Can you safely take Bumetanide or Acetazolamide (Diamox) if you have a Sulfonamide allergy?

I was contacted by a reader in Italy whose child with autism may respond to bumetanide, but has a sulfonamide allergy and got a skin reaction (hives). She had to stop giving the drug, but wanted to know how she could re-start bumetanide.

Other readers have pointed out how they dare not try bumetanide because they know their child has a sulfonamide allergy. I think our longtime reader Tanya is one example.

 

Key Point to Note

Most people discover their sulfonamide after being giving an antibiotic in early childhood.

It is now well established that many (but not all) people with an allergy to sulfonamide antibiotics can safely take a sulfonamide diuretic like Bumetanide or Diamox/Acetazolamide. This is presented in case studies later in this post.

 

Sulfonamide Drugs

Many common drugs are “sulfonamides”. Their chemical structure includes a sulfonyl (–SO2) group attached to an amine group (–NH2). They include common antibiotics, like erythromycin, many diuretics (bumetanide, furosemide, acetazolamide (Diamox), some anticonvulsants (zonisamide) and some anti-inflammatory drugs (sulfasalazine).

 

Sulfonamide Allergy

Many parents discover early in their child’s life that their child has a sulfonamide allergy. Sometimes this is abbreviated to a “sulfa allergy.”

The symptoms of a sulfonamide allergy can vary but may include:

• Skin reactions (rash, hives, or itching)
• Fever
• Swelling
• Respiratory issues (shortness of breath)
• Anaphylaxis (in severe cases)

Usually the symptoms are minor, but once diagnosed the parents usually take note never to give their child any sulfonamide drug.

 

If you have the allergy must you avoid all sulfonamide drugs?

The standard assumption has been that if you have a sulfonamide allergy you cannot take Bumetanide or Acetazolamide (Diamox).

Upon further investigation in the research, this may not always be true.

 

What happens when there is no alternative drug?

When treating ion channel/transporter dysfunctions there may not be a non-sulfonamide alternative.

Acetazolamide (Diamox) is documented in the literature as a case in point. Bumetanide has not yet made it to the literature.

Furosemide fortunately has been researched and a safe desensitization protocol exists. Furosemide is a very similar drug to bumetanide.

 

Desensitization strategies

I did recently write about enzyme potentiated desensitization, which is an old, mostly overlooked, technique to overcome allergic reactions. I was interested in pollen allergy.

The best-known kinds of desensitization are allergy shots and more recently overcoming nut allergies, which gets media attention. 

Oral immunotherapy for peanut allergy in young children

The study also found that the youngest children and those who started the trial with lower levels of peanut-specific antibodies were most likely to achieve remission. 

“The landmark results of the trial suggest a window of opportunity in early childhood to induce remission of peanut allergy through oral immunotherapy,” says NIAID Director Dr. Anthony Fauci. “It is our hope that these study findings will inform the development of treatment modalities that reduce the burden of peanut allergy in children.”

 

I did wonder that if it works for nuts then why not bumetanide.

It turns out that I am not the first to consider desensitization to a drug allergy. The best known method is rapid drug desensitization (RDD), usually intravenous, which opens a window to be able to start taking a drug you are allergic to. Once you stop taking the drug, you then again become allergic to it.

The other approach is more like dealing with nut allergies, it is called slow drug desensitization (SDD) and involves taking a tiny initial dose and then slowly increasing it over weeks and months.

Drug desensitization is normally done in hospital as part of some therapy when you absolutely must have a drug that you are allergic to.

The paper below contains information on a very large number of common drugs where drug desensitization has been successfully carried out.

 

Desensitization for the prevention of drug hypersensitivity reactions

Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca²⁺ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal anti-inflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.

Two categories of desensitization protocols are currently available: RDD and slow drug desensitization (SDD). RDD is recommended for immediate reactions, both allergic and nonallergic. The most widely used RDD protocol is doubling the dosage every 15 minutes until the therapeutic dose is achieved. SDD is recommended for type IV delayed hypersensitivity reactions with T cell involvement, and can be performed both orally and intravenously. There is as yet no consensus on SDD protocols, including the initial dose, dose increments between steps, and dosing interval. Further clinical experience and research are required to establish the role and efficacy of desensitization for delayed reactions.

H1 blockers, H2 blockers, and glucocorticoids can be used as premedication. Aspirin and montelukast block the end products of the arachidonic acid cascade and decrease the incidence and severity of BTRs. NSAIDs can help to control the symptoms of cytokine release syndrome. Glucocorticoids alone are not recommended because they cannot prevent the initial degranulation of mast cells. 

The desensitization process is known to be antigen-specific, as the level of drug-specific immunoglobulin E (IgE) decreases but the levels of other allergen-specific IgE remain consistent throughout the treatment period. However, the cellular and molecular mechanisms underlying drug desensitization are not yet fully understood.

Aspirin/NSAID desensitization is considered for patients with cardiovascular or musculoskeletal diseases who require aspirin or NSAID administration for prolonged periods.

