Autism and Non-Antibiotic Properties of Common Beta-lactam Antibiotics

If you are looking for personalized medicine, you or your doctor need to be a good detective. Not to mention you need some clues.

If you are treating a condition like autism and certain things cause a marked change in the severity of the condition, these are pretty good places to start.

In the case of our reader in Delhi, it is Beta-lactam antibiotics (penicillin, amoxicillin etc), that consistently seem to improve her son’s autism. Improvement during treatment with antibiotics is reported quite often in autism, but with all kinds of different antibiotic.  Nothing is simple.

For non-medical readers, there are several categories of antibiotics; common types including:-

·        Beta-lactams (e.g. Penicillins)

·        Macrolides (e.g. Erythromycin, Azithromycin)

·        Fluoroquinolones (e.g. Ciprofloxacin) 

·        Tetracyclines (e.g. Minocycline) 

Macrolides have already had a dedicated post about their immunomodulatory effects, which did also cover some history about Poland from Monty's homework.

Macrolide Antibiotics for Some Autism? Or better still, Azithromycin analogue CSY0073, or just Nystatin?

Beta Lactam Antibiotics

In earlier posts we came across something called glutamate transporter GLT1 (also known as EAAT2).

Glutamate is the major excitatory neurotransmitter, and is inactivated by uptake via GLT-1 (EAAT2) and GLAST (EAAT1) transporters.

Many people given the observational diagnosis of autism appear to have an underlying imbalance between excitatory and inhibitory neurotransmitters (E/I imbalance). By correcting the specific type of E/I imbalance, even profound symptoms of autism including MR/ID and epilepsy can be moderated. If you have autism and/or epilepsy tuning your E/I imbalance is likely the most important step you can take.

Some drugs increase the expression of GLT-1 and so reduce the amount of glutamate. Macrolide antibiotics are one of these drugs.

So if a person has too much glutamate and this causes/contributes to their E/I imbalance then improved behaviour while taking penicillin antibiotics, who have a simple explanation.

Since you would not want to take penicillin forever you would then look for a non antibiotic drug that also increases the uptake of Glutamate. Once such drug, Riluzole, does exist and has already been trialed on children with OCD. 

But beta-lactams have other effects, so it is not certain that GLT-1 accounts for the beneficial effect sometimes found in autism. Fortunately some researchers have assembled most previous research into a single review paper. This paper does not mention autism and does miss some things out.

Review of Antibiotic and Non-Antibiotic Properties of Beta-lactam Molecules.

There are seven categories:-

·        Antibiotic

·        Epileptogenic

·        Neuroprotective

·        Analgesic

·        Immunomodulatory

·        Anxiolytic

·        Antineoplastic

Antibiotic Effect

We all know something about bacteria. If you have a bacterial infection like an ear infection your doctor might prescribe you an antibiotic.

As well as inflaming your ear, the bacteria may well affect gene expression. We saw in a previous post that bacteria and viruses change the expression of many genes, but the study of this is in its infancy. In autism we know that many genes are miss-expressed, but this varies from person to person. So a bacteria or virus has the potential to make autism worse (e.g. PANS and PANDAS), but also better. Bacteria are not always bad.

A person whose autism responds to an antibiotic might have bacteria that are worsening his autism. This is simplest of explanation of all.

The question then is where is the bacteria? If it is an intestinal bacterium this could be proven by using an antibiotic that only works there, like Vancomycin.

Epileptogenic effects

In this review they concluded the effects relate to GABA and here we are talking about negative effects. 

penicillin is a potent epileptogenic agent = it is capable of causing an epileptic attack

“This could mean that penicillin is a competitive GABA specific antagonist, which would further explain its epileptogenic properties.”

The paper omits to point out that in some people beta-lactams protect from epileptic seizures. The effect on Glutamate is likely at least sometimes what stops seizures.

Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature

The really clever thing in the above case report is that appears that the effect on glutamate may be by an epigenetic mechanism (via GLT1), since the effect is long lasting. Read later in this post about the epigenetic effects of beta-lactams.

Neuroprotective properties

“These results suggest that the neuroprotective effect induced by beta-lactam antibiotics is due to their capacity to stimulate GLT1 expression and thus regulate the concentration of glutamate in the synaptic cleft. GLT1 is a glutamate transporter inducing its reuptake by astrocytes preventing excessive glutamate concentration in the synaptic cleft

It was subsequently shown that the neuroprotective effect of BLMs was due not only to glutamate down regulation, but also to a diminished glutamate-induced intracellular Ca2+ concentration and an increased uptake of glutamate

Another probable mechanism of neuroprotection induced by BLMs is down-regulation of oxidative stress and modulation of apoptotic pathways shown in rat spinal cord when CFX was administered for 7 days prior to induction of constrictive neuropathy. This effect was apparently mediated by both a reduction in proapoptotic proteins Bax, and an increment in the antiapoptotic protein Bcl2.

