivery to the brain. It can be caused by ischemia from a brain injury, or low RBC (my son has low RBC), or blood vessel damage from a suction cap used during c-section delivery (also the case in my son). HBOT also works in these cases.
3. Seizures and abnormal EEG activity. These act as reboot signals in the brain, preventing learning. Landau-Kleffner syndrome is known to cause regressive autism between ages 2 and 8yo. These are treated by anti-seizure meds like Valproic acid, Trileptal, Lamictal. LKS is treated mostly with corticosteroids as the first line of defense and Valproic acid. LKS is recoverable. I wonder how many of the Suramin trial patients had LKS or seizures or abnormal EEG activity. Doing a 24hr EEG is a must for newly diagnosed patients.
4. Genetic mutations affecting brain development, neurotransmitter balance, etc. For instance, my son has homozygous MTHFR A1298C mutation. It affects the production of serotonin (low serotonin causes anxiety) and dopamine (low dopamine results in low motivation and impaired focus and learning). Sometimes autism appears as a severe case of anxiety. Dr. Goldberg's main treatment of autism is based on SSRI. I personally know parents and also read parent stories whose children started talking on SSRI. Another mutation that can cause neurotransmitter imbalance is related to GAD, which converts glutamate into GABA. Low-functioning GABA receptors are responsible for social deficits, anxiety, sensory problems. Increasing serotonin and GABA are key treatments in these cases. Peter's polypill includes Bumetanide that helps GABA receptors to regain their inhibitory function.
5. Childhood schizophrenia. Before autism became a diagnosis, these children were diagnosed with childhood schizophrenia. Schizophrenia can officially be diagnosed in adolescence. Many autism diagnosed kids today will be re-diagnosed as schizophrenics later in life. You have to look at mutations that can cause schizophrenia. One of these mutations reduces D Serine levels in the brain, which affect NMDA receptor activity, and associated positive (mood) and negative (cognition) symptoms of schizophrenia. Sarcosine is an interesting supplement that helps to increase glycine levels in the brain (glycine acts as D Serine) and fight both positive and negative symptoms. It is currently studied as a potential drug for schizophrenia.
6. Allergies (food, environmental). In many cases they lead to brain inflammation. Many kids improve on CFGF. Quercetin stabilizes mast cells & reduces CRH hormone that stresses adrenal glands. It helped my son a lot. EGCG inhibits histidine conversion to histamine and stabilizes mast cells. But these are not cures. IVIG would give a more permanent fix.
7. Toxins, viruses, bacteria. There was a mother who discovered that one of her facial creams contained mercury and her autistic daughter liked to leak her face. Once she discovered that here cream contained mercury, she did chelation and cured her daughter. Many autistic kids have Lyme disease and improve significantly on a Lyme herbal protocol (boosting TH1 immune system). Poor gut flora, bad bacteria need to be treated too. Dr. Nemecheck is convinced that autism is caused by bad bacteria in small intestine. His protocol is based on giving Inulin (FiberChoice) and large amounts of phish oil.
Fascinating!
Deletehttp://naviauxlab.ucsd.edu/wp-content/uploads/2017/05/Naviaux-QA-5-26-17-v19.pdf
Many key questions answered. Enjoy,
AJ
Thanks, AJ. This is an interesting statment by Dr. Naviuax:
Delete"But sometimes the CDR gets stuck... When this happens, cells behave as if they are still injured or in eminent danger, even though the original cause of the injury or threat has passed. On a molecular level, the defended set points for cellular homeostasis are altered. This creates a pathological metabolic memory—an abnormal cellular response—that leads to chronic disease."
I am not an expert in biology, but this theory of "metabolic memory" is something new. And if it indeed exists and can be turned off by Suramin or alike, Dr. Naviaux should receive a Nobel prize because no one has figured out how to turn off chronic inflammation. Even IVIG doesn't give permanent results. Suramin is just an antagonist of P2X receptors. Every time you start antagonizing receptors, the body reacts by upregulating them. The disequilibrium caused by these changes causes withdrawal when the drug is stopped (suddenly you have too many receptors and no antagonist, things are even worse than before the drug).
This comment has been removed by the author.
DeleteAJ, thought you might like to see this - esp. since your daughter, like my son, has benefited from b6
ReplyDeletehttps://molecularautism.biomedcentral.com/articles/10.1186/s13229-016-0109-5
"In addition, the cell danger response also yields relative vitamin B6 deficiency and the enzyme kynureninase is B6 dependent [65]; hence, a cell danger metabolic response in the presence of adequate tryptophan intake could also explain the decreased kynurenine and increased xanthurenic and quinolinic acid observed here (Fig. 4). Interestingly, these abnormalities have been sometimes overcome with vitamin B6 supplementation [67], a therapeutic approach initially proposed for ASD in conjunction with magnesium supplementation [68]. In light of the present data, B6-Mg++ supplementation in ASD may deserve further scrutiny in urinary biomarker-driven therapeutic trials"
If there is a deficiency in b6 or else if current supplies have been exhausted, then you will get more quinolinate converred into NAD+. However, there is a rate limiting enzyme for its synthesis. Ideally, you would want to find some drug or other substance to upregulate the enzyme in lieu of excess kynurenine being converted into quinolinic acid.
DeleteThe bcaa therapy I employ was for this theoretical reason in that less kynurenine getting into the brain means less quinolinic acid. I also employed a apigenin which is a good IDO inhibitor as well as p5p for the reasons you mentioned tanya. I still employ these intervention daily today. If you are worried about low serotonin in the brain then supplement 5-htp. Whether improvements in my son are from kynurenine restriction or preventing excess dopamine in the brain, I really don't know.
Hi Tanya,
DeleteHope you had a great weekend!
I thought I had replied earlier, but it was on my iPhone so it either didn't go through or I'll have two responses.
This paper is awesome - there is so much great info in it, but the key piece may be what you posted, as it seems to validate aspects of the Naviaux hypothesis.
I've been so busy all weekend, I didn't get a chance to start my list of P2X and P2Y antagonists, but I think I remember berberine, Naringin, and Emodin were on there, as well as Amentoflavone (most of these were P2X7 antagonists I believe).
The fact that B6 may be helping this way could explain why I've had good results with it (thanks to you!).
My hope is that we find good usable antagonists to most if not all the P2Xs and P2Ys so that we can somewhat mimic what Naviaux has done and see what impact it makes.
