Boosting Bumetanide with an OAT3 Inhibitor?

Today’s post was prompted by our reader Ling, who highlighted research suggesting another way to improve the potency of bumetanide, a drug many readers have found reduces the severity of autism.

Sometime a little extra boost is necessary

There is an ongoing debate in the literature about how poorly bumetanide crosses into the brain and whether the theoretical chloride-lowering benefit can actually take place in humans.  Well for many readers of this blog, we know the answer.

Nonetheless there are efforts underway to improve the potency of bumetanide in neurological disorders. There is a prodrug called BUM5 which has been shown to reverse types of seizure that bumetanide could not, due to much greater potency in the brain.

The French bumetanide researchers are themselves looking to develop a more potent drug.

Ling highlighted a recent paper that suggested using an old drug called Probenecid to increase the concentration of bumetanide in the brain (and plasma) threefold.

This is not a new idea, during World War Two when antibiotics were in short supply, the same drug Probenecid was used to increase the potency of antibiotics to reduce how much you needed to give patients.

Pharmacodynamics

What we want to do is increase the concentration of bumetanide in the brain and ideally increase the half-life.  Both should increase its effect.

The recent research shows that in mice Probenecid does indeed have the effect we want, but humans are not mice.

A very old study looked at the effect in humans of Probenecid on a very similar diuretic called furosemide.

Pharmacodynamic analysis of the furosemide-probenecid interaction in man

The graph above shows that probenecid had a dramatic effect on the potency of the diuretic. Consider the area under the curves lines.  The area is a proxy for the effect of the drug (but it is a log scale).  After eight hours the furosemide alone has gone to zero, whereas when probenecid is added it is as potent as furosemide was alone after 90 minutes.

The recent study highlighted by Ling:-

The organic anion transport inhibitor probenecid increases brain concentrations of the NKCC1 inhibitor bumetanide.

Bumetanide is increasingly being used for experimental treatment of brain disorders, including neonatal seizures, epilepsy, and autism, because the neuronal Na-K-Cl cotransporter NKCC1, which is inhibited by bumetanide, is implicated in the pathophysiology of such disorders. However, use of bumetanide for treatment of brain disorders is associated with problems, including poor brain penetration and systemic adverse effects such as diuresis, hypokalemic alkalosis, and hearing loss. The poor brain penetration is thought to be related to its high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, but more recently brain efflux transporters have been involved, too. Multidrug resistance protein 4 (MRP4), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 2 (OATP2) were suggested to mediate bumetanide brain efflux, but direct proof is lacking. Because MRP4, OAT3, and OATP2 can be inhibited by probenecid, we studied whether this drug alters brain levels of bumetanide in mice. Probenecid (50 mg/kg) significantly increased brain levels of bumetanide up to 3-fold; however, it also increased its plasma levels, so that the brain:plasma ratio (~0.015-0.02) was not altered. Probenecid markedly increased the plasma half-life of bumetanide, indicating reduced elimination of bumetanide most likely by inhibition of OAT-mediated transport of bumetanide in the kidney. However, the diuretic activity of bumetanide was not reduced by probenecid. In conclusion, our study demonstrates that the clinically available drug probenecid can be used to increase brain levels of bumetanide and decrease its elimination, which could have therapeutic potential in the treatment of brain disorders.

Supporting research on organic anion transporters

As is often the case, there is already a wealth of research that we can draw on and it does indeed look like an OAT3 inhibitor should modify the pharmacodynamics of bumetanide in a very helpful way. But questions do remain.

POTENT INHIBITORS OFHUMAN ORGANIC ANION TRANSPORTERS 1 AND 3 FROM CLINICAL DRUG LIBRARIES:DISCOVERY AND MOLECULAR CHARACTERIZATION

Identification of hOAT1 and hOAT3 inhibitors from drug libraries

The NIH Clinical Collection (NCC) and NIH Clinical Collection 2 (NCC2) drug libraries used for HTS consisted respectively of 446 and 281 small molecules (727 total) approved for clinical use or having a history of use in human clinical trials. The clinically tested compounds in the NCC and NCC2 libraries are highly drug-like with known safety profiles. At the indicated concentrations, 92 compounds resulted in 50 % decrease in hOAT1-mediated 6-CF transport, whereas 262 compounds resulted in 50 % decrease in hOAT3-mediated 6-CF transport (Fig. 2). All of the 92 hOAT1 inhibitors were also inhibitors for hOAT3 but with a different potency. Among the 262 inhibitors for hOAT3, 8 compounds were specific for hOAT3 (Table 1), i.e., they lacked appreciable inhibitory activity for hOAT1. For example, stiripentol inhibited hOAT3 with an IC₅₀ of 27.6 ±1.28 μM, but it barely had any effect on hOAT1 (not shown). These inhibitors for hOAT1 and hOAT3 included classes of anti-inflammatory, antiseptic/anti-infection, antineoplastic, steroid hormones, cardiovascular, antilipemic, CNS, gastrointestinal, respiratory and reproductive control drugs.

