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Friday, 23 February 2018

Verapamil or Rezular (R-verapamil) for Irritable Bowel Syndrome (IBS)?



A nasty condition that is equally nasty to spell - diarrhoea/diarrhea


Today’s post may help to explain why some people’s GI problems seem to vanish when they take Verapamil for their autism.

Verapamil is usually prescribed as an L-type calcium channel blocker, to lower blood pressure. This type of ion channel is widely expressed in the brain, the heart and the pancreas. The pancreas is where your body makes those digestive enzymes. Mast cells that release histamine also contain L-type calcium channels.

Verapamil blocks the L-type calcium channel Cav1.2, which in posts a few years ago I showed could be relevant for some types of autism. An extreme dysfunction of this ion channel leads to Timothy Syndrome, which is a single gene variant of autism with severe heart defects.  There is now some more recently published research which I have highlighted below.


L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value. Organic calcium channels blockers are clinically used since decades for the treatment of hypertension, cardiac ischemia, and arrhythmias with a well-known and excellent safety profile. This pharmacological benefit is mainly mediated by the inhibition of Cav1.2 channels in the cardiovascular system. Despite their different biophysical properties and physiological functions, both brain channel isoforms are similarly inhibited by existing calcium channel blockers. In this review we will discuss evidence for altered L-type channel activity in human brain pathologies, new therapeutic implications of existing blockers and the rationale and current efforts to develop Cav1.3-selective compounds.


The L-type calcium channels (LTCCs) Cav1.2 and Cav1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. Separately, CACNA1D has been found to be associated with BD and autism spectrum disorder, as well as cocaine dependence, a comorbid feature associated with psychiatric disorders. Despite growing evidence of a significant link between CACNA1C and CACNA1D and psychiatric disorders, our understanding of the biological mechanisms by which these LTCCs mediate neuropsychiatric-associated endophenotypes, many of which are shared across the different disorders, remains rudimentary. Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Cav1.2 and Cav1.3. Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Cav1.2- and Cav1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

I have crossed these ion channels off my “to do” list because I have found an effective therapy that works for my son and for the children of some other readers.  It does not work for everyone, but that should not come as a surprise. I think those with mast cell disorders and/or major GI problems are most likely to be responders. 

As well as halting the cascade of anxiety towards self-injury, reducing allergy, it was reported that Verapamil made long term GI symptoms vanish.

In your pancreas β-cells make insulin. These β-cells have Cav1.2 calcium channels. In people with type-1 diabetes their β-cells have died so their pancreas produces no insulin. In people with the increasingly common type-2 diabetes, they start out with enough insulin but their body has a reduced sensitivity to it; often as they age their β-cells begin to die, at which point they start having to inject insulin like a type-1 diabetic. We saw that by blocking Cav1.2 you can stop these β-cells from dying. This means that a person with type-2 diabetes should take Verapamil to maintain their pancreas producing insulin.

Without wanting to go further into how the pancreas functions, I assumed that perhaps there were other Cav1.2 calcium channels involved in producing enzymes in the pancreas that might result in digestive problems in some people, that in turn produce symptoms of IBS.

I already highlighted in a post that Verapamil also affects an interesting potassium channel called Kv1.3. This channel is involved in the inflammatory response and this is the channel that TSO parasites use to trick their host into not attacking and expelling them.

It appears that Kv1.3 is over expressed in auto-immune diseases including MS. So inhibitors of this ion channel are potential treatments for MS. Add TSO parasites to that list of novel MS therapies!

Some venoms are Kv1.3 inhibitors and may form the basis of new drugs.


Since autism is in-part an auto-immune disease a Kv1.3 inhibitor could be therapeutic.
Verapamil does inhibit Kv1.3, but I do not know if it is to a therapeutic extent.  Most drugs have numerous effects but only one dominant one.


Melatonin MT1 and Serotonin 5-HT2b receptors

Today we learn that two further receptors are affected by Verapamil, one Melatonin and one Serotonin.

Melatonin, at high doses, we saw in an old post has potent beneficial effects on some GI conditions and trials showed it to be as effective as prescription drugs for those conditions. Melatonin is very cheap, but cannot be patented, so will not be researched seriously.