With respect to Berberine and Naringin, I've had to put them on hold as they are quite bitter, and I've been working on solutions to it. I may have come up with a very creative one, but want to test it first.
Hope all is well with you Tanya, It's always nice chatting with you, and have a wonderful day!
AJ
What about Kudzu the herb which could also be used as an APT?
ReplyDeletePeter,
ReplyDeleteDr. Naviaux, in a recent interview, appeared very cautious, to the point of even saying that either the results he got were wrong (small sample size) or could be pretty break throughing...pardon the grammar. He does acknowledge that its too preliminary and gives scenarios under which suramin will fail as a therapy...it includes a situation where repeated suramin infusions fail to bring significant improvements after the intitial boom. So, I think he is not peddling a dream and is quite realistic.
Does your lack of enthusiasm revolve around use of suramin or the proposed mechanism of its action, or the CDR theory and/or purinergic signalling, being singled out as a possible cause behind many autisms.
Kritika, I think Naviaux is suggesting his CDR is a consequence of autism, not a cause of autism. So whatever caused your particular autism has triggered other metabolic changes and some of these can be reversed by Suramin. This is very helpful.
DeleteIt may be that for example, in late regressive autism that causes ID, there might be complex 1 mitochondrial dysfunction. The data might show that in these people suramin causes a profound improvement. Then we would know that people who already tested positive for this dysfunction, should make a big effort to get suramin.
So there is a lot of work to be done. If I was doing the research, in India naturally, I would do a whole series of off-label experiments to figure out exactly who benefits. Then I would do a large clinical trial to prove to the world what I had already established privately in the mini-experiments. Quite possibly in India the ethics committee in the University Hospital would allow this approach. It looks like in the US you cannot do this.
I have already suggested to one researcher to consider a trial on his son who fits the above criteria.
Peter, have you heard about PERK/eIF2α signaling? This pathway is getting some attention of researchers as a new potential drug target for Alzheimer's: http://www.bbc.com/news/health-39641123
ReplyDeleteThe novel approach is focused on the natural defence mechanisms built into brain cells. When a virus hijacks a brain cell it leads to a build-up of viral proteins. Cells respond by shutting down nearly all protein production in order to halt the virus's spread... The brain cells shut down production for so long that they eventually starve themselves to death. This process, repeated in neurons throughout the brain, can destroy movement, memory or even kill, depending on the disease. It is thought to take place in many forms of neurodegeneration, so safely disrupting it could treat a wide range of diseases.
A similar mechanism of activated PERK/eIF2α signalling can exist in autism. Baclofen and Alpha-Linolenic Acid are known to inhibit this signaling.
In one model of autism (TSC1/2) PERK/eIF2α is indeed implicated.
DeleteRegulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes
https://www.nature.com/articles/ncomms12185
The very similar sounding eIF4E definitely is implicated in some autism (including, but not limited to fragile X)
eIF4E inhibitors for Autism – Why not Ribavirin?
https://epiphanyasd.blogspot.com/2017/03/eif4e-inhibitors-for-autism-why-not.html
In reality there will be hundreds of such mechanisms that can lead to a diagnosis of autism.
The number of safe possible therapies is very limited and so I continue to favour "responsible trial and error". I have trialed Baclofen; it has several plausible modes of action.
There are several good sources of Alpha-Linolenic Acid, including Flaxseed oil.
This series of interviews with parents from the 2017 trial is well worth reading.
ReplyDeletehttp://www.sandiegouniontribune.com/business/biotech/sd-me-autism-parents-20170525-story.html
Peter,
DeleteThis interview moved me to tears. Its like living those experiences. You know, my son has these phases..few days back he put on his toy goggles, then on me, then pushed them back up onto my head and finally put it on himself pusheing them back hero style, rushing to see in the mirror how it looked. He has a new game...switching of all lights in the bathroom and closing the door with tweo of us inside and I am supposed to make scary faces and noises. These are interactions most parents take for granted. But as parents to autistic kids, we keep recording, on paper, in words, and in our minds eye. Keeping a tight rein on our hopes. If Dr. Naviaux already has an idea on whom suramin will work and if the sample was not random but consisted of preselected candidates, I think it is very intelligent of him and good for us.
If any researcher in India trials off label suramin for asutism, I will go take my place in the line, trying for first place but ready to stand at the end, waiting.
Regards
Kritika, have you tried corticosteroids? They too like Suramin can give you a glimpse for a few weeks of what your child would be like without autism. They are much easier accessible - just find a doctor willing to prescribe them. I have read many parent testimonies who saw remarkable improvements on corticosteroids, which dissipated after stopping the treatment, and the parents were crushed and wanted the gains to continue.
DeleteAnonymous,
DeleteFirst, if you are parenting an autistic child, hold yourself together. If not, you can't begin to imagine how it is...i can't imagine how it is to be a parent to a nine year old who cant chew and can tolerate food only when it is placed deep inside his mouth, nearvthe tongue base...day in and day out. My son can use a spoon, swallow pills, use a straw. What i mean to say is that at this stage it would not be prudent to invest emotionally in any drug therapy for autism. But it would not help anybody to be dismissive about new reaearches. I think there is no one shot drug at present..i am aware of corticosteroids..all we are getting are phases of improvements but we carry on hoping some of them might stick.. sometimes they do.
Glimpse of what my child can be...i have had enough glimpses, a result of his natural biological rythems acting in complex interactions with weather, diet, physical activity. What is important is...like a previous comnent pointed out...can the drug leave you in a worse condition following its withdrawal and under what conditions. Can it potentially cause irreversible damage...if yes, then in what percentage of those trialled with it. I know of a child who regressed permanently after following a gfcf diet. My son regresed for a day or two when supplemented with a regular multivitamin, given at half the regular dose. Too many questions with no easy answers. But let us not close the doors and windows on new information. Its elementary...
Research in less developed countries, the current thinking is that the results may be less reliable
ReplyDeleteDr. Naviaux’s recent trial is primarily on safety and pharmacokinetics, not primarily on efficacy. We cannot criticize his study subjects number is too small, as long as the core question pharmacokinetics is answered.
subjects number is small should not be a concern at this stage as long as the selection process is clearly stated, and the potential bias is understood.