Table 1

hOAT3-specific Inhibitors

Stiripentol	Cortisol succinate	Demeclocycline
Penciclovir	Ornidazole	Benazepril
Chlorpropamide	Artesunate

Table 2

Highly potent inhibitors for hOAT1 at peak plasma concentrations

Amlexanox	Telmisartan	Mefenamic Acid
Oxaprozin	Parecoxib Na	Meclofenamic Acid
Nitazoxanide	Ketoprofen
Ketorolac Tromethamine	Diflunisal

Table 3

Highly potent inhibitors for hOAT3 at peak plasma concentrations

Mefenamic Acid	Meclofenamic Acid	Pioglitazone
Oxaprozin	Nateglinide	Amlexanox
Ketorolac Tromethamine	Diflunisal	Nitazoxanide
Irbesartan	Valsartan	Telmisartan
Balsalazide	Ethacrynic Acid

We further increased the stringency of our selection criteria by incorporation of peak unbound plasma concentration of drugs since, for drugs tightly bound to plasma proteins, the free concentration in plasma is a better estimate of the drug level interfering with OAT transport function. Further screening using the peak unbound plasma concentration yielded three inhibitors of hOAT1 (Table 4) and seven inhibitors of hOAT3 (Table 5) with potency >95% inhibition.

Table 4

Highly potent inhibitors for hOAT1 at peak unbound plasma concentrations

Compounds	IC50 in COS-7 cells (μM)	Cmax (μM)	Cmax Unbound (Cu.p) (μM)	Cu.p/IC50
Oxaprozin	0.891±0.292	50116	5.01*	5.62
Mefenamic Acid	1.085±0.124	83.0*	8.30*	7.60
Ketorolac Tromethamine	0.653±0.130	9.5017	0.10017	0.150

Table 5

Highly potent inhibitors for hOAT3 at peak unbound plasma concentrations

Compounds	IC50 in COS-7 cells (μM)	Cmax (μM)	Cmax Unbound (Cu.p) (μM)	Cu.p/IC50
Nateglinide	0.860±0.0953	18.018	0.23019	0.270
Oxaprozin	0.870±0.0704	50116	5.01*	5.76
Nitazoxanide	0.154±0.0711	31.2▪	0.0300▪	0.200
Valsartan	0.250±0.143	14.820	0.85021	3.47
Ethacrynic Acid	0.662±0.261	30.922	0.600▲	0.910
Diflunisal	0.720±0.290	496▪	0.490▪	0.680
Mefenamic Acid	1.75±0.258	83.0*	8.30*	4.74

Regulatory Requirements

The FDA and EMA require that the drug interaction liability of this transporter be evaluated in vitro for drug candidates that are renally eliminated. OAT3 contributes to renal drug clearance and transporter – mediated renal drug interactions. Based on the in vitro substrate and inhibition data, decisions are made for OAT transporter–based clinical drug interaction trials, typically with probenecid.

Localization	Endogenous substrates	Substrates used experimentally	Substrate drugs	Inhibitors
Kidney, proximal tubule, basolateral membrane. Brain, choroid plexus and blood–brain barrier	prostaglandin, uric acids, bile acids; conjugated hormones	E3S, furosemide, bumetanide	NSAIDs, cefaclor, ceftizoxime	probenecid, novobiocin

FDA guidance on transporter related drug-drug interactions

APPENDIX A- Tables

Table 1. Major human transporters

Gene                  Aliases          Tissue                 Drug Substrate                  Inhibitor     

SLC22A6          OAT1       kidney,             acyclovir,                      probenecid

                                                                   adefovir,                      cefadroxil

    methotrexate,             cefamandole

    zidovudine                   cefazolin

SLC22A7          OAT2      liver, kidney    zidovudine                  

SLC22A8          OAT3     kidney, brain   cimetidine,                  probenecid

methotrexate             cefadroxil

zidovudine                  cefamandole

                                   cefazolin

Conclusion

This is a classic case where a little inexpensive experiment could be of huge value.  You just use adult volunteers to test the effect on bumetanide pharmacodynamics of a small number of OAT3 inhibitors.

