Hôtel de Ville (City Hall) Tours, France, Gateway to the Loire Valley and Home to iBrain
Source: https://commons.wikimedia.org/wiki/user:Tango7174
We do seem to be going round in circles in this blog. One doctor reader contacted me recently to tell me about Pentoxifylline for cognitive improvement. I told him that I am not surprised and that in the world of autism Pentoxifylline has been known to be beneficial for half a century.
The abstract below
is from a Japanese paper in 1978
On our experience in using pentoxifylline for abnormal behavior and the autistic syndrome
Abstract
Describes the successful use of
pentoxifylline (150–600 mg/day) with 3–15 yr old children with abnormal
behavior (e.g., self-mutilation, aggressiveness, and hyperkinesis) and with
autism. It is noted that while the drug was effective in reducing symptoms of
autism, developmental factors in the disorder should not be ignored.
You might wonder why it has not been widely adopted, at least for some people with autism.
When it comes to
Potassium Bromide (KBr) I found a case history from 150 years ago of its
successful use in a little girl with epilepsy, autism and impaired cognition. She
was treated at what is today London’s top children’s hospital, Great Ormond
Street.
KBr was the original
treatment for epilepsy. It is still used
in countries following German medicine; indeed, it is can be the only effective
treatment for those with Dravet Syndrome.
Interestingly, Great
Ormond Street Hospital has restarted the use of KBr in childhood epilepsy,
specially importing its drugs from Germany.
Bromide for epilepsy – Great Ormond Street Hospital
https://www.gosh.nhs.uk/conditions-and-treatments/medicines-information/bromide-epilepsy/
In the US, KBr is only used for canine and
equine epilepsy. It does not work well
on cats, incidentally.
Back in 2016, I did propose KBr as an
add-on therapy for those with autism who respond to bumetanide. This was part of my effort to develop a “super
bumetanide”, to increase the bumetanide effect.
In a quote from today’s feature paper, from iBrain at the University of Tours, France:-
“beneficial effects (of bromide) were superior to those of chronic bumetanide administration”
in one mouse model of autism.
When I was asked to give a presentation
in the US on bumetanide for autism, there was one condition, “please don’t
mention potassium bromide … we don’t want people trying it.”
Yes, it’s OK to talk about treating
autism, but please don’t actually do it.
Move forward a few years and a doctor friend
recently highlighted to me a new paper from France proposing Sodium Bromide for
autism.
I did rather think here we go again, been
there done that.
My conclusion back in 2016 was that yes
it does provide a benefit; but it does have some drawbacks. It has a very long half-life, meaning if you
keep taking the same daily amount, it will take 5 weeks to reach its peak level
in your bloodstream.
It does increase mucous secretions, in a
dose dependent fashion. This is not a
problem in canine epilepsy, but in humans it will lead to spots (bromo-acne). It could make asthma worse.
In the case of children with Dravet Syndrome,
they have a high rate of death from epilepsy, or SUDEP (Sudden unexpected death in epilepsy).
So, I don’t suppose parents are going to worry about a few spots.
Potassium bromide in clinical trials for Dravet Syndrome
Potassium bromide has not been
tested in randomized clinical trials specifically for Dravet syndrome patients.
Some small studies suggest, however, that it might benefit Dravet syndrome
patients.
A retrospective study analyzed data from 32
Dravet syndrome patients carrying an SCN1A mutation. Six patients received potassium
bromide temporarily as monotherapy, while 26 patients received the medication
as add-on therapy. The mean treatment duration was 47 months with a mean
maximum daily oral dose of 63.2
mg per kilogram (kg) body weight of potassium bromide.
Three months after treatment
began, 31 % of the
patients experienced complete seizure control. Seizures were reduced by more than 75% in 6% of the
patients, and by
more than 50% in 19% of them.
My old post from 2016:
Potassium Bromide for Intractable Epilepsy and perhaps some Autism
My idea was to see if you can get a meaningful benefit from a low dose and avoid any side effects. Rather than the 63.2 mg/kg for Dravet Syndrome seizures, I thought a reasonable dose was 8 mg/kg to further treat the E/I imbalance in Bumetanide responsive autism. Why 8mg/kg? Well, that was half a tablet.