The temporary tolerance to aspirin/NSAIDs lasts 48 to 72 hours after desensitization. Therefore, hypersensitivity reactions can recur 2 to 5 days after discontinuation if the therapeutic dose is not continued.

 

DHR to β-lactams, such as penicillin or cephalosporin, is more common than that to non-β-lactams. Desensitization can be performed for both immediate and delayed hypersensitivity reactions. The protocol should be selected based on patient characteristics, hospital capacity, and physician preferences. It is generally started with 1/1,000 of the therapeutic dose and then increased by 2 to 3-fold every 15 minutes to 5 hours. Oral administration is preferred due to its ease, safety, and effectiveness. Desensitization to penicillin and cephalosporins has been well established. Successful desensitization has also been reported for other β-lactams, such as carbapenem and monobactam, and non-β-lactams, such as vancomycin, clindamycin, metronidazole, macrolides, aminoglycosides, tetracycline, and ciprofloxacin.

Successful desensitization to other antimicrobials has also been reported for antifungals, such as amphotericin B, fluconazole, itraconazole, voriconazole, and micafungin, and for antivirals, such as acyclovir, valganciclovir, ribavirin, and nevirapine.

 

Furosemide desensitization

There is no literature specific to bumetanide but there is on the very similar drug furosemide.

 

RAPID ORAL DESENSITIZATION TO FUROSEMIDE

Furosemide is a commonly used loop diuretic that contains a sulfonamide group. Although there are rare reports of hypersensitivity to furosemide, severe reactions, including anaphylaxis, have been reported. Ethacrynic acid, the only loop diuretic without a sulfonamide moiety, is no longer available in oral formulation, thus posing a dilemma in the outpatient treatment of patients with furosemide allergy.

Published protocols for furosemide desensitization include rapid intravenous administration and oral protocols lasting 3 to 10 days.3–5 The oral protocols were performed in patients with non–type I hypersensitivity reactions. We present a rapid, oral protocol for desensitization in a patient with presumed type 1 furosemide allergy manifesting as urticaria.

 

Desensitization to sulfonamide-containing antibiotics has been extensively used, but desensitization to furosemide is uncommon. The oral protocols previously described took 3 to 10 days and were performed in patients with non–type I hypersensitivity reactions, one with pancytopenia and the other with pancreatitis. The patient with a type I hypersensitivity reaction underwent an intravenous desensitization protocol. Rapid oral desensitization to a loop diuretic has not been previously described. The potential advantages of oral desensitization are that it is probably safer than intravenous desensitization, it may be more cost-effective in terms of monitoring and staff requirements, and it may be possible to perform in an outpatient setting. We propose our protocol as a novel approach to furosemide desensitization therapy for patients with non–life threatening reactions to furosemide. Further progress in the diagnosis and treatment of hypersensitivity to sulfonamide drugs will require identification of the major antigenic determinant and standardization of skin testing and specific IgE testing.

I think we should say good work to Dr Naureen Alim, then at Baylor College of Medicine Houston, Texas.

If anyone wants to desensitize to a bumetanide allergy I think she is the one to contact for advice. She is easy to find via Google. 

Here is another case example. 

Desensitization therapy in a patient with furosemide allergy

Allergy to furosemide is a rare phenomenon. Desensitization to this sulfa-containing drug has not been frequently performed. We describe a patient with severe congestive heart failure and type I allergy to furosemide. Because of the severity of her condition, we decided to use a rapid intravenous desensitization protocol. Following the desensitization, the patient was treated with intravenous and oral furosemide with a dramatic improvement in her clinical state. We suggest that rapid desensitization may be a safe and effective way of introducing furosemide to allergic patients for whom loop diuretics are urgently indicated.

 

In the case of Acetazolamide, here is one published desensitization method:

  

Desensitization to acetazolamide in a patient with previous antimicrobial sulfonamide allergy

Acetazolamide is a carbonic anhydrase inhibitor that is frequently used in the management of idiopathic intracranial hypertension. Acetazolamide is a sulfonamide agent; specifically, it is a non sulfonylarylamine, which lacks the amine moiety found at the N4 position that is seen in sulfa antibiotics. 

Sulfonamide antibiotics contain a substituted ring at the N1 position that is thought to be the driving factor in immediate hypersensitivity reactions.  

Although sulfa allergies are commonly reported, there is no evidence to suggest cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. However, patients can report a history of allergy to both categories of drugs. We present a rapid desensitization protocol to acetazolamide in a patient with history of immediate hypersensitivity reactions to both a sulfonamide antibiotic and acetazolamide. 

We formulated a 12-step intravenous protocol that was performed in the intensive care unit setting (Table 1). Informed consent was provided by the patient, and she tolerated the procedure well without any adverse reactions. The desensitization procedure took 395 minutes or approximately 6.5 hours. She was monitored overnight in the hospital and was observed the following morning after taking 500 mg of acetazolamide orally to ensure tolerance. She was thereafter able to continue her recommended dose of acetazolamide without any issues to date.

 

Allergy to a sulfonamide antibiotic does not always mean you will be allergic to the non-antibiotic sulfonamide drugs.