There are now hundreds of kids in France who take bumetanide, meaning hundreds of parents who are probably more than willing to give up a day to sit in a clinic and give hourly blood samples, so their child might benefit.

Would this common sense approach be followed? Or would it be the case that it needs hundreds of thousands of dollars/euros to do a trial and we wait 3 years for the result?

Progress towards the Approval of Bumetanide as a Drug to treat Core-Autism

This blog is seen by many as being  bumetanide-inspired, so it is only fair to highlight the recently published Bumetanide for autism Phase IIb results. This study probably will not get the attention it should get in the media, in part because it is French and not American. 

Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders

This was a trial based on 90 days of taking the drug, while some readers of this blog have been using bumetanide for years. 

Nonetheless, there are some interesting things in the study, most importantly is that you can see the guiding hand of the drug approving agency (the European Medicines Agency).  They have specified how to measure the results (the CARS rating scale), the level of severity of autism to test the drug on (severe) and the age group (2-18 years old).

In this blog we know that autism is very heterogeneous and that while bumetanide can be highly effective, there is a large group that do not respond.  This trial did not use any kind of biomarker and so it contains a broad mix of responders and non-responders.

The good news is that even though only about 30-50% of people with an autism diagnosis seem to be responders, this was more than enough to make the drug look effective in a trial of just 88 people.

The small sample size does throw up anomalies, like giving the impression that 0.5mg twice a day  is more effective than 1mg twice a day, on some measures. 

The most effective treatment, judged by the authors, was 2mg twice a day, but it was ruled out for the Phase III trial because of side effects.  

“Clearly this trial must be viewed as a source of data on the safety and dose-ranging usage of bumetanide and it provides further support to justify a large multisite European Phase III trial.

We report here the results of a multicenter phase II dose-ranging study conducted according to a pediatric investigation plan approved by the EMA to determine the optimum bumetanide dose in ASD children and adolescents aged 2–18 years. To achieve these aims, the study population was divided into four subgroups receiving three doses of bumetanide (0.5, 1.0, 2.0 mg twice a day) or placebo. The distribution of age was the same in the four groups (2–4, 5–9, 10–13, 14–18 years old). The results of this trial confirm and extend our earlier observation that bumetanide improves the symptoms of ASD and that too in the full age range targeted. 

EMA imposed the age range from 2 to 18.

CARS has been selected by the EMA in their recent (2016) guidelines for evaluation of ASD core symptoms (Guidelines on the clinical development of medicinal products for the treatment of ASD, 25 December 2015).

The mean initial CARS scores were similar across all treatment groups in the six clinical centers and were above the cut-off for severe autism as required by EMA (>34). “

  

Placebo Effect

In the CARS scale, a score greater than 30 is the threshold for autism.  The higher the score, the more severe the autism. The regulator required that people in the trial had a CARS score greater than 34 to be eligible for the trial. The average CARS score for those in the trial was 41, so you would need an average improvement of 11 to potentially make them all “better” (this is a simplification).  This just shows the meaning of improving by 8 CARS points.  It is a big deal.

Here you see what happens when half a study group are not responders to bumetanide and you see a large group who either show minor improvement or get worse.  This is just the expected background noise in all autism trials.  There is even one person who improved greatly (>8 on the CARS scale) just by taking the placebo.

 Change in the completers of the total CARS score from screening to day 90 after bumetanide (blue bars; n=52) and placebo (orange bars; n=21). All changes were calculated from the initial values for each individual participant at screening. Note a significant amelioration of the CARS scale after the treatment period (>4) is almost entirely restricted to the bumetanide-treated patients (only placebo). CARS, Childhood Autism Rating Scale.

Thirty bumetanide- and five placebo-treated showed an attenuation of more than 4 of whom 23 treated and only one placebo showed an amelioration of more than six Childhood Autism Rating Scale (CARS) scores, and 13 of these and only one placebo showed an attenuation of more than 8 points. The differences between placebo- and bumetanide-treated patients having more than 4, 6 or 8 points attenuation are highly significant.