Sodium Bromide for Autism, proposed by the French researchers
Autism Spectrum Disorders (ASD) are
neurodevelopmental disorders whose diagnosis relies on deficient social
interaction and communication together with repetitive behavior. To date, no
pharmacological treatment has been approved that ameliorates social behavior in
patients with ASD. Based on the excitation/inhibition imbalance theory of
autism, we hypothesized that bromide ions, long used as an antiepileptic
medication, could relieve core symptoms of ASD. We evaluated the effects of
chronic sodium bromide (NaBr) administration on autistic-like symptoms in three
genetic mouse models of autism: Oprm1−/−, Fmr1−/− and Shank3Δex13-16−/− mice.
We showed that chronic NaBr treatment relieved autistic-like behaviors in these
three models. In Oprm1−/−
mice, these beneficial effects were superior to those of chronic bumetanide
administration. At transcriptional level, chronic NaBr in Oprm1 null
mice was associated with increased expression of genes coding for chloride ions
transporters, GABAA receptor subunits, oxytocin and mGlu4 receptor. Lastly, we
uncovered synergistic alleviating effects of chronic NaBr and a positive
allosteric modulator (PAM) of mGlu4 receptor on autistic-like behavior in
Oprm1−/− mice. We evidenced in heterologous cells that bromide ions behave as PAMs
of mGlu4, providing a molecular mechanism for such synergy. Our data reveal the
therapeutic potential of bromide ions, alone or in combination with a PAM of
mGlu4 receptor, for the treatment of ASDs.
Compromised E/I balance in ASD may result
from several neuropathological mechanisms. On the excitation side,
glutamatergic transmission was found altered both in patients and animal
models, although in different directions depending on genetic mutations/ models
[9, 18, 19]. On the inhibition side, decreased levels of GABA [20] and
expression of GABAA and GABAB receptors (postmortem analyses, [21, 22]), as
well as genetic polymorphisms in GABAA receptor subunits [23, 24], have been
detected in patients with autism. Accordingly, decreased GABAergic
neurotransmission has been reported in several ASD models [25–29].
Alternatively, it was proposed that GABA neurons remain immature in ASD,
maintaining high intracellular concentrations of chloride ion (Cl−) whose
efflux through activated GABAA receptor induced neuronal depolarization [30].
Intracellular Cl− concentration is under the control of the main Cl− importer
NKCC1 (Na+-K+-2Cl− cotransporter) and its main exporter KCC2. Therefore
blocking NKCC1 using the loop diuretic and antiepileptic drug [31, 32]
bumetanide appeared a promising therapeutic approach in ASD. Accordingly,
bumetanide improved autistic-like phenotype in rodent models of ASD [33] and relieved
autistic behavior in small cohorts of patients [34, 35].
Bromide ion (Br−) was the first effective
treatment identified for epilepsy [36] and long used as anxiolytic and hypnotic
[37]. With the advent of novel antiepileptic and anxiolytic drugs, its use was
progressively dropped down, although it remains a valuable tool to treat
refractory seizures [38, 39]. At molecular level, Br− shares similar chemical
and physical properties with Cl−, allowing it substituting Cl− in multiple
cellular mechanisms. These include anion influx through activated GABAA
receptor, with higher permeability to Br− compared to Cl− resulting in neuronal
hyperpolarization [40], and transport through the NKCC and KCC cotransporters
[41, 42]. In view of the E/I imbalance theory, these properties point to Br− as
an interesting candidate for ASD treatment.
Here we assessed the effects of chronic sodium bromide administration on core autistic-like symptoms: social deficit and stereotypies, and a frequent comorbid symptom: anxiety, in three genetic mouse models of autism with different etiologies: Oprm1−/−, Fmr1−/− (preclinical model of Fragile X syndrome) and Shank3Δex13-16−/− mice, lacking the gene coding the mu opioid receptor or the FMRP protein for the formers, or the exons 13−16 of the Shank3 gene, coding for the PDZ domain of the SHANK3 protein, for the later. Altered E/I balance and/or modified expression of involved genes have been reported for these three models [28, 43–47]; the Oprm1 knockout model presents the advantage of limited impact on learning performance [44]. We evidenced that Br− treatment alleviates behavioral deficits in these three models and increases expression of various genes within the social brain circuit of Oprm1 null mice. We unraveled that Br− not only increases mGlu4 receptor gene expression but also potentiates the effects of the positive allosteric modulator (PAM) of mGlu4 VU0155041, in Oprm1−/− mice and in hetero[1]logous cells. Our data reveal the therapeutic potential of Br− administration and its combination with a PAM of mGlu4 receptor for the treatment of ASD.