CFX (Ceftiaxone) may induce neuroprotection by other mechanisms besides GLT1 overexpression. Yamada and Jinno [51] reported that the antibiotic reversed axotomy-induced up regulation of GFAP, a neuronal damage marker, and increased neuronal survival; apparently not only through glutamatergic regulation, but also by direct reduction of glial hypereactivity. Supplementary to this is the finding of an attenuation of microglial activation induced IL-1 expression in an ischemic injury model when CFX was administered as a pre-treatment [52]. This result may indicate a direct action on glial cells since partial reduction of astrocytes and microglia was observed.”

Analgesic (pain killing) Properties

“Interestingly, despite the widespread clinical use of BLMs (beta-lactams), some of their known non-antibiotic effects have been either disregarded or misinterpreted as resulting from bacterial microbiome regulation. For example, Caperton, Heim-Duthoy [54] hypothesized that chronic inflammatory arthritis could have a bacterial component and that therefore the clinical course of a patient could be affected by administration of CFX (Ceftriaxone).

Both the anti-inflammatory and neuromodulating effects exerted by BLMs either peripherally or centrally may be related to their analgesic properties in some pathologies that are difficult to treat such as the complex regional pain syndrome [65] or to the analgesic effect of a single preoperative dose of CFX in a clinical protocol [66].

Immunomodulatory Properties 

Not many people seem to have read this paper. They did not flesh out immunomodulation, so I draw on a different paper. People who write about immunomodulation usually say that beta-lactams do not have this effect, but that appears to be incorrect. 

Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin

Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell–mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in non-obese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.

 Anxiolytic effects (reduce anxiety)

“CA (Clavulanic acid) has proven effective as an anxiolytic drug, since it was reported that this drug diminished anxiety-like conduct in both rodent and primate models”

Antineoplastic effects (preventing tumors)

“CFX (Ceftriaxone) elicit antitumor activity both in vitro and in vivo models”

Addiction

Addiction did not appear in the chart above, but it gets a mention in the text 

“When tested in an opiate dependence model, both CFX [72] and CA [73] inhibited both physical dependence and withdrawal symptoms. This could mean that the effect shown by CFX is not due to its particular molecular structure, but can be reproduced by other BLMs (several BLMs effects shown on Fig. 3)

Other effects

“CA (Clavulanic acid) has been shown to increase dopamine release”

Epigenetic Effects

These were not mentioned in the paper, but I do think epigenetics is a fundamental part of many diseases, including much autism.

The paper really explains why short term use of beta-lactams can stop a person with epilepsy having seizures for a long time.

Off-Target drug effects resulting in altered gene expression events with epigenetic and"Quasi-Epigenetic" origins.

This review synthesizes examples of pharmacological agents who have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include "quasi-epigenetic" mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale. We explore these avenues with four examples of conventional pharmaceuticals and their unintended, but not necessarily adverse, biological effects. The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. In addition, we report on more canonical epigenome changes associated with pharmacological agents such as lithium impacting autophagy of aberrant proteins, and opioid drugs whose chronic use increases the expression of genes associated with addictive phenotypes. By expanding our appreciation of transcriptomic regulation and the effects these drugs have on the epigenome, it is possible to enhance therapeutic applications by exploiting off-target effects and even repurposing established pharmaceuticals. That is, exploration of "pharmacoepigenetic" mechanisms can expand the breadth of the useful activity of a drug beyond the traditional drug targets such as receptors and enzymes.

DAO inhibition

As our reader Agnieszka pointed out in the comments section, one commonly prescribed beta-lactam antibiotic called Augmentin contains a second antibiotic, Clavulanic acid, to boost its effectiveness; by chance is also a very potent DAO inhibitor. Diamine oxidase (DAO), also known as histaminase, is an enzyme in your body that is used to inactivate histamine. Histamine is found in food that you eat as well as being produced in your body and released by your mast cells during an allergic reaction.

DAO neutralizes the histamine in food so it does not enter your bloodstream.

So this particular antibiotic should be avoided by those people who are histamine intolerant and so do not produce enough DAO. This is about 1% of the general population, but might be more common in those with autism although there is no data on this subject.

Some people believe that ADHD is associated with a reduced level of DAO.