Side effects 

As we have seen in feedback on this blog the harmful side effects of bumetanide are dehydration and low levels of potassium. These side effects are entirely manageable, but that job is for the parents. 

I was interested in the chart below which measures the potassium levels during the trial of the four groups. I assume green (placebo), blue (0.5mg), red (1.0) mg, black (2.0mg)

  

 Points perhaps unbeknown to the authors

An important point we have seen on this blog is that intracellular levels of chloride vary under the influence of inflammation (which affects KCC2 expression).  This results in some people responding well to bumetanide at some times and apparently not at others.

We also noted that bumetanide does not cross the blood brain barrier very well and so in some people with high levels of intracellular chloride they may appear not to respond to bumetanide, not because they do not have elevated Cl-, but because it is just too high for bumetanide to show effect. 

Taken together the point is that if at any one time say 40% of people with autism are responders, there may be another x% who are potential responders to a similar but more potent therapy.

If you trial bumetanide in the summer and have a pollen allergy, it may appear not to work, as in the case of my son. Fortunately I did my trial in the winter.

New information


Dr Ben-Ari told Medscape Medical News that the phase 3 study, which is approved by the European authorities, will be performed in about 400 children in five EU countries. The patients will receive 1 year of treatment, and they will reflect the entire pediatric autism population.
"We hope to get the drug on the market in Europe for autism by the end of 2021," he said.

Source: http://www.medscape.com/viewarticle/877562#vp_2



As some wise older person told me many years ago, "things take time".  In the world of autism, things seem to take forever.

Take your Bumetanide Studies with a Pinch of Salt

This blog does try to be based on evidence, but sometimes you do have to question the validity of what appears in peer reviewed journals.  It might concern what does, or does not cross the blood brain barrier, or what works in vivo versus in vitro.

Two interesting papers were recently brought to my attention regarding Bumetanide.

With a pinch of salt is an English idiom which means

to view something with skepticism 

In Tyler’s paper it was rats with epilepsy showing big improvements when taking Bumetanide. 

In Agnieszka’s paper, involving mice and Chinese hamsters, researchers are making the point that so little Bumetanide crosses into the brain that its therapeutic value is limited. 

So which is true? 

Well it seems that in some humans with autism enough bumetanide crosses the blood brain barrier (BBB) to show a positive effect.  Perhaps if a more penetrative analogue of Bumetanide was developed, it would show even greater effect, otherwise adjunct therapies may be needed (Acetazolamide, potassium bromide, estradiol etc) to gain the full benefit of lowering intracellular chloride. 

In the past I have made the case for bumetanide possibly reducing the incidence of epilepsy developing in autism and that this really would be important. This does not mean that one person with autism might not develop epilepsy around the same time he started taking bumetanide. In the study below the rats with seizures seemed to be protected by bumetanide and the number of harmful neural connections detected in the brain was significantly reduced. 

Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain.

Abstract

There is accumulating evidence that bumetanide, which has been used over decades as a potent loop diuretic, also exerts effects on brain disorders, including autism, neonatal seizures, and epilepsy, which are not related to its effects on the kidney but rather mediated by inhibition of the neuronal Na-K-Cl cotransporter isoform NKCC1. However, following systemic administration, brain levels of bumetanide are typically below those needed to inhibit NKCC1, which critically limits its clinical use for treating brain disorders. Recently, active efflux transport at the blood-brain barrier (BBB) has been suggested as a process involved in the low brain:plasma ratio of bumetanide, but it is presently not clear which transporters are involved. Understanding the processes explaining the poor brain penetration of bumetanide is needed for developing strategies to improve the brain delivery of this drug. In the present study, we administered probenecid and more selective inhibitors of active transport carriers at the BBB directly into the brain of mice to minimize the contribution of peripheral effects on the brain penetration of bumetanide. Furthermore, in vitro experiments with mouse organic anion transporter 3 (Oat3)-overexpressing Chinese hamster ovary cells were performed to study the interaction of bumetanide, bumetanide derivatives, and several known inhibitors of Oats on Oat3-mediated transport. The in vivo experiments demonstrated that the uptake and efflux of bumetanide at the BBB is much more complex than previously thought. It seems that both restricted passive diffusion and active efflux transport, mediated by Oat3 but also organic anion-transporting polypeptide (Oatp) Oatp1a4 and multidrug resistance protein 4 explain the extremely low brain concentrations that are achieved after systemic administration of bumetanide, limiting the use of this drug for targeting abnormal expression of neuronal NKCC1 in brain diseases.