  

Use of Acetazolamide in Sulfonamide-Allergic Patients With Neurologic Channelopathies

The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved substantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction.

Conclusions

These 3 cases confirm that the carbonic anhydrase inhibitor acetazolamide can be given to patients with a history of allergic skin rash with antibiotic sulfonamide.

 

Acetazolamide has been used for the treatment of episodic ataxia type 2, with benefit in 50% to 75% of patients. In episodic ataxia type 1, acetazolamide was also effective in decreasing attack frequency. Acetazolamide is also effective in the periodic paralyses. Carbonic anhydrase inhibitors have been used to prevent altitude sickness, to lower intraocular pressure in open-angle glaucoma, and to treat refractory absence, myoclonic, and catamenial epilepsy as part of multidrug regimens. Acetazolamide has recently been used for hemiplegic migraine and idiopathic intracranial hypertension. 

The lack of available clinical or pharmacological evidence to support cross-reactivity between sulfonamide antibiotics and acetazolamide lends supports to the use of acetazolamide to treat patients with episodic ataxia and periodic paralysis. Of our 3 sulfonamide-allergic patients, 2 improved in symptoms after treatment with acetazolamide and none of the 3 had a hypersensitivity reaction. We conclude that a sulfonamide allergy should not be a contraindication to treatment with acetazolamide in patients with neurologic channelopathies. 

 

Acetazolamide and sulfonamide allergy: a not so simple story

 Allergies and adverse reactions to sulfonamide medications are quite common. Two distinct categories of drugs are classified as sulfonamides: antibiotics and nonantibiotics. The two groups differ in their chemical structure, use, and the rate at which adverse reactions occur. Cross-reactivity between the two groups has been implied in the past, but is suspect. Acetazolamide, from the nonantibiotic group, is routinely used in the prevention and treatment of high altitude issues and may not need to be avoided in individuals with a history of sulfonamide allergy. This review addresses the differences between the groups and the propensity for intergroup and intragroup adverse reactions based on the available literature. We also examine the different clinical presentations of allergy and adverse reactions, from simple cutaneous reactions with no sequelae through Stevens-Johnson syndrome and anaphylaxis, with risk for significant morbidity and mortality. We offer a systematic approach to determine whether acetazolamide is a safe option for those with a history of allergy to sulfonamides.

Sulfonamide-containing antibiotics are the second most frequent cause of allergic drug reactions, after the b-lactams (penicillins and cephalosporins). In one large study, the incidence of reactions to trimethoprim–sulfamethoxazole (TMPSMX) was 3% of patients exposed, compared with 5% for amoxicillin. The incidence of reactions to nonantibiotic sulfonamides is not well established; it is clearly less than with antibiotics.

 

There are several approaches to the use of sulfonamide drugs (specifically acetazolamide) in patients with past reactions to this class of medications. The choice of strategy depends on the type and severity of the previous reaction, as well as the class of drug (antibiotic versus non antibiotic) and the risk–benefit profile for the patient. However, regardless of the approach, the risks of subsequent reactions cannot be completely eliminated, and a thorough discussion between the medical provider and the patient should include this point so that an informed decision regarding the use of acetazolamide can be made. The safest approach for the patient with any prior reaction to a sulfa drug, multiple drug allergies, or penicillin allergy would be to avoid all drugs in the sulfonamide group, including acetazolamide.

 

Avoidance of the entire sulfonamide drug group is warranted for individuals whose previous reaction included a serious and/or life-threatening condition such as anaphylaxis, SJS, and TEN. Any form of reexposure to the precipitating drug or a sulfonamide in the same group is strictly contraindicated. Published evidence has shown that SJS/TEN can recur with even minor reexposures and may be more severe in the second episode. Even though SJS/TEN reactions are so far not associated with nonantibiotic sulfonamides, because of the severity and life-threatening nature of these reactions, a safe practice is to avoid all sulfonamides in patients with past SJS or TEN from sulfonamide containing medications.

 

This paper was published in a journal on high altitude medicine. That is why the suggested alternatives are staged ascents of the mountain and oxygen.

  

Conclusion

The first key point is that you can have an allergy to sulfonamide antibiotics and have absolutely no negative reaction to sulfonamide drugs like bumetanide and acetazolamide (Diamox).

If you do have a mild allergic reaction to a sulfonamide drug, there are desensitization strategies that are proven to work in many people.

It looks like rapid oral desensitization to bumetanide and acetazolamide is likely possible, based on what has been shown possible with furosemide and a wide variety of other drugs.

Clearly the level of sensitivity and hence the nature of the allergic reaction can vary massively from person to person, this is why rapid desensitization usually takes place in hospital.

If you opt for the slower process, much less is known, because it is not generally used. If you did it in hospital it would require a very long stay and so would be hugely expensive.

It is suggested that slow drug desensitization (SDD) should be much more long lasting and hopefully might become permanent – as is the hope for nut allergy treatment.