Indeed there is a patent to treat ADHD with a combination of DAO and caffeine.

Diamine oxidase for use in the treatment or prevention of attention deficit hyperactivity disorder (ADHD)

[0087] DAO can also be mixed with caffeine, strengthening the role of prevention and treatment of attention deficit hyperactivity disorder. Thus, also disclosed herein compositions comprising DAO and caffeine. 

[0088] Caffeine, a xanthine alkaloid group having stimulating properties for the treatment of attention deficit hyperactivity disorder. 

[0089] DAO content of the present invention per unit dose 0 · l-50mg, preferably 2-20mg. 

[0090] The present invention is caffeine content per unit dose 1-lOOmg, preferably 5-50mg. 

[0091] for the prevention and treatment of attention deficit hyperactivity disorder DAO or compositions comprising DAO may be before a meal or postprandial meal administration.

[0092] The use of DAO of the invention or compositions comprising DAO directly affect blood histamine levels, thus affecting the symptoms of attention deficit cumulative histamine levels induced hyperactivity disorder.

You can actually buy DAO supplements and of course caffeine.

Perhaps people consuming DAO inhibitors long term, such as NAC and Verapamil, and have chronic allergies or mast cell disorders might benefit from extra DAO. 

Evaluation of the inhibitory effect of various drugs / active ingredients on the activity of human diamine oxidase in vitro

Most DAO is actually in your digestive tract, where the dietary histamine is.

You can measure DAO levels in your blood.

Serum diamine oxidase (DAO) activity as a diagnostic test for histamine intolerance  

We can conclude that determination of DAO activity in serum is a useful diagnostic tool, together with detailed history to differentiate between food allergy and histamine intolerance.

We found that DAO activity was significantly lower in patients than in healthy control subjects.

Conclusion

I think there is plenty of food for thought here for parents of children whose autism and/or epilepsy improves when taking a beta-lactam antibiotic.  Hopefully some people will figure out which effect is the beneficial one and find something else to replicate it.

There is a lot previously written in this blog about upregulating GLT1, other than by a beta-lactam. My favoured option was Riluzole, but Bromocriptine will also do this, among its other actions. Riluzole is a drug for ALS, that has been trialed in children with OCD, without side effects.    

People technically without histamine intolerance (normal levels of DAO) who incidentally take large amounts of DAO inhibitors, may end up exacerbating an existing mast cell related problem. One potential solution for that small group might be taking an OTC DAO supplement.

Macrolide Antibiotics for Some Autism? Or better still, Azithromycin analogue CSY0073, or just Nystatin?

Magical Poland

Today’s post is about yet another reason why some people with autism might have a positive behavioral response while on antibiotics. Today it is the turn of macrolide-type antibiotics, which have proven immunomodulatory effects.

To get the immunomodulatory benefits, without worsening antibiotic resistance, a neat solution called CSY0073 is coming. Nystatin is another possibility.

One of the best papers happens to come from a pair of researchers from Lodz (Łódź, pronounced “Wudge”) in Poland. This blog has many Polish readers. 

I was recently helping my son, Monty aged 14 with ASD, with his geography presentation on Poland.  I used to travel quite a lot to Poland and I am familiar with its turbulent history. So today’s picture above is actually from Monty’s PowerPoint presentation on Poland. As musical backing, we added one of Chopin’s Polonaises, since Monty is the piano man and Chopin was born in Poland. Polonaise (Polonez) is the name of a type of Polish dance and yes, Monty did dance to the music for his classmates.

The Germans and the Russians have changed the make-up of Poland profoundly and someone has produced the animated map above to illustrate this (it should play automatically). Lodz used to be a textile city with a population one third Jewish, who were later exterminated.  Lviv (Lwów), another large and once Polish city, also had a large Jewish population which the Germans exterminated. Then the Soviets gave the then Lwów (Lviv) to Ukraine and deported the Polish population.  The Soviets gave the German city of Breslau to Poland and it became Wrocław; most Germans were deported and many Poles from Lviv were relocated there.

Gdansk (Danzig) changed hands as well and, as Monty informed his class, they even had their own currency. Few outside Poland will recall Gdansk was home to Lech Wałęsa and his Solidarity Movement.  Monty’s elder brother knows about Solidarity and Katyn (see below) and we agreed Lech will for sure not be on Vladimir Putin’s Christmas list. 

