The Hungarian flag, for clever Laszlo Prokai
Lupron – partially right, but for the wrong reason?
In the US there undoubtedly are some quack therapies for autism, however on occasion we have seen that you can stumble upon an effective therapy for entirely the wrong reason. In the history of medicine there are drugs that were stumbled upon, or created by accident.
In the case of the “Lupron protocol” which was promoted by a father and son (Geier and Geier), an extremely expensive therapy was apparently applied to hundreds of children, before being shut down by the medical regulators.
Without going into all the details, Geier’s therapy combined chelation (antioxidants) and a drug called Lupron that causes a dramatic reduction in testosterone levels. In the jargon, it causes hypogonadism - diminished functional activity of the gonads (the testes in males or the ovaries in females). Lupron is another of those drugs that costs ten times more in the US than in the normal world. So a single injection of Lupron, depending on the dose, costs up to $1000 in the US. Lupron is approved for use in children, male and female, with early onset puberty.
The case attracted media attention because Geier was also heavily involved in the idea that vaccines could cause autism and because patients were reportedly paying up to $50,000 for the complete therapy.
Geier was naturally a target for the anti-quack movement and why treat autism at all movements. He features in their books and blogs.
Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure (no link provided on purpose)
Still making the news in 2018.
Regulators who targeted controversial autism doctor may pay millions for humiliating him
In this case I think Geier stumbled upon a rather extreme, partially effective therapy but for the wrong reason. I doubt such an expensive potent drug is needed to produce the same beneficial effect, in that sub-group that appear to respond.The fact that Lupron is so expensive in the US, may indeed contribute to the desire parents had for it. There is a term in economics called a “Giffen good”; it is for the type of good that the more it costs the more you want it, like those very expensive hand bags people buy.
Personally I like inexpensive autism therapies, available to all.
Having read so much about autism, I am much less critical of those putting forward alternative ideas and therapies. It is very easy to get something right for entirely the wrong reason in medicine, which is something that is highly unlikely in many areas of science.
What I do not like is the predatory nature of some people with unusual ideas and therapies who treat autism. This is almost exclusively a North American phenomenon. Some parents will pay nothing to treat autism, for example some in countries with socialized medicine, while others would sell their house for a hope of an improvement.
The name Geier comes from the German word for vulture, maybe not the ideal surname for a healthcare worker.
If you read the following article from the Baltimore Sun you will see that there likely were some responders to this therapy:-
Lupron therapy for autism at center of embattled doctor's case
"Wessels, who lives in Rock Rapids, Iowa, took Sam to see Geier in his Indianapolis office two years ago. She said there were months of genetic and hormone tests, and then the diagnosis. She began injecting Sam with Lupron daily.
She said the diagnosis made sense to her. Sam was not only having trouble communicating and difficulty learning, but he was tall for his age, had hair on his legs and began constantly masturbating by the time he was 5.
She said there was no "wow" moment where Sam snapped out of his autism, a spectrum of disorders where sufferers lack an ability to communicate and interact properly. But in the course of the next year, Sam's reading improved from 35 words a minute to 85 and he focused in class. He stopped masturbating as much.
Wessels thought Sam was naturally advancing and planned to taper the Lupron at some point — at 9, he had reached the generally accepted age limit for a precocious puberty label.
The day came abruptly four months ago when a nationwide shortage cut off Sam's supply. Wessels said she saw Sam return to his old habits, from flapping his hands, to pacing, to forgetting how to get to his classes.
"I felt like I got a glimpse of the child my son was meant to be, not the one autism gave me," said Wessels, fighting back tears. "It's so sad to watch your child fade away again."
Lupron and RORalpha
Regular readers of this blog may have noticed an entirely different reason Lupron might be beneficial in a sub-group of people with autism. It has nothing to do with vaccines and mercury-containing thimerosal preservative.
Reducing testosterone in boys is going to have effects like increasing estradiol.
The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER.
androgen receptor = AR
estrogen receptor = ER
We have seen that RORA is suggested to act like a central point/nexus that affects dozens of biological processes disturbed in autism, making it a key target for therapy.
Other drugs that affect androgen receptors and are suggested in some autism?
Are there any other alternative autism therapies that affect testosterone and so androgen receptors? The answer is yes; this time a very cheap one called Spironolactone, that has been mentioned earlier in this blog.
The MAPS doctor known to some readers of this blog, Dr Rossignol, was one of the coauthors with the late Dr Bradstreet, in a hypothesis regarding Spironolactone.
Spironolactone is a potassium sparing diuretic, but also has the effect of shifting the balance between testosterone/estradiol towards estradiol, this makes it a useful therapy to treat acne for which it is sometimes prescribed. It seems to help some with autism.
I think any drug/supplement suggested to affect RORA in the right direction, will likely be reported to also improve acne, even if that sounds rather odd. If it does not improve acne, it lacks potency. Not all acne remedies will affect RORA.
I think any drug/supplement suggested to affect RORA in the right direction, will likely be reported to also improve acne, even if that sounds rather odd. If it does not improve acne, it lacks potency. Not all acne remedies will affect RORA.