When posed the initial question by our reader wanting to use bumetanide, I was thinking along the lines of slow drug desensitization (SDD), because this is how you would treat a pollen allergy. If rapid oral desensitization will work for taking bumetanide once a day that would be great. To maintain the protection from allergy it might be safer to take a small second daily dose.

 

Here is a quick overview of desensitization options for sulfonamide allergy:

• Rapid Desensitization (RDD):
• Faster process (hours)
• Temporary tolerance achieved
• May be repeated if needed
• Slow Desensitization (SDD):
• Slower process (days, weeks, or months)
• Might offer a greater chance of longer-lasting
• Still requires close monitoring

Important Considerations:

• Always consult your doctor: They can assess your allergy severity, treatment options, and the suitability of desensitization if necessary.
• Desensitization is not without risks: It requires careful monitoring.

 

I for one found this an interesting investigation and with promise for parents of those with severe autism who have been unable to trial Bumetanide due to a sulfonamide allergy. 

Hopefully our reader Dr Antonucci will follow up on this and make a bumetanide desensitization protocol for those people with autism and a sulfonamide allergy. Maybe he has already done it. It looks very achievable.

Advances in personalized medicine to treat Autism/IDD – Rett syndrome as an example. Also, Piperine to upregulate KCC2, but what about its direct effect on GABAa receptors?

 

Source:  https://www.cell.com/neuron/pdf/S0896-6273(21)00466-9.pdf

Today’s post is drawn from a workshop I am invited to present at an autism conference in Abu Dhabi.

I decided to talk about advances in personalized medicine – no surprise there.  Since I have 2 ½ hours, I thought I will need some interesting examples to maintain the audiences interest.  One such topic is going to be Rett syndrome.

I regard Rett syndrome and all the other such syndromes in this blog as “single gene autisms” (monogenic autism).  If you apply the American DSM classification, from 2013 onwards Rett syndrome is no longer part of autism.  Hopefully there are no such purists attending in Abu Dhabi. 

Two gene therapies for Rett syndrome are currently undergoing human trials and one drug therapy has been FDA approved.  This looks very encouraging, so let’s dig a little deeper.

Rett syndrome can present with a wide range of disability ranging from mild to severe. 

Rett syndrome is the second most common cause of severe intellectual disability after Down syndrome.

Other symptoms may include:

•      Loss of speech

•      Loss of purposeful use of hands

•      Loss of mobility or gait disturbances

•      Loss of muscle tone

•      Seizures or Rett “episodes”

•      Scoliosis

•      Breathing issues

•      Sleep disturbances

•      Slowed rate of growth for head, feet and hands

Here are the new therapies: 

TSHA-102: This gene therapy, developed by Taysha Therapeutics, is a gene replacement therapy that aims to deliver a functional copy of the MECP2 gene to brain cells.  It utilizes an AAV-9 virus to carry the miniMECP2 gene product into cells for the body to produce more MeCP2 protein, which is deficient in Rett syndrome. As of February 2024, Taysha completed dosing for the first cohort (low dose) in their REVEAL Phase 1/2 adolescent and adult trial in Canada, with positive interim data on safety. They are also conducting trials in the US for both pediatric and adolescent/adult populations.

NGN-401: This gene therapy, by Neurogene Inc., employs a different approach. It uses an AAV9 vector to deliver a regulated version of the MECP2 gene called EXACT. This technology aims to control the amount of MECP2 protein produced by the gene, mitigating the risk of overproduction. NGN-401 is currently in a Phase 1/2 trial for girls with Rett syndrome aged 4 to 10 years old.

Daybue (trofinetide)

Daybue is the first and only FDA-approved treatment specifically for Rett syndrome in adults and children two years of age and older. It is not a gene therapy, but rather a medication taken orally.

The optimistic AI generated view:

Here's a breakdown of Daybue for Rett syndrome:

• Mechanism: The exact way Daybue works in Rett syndrome isn't fully understood, but it's believed to target neuroinflammation and support synaptic function.
• Dosage: The recommended dose is based on the patient's weight and is taken twice daily, morning and evening, with or without food.
• Administration: Daybue comes as an oral solution and can be taken directly or through a gastrostomy tube if swallowing is difficult.
• Efficacy: Studies have shown that Daybue can improve symptoms of Rett syndrome, including reducing scores on the Rett Syndrome Behavior Questionnaire (RSBQ) and showing improvement on the Clinical Global Impression-Improvement (CGI-I) scale.
• Side Effects: The most common side effects of Daybue are diarrhea and vomiting. Weight loss can also occur in some patients. It's important to consult with a healthcare professional for monitoring and managing any potential side effects.

Daybue is an expensive medication. Here's what we know about the cost:

• List Price: The list price of Daybue is around $21.10 per milliliter.
• Annual Cost: This translates to an estimated average annual cost of around $375,000 for patients.
• Dosage Variability: It's important to note that the dosage of Daybue is based on a patient's weight, so the annual cost can vary depending on the individual.