It is better to do study expensively & slowly; than to do study less reliably. That is why while IT is out-sourced to India etc, not clinical trials. Yi
ReplyDeleteThis study was clearly design to satisfy regulatory bodies such as FDA. Further phase-II studies will be followed (hope very soon). They also used < an independent data and safety monitoring board (DSMB)>.
ReplyDeleteThey usually try to make the results relatively easy to interpret
I think the beauty of this study is that it demonstrated proof of principle (really it was proof of mechanism).
Re: cell danger response biomarkers.
All the 5 subjects had positive effects, therefore the treatment efficacy may not be ‘gene defect type’ specific, and can be applied to many patients.
It is a pity to see that suramin was not ‘disease modifying’ in this study. However, further studies will long term dosing may have different results.
Regarding < Anonymous > ‘s comments, not every patient appreciate that academic physicians are usually under huge amount of stress, so to keep the studies going, to keep the lab open, to keep research associates and post-doctoral fellows paid etc..
This study was not design to know what is , this can be better known when the dosing regime is decide (dosage per injection, intervals, total treatment duration) - Yi
There are so many Anonymous here that it is hard to understand which one is referenced. Suramin is by no stretch of imagination a safe drug. Wikipedia used to contain the following warning, which either accidentally on on purpose was removed by someone:
ReplyDelete"There is a greater than 50% chance of adrenal cortical damage, but only a smaller proportion will require lifelong corticosteroid replacement."
You can still read this warning on websites, which don't allow free editing by everyone, like this one http://www.bionity.com/en/encyclopedia/Suramin.html
I, as a farther of an autistic child, would be OK with such high risk of adrenal damage from Suramin AND paying thousands of dollars for the treatment if it had a chance to cure my child of autism. But as any other treatment, Suramin effects only last as long as the treatment. And you can't just put a child on a chronic Suramin treatment (say 1 IV/month) to keep the gains going because then for sure you will irreversibly damage that child's adrenal glands or kidney. By the way, the same serious side effect of damaging adrenal glands exists for corticosteroids such as prednisolone. That is why it is given only for a few months. Prednisolone is also very effective for regressive autism and can actually make the gains stay (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022403/): "By approximately one year after cessation of steroid therapy those 17 subjects who had demonstrated clinical language improvement maintained and/or further improved their performance after cessation of treatment."
I am still confused about the goal of the Suramin study. To prove Dr. Naviaux' theory of metabolic memory and that it can be turned off permanently by Suramin? He already failed to show that in his previous mice studies and in the present human study (http://www.nature.com/tp/journal/v4/n6/full/tp201433a.html): "Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice". The suramin effect in human subjects of his most recent study also was lost after 5 weeks.
So, suramin requires monthly IV's to keep the gains going. But that is dangerous due to potentially serious side effects. If Dr. Naviaux wants to find that "memory" to a no-longer present cellular threat, he should be looking at immune memory B-cells. These are the cells that get activated by vaccines and are responsible for many cases of regressive autism (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361046/).
Re: Anonymous 30 May 2017 at 20:47
ReplyDeleteSuramin is by no stretch of imagination a safe drug.
but as any other treatment, Suramin effects only last as long as the treatment.
RE: And you can't just put a child on a chronic Suramin treatment (say 1 IV/month) to keep the gains going because then for sure you will irreversibly damage that child's adrenal glands or kidney. [Honestly I think we do not know yet. I would think this chronic dosing at low levels can be safe though inconvenient.]
I am still confused about the goal of the Suramin study. [goal: 1. whether the dosage dose can be safe in the special target population, 2. drug biodistribution in vivo in the special target population, 3. Proof of principle of drug bioaction, including cell danger response/clinical improvement]
So, suramin requires monthly IV's to keep the gains going. But that is dangerous due to potentially serious side effects. [Honestly I think we do not know yet. I would think this chronic dosing at low levels can be safe though inconvenient.] Yi
http://www.sciencealert.com/a-100-year-old-drug-shows-extremely-promising-results-for-treating-autism-symptoms
ReplyDelete<< so what's now needed is large-scale trials to potentially confirm these initial findings, and investigate potential risks and side-effects, and whether suramin could even be used in the long term.
"We have plans for five additional studies over the next five years to collect all the data the FDA will need to decide about the approval of suramin for autism," says Naviaux.
He also notes that even if suramin itself doesn't turn out to be the right treatment for ASD symptoms, these preliminary results might spark interest in the development of new antipurinergic drugs >> - Yi
Hello Peter,
ReplyDeleteJust read your comment on another site suggesting how finding a new use for an old drug, suramin, could elicit somebody's financial interest. In 2015, Dr. Naviaux had said that following his initial publication about suramin/antipurinergic therapy for autism, a number of drug companies are trying to manufacture new drugs with similar mode of action. Do you have any information on any progress made on this front.
Secondly, suramin serious side effects are liked to a damage to adrenal cortex, kidney and accelerating growth of certain tumours. Is the dose used for the recent autism study and that found to cause adrenal cortical damage comparable.
Thirdly, although much disappointment has been shown regarding the transient benefits of suramin, we have to remind ourselves that often repeat dose of certain drugs lead to a permanent of reasonably extended suppression...Cure??? of a health issue. Many auto immune disorders, which if unmanaged, could be potentially fatal, do tend to pass away peacefully, after a year of too, through sometimes intensive management during the acute phase.
It would be helpful to remain sceptically positive about Dr. Naviaux s research at this stage, don't you feel?
Kritika, there is plenty of interest for other kinds of disease, including GI problems. Here are some examples:-
Deletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340257/table/T4/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340257/table/T5/
These drugs are not being designed with autism or Naviaux in mind, but might be helpful.
Naviaux used a very low dose to avoid side effects. I think he originally saw Suramin as research drug to test his theory, not as a long term therapy.
At a higher dose the effect might have been more profound and would have been longer lasting.
It certainly is possible that continued use might become disease changing, or it might be the case that continued use leads to a reduced effect. We will just have to wait 5-10 years and see.
It is always best to remain optimistic. Perhaps one of the drugs being developed for arthritis can be repurposed for autism.
Unfortunately, big pharma has never focused on autism in their drug development even though autism reached 1 in 50, the same rate as Alzheimer's. But you see multiple big pharma companies developing novel Alzheimer's drugs. The only reason for this lack of focus on ASD drugs I can come up with is that many cases of developmental disorders are now diagnosed as ASD. There is no consistent cause of ASD as in Alzheimer's.
DeleteIn the animal studies, chronic dosing of Suramin was associated with structural benefits.
DeleteAntipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model. Mol Autism 2015;6:1.
Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model. PLoS ONE 2013;8(3): e57380.
-- hope it will be fast tracked. Yi
Interesting that Bob Naviaux hopes to do a trial of Suramin in ME/CFS later this year. Naviaux has been working with Ron Davis and his Nobel Laureate colleagues as part of the Open Medicine Foundation project.
ReplyDeleteWhat could be of particular interest is Naviaux and Davis have seen problems with Pyruvate metabolism in ME/CFS. Norwegian and Australian teams have seen problems with a different part of Pyruvate metabolism in ME/CFS.
Suramin kills the protozoa in African Sleeping Sickness by acting on its Pyruvate metabolism.
You can find out more about Ron Davis and OMF at https://www.omf.ngo/
My interest in all this is that I have both autism and ME/CFS, so it really catches my eye that Naviaux is looking at both autism and ME/CFS in a similar light.
Regards, C
C, you may want to read Naviaux's Q&As
Deletehttp://naviauxlab.ucsd.edu/wp-content/uploads/2017/05/Naviaux-QA-5-26-17-v19.pdf
here he says that:-
"Our research is aimed at finding a unifying cause for autism and an explanation for why it, and nearly 20 other chronic diseases have been increasing over the past 30 years. Our research is leading us to the conclusion that autism is caused by a treatable metabolic syndrome in many children."
I my own blog I have already started to write about autism as a metabolic syndrome, with a view to finding individual drugs with multiple beneficial effects.
He mentions in his text that Suramin made some kids start to sing. That was my own observation of two metabolic modifying drugs (not anti-purinergic drugs) that I investigated.
As AJ pointed out in http://naviauxlab.ucsd.edu/wp-content/uploads/2017/05/Naviaux-QA-5-26-17-v19.pdf
ReplyDeleteMost of the concerns are answered there, I cannot help but copy their 2 Q%As here:
Q9: What about the side effects of suramin?
A9: We did not find any serious side effects or safety concerns in this first study of a single, low-dose of suramin. The low-dose that we used produced blood levels of 5-15 μM and has never been tested for any disease in the nearly 100 years that suramin has been used in medicine. All previous uses of suramin have been at medium doses for sleeping sickness that produced blood levels of 50-100 μM for 1-3 months, or high doses for cancer chemotherapy that produced blood levels of 150-270 μM for 3-6 months.
Q12: Will suramin need to be given for life?
A12: I don’t think so, but we don’t have the science to answer this question yet. More studies
will be necessary to see if improved development can become self-sustaining without the need
for regular suramin treatment.
--Yi
Again, I will repeat that antagonizing receptors doesn't work long term, any receptors, not just P2X. If antagonists had any lasting effect, we would have cured such diseases as arthritis, diabetes, etc. Please read about upregulation and downregulation in Wikipedia: https://en.wikipedia.org/wiki/Downregulation_and_upregulation
DeleteI will quote: "Receptors are created, or expressed, by the DNA of the cell, and they can be increased, or upregulated, when the signal is weak, or decreased, or downregulated, when it is strong... Some receptor agonists may cause downregulation of their respective receptors, while most receptor antagonists temporarily upregulate their respective receptors. The disequilibrium caused by these changes often causes withdrawal when the long-term use of a drug is discontinued. However, the use of certain receptor antagonists may also damage receptors faster than they upregulate (internalization of receptors due to antagonism). Upregulation and downregulation can also happen as a response to toxins or hormones."
As far as Suramin is concerned, there are several drugs in development with similar antagonistic action on P2X receptors for "a variety of disorders, including thrombosis (P2X1), chronic neuropathic and inflammatory pain (P2X3, P2X2/3, P2X4, P2X7), dysfunctional urinary bladder (P2X1, P2X3, P2X2/3), rheumatoid arthritis and osteoarthritis(P2X7), and depression (P2X7)" - taken from http://onlinelibrary.wiley.com/doi/10.1002/wmts.1/pdf. If you continue reading this article, you will find out that an investigational drug PPADS "tends to have a similar potency or be slightly more potent than Suramin... The antagonistic actions of PPADS tend to develop and reverse slowly." REVERSE! Kudzu, contains P2X antagonist Puerarin, has been used in China and Japan to treat inflammation and pain. Surely there is more than enough evidence of how P2X antagonists work. So far none of them, including the natural one, were able to cure autism.
The only permanent way to stop activation of P2X receptors in chronic inflammation is to stop cells from releasing ATP into extracellular space, which acts as an agonist of P2X receptors. It is a defense mechanism of the cells against existing or perceived(?) infection or stress. Unless Dr. Naviaux thinks that the following circular reaction possible in the absence of threat: P2X receptors get somehow activated, activated P2X receptors cause inflammation, which in turn causes cells to release more ATP, which in turn activate P2X even more, and so one. If such scenario indeed was possible, then breaking this inflammation-ATP-P2X-inflammation circle may help. But so far, nobody was able to stop chronic inflammation without repairing the immune system through IVIG or bone narrow transfer.
V
I forgot to add that back in 2013, in this article http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057380, Dr. Naviaux admitted that "long-term therapy with suramin in children with autism is not an FDA-approved usage, and is not recommended because of potentially toxic side effects that can occur with prolonged treatment". So, he knows that Suramin can damage organs in long-term use. He also already knows that a single dose use only lasts 5 weeks. Then why is he pursuing more and more studies of Suramin? Perhaps he eyes a Nobel prize for his theory of P2X role in autism but really doesn't care about practicality and safety of his Suramin treatment approach. You have to consider an emotional impact of his studies on parents. Their children are given a drug (through a traumatic IV infusion that lasts for an hour or so - they need to do it slowly), which make them to improve, and then the gains disappear. How do you think parents feel knowing that they can't keep the gains?
DeleteV
V,
DeleteEven if suramin does not prove to be effective but Naviaux is able to prove that many autisms may have a metabolic basis and hence potentially treatable, it will bring about a shift in not only how autism but a number of chronic pathologies are viewed and treated. If he gets a Nobel, it would be a mito cocktail dose into autism treatment therapies. And please do not go on and on about traumatic IV s...it does not help anyone by you acting so naive. And about the parental expectations, what about the trauma related to bringing up a child who seems to be so uncomfortable with his own being and in his own skin and to accept that there is no hope as autism is a severe lifelong neurodevelopmental disorder with a likely genetic basis.