In fact there are numerous ways to affect testosterone and estradiol and they are well documented on the internet because of all the males who are trying to become females (the transgender community).
Donald Trump and his personal physician declared they take a small daily dose of the drug finasteride, which is why both of them have such a full head of hair, and why Trump can brag about his low PSA result. This drug is used to treat an enlarged prostate and at a lower dosage, hair loss. It works by decreasing the production of dihydrotestosterone (DHT), an androgen sex hormone, in certain parts of the body like the prostate gland and the scalp.
Lupron might be too expensive in the US for males becoming females, but the other testosterone/estradiol modifying drugs seem to be very widely used/abused, depending on your views.
“Normal” levels of male/female hormones
One criticism of Geier was that while he did many different tests to measure testosterone in his patients, he seemed over willing to prescribe his highly potent testosterone reducing drug. It was reportedly not the case that he only used Lupron on patients with extremely elevated levels of testosterone.
In fact what are normal levels of male/female hormones?
There does not seem to be a normal level, rather a very wide range. the charts below are in adults.
Serum total T (A) and bioavailable T (B) levels as a function of age among an age-stratified sample of Rochester men (solid lines, squares) and women (dashed lines, circles).
Serum total estrogen (A) and bioavailable estrogen (B) levels as a function of age among an age-stratified sample of Rochester men (solid lines, squares) and women (dashed lines, circles).
Affecting Testosterone/Estradiol Just in the Brain
I do sometimes receive comments asking about possible future autism drugs in the pipeline, I even once had a section called “Future Drugs”. Things move so slowly I now really only focus on repurposing what is already available.
However, a really interesting new drug, DHED, is being developed to increase the level of the hormone estradiol just in the brain. Now as regular readers will know, in autism there is a lack of estradiol and a reduction in the expression of estrogen receptor beta. We know that estradiol is highly neuroprotective and that estrogen receptors in the brain modulate RORa, which is one of those switches that control a large group of genes often disturbed in autism. So a new drug developed to help post-menopausal women has potential to be repurposed to treat neurological disorders like autism and indeed Alzheimer’s.
Interestingly for me is that the lead researcher, a Hungarian called Laszlo Prokai, also researches another hormone, TRH, that I wrote about extensively a long ago in this blog. TRH is potentially another very useful therapy inside the brain.
Thyrotropin-releasing hormone (TRH), is a releasing hormone, produced by the hypothalamus, that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary. Thyroid-stimulating hormone (TSH) then goes on to stimulate the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body.
As I discovered a few years ago, TRH does much more within the brain, as a result it has antiepileptic properties and mood enhancing properties. The US Army is funding the development of a TRH nasal spray for ex-combatants with mood disorders and a risk of suicide. Antidepressants like Prozac have the odd side effect of increasing suicidal tendencies.
A TRH super-agonist (Ceredist) already exists in Japan, so I could never really understand why the US Army did not just get that drug approved by the FDA.
More Laszlos please
The big gap in all neurological disorders is translational research, which means actually converting all the existing knowledge into usable therapies for humans.
So it looks like we need more people like Laszlo; in fact there is another - Katalin Prokai-Tatrai, I assume it is his wife.
So like we already have the very talented duo Chauhan & Chauhan, we have Prokai & Prokai. What we would ideally want is Prokai & Prokai to translate the knowledge of Chauhan & Chauhan into human therapies.
As described in one of their papers:
Our laboratory has been involved in medicinal chemistry-driven research with attention to facilitating drug delivery of central nervous system (CNS) agents via prodrug approaches.
This is important because there are clever drugs that would be useful to treat brain disorders but you cannot get them through the blood brain barrier (BBB). So making a new compound that can cross the BBB and then converts back to the original drug is a neat solution.
Dr. Prokai's current research focuses on
(1) Novel therapies against neurodegenerative and ophthalmic diseases using site-selective prodrugs
(2) Development and use of proteomics in aging research, studying neurodegenerative diseases and cancer, with especial attention to quantitative expression profiling and oxidative stress-associated posttranslational modifications
(3) Discovering new therapeutic agents based on neuropeptides and peptidomimetics as lead molecules.
(2) Development and use of proteomics in aging research, studying neurodegenerative diseases and cancer, with especial attention to quantitative expression profiling and oxidative stress-associated posttranslational modifications
(3) Discovering new therapeutic agents based on neuropeptides and peptidomimetics as lead molecules.