Insurance and Assistance Programs:

• The high cost of Daybue highlights the importance of insurance coverage. Whether insurance covers Daybue and to what extent will depend on your specific plan.
• The manufacturer, Acadia Pharmaceuticals, offers a copay program called Daybue Acadia Connect. This program may help eligible commercially insured patients pay $0 for their monthly prescription.

What are the parents' groups saying? 

Not as good as you might be expecting for $375,000 a year.

Affordable potential alternatives to Daybue/Trofinetide

Daybue/Trofinetide is the product of decades of research into a growth factor called IGF-1.

It is a complicated subject and as usual the abbreviations can be confusing.

As you will see below there already is an OTC product commercialized by one of the original researchers, Dr Jian Guan.

One Rett syndrome parent, who reads this blog, has trialed cGP and sees a benefit. You rather wonder why the Phelan-McDermid, Pitt Hopkins, Angelman and Prader-Willi parents don’t follow him and splash out 50 USD and make a trial.

 

 

Gene-therapy

Gene therapy is undoubtedly very clever and ultimately will likely be the best therapy.  It still may not be that silver bullet.

To be effective gene therapy needs to be given at a very young age, ideally as a fetal therapy prior to birth. Note that we saw that in the Rett mouse model they gave bumetanide to the pregnant mother just before birth.

Fetal therapy is not a crazy idea and much is already written about it; many pregnancies are terminated because genetic anomalies are detected prior to birth. Down syndrome is the best-known example. Fetal therapy is realistic for some disorders.

Girls with Rett syndrome are often diagnosed first with idiopathic autism and then years later with a more precise diagnosis of Rett syndrome. This is a common experience among readers of this blog.

Classic Rett syndrome 

The average age of diagnosis for this form is around 2.5 years old in the US and 5 years old in the UK.  Why do you think that is?

Research in mouse models has shown that the effect of gene therapy ranges from curative when given extremely young to more limited the later it is given.

Off-target effects

Gene therapy has the potential for off-target effects. This is a significant concern in the field and researchers are actively working on ways to minimize these risks. Here is a breakdown of what off-target effects are and why they matter:

During gene therapy, a modified gene is delivered to target cells with the aim of correcting a genetic defect.

Ideally, the modified gene integrates into the intended location in the genome.

However, there's a chance it might insert itself into unintended locations (off-target sites).

Potential Consequences of Off-Target Effects

Disrupting normal genes at off-target sites could lead to unpredictable and potentially harmful consequences. This could include triggering uncontrolled cell growth, which is a risk factor for cancer.

It can also cause unexpected side effects depending on which genes are accidentally disrupted.

Minimizing Off-Target Effects

Researchers are developing various strategies to improve the accuracy and specificity of gene therapy techniques.

This includes using more precise gene editing tools like CRISPR-Cas9 with optimized guide RNAs to reduce off-target edits.

Additionally, researchers are working on methods to detect and potentially repair any off-target modifications that might occur.

Over-expression of the target gene

Yes, there is a possibility that the replaced gene in gene therapy could overproduce the expressed protein. This can be a potential complication and researchers are working on ways to control the level of protein expression. Here's a breakdown of the concern:

• Gene Dosing: Ideally, gene therapy aims to deliver a functional copy of the gene at the right amount to compensate for the deficiency.
• Overproduction Risks: However, if the delivered gene is too active or multiple copies are inserted, it can lead to overproduction of the protein.

Consequences of Protein Overproduction:

• Overproduction of a protein can disrupt the delicate balance in the cell, potentially leading to cell dysfunction or even cell death.
• In some cases, the protein itself might have harmful effects if present in excessive amounts.

Controlling Protein Expression:

Researchers are developing several strategies to control protein expression in gene therapy:

• Promoter selection: Using promoters that have a weaker switch can help regulate protein production.
• Viral vectors: Engineering viral vectors to control the number of gene copies delivered to cells.
• Inducible systems: Developing gene therapy methods where the expression of the introduced gene can be turned on and off as needed.

The cost of gene therapy

•      Despite the high cost, gene therapy can be a cost-effective treatment for some diseases. This is because it can eliminate the need for lifelong treatment with other medications.

•      Here are some examples of the cost of currently available pediatric gene therapies:

•      Luxturna (gene therapy for Leber congenital amaurosis type 10): $425,000

•      Zolgensma (gene therapy for spinal muscular atrophy type 1): $2.1 million

•      Skysona (gene therapy for adrenoleukodystrophy): $3 million

Piperine to correct KCC2 expression in Rett syndrome?

One key feature of Rett syndrome is impaired cognition.

As regular readers are aware, there are many types of treatable intellectual disability (ID).

One type of treatable ID is caused when the GABA developmental switch fails to occur shortly after birth.  This creates an excitatory/inhibitory imbalance in neurons which impairs cognition and lowers IQ.

The faulty GABA switch is a feature of many types of autism, but far from all of them.

By using pharmaceuticals to lower chloride within neurons, you can compensate for the failure of the GABA switch.