A very charismatic older Pole in Warsaw once told me “the Russians were our brothers, your friends you can chose”. Having also been to Russia many times in the early 1990s, just after the collapse of the Soviet Union, I should point out there are plenty of nice Russians too. An old Russian former naval commander in St Petersburg  once told me how his father always kept a packed bag by the front door at home, in case the NKVD (Stalin’s secret police) came knocking at the door in the middle of the night. Half a million Russians were taken during Stalin’s purges 1936-8. In 1940 the same NKVD perpetrated the Katyn massacre, when 22,000 Polish army officers, policemen and “intellectuals” were killed.  In a sad twist of fate in 2010 a Tupolev plane carrying the Polish president, senior politicians, senior army officers and other leading Poles to a commemoration of the Katyn massacre crashed in very bad weather trying to land at Smolensk.  The cockpit voice recorder showed that the crew were too intimidated by the President to divert the plane and be late for the ceremony, so they all died.  History repeated itself.

The Poles and Russians do share traumatic histories and many like drinking too much vodka. As Monty’s classmates learned, “vodka" is one diminutive form of the Slavic word voda (water). They like diminutives and you can even make your own.  The Russians have a diminutive of vodka, водочка (vodochka).

Back to science …

Macrolide Antibiotics 

Macrolide antibiotics are widely used across the world, the most popular ones are:-

• Azithromycin
• Clarithromycin
• Erythromycin
• Fidaxomicin
• Telithromycin

As readers will know, you normally take an antibiotic short term to treat a bacterial infection.

It was discovered that this class of antibiotic also has immunomodulatory and anti-inflammatory properties.  They became used long-term to treat conditions like cystic fibrosis, COPD (Chronic Oppressive Pulmonary Disease) and sometimes even asthma.

The problem is so-called “population antimicrobial resistance” associated with chronic macrolide use, which means these antibiotics can stop working for everyone else.

The good news is that not all macrolides have antibiotic properties and analogues (slightly different version) of both azithromycin and erythromycin are being developed to give the immunomodulatory and anti-inflammatory properties, without risking antimicrobial resistance.

Of course what will happen is that the new drugs will be far more expensive than the old ones and so the old ones will continue to be used. Such is the world.

So first we will review the science showing these special properties of Azithromycin, which can apparently work wonders for some people with autism plus allergy, although the research below talks about other inflammatory diseases.

Here is the paper from Poland:-

Immunomodulatory and anti-inflammatory properties of macrolides

 Macrolides are a group of antibiotics whose activity is ascribable to the presence of the macrolide ring, to which one or more deoxy sugars may be attached. Two properties are inherent in this group of antibiotics, the immunomodulatory and the anti-inflammatory actions, ensuring great efficacy in a wide spectrum of infections. Macrolides demonstrate several immunomodulatory activities both in vitro and in vivo. They can down-regulate prolonged inflammation, increase mucus clearance, prevent the formation of bacterial biofilm and either enhance or reduce activation of the immune system. According to given properties and exceptional effects on bacterial phatogens, the macrolide antimicrobial agents have been found to serve a unique role in the management of chronic airway disorders, including diffuse pan bronchiolitis, cystic fibrosis and chronic obstructive pulmonary disease. Use of macrolides can result in clinical improvement in patients with severe, chronic inflammatory airway diseases, improving their spirometry indicators, gas exchange and overall quality of life. 

Anti-inflammatory and immunomodulatory effects Macrolides have a direct antimicrobial effect but more importantly, also modulate many components of the immune response. Because of this anti-inflammatory or immune modulating effect, macrolide antibiotics have been widely used as a maintenance treatment for various chronic inflammatory airway diseases [1]. Interest in the immunomodulatory effects of macrolides began with showing that in patients with bronchial asthma, requiring glucocorticoids administration, application of macrolide antibiotics allowed for reducing steroids dose [6]. This phenomenon is known as ‘sparing effect’.

After more than 30 years, macrolides still hold a vital place in our therapeutic armamentarium. They possess immunomodulatory and anti-inflammatory actions extending their antibacterial activity. Indeed, they are able to suppress the “cytokine storm” of inflammation and confer an additional clinical benefit through their immunomodulatory properties. The majority of cells, involved in both the innate and adaptive immune responses, are influenced when macrolide antibiotics are administered.

Suppressing a cytokine storm is not easy. Atorvastatin can also do this.