In particular:
· Molecular mechanisms of estrogen neuroprotection
· Molecular pharmacology of thyrotropin-releasing hormone
“10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) is an orally active, centrally selective estrogen and a biosynthetic prodrug of estradiol which was discovered by Laszlo Prokai and colleagues. Upon systemic administration, regardless of route of administration, DHED has been found to selectively and rapidly convert into estradiol in the brain, whereas no such conversion occurs in the rest of the body. Moreover, DHED itself possesses no estrogenic activity, requiring transformation into estradiol for its estrogenicity. As such, the drug shows selective estrogenic effects in the brain (e.g., alleviation of hot flashes, neuroprotection) that are said to be identical to those of estradiol, whereas it does not produce estrogenic effects elsewhere in the body. DHED has been proposed as a possible novel estrogenic treatment for neurological and psychiatric conditions associated with hypoestrogenism (e.g., menopausal hot flashes, depression, cognitive decline, Alzheimer's disease, and stroke) which uniquely lacks potentially detrimental estrogenic side effects in the periphery
Highlights
· Treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, for 8 weeks decreased amyloid precursor protein in APPswe/PS1dE9 double-transgenic mice
· DHED treatment reduced brain amyloid-β peptide levels
· DHED-treated APPswe/PS1dE9 double-transgenic mice had higher cognitive performance compared to untreated control animals
· DHED treatment faithfully replicated positive neurobiochemical effects and consequent behavioral improvement observed for 17β-estradiol
· DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment did.
Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs
Medicinal Chemistry: Compound could lead to estrogen therapies with fewer side effects
Estrogen levels drop in the brains of women who have gone through menopause or had surgeries to remove their ovaries. This hormone deficiency can lead to hot flashes, depression, trouble sleeping, and memory deficits. Hormone replacement therapies can improve women’s quality of life, but taking estrogen has its own problems, such as increased risk of breast and uterine cancer.
A new compound could avoid the source of these side effects—the action of estrogen on cells outside the.
Laszlo Prokai of the University of North Texas Health Science Center and coworkers identified 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), which is converted to the main human estrogen, 17β-estradiol, in the brain and not elsewhere in the body. An enzyme expressed only in the brain reduces DHED to estradiol.
The researchers injected DHED into female rodents without ovaries and showed that estrogen levels jumped in the brain but not in other tissues. Then, through a series of experiments, they demonstrated that the compound had only neurological effects.
“It’s exactly the right strategy for avoiding the cancer risks and gaining the benefits in the brain,” says Bruce S. McEwen, a neuroendocrinologist at Rockefeller University. He thinks the next step is to show that the compound doesn’t have toxicity problems so that clinical trials in people can start. The researchers are planning such studies in hopes of moving the compound “from the bench to the bedside,” Prokai says.
Why is Estradiol good for your brain?
You may be wondering why I give so much time on this blog to female hormones. There is a lot of evidence beyond RORa, that estrogen/estradiol and its receptors are very important to healthy brain function.
The paper below is very interesting and worth a read.
Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer’s disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain.
However, estrogen actions on mitochondria are not exclusively related to such mechanism. Estrogen also regulates mitochondrial functions through their classical nuclear mechanism, i.e., transcriptional regulation of nuclear-encoded mitochondrial proteins. It is known that estrogen regulates the nuclear transcription of different proteins affecting mitochondrial function such as nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-gamma coactivator 1 (PCG-1). Hence, this regulation is critical for the activation of nuclear genes encoding proteins involved in mitochondrial biogenesis as well as in the mitochondrial electron transport chain complexes. It also regulates the transcription of mitochondrial transcription factor A (TFAM), which translocates into mitochondria and initiates transcription and replication of mtDNA
Note PCG-1 above, (a typo for PGC-1, I believe) for all those interested in treating mitochondrial dysfunction. We saw previously that PGC-1α is a master regulator of mitochondrial biogenesis.
It turns out that Estrogen is key to many aspects of Mitochondria, and the paper below from 2017 probably deserves its own post. Lack of estrogen or miss-expression of estrogen receptors in the brain is inevitably going to disrupt mitochondrial function.
Estrogens coordinate and integrate cellular metabolism and mitochondrial activities by direct and indirect mechanisms mediated by differential expression and localization of estrogen receptors (ER) in a cell-specific manner. Estrogens regulate transcription and cell signaling pathways that converge to stimulate mitochondrial function- including mitochondrial bioenergetics, mitochondrial fusion and fission, calcium homeostasis, and antioxidant defense against free radicals. Estrogens regulate nuclear gene transcription by binding and activating the classical genomic estrogen receptors α and β (ERα and ERβ) and by activating plasma membrane-associated mERα, mERβ, and G-protein coupled ER (GPER, GPER1). Localization of ERα and ERβ within mitochondria and in the mitochondrial membrane provides additional mechanisms of regulation. Here we review the mechanisms of rapid and longer-term effects of estrogens and selective ER modulators (SERMs, e.g., tamoxifen (TAM)) on mitochondrial biogenesis, morphology, and function including regulation of Nuclear Respiratory Factor-1 (NRF-1, NRF1) transcription. NRF-1 is a nuclear transcription factor that promotes transcription of mitochondrial transcription factor TFAM (mtDNA maintenance factorFA) which then regulates mtDNA-encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed.
Estrogens exert direct and indirect effects on mitochondrial function in a cell-specific manner through activation of membrane-initiated ERα, ER β, and GPER activity and by direct genomic binding of ERα and ERβ to regulate nuclear gene transcription. While still controversial, estrogens also activate mitochondrial localized ERα and ERβ in a celltype-dependent manner. One key nuclear gene increased by E2 is NRF-1 that regulates the transcription of nuclearencoded mitochondrial genes, including TFAM which increases transcription of mtDNA-encoded genes. Thus, E2 coordinates nuclear and mitochondrial gene transcription via NRF-1. Activation of UPRmt also activates ERα and increases NRF-1. E2 also regulates the transcription of genes regulating mitochondrial morphology, enzymes in the TCA cycle and OXPHOS pathways, and mitochondrial protein Snitrosylation. Depending on the cell type, E2 regulates mitochondrial biogenesis and bioenergetic function.