You have made important points about possible difficulties in treating chronic inflammations and how long term use of receptor antagonist might not work and might even backfire, but you dilute your serious concerns with non serious others which make you seem like a disgruntled family member. Please do not mind but your perceptions could be greatly enlightening if you could differentiate between the critical and the non critical.
I added in my post but it was lost after pre-viewed the post. This happened twice, if I pre-view a post, some text will be lost.
ReplyDeleteHonestly we believe that unless a person has a PhD degree in the related field, then he/she would not be able to criticize a research article such as Dr Naviaux’s.
I have a medical degree, a PhD unrelated to DR Dr Naviaux’s field, and worked in the R&D section of a major pharma. I do not fully understand Dr Naviaux’s theory, but I can appreciate it is a beautifully designed study.
To perform a clinical trial is hugely resource intensive, involve a team of scientists (see the co-authors list of Dr Naviaux’s paper), and lots of careful planning and consultation.
There are many reasons why chronic dosing will be more useful, first is that the skills learned can be retained, and this can be potentially an exponential process; secondly, as demonstrated in the animal study, brain structural benefits, and maybe others. To cure a disease is another matter, and massive improvement is another. I would expect the statement <> is associated with deeper thinking.
For such a beautifully planned and executed study, I have already seen a number of unjustified critiques here. Importantly, this clinical trial should be viewed as a part of a series of studies, past animal studies, and future more clinical studies. Dr Naviaux is painstakingly pushing things forwards.
-Yi
Dr Naviaux’s have participants from the following dept. and institutions
ReplyDeleteDepartment of Medicine, UCSD,
Department of Pediatrics, UCSD,
Department of Pathology, UCSD,
Department of Neurosciences, DCSD,
Clinical and Translational Research Institute (CTRI), UCSD,
Department of Family Medicine and Public Health, UCSD,
Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD,
Alliant International University,
Department of Psychology, San Diego State University,
The Research in Autism and Development Laboratory (RAD Lab), University of California,
Institute for Neural Computation, University of California,
Pediatric Neurology Therapeutics, San Diego,
Pls do believe that all clinical trials involve pain-taking planning.
- As AJ suggested, the best way now will be to search whether there are available substance (with relatively safe profile) which has similar actions as Suramin’s. / Yi
Inhibition by imipramine of ATP-evoked responses in rat ... - NCBI
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pubmed/9514927 -
Conclusion:These results show a new pharmacological profile of imipramine, namely the inhibition of P2X2 receptors.
Not at all sure if this drug has a relatively safe profile for children, but it could be an option for adults.
Peter, have a look at this paper about saffron as a P2X7 inhibitor.
ReplyDeleteSaffron reduces ATP-induced retinal cytotoxicity by ... - NCBI - NIH
https://www.ncbi.nlm.nih.gov/pmc/.../PMC4749535/ -
In case you don't know saffron, it's a spice cultivated in Greece and people use it in food and drinks to give a distinct taste. It's too strong and you can only use a tiny amount. We all know that it's the greatest antioxidant.
Petra,
DeleteIn India too we use saffron, though its very expensive and its supposed to have potent beneficial properties. In fact my mother had been pestering me to start using sprinkles of saffron on my sons food.
Mother knows best!
Tmme toisten to
Petra, there are special saffron supplements made for people with that type of eye problem. We do not know which of the P2X and P2Y receptors relate to autism, but saffron does seem a safe way to target P2X7.
DeleteWhat could be the connection between saffron and aggressive behavior, I followed the treatment given by the doctor with a syrup prepared with saffron and the effect was disastrous, screaming, aggression that disappeared 4 days after I stopped the treatment and reappeared when I started again.
DeleteDenisa, saffron is usually seen as having beneficial properties. It is a monoamine oxidative inhibitor which makes it an antidepressant. It is also antioxidant and anti-inflammatory.
DeleteIt also has an effect on the excitatory neurotransmitter glutamate. Too much glutamate will lead to over stimulation and aggression. The exact mechanism behind saffron's effect on glutamate is not fully understood. One key cause of aggression is when there is an imbalance between exitatory and inhibitory functions in the brain.
Another good example is giving a GABA stimulating drug to a bumetanide-responder, they will get very aggressive. This is due to an increase in excitatory signaling, since GABA works in reverse in this sub-group of people with autism.
Would a GABA stimulating drug be versed?
DeletePeter, your idea to counter excess P2 signaling by reducing P1 signaling looks very interesting in my son's case and I'll try to apply this.
ReplyDeleteSome benzodiazepines are adenosine agonists and thought that the paradoxical effect of benzodiazepines might be due to adenosine dysfunction which affects gaba and other neurotransmitters. Could this be possible? As you mention blocking P1 would be a better idea before blocking P2 if I understood it well.
I think we could block adenosine with orthosiphon stamineus, known as Java tea. If you are interested have a look at it as it has numerous benefits related to ASD pathology.
FYI Peter, its unlikely that we are going to get our second trial...Naviaux's lab is running out of funding for both autism and ME/CFS trials
ReplyDeleteI think in the end he will get funding, but it may take years. He needs to get support from other leading researchers, or even ask the Saudis, who do fund autism research.
DeleteHi Peter, Anon and community,
ReplyDeleteAny idea how much Naviaux needs for ASD? I'm assuming around $1M.
If there was a Kickstarter (or something similar) to fund him, I'd pledge $2,000, as we'd only need 499 other people to pledge $2,000 each.
With around 4,000,00 people with ASD in the US and Canada, you would think there would be at least 500 families who would each be willing to pledge $2,000 towards research that had the potential to improve their kids.
Why do we have to wait for a philanthropist or government institution when we have the power ourselves? $1,000,000 from a single source is the same as $1,000,000 from 1,000 sources.
Just my 2 cents
AJ
AJ, unfortunately I think you will find that the cost to take Suramin all the way forward in the US to approval as an autism drug would cost vastly more than $1m, more like $20 to $40 million. Everything to do with healthcare in the US is absurdly expensive.
DeleteI recall being told the cost to approve bumetanide in Europe and why they gave up with the US, the costs were just crazy.
The company that went bankrupt trying to develop Arbaclofen for autism burnt through $40million.
This is why I focus on repurposing existing drugs that are already in your local pharmacy.