  

New mech­an­ism un­der­ly­ing epi­lepsy found

Prolonged epileptic seizures may cause serious problems that will continue for the rest of a patient's life. As a result of a seizure, neural connections of the brain may be rewired in an incorrect way. This may result in seizures that are difficult to control with medication. Mechanisms underlying this phenomenon are not entirely known, which makes current therapies ineffective in some patients.

A study conducted with a rat epilepsy model at the Neuroscience Center of the University of Helsinki showed that a change in the function of gamma-aminobutyric acid (GABA), a main neurotransmitter in the brain, is an underlying cause in the creation of harmful neural connections.

After a prolonged convulsive seizure, instead of the usual inhibitory effect of the transmitter, GABA accelerates brain activity. This, in turn, creates new, harmful neural connections, says Research Director Claudio Rivera.

The accelerating effect of GABA was blocked for three days with a drug called bumetanide given soon after a seizure. Two months after the seizure, the number of harmful connections detected in the brain was significantly lower.

"Most importantly, the number of convulsive seizures diminished markedly," says Claudio Rivera.

In this study, new indications may be found for bumetanide in the treatment of epilepsy. Bumetanide is a diuretic already in clinical use. Extensive clinical studies have already been conducted with bumetanide regarding its ability to reduce the amount of convulsions or prevent them entirely in the acute phase of seizures. This, however, is the first time that bumetanide has been found to have a long-term effect on the neural network structure of the brain.

Further study of the newly found mechanism may eventually help limit the exacerbation of epilepsy and prevent the onset of permanent epilepsy after an individual serious seizure. It may also be possible that a similar mechanism is responsible for the onset of epilepsy after a traumatic brain injury.

"The next step is to study bumetanide both by itself and in combination with other clinically used drugs. We want to find out the ways in which it may offer additional benefits in the treatment of epilepsy in combination with and even in place of currently used antiepileptic drugs," says Claudio Rivera.

Vitamin D and Autism

Two medical readers of this blog highlighted this recent paper showing an apparent universal benefit of vitamin D supplementation in autism.

Is it too good to be true?  Time for the pinch of salt?

One important point to note is that this study was in Egypt and, although sunny, are children there eating food that has already been fortified with vitamin D, like it is in Western countries?

Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder

Abstract

BACKGROUND:

Autism spectrum disorder (ASD) is a frequent developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and nonverbal communication, and stereotyped patterns of interests and activities. It has been previously reported that there is vitamin D deficiency in autistic children; however, there is a lack of randomized controlled trials of vitamin D supplementation in ASD children.

METHODS:

This study is a double-blinded, randomized clinical trial (RCT) that was conducted on 109 children with ASD (85 boys and 24 girls; aged 3-10 years). The aim of this study was to assess the effects of vitamin D supplementation on the core symptoms of autism in children. ASD patients were randomized to receive vitamin D3 or placebo for 4 months. The serum levels of 25-hydroxycholecalciferol (25 (OH)D) were measured at the beginning and at the end of the study. The autism severity and social maturity of the children were assessed by the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and the Autism Treatment Evaluation Checklist (ATEC).

RESULTS:

Supplementation of vitamin D was well tolerated by the ASD children. The daily doses used in the therapy group was 300 IU vitamin D3/kg/day, not to exceed 5,000 IU/day. The autism symptoms of the children improved significantly, following 4-month vitamin D3 supplementation, but not in the placebo group. This study demonstrates the efficacy and tolerability of high doses of vitamin D3 in children with ASD.

CONCLUSIONS:

This study is the first double-blinded RCT proving the efficacy of vitamin D3 in ASD patients. Depending on the parameters measured in the study, oral vitamin D supplementation may safely improve signs and symptoms of ASD and could be recommended for children with ASD. At this stage, this study is a single RCT with a small number of patients, and a great deal of additional wide-scale studies are needed to critically validate the efficacy of vitamin D in ASD.

Conclusion

Take your research with a pinch of salt.

Time to update the Autism Polypill?

It has been a long time since I added anything new to my autism Polypill. This is the combination of therapies that consistently, and materially reduce the symptoms of autism in Monty, now aged 13 with ASD.