This treatment can be achieved by:

1.     Blocking or down regulating NKCC1

2.     Up regulating KCC2

In the paper below they look at up regulating KCC2

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. There are currently no approved treatments for RTT. The expression of K⁺/Cl⁻ cotransporter 2 (KCC2), a neuron-specific protein, has been found to be reduced in human RTT neurons and in RTT mouse models, suggesting that KCC2 might play a role in the pathophysiology of RTT.

Injection of KEEC KW-2449 or piperine in Mecp2 mutant mice ameliorated disease-associated respiratory and locomotion phenotypes. The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders involving dysregulation of KCC2.

Thus, our data demonstrate that activation of the SIRT1 pathway or the TRPV1 channel enhances KCC2 expression in RTT human neurons.

Treatment with piperine (10 μM), an activator of the TRPV1 channel (51), induced a significant rise in KCC2 expression in cultured human neurons 

We already knew this was likely from earlier research from Ben Ari, see below for a reminder.  Is Piperine an interesting option for those restricted to OTC interventions?

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth

Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2-/y mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutamatergic/GABAergic PSCs ratio is enhanced, hyper-synchronized activity is present and metabotropic long-term depression (LTD) is impacted. One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

Treating the mother prior to delivery with bumetanide was a partially effective therapy in the mouse model of Rett syndrome.

Piperine

Bumetanide is cheap and very possibly effective in human Rett syndrome, but it is a prescription drug.

Piperine is an OTC supplement and a compound found in black pepper. By activating the TRPV1 channel it causes an increase in expression of the KCC2 transporter that allows flow of chloride out of neurons. So piperine should lower chloride inside neurons.  Piperine can cross the blood brain barrier, so when taken orally it should have some effect on intracellular chloride.

Piperine is also a positive allosteric modulator of GABA_A receptors

This means that piperine multiplies the effect of whatever GABA is around. This means that in typical people piperine should have anti-anxiety effects.

Piperine was recently found to interact with a previously unknown  benzodiazepine-independent binding site.

Researchers are currently toying with the piperine molecule to try and separate the effect on TRPV1 from the effects on  GABA_A.  They want to create 2 new drugs.

1.     a selective TRPV1 activator

2.     a selective GABA_A modulator (PAM)

Piperine as an alternative or complement to Bumetanide?

One effect of piperine would be great to have (TRPV1 activator) but the second effect would not be helpful (positive allosteric modulator of GABAA).

The question is what is the net effect. Nobody will be able to answer that without a human trial.

I was advised long ago by one drug developer than it is best to focus on reducing flow into neurons via NKCC1, rather than increase its exit by KCC2, because nobody had yet been successful with KCC2; many have tried.  KCC2 plays a key role in neuropathic pain and that is why it has been researched.

Conclusion

We did see years ago that taking coffee with your bumetanide made sense. Coffee contains compounds that are OAT3 inhibitors and slow down the excretion of bumetanide from the body; coffee increases the effect of bumetanide. You can achieve something very similar by just increasing the dose of bumetanide.

Taking black pepper (piperine) with your bumetanide might be good, or might not be. It certainly would be easy to find out. As with Daybue/Trofinetide, the result is likely to vary from person to person. If GABA function, post- bumetanide, is still a bit excitatory amplifying GABA signaling will make autism worse. If GABA function has been shifted to inhibitory then amplifying GABA signaling will be calming.

Gene therapy will require much earlier diagnosis of single gene autisms.

“Precision medicine” therapies like Daybue/Trofinetide may not be that precise after all and large variations exist in the response, even among children with the same affected gene.

The huge expense means that for most of the world they will see no benefit from gene therapy or indeed “precision medicine.”

The low hanging fruit is to repurpose affordable existing drugs and get the benefit from their secondary effects.  This is what I term personalized medicine.

The research clearly indicates that some girls with Rett syndrome likely will benefit from Bumetanide therapy. For a young child this therapy would cost 50 US dollars/euros a year, if you pay the actual price for generics.

Why are they trialing genetic therapies for Rett instead of first doing the obvious thing and trialing cheap bumetanide? They will likely be able to sell the gene therapy for $2 million a shot.  There is little interest in trialing a $50 a year therapy.

Our new reader from Turkey, MÜCADELECI ANNE DENIZ ( = FIGHTING MOTHER DENIZ), likely does not have $2 million to spend, but seems to be on the way to creating her own personalized medicine therapy for her son. Good luck to her.

As to the cGP Max supplement, it seems to work for some and have no effect in others. Nobody has reported any side effects. It looks worth a try for Rett syndrome.  As a supplement it is not cheap, that is until you see what they charge for Daybue. 

Monty in Montevideo and Recent Advances in Autism Research

It is nice to have a city named after you and Monty finally visited “his” city, Montevideo in Uruguay.

I suppose my city would be St Petersburg, which I have visited several times.

A really impressive city in Latin America is Buenos Aires; it has a very large central area with beautiful architecture. It enjoyed several decades of great wealth, the “golden age,” when the city was laid out. In 1930 there was a military coup and the party was over. It has been boom and bust ever since.

We visited what they call the Southern Cone of Latin America, which is made up of Argentina, Chile and Uruguay. We went from Buenos Aires all the way down to Tierra del Fuego.