Hi Peter,
ReplyDeleteI thought the last one had cost $500K (but went over budget) and that the next one was only going to be about twice the size.
If it is going to cost $20 - 40 million, then that's a problem (especially for a drug that is long off patent).
AJ
Hi Peter,
ReplyDeleteDr. Naviaux did a talk at TACA Conference this weekend and it has been posted here for anyone interested: https://vimeo.com/239193768
Thanks for highlighting this.
DeleteHi Anon, Just wanted to say thanks so much for posting this!
DeleteAJ
Im watching the video now as we speak and my mouth just literally fell open, especially when he started talking about the CDR.
DeleteThis seems to be in line with what my 'gut feeling' has told me all the time and that Ive only recently been internally connecting the dots.
Ive proposed Peter about a water sensory system, controlling oxytocin/vasopressin release, aswell as other sensory systems that seems to be dysregulated.
Not to mention my experience with my rare unwillingly induced alcohol binges to induce a response, as Peter knows about me, I look forward to the hangover!!!! could this be related to CDR Peter? Cause it certainly seems as this is what is going on.
Hi Aspie,
DeleteThe thing that always made me think that Naviaux has figured it out is the fact that people with ASD have so many unusual results in so many different systems, that there had to be an overarching issue. And CDR may just be that.
I did lots of research many months ago on natural anti-purinergic treatments, and after watching this video, will revisit that research and see if anything new has popped up.
I'll share whatever I find, and if you find anything on antipurinergic (e.g. anti P2X7R) therapy, please share.
AJ
Also, further to the presentation, a group of parents are starting a campaign to raise awareness and funds for further research at Naviaux Lab, please have a look and share.
ReplyDeleteFacebook Group Link: https://www.facebook.com/groups/260176594325901/permalink/562352220775002/?comment_id=562458434097714¬if_id=1508883015013056¬if_t=group_comment_reply&ref=notif
Hopefully that works but if it does not then in search tab enter: Support Naviaux Research and you will be taken to closed group.
Also fundraising page: https://giveto.ucsd.edu/make-a-gift?id=9185a895-aaf5-4f91-a8fc-3ff44b719e24
As I said here before, Suramin will never be approved as a treatment for autism, ever. Its effects don't last more than 4 weeks, require continuous use, which is not recommended even by Dr Naviaux himself (read his articles), "there is a greater than 50% chance of adrenal cortical damage" https://www.wikidoc.org/index.php/Suramin. The so-called CDR response is due to ATP agonism of purinergic P2 receptors. "When a cell was injured or lysed by a virus, ATP and other nucleotides and metabolites were released into the surrounding area, creating a bright chemical flare warning other cells of the danger and the presence of a pathogen." Instead of resolving the underlying cause of extracellular overproduction of ATP (removing virus, toxins, etc), Dr Naviaux proposed to block the ATP receptors with SUramin. It is like someone shouts "fire" and instead of putting out that fire, Suramin closes your ears. How does that help? Fire (virus, toxin, etc) is still there. If you feel so excited about Suramin, try corticosteroids. You will see a similar effect without waiting for an FDA approval of Suramin, which will never happen.
Delete- "As I said here before"
DeleteSaid the anonymous poster without a name ... talk about lack of credibility (which is further exacerbated by nonsensical content).
-"Suramin will never be approved as a treatment for autism, ever."
Um, even Dr. Naviaux has said that. The point of the Suramin trials by Dr. Naviaux is proof of concept. What this means is ... oh, why bother, you are clearly not capable of understanding even basic concepts.
- "Its effects don't last more than 4 weeks, require continuous use,"
Like almost every drug on the market. Most drugs are for chronic use Einstein. Ever heard of Crestor, Lipitor, Remicade, and the vast majority of other drugs?
- "which is not recommended even by Dr Naviaux himself"
Um, Naviaux has already said his intent isn't to get Suramin approved.
- "Instead of resolving the underlying cause of extracellular overproduction of ATP (removing virus, toxins, etc), Dr Naviaux proposed to block the ATP receptors with SUramin. It is like someone shouts "fire" and instead of putting out that fire, Suramin closes your ears. How does that help?"
- Oy vey are you ever clueless (or is it that insane grudge you still have against Naviaux for "torturing" your kid that drives you to attack Naviaux at every turn?).
Most drugs on the market today don't treat the issue on a one-and-done basis, and many don't address the root cause. Again, people take Crestor every day, they take MS drugs regularly, they take insulin every day, T2D meds, and on and on, and none of which eliminate the disease but improve the lives of the patients.
Based on your advice, people with T1D should stop taking insulin since the root cause is that their body attacked their Beta cells versus their inability to produce insulin. People who have high cholesterol should stop taking Crestor since the drug doesn't address the underlying cause of the high cholesterol. People with MS should stop taking their meds since they only dampen the immune system versus addressing the cause of the autoimmune disease itself. People with severe asthma should stop taking their inhalers since they don't address the root cause of asthma.
This is literally the dumbest medical advice in the history of medicine, and would be laughed at by anyone who has even been within 100 miles of med school (even the janitors in med school know more than you).
You clearly literally have no clue about the world of medicine, but seem "triggered" by anything Naviaux related. Move on, he used a needle to get blood from your kid, and somehow this was a shock to you - that's how it works genius. Get a clue.
"If you feel so excited about Suramin, try corticosteroids."
- Dear lord, you need help. Seriously. Professional Help. Naviaux Derangement Syndrome...Population = 1 mentally and emotionally unstable woman
I AM ANONYMOUSE!
Brilliant rebuttal ANONYMOUSE marred by gender bias....MAEU 'woman'? You certain of that cowboy?
Delete"Brilliant rebuttal ANONYMOUSE"
DeleteYes. Yes, it was.
"marred by gender bias....MAEU 'woman'? You certain of that cowboy?"
I'm actually cowGIRL ... why are you so gender biased that you would assume that I am a man? Just because my response was brilliant, you assume that I am a man? Only a man can make a brilliant rebuttal. Shame Shame
P.S. Next time you want to accuse someone of gender bias (the only card you could play after you were PWNED), make sure you don't include gender bias in your own message.
I AM ANONYMOUSE!
Oh, ANONYMOUSE, I take my compliment about your brilliance back but I still think you are a 'cowboy' as a cowgirl would have got the idea behind the deliberate and intentional introduction of gender bias in my message...or you a cowgirl on the spectrum?