17β-estradiol is not only a reproductive hormone that is important only in women but it is also of immense importance for development and health in men. Although there is strong evidence from both human and animal studies that estrogen is protective in various brain diseases however, its adverse effect in classic target tissues such as uterus (17β-estradiol behaves as a full agonist on both estrogen receptor (ER) isoforms) is a matter of debate. ER subtype selective ligands are valuable tools for deciphering the specific roles of ER (α and β) in physiology and diseases. These compounds have a strong potential for development as therapeutics as these initiate estrogen signaling in brain but lack the mitogenic effects in other tissues such as ovaries and breast. Moreover, the existing and newer ERsubtype selective agonists will continue to be very valuable tool for deciphering the specific roles of ERα and ERβ
Severity of symptoms of schizophrenia is greater in males as compared to premenopausal females. Women have been shown to differ in symptom severity depending on the phase of the menstrual cycle. Higher rates of relapse in women with schizophrenia are also observed during the postpartum period (low estrogens), whereas relapse is low during pregnancy (high estrogens). During menopause, women are at risk of developing a new schizophrenic illness. Additionally, premenopausal women appear to have a superior response to typical antipsychotics compared to men and postmenopausal women. Estrogen plays a protective role in women with schizophrenia. Estrogen treatment may reduce negative symptoms in schizophrenic women. Estradiol may exert neuroprotection by several mechanism that may even vary among different brain regions.
Non drug therapies:-
Overeating and smoking will increase your level of estrogen. We saw earlier that in males testosterone is converted to estradiol in fat tissue.
Not to forget the other part of the Mediterranean Diet:-
Conclusion
Just as we saw that using high doses of antioxidants is beneficial in numerous medical conditions, where nobody calls it chelation, drugs that reduce testosterone or increase estradiol in the brain are not quack therapies, even when proposed by apparent vultures. It pays to keep an open mind.
Hormone replacement therapy (HRT) is a big business and if you can introduce a drug with less side effects, it should sell at a premium price, meaning DHED really should get commercialized.
DHED should be more effective than estradiol for treating neurological disorders because it can be given at a higher dose. In males there is no risk of feminization.
Contrary to what is sometimes quoted, estradiol lowers the risk of prostate cancer and is used to treat aggressive forms of it. High levels of testosterone are linked to prostate cancer and that is why Lupron is sometimes used.
Circulating levels of estradiol vary dramatically. People with a low level of estradiol might well be able to safely increase body-wide 17β-estradiol, rather than waiting a decade for DHED.
High levels of estrogen/estradiol in males may contribute to the extended healthy life expectancy in those with a soy-rich diet, as we will see in the forthcoming post on the Okinawan Diet and aging.
Spironolactone does have the advantage of increasing potassium levels, so someone with autism who responds to bumetanide and has high testosterone/ low estradiol and/or reduced expression of ERβ might see a benefit; I think it might require a high dose.
DHED looks interesting particularly for those with higher plasma estradiol but reduced ERβ in the brain.
I think the lady from Rock Rapids, Iowa in the earlier press report on Lupron, whose son had very hairy legs and responded to Lupron, should try some estradiol, or just get him to drink a great deal of soy milk. This really should have a similar kind of effect.
It appears that some mitochondrial disease is linked to estradiol and estrogen receptors ERα and ERβ. DHED might be a very clever treatment to what is otherwise pretty much un-curable. So there will be a post on estrogens regulating life and death in mitochondria.
The implication is pretty simple – more estrogen/estradiol please, if you want to live a bit longer, or if your brain does not work so well.
Thanks for the post --- Based on your post -- Do you think this is quasi related: Acne and all the hormones and inflammation....One of my daughters who is NT is on spironolactone for her acne and think it has good benefits on her mood.
ReplyDeletewww.sciencedaily.com/releases/2018/02/180207120651.htm
In an analysis of one of the largest electronic medical records databases in the world, researchers found that patients with acne had a significantly increased risk of developing major depression, but only in the first five years after being diagnosed with acne.
It is thought that androgens and IGF-1 are needed for there to be acne. High levels of androgens in women are known to cause depression. Spironolactone reduces androgens and hence is good for acne and most likely avoids there being depression. So it makes sense that your NT daughter's mood improves by taking her acne treatment.
DeleteSpironolactone, by reducing androgens, might also likely have an effect on estrogens. Estrogens affect the sub-unit make up of GABAa receptors, this particularly can affect anxiety and in the extreme case, which is epilepsy, changes in estrogens and progesterone trigger seizures in females via this change in sub-unit expression of GABA receptors.
So hormones are very important and have numerous effects, some of which are highly complex.
Does anyone know what happened to autismweb?
