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Showing posts with label Azithromycin. Show all posts
Showing posts with label Azithromycin. Show all posts

Thursday 16 April 2020

Life with Autism under Lockdown






I thought there should be at least one post about how life has changed during Covid-19.  Where we live, Monty’s life goes on pretty much as before, now we are back to home schooling - but that is nothing new for us.

School starts at 9am, there are 3 or 4 classes a day online from school and then activities and exercises till 3.30pm. 

We have PE, art and music like at school.  Piano practice continues most days.

Monty’s latest addition to his routine is reading 30 pages a day of a novel in the evening.  Now that he has started, he insists on doing it every day.  Having finished the (boring) books from school, he is going to start reading his brother’s collection of Biggles novels. They are about a fictional fighter pilot, the series starts in 1916 and continues for 50 years (the author got old, but Biggles did not).  We are going to set the scene with one of the old epic films about fighter aces from 1914-18.

The parks are closed and we have a curfew starting at 5pm weekdays and now across the entire weekend.  If you live in a small apartment, as many people do in the areas with the most strict lockdowns, life clearly will be difficult for people who do not understand why their movements have suddenly been restricted.

In many countries parents have asked for special treatment for those with autism, so that they can go outside more often. This has just been implemented where we live.

Parents are now going outside to walk their child with autism during the curfew and then neighbours are calling the police to report them.  In some countries you can get a special paper confirming your right as a disabled person to be taken outside, when everyone else has to stay at home.

In our case, Monty accepts that schools, parks, restaurant and cafes are all closed, but he expects that come September life will return to normal and his brother will go back to University.  Monty is lucky to live in a house with a garden, so he has plenty of space and lots of things to do.

Life with autism under control is not so demanding, even under lockdown.

When Monty was eight years old, we had nine months of autism out of control, which then results in a self-imposed lockdown.  That period ended just before Monty started his Polypill therapy in 2012.

I would not want to be in lockdown with an adult-sized person with untreated severe autism.


The Big Issue

Recently I was asked for some advice by Monty’s assistant; her friend works publishing a magazine homeless/disadvantaged people sell on the street.  One of their best “sellers” is a young man with mild autism.  He actually lives with his parents – he is not homeless.  He is struggling under the lockdown, because the magazine is not being published; he still turns up at the office to collect his copies to sell, even though there are none.

The young man became very anxious and so his parents gave him something to calm his nerves (which turned out to be Valium).

I was told that he had been given some pills, but in spite of these pills he got worse and started being aggressive, which is totally out of character.  This was all (falsely) attributed to the Corona virus changes to life.

As usual you do have to double check the facts.  Where we live a man with “mild autism” does not mean a person with Asperger’s, it means a person with Autistic Disorder (i.e. severe autism), but not such a bad case, so the young man can walk to work by himself and has some speech. 

I was asked what pills the parents could ask for, to calm him down. I explained that for anxiety people with autism often get prescribed benzodiazepines, but for aggression and self-injury they might get antipsychotics.  Neither are a good choice in most cases.

“And … there should not be any side effects.
The pills he currently takes are just something very mild”

So, what pills had he been given? It was a local brand name I did not know, so I looked it up and it was Valium/Diazepam, the benzodiazepine.

Adult with autism going crazy after Valium? that sounds familiar.

You don’t want Valium, you want 2mg of Bumetanide.

People who show a negative reaction to benzodiazepine drugs, usually prescribed to calm you down, are very likely to be bumetanide responders.

Benzodiazepine drugs increase the effect of the neurotransmitter GABA. In most people GABA is inhibitory, so increasing its effect will calm you down and ultimately sedate you.

In people with GABA working in reverse, it acts as excitatory.  This will reduce cognitive function and affect mood and behavior.  If you “turn up the volume” of GABA by taking a Benzodiazepine drug like Valium, you will make such people go crazy, with aggression and self-injury.

Hopefully the parents of the young man will get my message and stop giving Valium.  It would be nice to think they will also start to give Bumetanide, but that is their choice and I assume they most likely will not.  A diuretic for autism? How crazy is that.



How crazy is an anti-malarial for Covid-19?

How are the French doing with an antimalarial and an antibiotic for Covid-19, that I referred to in an earlier post? Say farewell to Covid-19 in just five days, it appeared.







By now the French have treated thousands of people with their new off-label therapy.  Also being developed in Marseille is Bumetanide as an off-label autism therapy by Neurochlore.  It looks like free thinking is flourishing on the Cote d'Azur.   

The data below is from the Marseille University Hospital Institute for Infectious Diseases (IHU Méditerranée Infection) and the wider hospital group in Marseille called APHM, which means Assistance Publique-Hôpitaux de Marseille.

The public hospitals in Marseille have treated 4,337 Covid-19 patients and 78 died (1.8%).

Within that group 2,671 were treated at the specialist IHU hospital with the antimalarial hydroxychloroquine (and some with azithromycin in addition) and of those that received at least 3 days of treatment 11 died (0.4%).

I think we can infer that 1,666 patients did not have hydroxychloroquine and 67 died (4%).

So if taken sick with Covid-19 in Marseille, tell the ambulance:

         "IHU Méditerranée Infection et vite !!"

If needed you can add:

        "Appuyez sur le champignon!"





As I suggested in my post on Covid-19, hydroxychloroquine looks a very good bet.  The supposedly fact-based media (CNN, BBC etc) continues to say there is no hard evidence to support the use of hydroxychloroquine.  How much evidence do you need?

To measure the success of hydroxychloroquine, you just count the bodies.

If this is such a struggle, what hope is there to ever prove a drug can work for such an ill-defined condition as autism?

Until you have been vaccinated against Covid-19, it appears that what you need is hydroxychloroquine + azithromycin and some potassium, to treat the hypokalemia caused by Covid-19. Ideally you would also have a home test for Covid-19, which are getting much cheaper, so you do not take the drugs unnecessarily.

Fortunately where we live hospitals are routinely giving hydroxychloroquine + azithromycin, but ideally you would start the antiviral therapy before getting ill enough to go to hospital.

Tom Hank’s wife was complaining recently in the media about the side effects (nausea, vertigo etc) of the chloroquine she was given in hospital in Australia for Covid-19.  I think that is a little ungrateful. Untreated Covid-19 can have a pretty terminal side effect.






Thursday 30 November 2017

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:-

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:-

 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.


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.



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.
  

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.