RESULTS
Chronic sodium bromide relieved autistic-like
symptoms in Oprm1−/− mice more efficiently than bumetanide
Chronic sodium bromide relieved social
behavior deficits, stereotypies and excessive anxiety in Fmr1−/− and
Shank3Δex13-16−/− mice
Chronic sodium bromide modulates
transcription in the reward circuit of Oprm1−/− mice
Synergistic effects of chronic bromide and
mGlu4 receptor facilitation in Oprm1 null mice
Bromide ions behave as positive allosteric
modulators of the mGlu4 glutamate receptor
In conclusion, the present study reports the
therapeutic potential of chronic bromide treatment, alone or in combination
with a PAM of mGlu4 receptor, to relieve core symptoms of ASD. Beneficial
effects of bromide were observed in three mouse models of ASD with different
genetic causes, supporting high translational value. Moreover, bromide has a
long history of medical use, meaning that its pharmacodynamics and toxicity are
well known, which, combined with long-lasting effects as well as excellent oral
bioavailability and brain penetrance, are strong advantages for repurposing.
Conclusion
The
doctor treating Ida at Great Ormond Street 150 years ago noted that after treatment
with KBr she developed age-appropriate play skills. That is very much the same effect as bumetanide
in a young child with severe autism and IQ<70.
My
trials of 400mg of KBr produced a “bumetanide+” effect and feedback from other
bumetanide super-responders was in line with this. Higher doses than mine were
used.
The
effects of KBr overlap with those of Bumetanide, but it is possible that there may
be more KBr responders than Bumetanide responders. KBr has interesting effects beyond those of Bumetanide.
It is definitely worth considering KBr, even if the person is not a bumetanide
responder.
The French
researchers in today’s paper propose that Bromide be repurposed for autism –
they definitely have the right idea.
They did note the 8-14 day half-life in humans.
In
the advisory from Great Ormond Street it is noted:
“Your child will need to have regular blood tests to monitor the amount of bromide in their blood – this usually happens around four weeks or so after starting to take the medication, or four weeks after the dose is increased.”
I
think the aim should be maximize the benefits of KBr, without incurring the
side effects that will occur at high doses.
KBr might be best as an add-on therapy in autism.
The
60mg/kg dose from Dravet Syndrome is 8 times the bumetanide add-on dosage I
suggested.
One
of the models used in the French trial was that for Fragile X syndrome, the
others were the Mu Opioid Receptor Null model and the Shank3B−/−, lacking the
PDZ domain.
Fragile
X is one of the most common types of human autism and is apparent from facial
features. Bromide for human Fragile X ?
In
case you are wondering, whether to choose sodium bromide (NaBr) or potassium bromide
(KBr), it is the bromide ions (Br-) that are critical to its effect on the E/I
imbalance. Personally, I prefer KBr,
because most people have too much sodium and too little potassium in their diet. People taking bumetanide should be taking
extra potassium anyway.
Interestingly,
from the UK guidance: -
“Salt and salty foods can reduce how well bromide
works. Try to limit the amount of salty foods your child eats and do not add
salt to cooked foods if possible.”
One other
medical formulation of bromide is called triple bromide and contains three
different variations of bromide: ammonium bromide, potassium bromide and
sodium bromide.
Hopefully
it will not take 50 years to establish the usefulness (or not) of bromide as an
autism therapy.
It was mentioned first in this blog, back in 2016.
In 2017 some French people filed a patent, claiming to be the inventors of bromide as a treatment for autism.
WO2018096184- BROMIDE SOURCE FOR USE IN TREATING AUTISM SPECTRAL DISORDER