Low-dose, long-term macrolide therapy in asthma: An overview

Azithromycin as an immunomodulator

In addition to their antimicrobial properties, there are in vitro and animal data on the immunomodulatory or anti-inflammatory effects of macrolides.¹ Effects in humans were initially reported in the treatment of diffuse panbronchiolitis, in which macrolides are associated with improved lung function and prognosis based largely on non-controlled trial data and retrospective studies.¹ In cystic fibrosis, treatment for six months is associated with improved respiratory function and reduced respiratory exacerbations.¹¹ Azithromycin produced a small increase in lung function (mean 8.8%) at seven months in patients treated for bronchiolitis obliterans syndrome after lung transplant,¹² but was no different compared to placebo for bronchiolitis obliterans syndrome after haematopoetic stem cell transplant.¹³

Azithromycin and other macrolides have also been proposed for use in sepsis and epidemic respiratory viral infections to prevent cytokine storm.¹ It has been used for various respiratory and non-respiratory inflammatory conditions. However, this use has been controversial due to limited direct clinical evidence for many conditions, and concerns about increased antimicrobial resistance.^1,14 New non-antibiotic macrolides may provide immunomodulatory benefits without contributing to antimicrobial resistance.¹⁴

Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases.

Macrolide antibiotics have established efficacy in the management of cystic fibrosis and diffuse panbronchiolitis-uncommon lung diseases with substantial morbidity and the potential for rapid progression to death. Emerging evidence suggests benefits of maintenance macrolide treatment in more indolent respiratory diseases including chronic obstructive pulmonary disease and non-cystic fibrosis bronchiectasis. In view of the greater patient population affected by these disorders (and potential for macrolide use to spread to disorders such as chronic cough), widespread use of macrolides, particularly azithromycin, has the potential to substantially influence antimicrobial resistance rates of a range of respiratory microbes. In this Personal View, I explore theories around population (rather than patient) macrolide resistance, appraise evidence linking macrolide use with development of resistance, and highlight the risks posed by injudicious broadening of their use, particularly of azithromycin. These risks are weighed against the potential benefits of macrolides in less aggressive inflammatory airway disorders. A far-sighted approach to maintenance macrolide use in non-cystic fibrosis inflammatory airway diseases is needed, which minimises risks of adversely affecting community macrolide resistance: combining preferential use of erythromycin and restriction of macrolide use to those patients at greatest risk represents an appropriately cautious management approach.  

Changes in macrolide resistance rates since the introduction of long-acting macrolides Although erythromycin has been used since the 1950s, rates of macrolide resistance among respiratory pathogens were consistently low worldwide until the late 1980s. Since then, macrolide resistance rates have risen sharply, coincident with the introduction of long acting macrolides, particularly azithromycin (see later) but also clarithromycin.

  Conclusions The development of novel, non-antibiotic macrolides with anti-inflammatory properties, including EM703107 and CSY0073, holds great promise for delivering the benefits of macrolide treatment without the associated risks of antimicrobial resistance in the future. Until then, use of long-term macrolide antibiotics to treat respiratory disorders must be prudent. The benefits shown with maintenance macrolides so far have been modest in COPD and non-cystic fibrosis bronchiectasis, and their use should be limited to patients with more difficult (and otherwise optimally managed) disease. For non-cystic fibrosis inflammatory airways diseases, combining the preferential use of erythromycin along with restriction of macrolide use to only those likely to derive the greatest benefit represents a clinically appropriate, and ecologically responsible, management approach.

Azithromycin analogue CSY0073 attenuates lung inflammation induced by LPS challenge.

CONCLUSIONS AND IMPLICATIONS:

Unlike azithromycin, CSY0073 had no antibacterial effects but it did have a similar anti-inflammatory profile to that of azithromycin. Hence, CSY0073 may have potential as a long-term treatment for patients with chronic lung diseases.

  

EMA grants orphan status to Synovo anti-inflammatory for Cystic Fibrosis

Tuebingen, Germany: – German-based pharmaceutical discovery company Synovo GmbH today announced that the European Medicines Agency (EMA) has granted its anti-inflammatory drug with orphan (rare disease) status as a treatment for Cystic Fibrosis. Synovo refers to its candidate as CSY0073.

CSY0073 has been adjudged to provide an alternative to anti-inflammatory therapies that are also anti-bacterial, thus potentially contributing to a reduction in selection for antibiotic resistance. The drug is a novel compound that reduces inflammation and prevents recruitment of excess immune cells to diseased tissues. It is a non-antibacterial analog of the well-known antibiotic azithromycin, that is extensively used in many diseases of the lungs including Cystic Fibrosis.

  

Conclusion

We saw in earlier posts why beta lactam antibiotics might benefit some people with autism.

We came across the GLT-1 (EAAT2) transporter, the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. EAAT2 is responsible for over 90% of glutamate reuptake within the brain. Beta lactam antibiotics, like penicillin, upregulate EAAT2/GLT-1 and so reduce glutamate.