ReplyDeleteHad a wealth of information on the forums, now no forums left for biomedical discussion :(
Em, it looks like it closed down. Perhaps the site owner stopped paying the fees.
ReplyDeleteIt is a shame if all those thousands of comments have been erased.
There is now autismweb2.com, perhaps they can gain access to the old forums.
Peter, I am in a very bad place.
ReplyDeleteAre there any interventions that can help with attention and focus ? ADHD meds (both stimulants and non stimulants) have helped reduce severe hyperactivity (he sits and stares into space with a dazed expression) but they have done nothing for focus. Nothing.
Please help ! Anything at all out there that can improve attention / focus and motivation ???
GRT, the ADHD meds may have solved one problem only to create another. Best to ask your doctor
DeleteAn interesting study came out today which showed how even after clearing out a bed bug infestation, histamine levels remained 20 times higher than normal in the residence:
ReplyDeletePress Release:
https://www.sciencedaily.com/releases/2018/02/180212144202.htm
For people with suspected histamine issues, dealing with histamines released into the environment by insects such as bed bugs might be an issue to consider especially since actually removing the histamines seems to be about as difficult as removing pests such as bed bugs. For people with seasonal histamine issues it is with noting that cold temperatures will kill off most insects in a yard which usually means they are less of a problem in winter, aside from parasites like bed bugs, ticks, and fleas which can breed indoors.
Hi everyone,
ReplyDeleteI hadn't seen this posted so I wanted to share:
Chronic minocycline treatment improves hippocampal neuronal structure, NMDA receptor function, and memory processing in Fmr1 knockout mice.
Yau SY1, Bettio L1, Vetrici M1, Truesdell A1, Chiu C1, Chiu J1, Truesdell E1, Christie BR2.
Author information
Abstract
Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability, and is the leading known single-gene cause of autism spectrum disorder. FXS patients display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently there is no cure for this condition, however minocycline is becoming commonly prescribed as a treatment for FXS patients. Minocycline has been reported to alleviate social behavioural deficits, and improve verbal functioning in patients with FXS; however, its mode of action is not well understood. Previously we have shown that FXS results in learning impairments that involve deficits in N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity in the hippocampal dentate gyrus (DG). Here we tested whether chronic treatment with minocycline can improve these deficits by enhancing NMDA receptor-dependent functional and structural plasticity in the DG. Minocycline treatment resulted in a significant enhancement in NMDA receptor function in the dentate granule cells. This was accompanied by an increase in PSD-95 and GluN2A and GluN2B subunits in hippocampal synaptoneurosome fractions. Minocycline treatment also enhanced dentate granule cell dendritic length and branching. In addition, our results show that chronic minocycline treatment can rescue performance in novel object recognition in FXS mice. These findings indicate that minocycline treatment has both structural and functional benefits for hippocampal cells, which may partly contribute to the pro-cognitive effects minocycline appears to have for treating FXS.
https://www.ncbi.nlm.nih.gov/pubmed/29367010
AJ
AJ, that is interesting. Minocycline is another antibiotic with known immuno-modulatory effects. There will be a post on this subject. At least 3 classes of antibiotic have such effects, but the precise effect varies. So if you knew which cytokines were miss-expressed you could choose the matching drug. You actually would want the drug modified to no longer be an antibiotic, because long term use of antibiotics has disadvantages.
DeleteI think chronic inflammation is a key feature of most autism, which then triggers numerous other dysfunctions.
Yes, definitely interesting AJ!
Delete/Ling
Peter,
DeleteDo you also consider antimicrobial properties of antibiotics having some ameliorative effects on autism...probably chronic bacterial infections/imbalances and certain autistic individuals more sensitive to bacterial toxins. My sister as well as myself seem to benefit digestively by a short course of augmentin even in absence of any particular acute illness.
Could even mild elevated levels of bacterial metabolites be having significant neurotoxic impacts on some. I plan to keep a five day cefixime routine every four months on my son....will also talk to our doctor after a third trial (have carried out two with not to be missed kind of positive effects) how to take this forward. Probiotics become a slippery slope for my so that alternative of trying to keep a healthy microbiota does not work for us...unfortunately.
Kritika, bacteria certainly can have an effect in autism, but I think you have to look at which antibiotic gives a positive effect to know what is the likely mechanism.
DeleteBeta lactams have little immuno-modulatory effect but reduce the amount of glutamate, which would help some people.
Macrolides, fluoroquinolones and tetracyclines have known immuno-modulatory effects. If one of these helps in the absence of a bacteria, it is likely a reduction in inflammation is improving behaviour.
Minocycline was shown also shown in a trial to benefit MS.
Augmentin is a beta lactam, so its effect on you would seem to be killing bacteria somewhere.
Cefixime is also a beta lactam.
If you just want to kill bacteria in the gut and nowhere else, Vancomycin is a common choice taken orally.
I would ask your doctor about Vancomycin, because then you are identifying where the bacteria are. Perhaps things are growing in the gut that should not be there?