DeleteLets not make it uglier. You are clever...and I do pray something tangible comes out of Dr. Naviaux's research....he is brilliant too, like you.
Hold your horses, AnonyMOUSE. I respect your opinion, but it was mostly attacking me personally and self-flattering. Comparing Suramin to Crestor, Lipitor, Remicade, and Insulin is ludicrous. It only shows how little you know. Let me educate you. Crestor and Lipitor are inhibitors of the HMG-CoA reductase, an enzyme controlling cholesterol production. The purpose of insulin injections is to compensate for the lack of its production by pancreas. Controlling a rate-controlling enzyme or adding a protein that body lacks is different from modulating the activity of receptors by agonists or antagonists. Have you heard about downregulation and upregulation? Read here to educate yourself: https://en.wikipedia.org/wiki/Downregulation_and_upregulation Our cells maintain homeostasis through complicated feedbacks, whose purpose is to maintain the chemical signaling constant. For example, overweight individuals have chronic elevated blood glucose levels, which activate beta cells in pancreas to release more insulin. Over time, the beta-cell glucose receptors get downregulated (reduced in number) leading to diabetes and necessity to supply insulin though injections.
DeleteSuramin is P2 receptor antagonist, which means that it will block the P2 receptors. With chronic use of Suramin, the body will react by upregulating these receptors. More and more Suramin will be needed to produce the same effect. It is called tolerance (read about it). Eventually, the Suramin dose will reach levels at which it can damage internal organs. Even if it is not Suramin, but some other P2 blocker, there will be a similar P2 upregulation and tolerance.
Also, keep in mind that P2 receptors are involved in regulation of pain and inflammation – responses that (1) let us know about an injury and (2) protect from further damage. Blocking these responses chronically (if it is even possible) may not be a good idea. A much better idea is to eliminate the pathogen (virus, bacteria, toxin, allergen) that caused the cells to excrete ATP into extracellular space and activate these P2 receptors.
There are currently several orally bioavailable P2X7 inhibitors being researched for rheumatoid arthritis. One of them, AZD9056, was put on hold due to failure to reduce inflammation and had pretty bad side effects. Your best bet is to wait until one of those get FDA approved and then use them off-label for autism if that really works long term.
Can this immature behaviour by those involved be taken elsewhere? thank you...
ReplyDeleteI agree with you Aspie1983, it is a great idea!
DeleteValentina
Thought this was interesting for those interested in suramin/antipurinergic therapies:
ReplyDeleteLocal regulation of vasopressin and oxytocin secretion by extracellular ATP in the isolated posterior lobe of the rat hypophysis
https://www.ncbi.nlm.nih.gov/pubmed/10076181
"The effect of endogenous ATP on the hormone secretion was tested by suramin (300 microM), the P2 receptor antagonist. Suramin significantly increased the release of AVP, and the release of oxytocin was also enhanced."
As you can read above in the study Peter posted the partipants also had improvement in social functioning (possibly due to suramin increasing their vasopressin and oxytocin?)
I have not seen anyone mention that Suramin is also currently used as a chemotherapy drug. Unless I have misread it seems it facilitates apoptosis by encouraging ceramide accumulation. I have maternal immune activation as a result of a past Lyme disease infection and almost non-existent vitamin D levels that do not correct vis supplementation. My nonverbal autistic son has responded best to pyridoxine supplementation which I understand is antipurinergic. He gets eczema from gluten which responds to creams containing ceramide. B6 and vitamin D are both necessary for ceramide synthesis. Maybe we just need Suramin temporarily to restore proper apoptosis reversing this CDR "stuckness". Lots of estrogen driven cancers in our family as well as Adenosine Deaminase polymorphism.
ReplyDeleteMelanie, Pyridoxine (vitamin B6) is indeed converted into a P2‐purinoceptor antagonist.
DeleteVitamin B6 has long been suggested as an autism therapy, indeed Bernie Rimland, of DAN and ARI, was a big believer in high dose B6. His son reportedly still takes it.
Here is a recent Japanese study trying to identify who might respond to B6.
Potential identification of vitamin B6 responsiveness in autism spectrum disorder utilizing phenotype variables and machine learning methods
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172273/
Interesting. I actually have two sons with nonverbal autism as my immune system was activated during both pregnancies. My oldest does not respond to b6 and it actually makes him sensitive to sound whereas my youngest does and it removes his sound sensitivity. In looking for what they have in common the facts point to a lack of sphingomylinase (requires vit. D,B6 to make ceramide). If I've read the studies correctly ceramide is a potassium channel kv1.3 inhibitor. So is progesterone which dramatically puts out the inflammation I struggle with and is a VDR agonist. I hope to trial a phytoceramide supplement soon to see if it can also help dampen this chronic immune inflammation. I have interstitial cystitis that gets worse from potassium. Has something to do with ATP leakage which apparently is prevented by ceramide. I found a study stating sphingomylinase is protective against ulcerative colitis which I think points back to Kv1.3. UC would probably be a diagnosis my sons would receive if they were properly assessed which takes a miracle here in Canada.
ReplyDeleteMelanie, Kv1.3 is very interesting and has come up in 9 posts on this blog:
Deletehttps://epiphanyasd.blogspot.com/search/label/Kv1.3
If you want to read all those posts you need to click on "older posts" at the bottom left of the page, otherwise you just see the recent ones.
Verapamil might well help your son's UC and brain function. Read about Rezular in the Kv1.3 posts.
There are many Kv1.3 inhibitors
https://channelpedia.epfl.ch/ionchannels/3
Many people with autism use Nystatin for other reasons, but this is not supposed to make it to the bloodstream. I think some benefit is via Kv1.3.
In my son's therapy Verapamil and the statin (Atorvastatin) block Kv1.3.
Some people with autism who respond to Verapamil do find their GI problems disappear.
Melanie, what dose of B6 do you use?
DeleteBernie Rimland found that some people responded negatively to B6 like your other son, but that by adding magnesium the negative effect went away.
https://books.google.rs/books?id=tOZqDydjMMIC&pg=PA267&lpg=PA267&dq=vitamin+B6+sound+sensitivity&source=bl&ots=o6LLS3PSzW&sig=ACfU3U3TXsuBKjmTevlqnApny1rWV7gY7Q&hl=en&sa=X&ved=2ahUKEwiX9s-l5MHlAhXyunEKHe-hDzQQ6AEwD3oECAsQAQ#v=onepage&q=vitamin%20B6%20sound%20sensitivity&f=false
It is often a combination of B6 and Mg that people use.