I suggested that people with autism who improve on penicillin types antibiotics should get a similar effect from riluzole, which is now a generic drug.

People whose autism benefits while on macrolide antibiotics are benefitting from its immunomodulatory effects.

People with severe allergy and autism are likely to respond to long term moderate dose of macrolides. 

The problem of long term use of any antibiotic is that it contributes to the decline in its effectiveness for everyone else.

Some DAN-type doctors apparently do apparently give one year prescriptions for beta lactams.   I think these people likely should be on riluzole.

Some mainstream doctors prescribe moderate dose macrolide antibiotics long term to treat people with “over-active” immune responses. It appears many people with cystic fibrosis are treated long term with macrolide antibiotics.

I am informed that some people with autism and “over-active” immune responses respond very well behaviorally to long term use of macrolide antibiotics.

The best solution in the long run is for people to use non-antibiotic macrolides like CSY0073, from Synovo. If it turns to be very expensive, people will just use azithromycin.

In the meantime note there are other non-antibiotic macrolides sitting in the pharmacy. 

·        Nystatin is a non-antibiotic macrolide. As we know, DAN-type doctors widely prescribe Nystatin to treat “candida overgrowth” in autism. It is also a potassium channel (Kv1.3) blocker. 

·        The drugs  tacrolimus, pimecrolimus, and sirolimus, which are used as immunomodulators, are also non-antibiotic macrolides.

There look to be many interesting possibilities for those with autism and allergy/mast cell activation/ulcerative colitis/asthma etc. 

I wonder if the people with autism and allergy who respond to long-term Azithromycin use would see the same benefit from Nystatin?

Long term use of antibiotics will disrupt the gut microbiome, i.e. kill the good bacteria.  People should be aware of this and that in minimizing one problem, they may create another one. The non-antibiotic options are clearly best. If you have cystic fibrosis the advantages of an antibiotic clearly outweigh the disadvantages. 

Synergistic Benefit of Low Dose Dopamine (Greek Coffee) and Diuretics (Bumetanide/Furosemide); better than Bromocriptine?

I did think of highlighting this post to the Bumetanide researchers in France, but I do not think they would take it seriously.

Another one to mention would be this new study, funded by Rodakis, to look at why some antibiotics improve some autism.  Dr Luna at Baylor College is running the study.  Its basic assumption is that the effect must be to do with bacteria, but as our reader Agnieszka has highlighted, common penicillin type antibiotics increase expression of the gene GLT-1 which then reduces glutamate in the brain.  It has nothing to do with bacteria.  Maybe for other antibiotics the effect does relate to bacteria.

But if you tell Dr Luna about GLT-1, quite likely she will not be interested.  

Study to investigate connection between antibiotic use and autism symptoms

Researchers will compare the gut microbiome (bacteria, yeasts and fungi found in the gut) and metabolome (small biological molecules produced by the microbes) of those who experience a change in symptoms during antibiotic use to those who do not. The study may provide valuable insight into when and why these changes occur and how this information can be harnessed for future interventions.  

There is even a case study very well documented here:-

Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature

Petra, our regular reader from Greece, has pointed out that Bumetanide has a greater effect in her adult son, with Asperger’s, when taken with Greek coffee and suggested why this might be. 

Her reference is this article:- 

Added to Diuretics, Low-Dose Dopamine Renoprotective in Small Acute-HF Trial

It shows that the diuretic effect of low dose furosemide, with dopamine, is greater than the effect of high dose furosemide.

The diuretic effect of Furosemide is via the transporter NKCC2, which is the same affected by Bumetanide. 

NKCC2 is found in your kidneys, while the very similar NKCC1 is found in your brain.  Furosemide and Bumetanide affect both NKCC1 and NKCC2.

The caffeine in coffee is known to indirectly produce dopamine in your body.

Greek coffee is nothing like your instant coffee or watery Starbucks coffee, it contains a serious amount of caffeine. 

The question is how does dopamine interact with furosemide/bumetanide and will the effect in the kidney (NKCC2) also affect the brain (NKCC1). 

By more effectively blocking NKCC1 in neurons you would further lower chloride levels and potentially further improve cognitive functioning.  

This would further validate Petra’s observation. 

Then we would consider if there is an alternative to Greek coffee, or just accept that caffeine is the simplest and safest method to enhance Bumetanide.    

In the then end my conclusion is that coffee, or just the caffeine, is a better option than a selective Dopamine D2 receptor agonist.  But there is an interesting drug called Bromocriptine that may be better in some cases. 