Peter,
DeleteThanks for bringing in more lucidity to my thoughts. We have till date, in six years of my sons life, tried only two antibiotics, amoxicillin, more often and to a lesser extent cefixim (twice prescribed by our paed, once my own trial). And though augmentin (amoxicillin) does bring about good sleep and better behaviour in the first two-three days, followed by some not so good side effects, likely linked to disturbed microflora, the effect of cefixime is much more radical. Cefixime, a cephalosporin has been reported to have beneficial impacts on some with autism.
I wish I could trial antibiotics from all those categories when my son is not apparently sick, to pinpoint my sons most pressing issues. But that would be insane...or would it?
I do feel that antibiotics might be hitting multiple targets in my son....that is, a beta lactam antibiotic might be helping him by its antibacterial action as well as its effect on glutamate. The only way to segregate the effect would be to rule out any chronic infection...site of infection again a big question.
Ok Peter, vancomycin would help in identifying gi tract as the site of action in case it is so in case of my son because of its high specificity. Amoxicillin and cefixime target a much broader range of sites.
DeleteSo if we give vancomycin and see no effect, at least we rule out a gut infection. And then the good effects of cefixime might most likely be linked to its effect on glutamate....unless we have some other kind of infection. Is this what you are implying?
Hi Kritika,
DeleteWe used Vancomycin (it was either a week or 10 days, 3X day) and Nystatin (for a month, 2 X per day), and I gave my daughter probiotics and Sac Boulardii throughout the course, and ever since.
The Nystatin was for yeast and the Vancomycin for bacteria.
You noted that if you don't see any effect with Vancomycin, you can rule out gut infection, and I would simply suggest that it could be either bad bugs and / or bad yeast, so please keep the yeast in mind.
Interestingly enough, it was the OAT test that led us to do this as my daughter has absolutely no GI issues or symptoms. I assumed she was fine from a GI standpoint, but the OAT testing showed she had both bad bacteria and bad yeast.
We had absolutely no side effects from either the Vancomycin or the Nystatin. The Vancomycin had to be compounded as a syrup, and the Nystatin as well.
The combination of this, plus significant Gluten and Casein reduction (e.g. replaced Cow milk with Almond Milk), as well as my efforts to reduce sugar a bit, we saw the biggest change we have seen from any other intervention (and I have done a lot of them). There is no doubt that this resulted in very noticeable improvements in all facets. Not a cure by any means, but the improvements were obvious.
Kritika, if you do go down the Vancomycin route, you may want to do Nystatin at the same time to really rule out GI infection as yeast could be your son's issue, and also I would suggest using a probiotic + Sac Boulardii, as eliminating the bad bugs is half the battle, and the other half is replacing them with good bugs.
If you can, I would suggest the gluten / casein elimination (as much as possible) activity at the same time, with a reduction in sugar if you can. You can use Stevia instead of sugar. This really worked for us.
I hope this helps Kritika!
AJ
Hi AJ,
DeleteThank you so much for that information. We had carried out an entire battery of tests, both blood and urine, to rule out amino acid imbalances, metabolic errors, acidemias and mitochondrial issues. Those tests did not check for presence of pathogenic microbes. It would be kind of you if you could just give me what parameter was use d as an indicator of candida and harmful bacteria in the OAT test in case of your daughter. Probably I could request for something similar here. Or I could request for a CDSA panel. I think this along with some kind of examination of his immune status would give us lot of valuable information. I wish rather than us parents going to the doctor again and again, pressing for tests, which the doctor thinks are unnecessary and indicative of parents inability to accept their childs autism, they would, on their own, offer every kind of test to a willing parent. Expenditure? Its a joke.
One more query. How did your kudzu trial turn out? That my son would not react so badly to most supplements (read all) is my second wish.
Bye for now. Always a wellwisher.
Hi Kritika,
DeleteI'm always happy to help an ASD parent, and I consider you a friend, so I'm that much happier to help.
Kritika, the following is the link to the OAT test we did. It's through Great Plains Lab, and they actually operate worldwide, so you could also run tests here:
https://static1.squarespace.com/static/560ac814e4b067a33438ecea/t/56157053e4b074e29ffe5209/1444245587632/OrganicAcidsSampleReport.pdf
My daughter's category is females under 13, so her parameters are different than those shown.
1. Under Yeast and Fungal markers, she scored a 4.0 on Tartaric while the reference range is up to 3.9. So very slightly over.
2. Under Arabinose, she scored a 137 while the reference range is up to 56, so noticeably high.
3. Under Bacterial Markers, she scored a 13 under 4-Hydroxybenzoic and the reference max is 2, so quite high
4. Under 4-Hydroxyhippuric, she scored a 119 while the reference max was 27, so again, quite high.
5. Under Clostridia markers, she scored a 34 under 4-Hydroxyphenylacetic while the reference max was 30, so a bit high
6. Under HPHPA, she scored a 528 while the reference max was 227, so quite high on this one.
Again, this came as a bit of a surprise to me as her GI health was completely unremarkable throughout her life. No gas, bloating, diarrhea, etc. But we attacked it and I am now a believer in the gut-brain axis as a contributor to at least some ASD.
I don't know if it was replacing bad bacteria with good, replacing bad yeast with good, cutting out gluten, or cutting out casein, but least one of these made a noticeable change.