Santiago, the capital of Chile, looks to be booming. It has a small historic centre and everything else is new.

Montevideo was more what I expected, except for the graffiti everywhere which makes it look less safe than it likely is. Uruguay has many beautiful beaches, but until you get away from the vast River Plate estuary (Río de la Plata = river of silt) and to the Atlantic ocean the water is a dirty brown colour.  Monty would not go in the water.

Southern Chile and Argentina have some stunning scenery with volcanoes, mountains and glaciers.  It looks great, but it is no longer the cheap backpacker destination it once was.

 

 

Back to the Autism Research

The highlight from the recent research comes from The RIKEN institute in Japan. It does go some way to explaining why so many people with autism appear to have nothing in their genetic results to explain their condition.

Normally, when you have your state of the art whole genome screening (WGS) the geneticist who interprets the results is looking for mutations in one of the many hundreds of known “autism genes” and nowadays, hopefully, in the non-coding areas next to them. Whole exome screening (WES) just looks at the 2% of the genome that has the instructions for how to make each of your 22,000 genes. The other 98% includes things like promoters that increase activity of a specific gene.

Many people with autism appear to show no mutations that are relevant.

The Japanese have figured out one of the reasons why this is the case. There are other reasons.

Our genetic material is not stored on something like a long role of paper, which is like a two-dimensional object.  It is a three-dimensional twisted object all folded up. As a result, the DNA physically closest to each autism gene may not be the part expected. The Japanese use the term “topologically associating domain” (TAD) to define which zones of DNA are actually interacting with each other.

They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes.

This means that geneticists now need to go back to school and learn about the TAD of each autism gene. Or else just replace the geneticist with an AI generated report.

 

Mutation butterfly effect: Study reveals how single change triggers autism gene network

Researchers in the RIKEN Center for Brain Science (CBS) examined the genetics of autism spectrum disorder (ASD) by analyzing mutations in the genomes of individuals and their families. They discovered that a special kind of genetic mutation works differently from typical mutations in how it contributes to the condition. In essence, because of the three-dimensional structure of the genome, mutations are able to affect neighboring genes that are linked to ASD, thus explaining why ASD can occur even without direct mutations to ASD-related genes. This study appeared in the scientific journal Cell Genomics on January 26.

The researchers analyzed an extensive dataset of over 5,000 families, making this one of the world's largest genome-wide studies of ASD to date. They focused on TADs-;three-dimensional structures in the genome that allow interactions between different nearby genes and their regulatory elements. They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes. In this way, the new study explains why mutations can increase the risk of ASD even when they aren't located in protein-coding regions or in the promotors that directly control the expression of ASD-related genes.

 

"Our most important discovery was that de novo mutations in promoter regions of TADs containing known ASD genes are associated with ASD risk, and this is likely mediated through interactions in the three-dimensional structure of the genome."  

Atsushi Takata at RIKEN CBS

 

 

Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk

Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.

 

Bumetanide

 

I did come across a Chinese study with an eye-catching title:-

 

Can bumetanide be a miraculous medicine for autism spectrum disorder: Meta-analysis evidence from randomized controlled trials

 

Highlights

• Bumetanide showed significant and large effects on the overall core symptoms of ASD.
• Bumetanide’s efficacy on ASD is influenced by subjects’ age, dosage form, duration.
• Results of RCTs on bumetanide in ASD are moderated by study designs, measurement tools

A systematic search was conducted on PubMed, EMBASE, MEDLINE, PsyclNFO, Web of Science, Clinical Trials.gov, and references in reviews from the earliest available date to September 2023. Randomized controlled trials (RCTs) were identified that evaluated the efficacy of bumetanide in improving overall core symptoms (OCS) of ASD. Therefore, nine studies with 1036 participants were included in the study.

Results

Bumetanide showed significant effects on OCS of ASD (WMD = － 1.91, p = 0.006), particularly in sub-domains including relation to inanimate objects, adaption to environment changes, auditory response, near sensory responses, anxiety and hyperactivity. Moderating analysis indicated that a significant effect size of bumetanide on OCS of ASD was observed in specific subgroup, including 3–6 years old (WMD = －1.08, p = 0.008), the tablet (WMD = －2.80, p = 0.003), 3-month intervention (WMD = －2.54, p = 0.003), and the single-center studies (WMD = －2.80, p = 0.003).

Conclusions

Bumetanide has a large and significant impact on the OCS of ASD. Given the limited number and quality of included RCTs, future research should prioritize conducting large-scale trials focusing on sub-parameters or specific clinical features to comprehensively evaluate the efficacy of bumetanide in subpopulations of children with ASD.

Meanwhile, Professor Ben Ari has written another paper on why the phase 3 trial failed and has also published a book.

 

Bumetanide to treat autism spectrum disorders: are complex administrative regulations fit to treat heterogeneous disorders?