Not only is it a dopamine D2 receptor agonist, but Bromocriptine also “inhibits the release of glutamate, by reversing the GLT-1 (EAAT2) transporter”. 

We came across the GLT-1 (EAAT2) transporter when we found why some people with autism improve when on beta-lactam antibiotics (that include the penicillin ones).   

GLT-1/ EAAT2 is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. EAAT2 is responsible for over 90% of glutamate reuptake within the brain 

We saw that the drug riluzole approved for the treatment of ALS (Amyotrophic Lateral Sclerosis) upregulates EAAT2/GLT-1.

I suggested that people with autism who improve on penicillin types antibiotics should get a similar effect from riluzole.  But riluzole is one of those monstrously expensive drugs.  

Based on my logic, we would then think that bromocriptine should help treat ALS (Amyotrophic Lateral Sclerosis).  What did I find when I looked it up:- 

Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients. 

So then how much does Bromocriptine cost?  It is a cheap generic.  So a cost effective potential drug for ALS. 

Bromocriptine has two potentially useful functions (Dopamine D2 and GLT-1),but it has numerous other effects:- 

Bromocriptine blocks the release of a hormone called prolactin, but this should not be an issue for males. 

Risperidone, one of only two drugs approved for side effects of autism, can boost levels of prolactin.  Elevated prolactin levels are linked to a range of side effects, including gynecomastia, or growth of breasts, in men and boys.  This did not stop the drug being approved.

Bromocriptine agonizes the following monoamine receptors

• Dopamine D₁ family
• D₁ (K_i=682 nM)
• D₅ (K_i=496 nM)
• Dopamine D₂ family
• D₂ (K_i=2.96 nM)
• D₃ (K_i=5.42 nM)
• D₄ (K_i=328 nM)
• Serotonin 5-HT
• 5-HT_1A (K_i=12.9 nM)
• 5-HT_1B (K_i=355 nM)
• 5-HT_1D (K_i=10.7 nM)
• 5-HT_2A (K_i=107 nM)
• 5-HT_2B (K_i=56.2 nM)
• 5-HT_2C (K_i=741 nM)
• 5-HT₆ (K_i=33 nM)
• Adrenergic α family
• α_1A (K_i=4.17 nM)
• α_1B (K_i=1.38 nM)
• α_1D (K_i=1.12 nM)
• α_2A (K_i=11.0 nM)
• α_2B (K_i=34.7 nM)
• α_2C (K_i=28.2 nM)
• Adrenergic β family
• β₁ (K_i=589 nM)
• β₂ (K_i=741 nM)

  

This is why drugs have side effects. 

But for people with ALS who cannot afford riluzole, the cheap generic bromocriptine might be a good choice.

How about bromocriptine for autism? 

Well there was a trial in Italy a long time ago on girls with Rett syndrome 

Bromocriptine in the Rett syndrome

Twelve typical cases of the Rett syndrome and one forme fruste were treated with bromocriptine for six months and then had a washout for two months followed by resumption of the bromocriptine treatment. During the first bromocriptine treatment there were improvements in communication and relaxation in some of the girls: a more regular sleep pattern was observed in 4 and a more varied facial expression in 8, and 4 girls began to utter a few words. The bouts of hyperpnea disappeared in 5 and grinding of the teeth in 3. There was also a reduction in stereotypic hand activities in 5 girls and signs of improved motor abilities in 3. The washout caused a general decrease in the positive effects of the previously administered bromocriptine and resumption of the treatment with this drug led to less marked improvement. Metoclopramide was tested in all the girls before the treatment, and it was noted that, while endorphins were hyporesponsive, prolactin was hyperresponsive. This test was repeated two months after the bromocriptine treatment had been performed and, while beta-lipotropin remained unchanged, beta-endorphin showed increased responsiveness.

Current use of Dopamine with Lower Dose Diuretics 

There is extensive knowledge of the effect of taking dopamine with a bumetanide type diuretic. 

Bumetanide by itself has a plateau above which a higher dose causes no further diuresis, but when combined with dopamine there is more diuresis.  Alternatively you can use a lower dose of bumetanide and get the same amount of diuresis by adding dopamine. 

Of interest to people with autism, it is found that you can reduce the amount of potassium lost for the same amount of diuresis.