As regular readers will be aware, due to the heterogeneous nature of autism, what works wonders for one person with autism may be totally ineffective, or even make matters worse, in another person with a different type of autism.

However, once you have found one therapy that is effective you have an opportunity to identify the underlying biological dysfunction that you have stumbled upon, without the need for any fancy genetic or metabolic testing.  Then you can look for other therapies for that dysfunction and other people who fall into that sub-group of autism and see what else works for them.

I am surprised how many people do respond to some of the therapies I am highlighting in this blog. 

Time to update?

I had been expecting to add the Biogaia Protectis probiotic bacteria to the Polypill.  It does indeed work in Monty and in other readers, but prolonged use does have a problem, at least in some people.  The behavioral effects fade and, in our case, it switches from suppressing allergy to promoting allergy.

The person who originally told us about Biogaia for autism uses the more potent Biogaia Gastrus, which contains the Protectis bacteria and a second one.  She uses a high dosage and uses it three weeks on and one week off.

Like some other readers found, Monty had an immediate negative reaction to the second bacteria in Biogaia Gastrus.  We are users of Biogaia Protectis, but not every day.

A long time ago I proposed the flavonoid Tangeritin/Sytrinol as a safe PPAR gamma agonist that is also a P2Y2 receptor antagonist. Research studies have shown that the flavonoids Tangeritin and kaempferol are antagonists at P2Y2 receptors and may be of interest as potential anti-inflammatory drugs.  Robert Naviaux, from the University of California at San Diego, believes that antipurinergic therapy is a key potential strategy to treat autism and also chronic fatigue syndrome and fibromyalgia.

The broccoli sprout powder already in the Polypill is a rich source of kaempferol.

Tangeritin/Sytrinol has been shown to have sufficient bioavailability to reduce the level of cholesterol in people with high cholesterol.   

KBr

The most likely contender to enter the Polypill for everyday use is potassium bromide (KBr), it does seem to tick all the boxes. 

·        It works

·        It continues to work after longer term use

·        Mode of action is understood

·        Safety record is very well understood

·        Effective at a low dosage

·        Not expensive, about 30 cents a day.  Much less if you use bulk KBr.

KBr should be effective in people who respond to bumetanide, since they both reduce intra-cellular chloride levels, but by different mechanisms.

In people who stop responding to bumetanide, I think KBr might be a good choice.  In responders to bumetanide, increasing inflammation due to an unrelated condition, may further reduce the expression of the KCC2 transporter that lets chloride exit neurons. So the inflammation increases the level of intracellular chloride and wipes out the benefit that was being produced by the bumetanide.  The effect of the KBr will be to reduce chloride again, this time by substitution with the relatively inert bromide.

It is also possible that some people with severe autism do not respond to bumetanide because their chloride level is so high that bumetanide is not sufficiently potent.  In those people the additive effect of KBr might just tip the balance.

In some countries bumetanide tablets include potassium chloride (KCl) to compensate for potassium lost in diuresis.  The cleverer thing in autism would be to add KBr, since you benefit from the K⁺ and the Br^-.

Due to the very long half-life, you need to take a low dosage of KBr for 4 to 6 weeks until you reach the peak level of Br^- in your body.  Only then can you judge whether you are a responder or not. 

What I am considering the autism dose (8mg/Kg) is far lower than the dose used for intractable pediatric epilepsy (30-50mg/Kg), specifically to avoid the known side effects.  The main side effect at high doses is bromo-acne. Children with intractable epilepsy opt for some facial spots over seizures.

Quite possibly a higher KBr dosage would be even more effective in autism, but then you will for sure be dealing with bromo-acne.

Summertime Add-ons

One conclusion from the gene studies is that often in autism and schizophrenia there are variances in the genes linked to the immune system. So the immune–related therapies that help Monty a great deal during spring and summer may indeed be applicable to a substantial sub-group of autism. For others they are likely to be ineffective.

I am hopeful of yet another step forward this summer using the amino acid L-histidine.  Histidine is very closely related to histamine and you might think that would be the last thing that could help in those prone to allergy-driven autism flare-ups.  However in an earlier post we saw that there is a paradoxical effect when raising the level of histidine, inhibits the release of histamine from mast cells.  We also saw that histidine has an inhibitory effect on mTOR, one of the suggested common core autism pathways that was highlighted yet again in the gene studies.

L-histidine, is an essential amino acid that is not synthesized in humans.  You have to eat it.