Kritika, given that Nystatin is apparently mild, one option is to assume there is bad yeast and use it without testing - the OAt testing cost me about $250 while the Nystatin cost me $90.
The one thing to watch out for is that when all the bad bugs and yeast start dying out, the release a lot of toxins and that causes something called the Herxheimer reaction (also known as Die-off reaction). In a way, its a good sign that you are killing the bad stuff. Please look this up for ways to deal with it, but I can tell you my doctor gave us Activated Charcoal supplements, so please keep this in mind. It's an easy way to keep your son from feeling sick while the bad bugs are releasing their toxins.
In terms of expenditure, my province refused to pay for my daughter's genetic testing and so I paid for it out of pocket. The test costs $3,500 US. I'm just waiting for results now, should be getting this any day now.
The beauty of the test was that it used a cheek swab for my daughter, and saliva from my wife and I (they are also running our DNA so that they compare the ~2,000 genes between us to see if there is a mutation relative to us)
As far as Kudzu, I still l use it as we did see a difference on it on the social side. I believe the person who noted it was using 600mg X 2, but we only use 300mg X 2. I can't remember her name but she said there was a clear difference at 600mgs X 2.
I'm actually about to bump it up to 500mg X 2 soon as I switched from the Vitacost Kudzu to Swanson, and they capsules have different dosages.
As always Kritika, I wish the best for you, your son, and your family!
AJ
AJ,
DeleteThanks once again friend..I am certain all that detailed information will will help me in looking up options. In India, in recent years, advanced diagnostic tests have become available. I will also try to find out if GPL alternative could be opted for here. Our neurologist had advised genetic testing, again possible here, but I guess we just got exhausted after the first round of tests. Good that you are going for all these tests.
Once again, thanks and wishing you all well
Kritika, yes if Vancomycin helps then you have located the problem. If it does not work either there is a bacterial problem outside the gut, which is certainly possible, or it is perhaps the glutamate reducing effect of the macrolide.
DeleteA small dose of Riluzole might be expected to give the same effect by stimulating glutamate uptake and so reducing the excitatory impact of glutamate.
It is certainly worth doing some detective work to find out why your son improves while taking macrolides.
Peter,
DeleteI will definitely get into action....detective work a la inspector clouseau.
Thanks for the suggestions.
Peter,
DeleteIn case I am able to get my hands on riluzole, which might be easier said than done, what would a safe, low risk dose be? My son just turned six. I was not able to find much information on the net regarding its use.
Regards
Kritika, there was a trial made on children with OCD and others on adults. The drug was well tolerated.
DeleteGoogle "Riluzole OCD" and you will find the studies.
"Drug: Riluzole
Active drug put into 10-mg capsules by NIH Clinical Center Pharmacy. Matched placebo capsules were also prepared by NIH Clinical Center Pharmacy. Dose up to 120 mg daily, divided into bid dosages."
A 50 mg tablet had an effect on me, it made me feel a bit lethargic and that was all. So I can imagine that in someone with too much glutamate, who is hyper and anxious it might have a good effect. Too little glutamate and then you will just become dopey.
Some people with classic autism start out dopey and so Riluzole is not for them. But some people with autism are constantly hyper.
I would think based on the OCD trials and some common sense 1/4 tablet would be prudent. You could even try 1/8 of a tablet.
Peter,
DeleteMy son is kind of hyperactive dopey, if you know what I mean. Sometimes he looks dazed, sometimes extremely alert, sometimes lethargic and at times hyperactive. See, I cant even define my son. He can be extremely focussed when he feels like.
I was also wondering if there could be phases when glutamate levels increase, if elevated histamine levels mimic the effect of high glutamate and if histamine and glutamate are linked.
Probably just try out a miniscule dose of riluzole on myself to see how it turns out. Also, I was wondering if the baking soda trick to settle a histamine flare also helps with histamine related issue s like frequent urination, insomnia, hyperactivity, irritability. We faced a month of this and my son also suffered with mild urticaria as season changed here. Anti allergens bring out problems of their own so I am not a big fan.
I guess, jury is still out on this one.
Peter,
DeleteI was really hesitant about sharing this. Along with the mild itch, my son also came down with a lingering runny nose and congestion and because colds never go away on their own but become worse requiring antibiotics, I gave him augmentin for four days (I was curious about its other effect also). Sleep inprovement the same day but after three days, happy, great eye contact, playful and then after four days, better speech. Eyes settling on me and lot of sweet smiley exchanges. And a very appreciative, mindful listening to a soft, lilting song hindi song, as if paying attention to each note. He replayed it four times.....not that I mind. So again a well defined positive impact though a little less than that of cefixime, I feel.
I will not play with antibiotics in the near future but will definitely put this up when I meet the paed. Lets see if he has any insights or can refer me to someone who has.
Kritika, while some researchers are saying macrolides are not immunomodulatory, by looking a bit deeper, others clearly do not agree. This needs a thorough literature search, so as not to repeat inaccurate findings.
DeleteMechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications
http://cmr.asm.org/content/23/3/590.full
Cytokine production.Cytokines and chemokines are key regulators of the inflammatory response, with both proinflammatory (e.g., TNF-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-1 [IL-1], IL-6, IL-8, and IFN-γ) and anti-inflammatory (e.g., IL-10) effects. Macrolides appear to decrease the production of proinflammatory cytokines that are detrimental to the host (48, 240).
Most likely it is a matter of degree, with some classes being more immuno-modulating and within that class, some drugs being very effective. For example it looks like while Azithromycin helps modulate cystic fibrosis, beta lactams do not.
This does not change the fact that beta lactams affect GLT1 and so reduce glutamate.
Kritika, what about the behavioral effect of OTC anti-inflammatory drugs like Ibuprofen? Does your son improve on those?
DeleteThere is even a recent study showing this potentially beneficial in schizophrenia:
https://www.ncbi.nlm.nih.gov/pubmed/28374670
"The findings suggest that the effect of IB on the production of inflammatory cytokines may benefit the health of schizophrenic patients."
There is a whole group of parents using NSAIDs to treat autism.
No Peter, my son does not improve on brufen. I had tried this last year after reading on your blog. Antiallergens and antiinflammatories backfire the second day of use by playing havoc with his sleep routine so I use them only when absolutely necessary. What if we have infections, and immune issues and glutamate issues, all three together? And macrolides are targeting all three?
DeleteThe closer 'I' get, the further I fall.
Kritika, next time you need a broad spectrum antibiotic ask for a non beta-lactam and note the effect.
DeleteAlright Peter. Thanks.
DeleteHi everyone
ReplyDelete2 more very interesting papers have dropped and I wanted to share them:
1.
https://medicalxpress.com/news/2018-02-lab-grown-human-cerebellar-cells-yield.html
http://www.nature.com/articles/s41380-018-0018-4
2.
http://wi.mit.edu/news/archive/2018/fragile-x-syndrome-neurons-restored-using-crisprcas9-guided-activation-strategy
AJ
You have really devalued the potential of this site by lauding Paul Offit as a good man. He is a vaccine industrialist who has made up to a hundred million from maiming babies and children.
ReplyDeleteThe Geiers have risked all to try and help stop the vaccinocide ongoing at this time.
Watch Paul Offit admit it himself. In his own words .
https://www.youtube.com/watch?v=c2cHZa8t98w
Lets talk about William Thompson ?
ReplyDeleteLets talk about Poul Thoresen ?
Lets talk about SimpsonWood ?
Lets talk about Themiserol ? Dr Frank Engley 1948 study
Lets talk about the Exley Brain samples of both autism and alzheimers and the MASSIVE aluminium contamination ?
You wont will you ? Because truth and science dont belong together for you !
Dear all,
ReplyDeleteI finally convinced my dr to give me a rx for Verapamil! My son is 7 with a rare genetic syndromes called Pitt Hopkins. He is extremely sensitive to medication so I started very slow. 1-2 mgs as we got an oral suspension compounded. I could see the effect quite obviously even with such a small dose. First day he was calmer but also more vocal, by day two however he becomes increasingly agitated... this happens all the time with meds... it happened when we tried bumentanide too... it works for a day or two but it’s like he’s not metabolizing it properly and then he becomes agitated? Any ideas?
Audrey, some people are very sensitive to the other substances in the drug, i.e. not the active ingredient, but colours, flavours etc. For most people these are never an issue, but for some people they cause problems. This has affected other people who follow this blog.
DeleteYou could check this by asking the compounding pharmacy for the exact same solution, but without the verapamil.
Thought it could be os some interest to know what is used in mice to activate estrogen receptor beta in research:
ReplyDelete"Phyto-β-SERM is a rationally designed combination of three clinical phytoestrogens (genistein, daidzein, and equol) and exhibits an 83-fold binding selectivity for ERβ over ERα. We have previously demonstrated that dietary supplementation with a clinically relevant dose of phyto-β-SERM resulted in significantly improved neurological outcomes in both menopausal and AD mouse models, without inducing estrogenic effects in reproductive tissues
[..]
The diet was designed to deliver to the mice a total amount of added phytoestrogens that is biologically equivalent to a daily intake of 50 mg in humans."
ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607839/
/Ling
And another paper from the same author, showing some of the effects of ERbeta in the brain:
ReplyDelete"BDNF was significantly downregulated in ERβ-/- but not ERα-/- mice, and the ERβ-/--mediated effect was brain-region specific. A 40% reduction in BDNF protein expression was found in the hippocampus of ERβ-/- mice; in contrast, the changes in BDNF were at a much smaller magnitude and insignificant in the cortex and hypothalamus. Further analyses in primary hippocampal neurons indicated that ERβ agonism significantly enhanced BDNF/TrkB signaling and the downtream cascades involved in synaptic plasticity. Subsequent study in ERβ mutant rat models demonstrated that disruption of ERβ was associated with a significantly elevated level of 5-HT2A but not 5-HT1A in rat hippocampus, indicating ERβ negatively regulates 5-HT2A."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523821/
Sorry for sounding like I'm marketing the supplement, but I just want to point out that Bacopa Monnieri works by antagonizing 5HT2A...
/Ling