    

Added to Diuretics, Low-Dose Dopamine Renoprotective in SmallAcute-HF Trial

Synergetic Effects of Dopamine and High－Dose Bumetanide in Patients with oliguria

The effects of a combination of dopamine and bumetanide were studied in eight patients with oliguria not responsive to conventional treatment. Dopamine was infused at a rate of 3 чg/kg/min and bumetanide was given as a 0.05-0.1 mg/kg bolus every 2 hours intravenously. Administration continued for 3 to 15 days. Urine output, blood urea nitrogen, serum creatinine, the ratio of urine to plasma osmolarity, free water clearance, and serum electrolytes were measured before, during, and after the administration period. Six of the eight patients responded with an increase in urine output and improvement of the other variables ; the other two did not. We conclude that the combination of dopamine and high-dose bumetanide is effective in increasing diuresis in critically ill patients in the early stages of oliguria

How does dopamine interact with NKCC1/2?

This is a very logical question, but there is something in the literature on this subject.  It does come from frogs, but it was all I could find.

Functional expression of the murine D₂, D₃ and D₄ dopamine receptors in Xenopus laevis oocytes

The different murine D2-type dopamine receptors (D_2L, D_2S, D_3L, D_3S, and D₄) were expressed in Xenopus laevis oocytes. The D2-type receptors were all similarly and efficiently expressed in Xenopus oocytes and were shown to bind the D2 antagonist [¹²⁵I]sulpride. They were all shown to activate Cl⁻ influx upon agonist stimulation. Using the diagnostic inhibitor bumetanide, we were able to separate the Na⁺/K⁺/2Cl⁻ cotransporter component of the Cl⁻ influx from the total unidirectional Cl⁻ influx. The D_3L subtype was found to operate exclusively through the bumetanide-insensitive Cl⁻ influx whereas the other D2-type receptors acted on the Na⁺/K⁺/2Cl⁻ cotransporter as well. The pertussis toxin sensitivity of the receptor-activated chloride influx via the Na⁺/K⁺/2Cl⁻ cotransporter varied between the various D2-type receptors showing that they may couple to different G proteins, and activate different second messenger systems.

In contrast to the D2 and D3 receptor subtypes, D4 receptor activity was not significantly altered by the presence of PTX, suggesting that in Xenopus oocytes it may couple with one or more PTX-insensitive G proteins to cause changes in Cl3 influx. By contrast, in the case of the D2 receptor, PTX reduced the total Cl3 influx mediated by the D2S isoform by approximately 67%, and that mediated by the D2L isoform by approximately 40% (Fig. 2A). However, the activities of the two components of this ion influx, namely the bumetanide sensitive Na/K/2Cl- cotransporter and the bumetanide-insensitive Cl- influx, differed between these two isoforms. While the bumetanide-insensitive Cl3 influx was reduced by approximately 60% by PTX for the D2L isoform, it was only slightly reduced for the D2S isoform (Fig. 2C). Thus, the majority of the inhibitory effect of PTX on the D2S-induced influx was caused by uncoupling from the signalling cascade that activates the Na/K/2Cl- cotransporter. On the other hand, the signal transduction pathway that activates the cotransporter after stimulation of the D2L receptor remained relatively unaffected by PTX (Fig. 2B), indicating that D2S and D2L couple to different G proteins when expressed in Xenopus oocytes. For the D3 receptor, both long and short isoforms showed a reduction (50^60%) in the presence of PTX, at the bumetanide-insensitive Cl- influx (Fig. 2C), whereas for both D3 receptor isoforms, PTX had little or no effect on the Na/K/2Cl- cotransporter, indicated by the bumetanide-sensitive component of the Cl3 influx (Fig. 2B).  

PTX = pertussis toxin

  

Caffeine among its many effects is effectively a dopamine D2/3 receptor agonist.

Caffeine mimics the effect of a dopamine D2/3 receptor agonist onthe expression of immediate early genes in globus pallidus.

Conclusion

As I understand from the large scale trial use of bumetanide use in autism, there is indeed an issue with hypokalemia (loss of potassium).  

I would think that this should be solvable using a supplement and dietary potassium.  Agnieszka pointed out that kiwis have the advantage of potassium with little carbohydrate, as do avocados. Bananas and orange juice are the traditional potassium-rich foods for people on diuretics. 

This is a case where the care giver has to play an active role, it is not just about the doctor prescribing a pill.  The care giver has to manage the process to minimize the side effects.  So potassium needs to be managed, as does fluid intake. 

For people who struggle with hypokalemia, the idea of a lower dose of bumetanide, but with dopamine, could be interesting.  The other method is to add a potassium sparing diuretic like spironolactone. 

For my son, the dietary option, plus 250mg of potassium twice a day, is very effective.  Now I just have to persuade him to take a Greek coffee with his breakfast. 

For people whose autism responds to penicillin type antibiotics and who take bumetanide then Bromocriptine might be interesting as a caffeine alternative.