Hey Peter, I actually emailed Agnieszka about Verapamil a few months back but upon discovering that it raises prolactin and lowers uric acid and blood pressure I had to set it aside as an option for us. I tried magnesium with my kids along with the B6 because every study seemed to indicate the need for them in combination but all three of us could just not tolerate the further lowering of blood pressure it caused. We have elevated levels of Adenosine as a result of ADA deficiency. We have Mennonite heritage and due to the founder effect we are aware of the high incidence of this polymorphism among our people. You may have heard of the Somali Autism cluster? Somalis also have a much higher incidence of ADA polymorphisms. I have been quietly reading your blog for years and letting it guide my to anything that might be relevant to our very specific subgroup of autism. When ADA polymorphisms are combined with vitamin D deficiency you actually end up with maternal immune activation and the inability to inactivate estradiol in the liver. This leads to thiamine and pyridoxine and riboflavin deficiencies. We actually had to pair the B6 with riboflavin for it to work. In a way I think we are using the riboflavin as an aromatase inhibitor.
ReplyDeleteMy children's autism was very much regressive as opposed to classical. They each reached a point around the age of two where they were experiencing chronic bacterial infections as a result of reduced immunity. These bacterial infections were addressed with broad spectrum antibiotics that introduced a major regression - loss of eye contact, language and the beginning of extreme anxiety and OCD. They have been nonverbal eversince. To me the logical intervention would be calcitriol as they are unable to convert vitamin D to it's active form but that is only available in Canada to those with rickets and psoriasis.
ReplyDeleteSorry, to answer your question, I had my youngest on 125 mg of pyridoxine and 25mg of riboflavin at each meal/3x Day. It put a stop to all self injurious behaviours. Unfortunately my ex-husband refuses to do anything that is not prescribed by a doctor and instead had him put on Ability which seems to be actually making the problem worse as his vitamin D deficiency makes him unable to breakdown peripheral serotonin and it is a serotonin agonist. The positives they see are negatives to me as he appears sedated.
ReplyDeleteMelanie, did you do any genetic testing? This might make it much easier to get things prescribed by a doctor. In Canada you have the option of UBC in Vancouver, where they do whole genome sequencing. Look at
Deletehttps://treatable-id.org/page0/diseases.html
You also have the option of commercial WES testing and it looks like they give discounts when asked.
Our Canadian reader AJ used GeneDX. They have an "autism panel" option in their exome sequencing.
Hi Melanie,
ReplyDeleteJust to clarify - I am not aware of low blood pressure issues on verapamil reported in children with autism. Verapamil dose used in ASD is lower than recommended for other conditions e.g. heart diseases or migraine.
One reader here reported galactorrhea in her child in the past, otherwise I am not aware of prolactin or uric acid issues on verapamil in autism. I checked uric acid on a few occassions in my son who has been on verapamil for more than 5 years now, it was always within normal range.
These are of course anecdotal reports, there were no formal studies and the number of children with autism treated with low dose calcium channel blocker is low worldwide. Potential benefits clearly outweigh the risks in most children or adults with autism though.
This paper is quite recent and provides the evidence that WES should be a first-tier genetic test in autism:
Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.
https://www.ncbi.nlm.nih.gov/pubmed/31182824
The result can help obtain treatment beyond antipsychotics, prescribed by a doctor.
Thanks everyone. We have only had the genetic testing done that was provided through CPRI here in London, Ontario. I believe it looks for Fragile x and other disorders common in autism. It showed nothing "abnormal". When I asked to trial Verapamil the doctor said " that's reficulous. It's a blood pressure lowering med." In other words "no". We were given two options resperidone or abilify as these are the two on list medications for autism here in Ontario. They only stopped resperidone because I requested a prolactin test and it showed it was dramatically raising his already high levels. My frustration is that I already had an intervention that was preventing SIB (B6 and B2). We were denied ABA therapy as we were told our children were too low functioning to benefit and have autism "plus". My ex-husband will not allow for any test that is not ordered by our doctor. I think I happened on this blog after trying to understand why my oldest son and I had such an extreme positive reaction to benfotiamine. There is a post by Seth Bitker on the topic. I have to work within the extreme limits placed on me by the system here in Canada and by my ex-husband. At this time that means B2 Benfotiamine/B6 inosine. I started trialling ceramides with myself and it is too soon to tell but they do seem to help with joint and bladder pain. It seems to help with the high potassium low sodium created by high levels of Adenosine. I would also like to trial Agmatine as like ceramide it is an ornithine decarboxylase inhibitor and low vit D creates problems with nitric oxide. But it comes in the form of Agmatine sulfate and anything sulfate makes our symptoms of ulcerative colitis worse. We are on a waiting list to see a pediatrician who has a son with autism and who will perscribe off list but it could be years before we get an appointment. Even in this case my first request would be Calcitriol and any antipurinergic that might be available.
ReplyDeleteMelanie, parents not agreeing on what to do about autism is very common.
DeleteIf you have autism "plus" you could ask your doctor to look at treatable-id.org from the UBC doctors or ask him to order the autism panel from GeneDX. With genetic testing the issue is normally the cost.
Thanks Peter. I looked at treatable-id.org and it looks very much like what they did for my kids at Sick Kid's in Toronto. They really do not have autism for a genetic reason. I look at our polymorphisms to determine the best way to treat but this is really an issue of ongoing Cell Danger response after a series of immune related stressors. This may not have ever happened if we had a different cluster of polymorphisms but it still required the external environmental insult. For example, I have some hereditary weakness that causes me to hallucinate when given aspirin. My mother is the same. When I contracted Lyme Disease 20 years ago along with the classic bulls eye rash I had severe Lyme arthritis that did not resolve until years later with Benfotiamine. I have come across studies that state that Lyme arthritis does not resolve in COX2 knockout mice. I would like to know how this might relate to the type of inflammation we have in case it would point to an intervention I haven't tried yet other then Benfotiamine. I know that COX 1 and 2 have been looked at in autism.
ReplyDeleteHi Peter,
ReplyDeleteBased on testimonies it seems even though the improvements are gone after few weeks but seems it is beneficial to continue with periodic usage of suramin. Did any one used it other than from trials, if so how did they procured it and how safe is this attempt. Thanks
Sudhakar