Introduction:

Extensive experimental observations suggest that the regulation of ion fluxes and, notably, chloride are impacted in autism spectrum disorders (ASD) and other neurodevelopmental disorders. The specific NKCC1 cotransporter inhibitor Bumetanide has been shown to attenuate electrophysiological and behavioral features of ASD in experimental models. Both pilot and phase 2 double-blind randomized independent trials have validated these effects with thousands of children treated successfully. Both brain imaging and eye tracking observations also validate these observations. However, final large phase 3 trials failed, with no significant differences between placebo and treated children.

Methods:

Here, I discuss the possible reasons for these failures and discuss the exclusive reliance on complex patent cooperation Treaty (PCT) regulations. Indeed, available data suggest that bumetanide responders could be identified by relying notably on EEG measures, suggesting that biological sub-populations of patients might benefit from the treatment.

Results:

These observations raise important debates on whether treating only a % of children with ASD is acceptable.

Discussion:

It is likely that in many disorders, the heterogeneity of the pathological event precludes a single general treatment for all, suggesting that trials centered on selective populations of responders might be essential for large clinical trials to succeed.

  Here is the new book:-

Treating Autism with Bumetanide

https://www.cambridgescholars.com/product/978-1-5275-1890-2/

In spite of its high incidence, extensive media coverage and major clinical burden to families, there is not a single approved European or American drug treatment of Autism Spectrum Disorders (ASDs). The dominant genetic and psychiatric approaches to treat ASDs have various limitations, suggesting that a novel global approach to understand and treat ASDs is warranted. Based on the authors’ converged expertise on brain development, ASD treatment and brain imaging, this book provides a fresh view of the disorder which is validated by experimental imaging and large clinical trials, culminating in the first large phase 3 final pediatric trial (on 400 children in EU countries and the US) using a repositioning of a drug used for decades to treat hypertension and edema. The convergence of experimental and clinical data on this disorder is unprecedented, confirming the potential of the drug to be the first pediatric treatment of ASDs.

After explaining the mechanisms underlying ASDs, we describe specific cases of children who, after treatment, considerably improved their sociability and reduced their agitation. The book also discusses the skepticism that the authors met from the tenants of pure genetics and psychiatry, and why the abyssal poverty of information on developmental disorders has hampered progress in understanding and treating ASD.

 

Bumetanide dosage is key – “wonderful effects from increasing from 0.5mg to 1mg” 

One recuring feature I have noticed from bumetanide use in the United States is the low dosage often used, as if these doctors want to show the drug is ineffective.

A reader recently contacted me about his young son who responded to the low dose of 0.5mg, but his autism doctor would not increase the dose.  The parent took matters into his own hands and increased the dose and then wrote to tell me about the “wonderful effects.”

 

Diuresis has stopped, but restarts at a lower dose

In a minority of cases bumetanide causes no diuresis. The question is whether it can have any effect in the brain if it causes no diuresis. Has the drug been absorbed at all?

One reader contacted me to tell me that her son, who has responded well to bumetanide for several years, stopped experiencing any diuresis. Then she told me that when she reduces the dose the diuresis returns.

There are many possible explanations, but perhaps those people who find bumetanide causes no diuresis should try a lower dose and see what happens.

 

Vasopressin/Desmopressin

Much of the research into the hormone vasopressin comes from Stanford. They have published a string of papers over the years. I think they are definitely on to something, but they are taking their time and may never commercialize the result.  

The very recent one is:

Vasopressin deficiency: a hypothesized driver of both social impairment and fluid imbalance in autism spectrum disorder

 

For some reason there is no abstract. 

Thanks to our reader Seth, I have now added the link below that takes you directly to  Stanford's website, which holds the full text version of the paper. 

https://med.stanford.edu/content/dam/sm/parkerlab/documents/da035ad7-7c80-41bd-a9a6-ee03a8bcc58d.pdf

The same group previously published a paper showing that people with ASD have a reduced level of vasopressin in their spinal fluid. As you can see in the chart below the level of oxytocin was normal.

There have also been successful trials using intranasal vasopressin in humans.

Cerebrospinal fluid vasopressin and symptom severity in children with autism

 

Vasopressin and oxytocin are closely related hormones and possibly some interactions are not yet fully understood.

Both these hormones can be given via a nasal spray.

 

The Bumetanide-Vasopressin interaction

Under normal circumstances you would never combine vasopressin with a diuretic.

Vasopressin stops you peeing and that it is why it is given to some children who wet their bed at night.

Bumetanide is a fast-acting diuretic that causes you to pee a lot.

So if you gave a diuretic to an elderly overweight person to reduce their blood pressure, it would be mad to also prescribe vasopressin.  The drugs are therefore contraindicated.

In autism we do not actually want the diuretic effects of bumetanide. We just want its effects on the brain.

The social and emotional beneficial effects of vasopressin have already been established by the existing Stanford research.

The combined effects of bumetanide + intranasal vasopressin might then be a win-win. Less autism and without the diuresis.

I was contacted long ago by a father whose daughter was prescribed Desmopressin, a synthetic analog of vasopressin that is an approved drug, and her autism markedly improved.

The Stanford research in humans uses a nasal spray that they have compounded specially rather than the commercially available Desmopressin.