The two isomers of Verapamil

When you think of a chemical you may think of its formula, but it can be more complex, as you might have learnt in high school chemistry.

The two compounds below are both thalidomide. R-thalidomide is effective against  insomnia and morning sickness, but the mirror image called L-thalidomide can cause birth defects.




This was discovered too late, for many people.

Many drugs are a mixture of Right and Left, confusingly they like to also call Left “S”. In Latin sinister is the adjective left and dexter is the adjective for right.

Recall Arbaclofen (R-Baclofen) ? I am sure Roche does, a $40 million bet that did not pay off.

Now we have R-Verapamil.

Pharmacology of R-Verapamil: A Novel Therapy in IBS
John Devane, Mary Martin, John Kelly

Racemic verapamil, primarily a cardiovascular agent, has been widely used off-label in patients with irritable bowel syndrome (IBS). Initial observations of its usefulness followed recognition of a high incidence of constipation with use in cardiovascular conditions. The enantiomers of verapamil are known to differ in cardiovascular potency, the S-isomer being much more potent than the R-isomer. In addition we found the S-isomer to be equiactive in relaxing vascular and colonic smooth muscle but the R-isomer to be 5-times more potent in relaxing colonic than vascular muscle. This selectivity led us to develop R-verapamil (Rezular) as a gut selective treatment in IBS and we have shown doses from 60mg/day to 240mg/day to greatly improve symptoms in non-constipation IBS patients. To better understand the mechanism by which R- verapamil improved the symptoms of IBS, we undertook an in-vitro screen of binding of R-verapamil to 147 receptors/receptor sub-types. Specific ligand binding was initially assessed using 10x-5 M verapamil and if there was greater than 50% inhibition of control specific binding, then binding at 8 different concentrations was tested andIC50 values (concentrationfor half-maximalinhibition of controlspecific binding (x10 -7M)) calculated. The therapeutic plasma concentration range of free R-verapamil was conservatively set at 0.1-3x10-7 M. Within this range R-verapamil showed affinity for 3 receptors: melatonin (MT1)(IC50 0.6), 5-HT2b (IC50 1.1) and L-type calcium channel (IC50 2.4). In addition compared with S-verapamil, R-verapamil showed stereoselectivity x40)for MT1 binding, whereas S-verapamil showed stereo selectivity (x3) for L-type calcium channel binding. R-Verapamil was selective for 5-HT2b relative to other 5-HT receptor sub types and affinity was low for 5-HT3(IC 50 3,400) or 5-HT4(>100) receptors.It was also highly selective for MT1(IC50 0.6) versus MT2 (IC50 >100) receptors. We conclude that R verapamil most likely exerts its therapeutic effects in IBS via a previously unrecognized mechanism involving combined effects at melatonin receptors, serotonin receptors and L type calcium channels

  

"In May 2009, Rezular (arverapamil) failed in Phase III development, where it underwent extensive evaluation in the ARDIS clinical trial programme in patients with IBS-D.

Phase III trials were taken up with patients already receiving treatment in the ARDIS-1 trial. In this randomised, double-blind, placebo-controlled, parallel group the efficacy and safety of Rezular (arverapamil) was assessed in about 1,200 patients.

Three doses of Rezular (arverapamil) were compared with placebo over a 12-week treatment period.

In September 2009, AGI announced that it plans to consider alternative uses of Rezular. The company believes that Rezular can prove effective in treating diarrhoea and non-diarrhoea related problems.

IBS is a common, but until recently poorly understood, disorder of the gastrointestinal (GI) tract. It is described as a functional disorder of the GI tract, in which there is no obvious underlying pathology.

IBS has proved notoriously difficult to diagnose and treat effectively. Until recently no drugs were specifically indicated for the treatment of IBS. Instead, patients would often seek over-the-counter (OTC) remedies to treat constipation, diarrhoea, abdominal pain and bloating associated with IBS.
AGI Therapeutics, Rezular (arverapamil) is a single enantiomer moiety of racemic verapamil, a cardiovascular drug that has been in clinical use for 35 years.

However, in contrast to currently available commercial forms of racemic verapamil (a mixture of two enantiomers), arverapamil shows preferential activity in treating the symptoms of IBS-D without the traditional cardiovascular actions of the racemic drug. It combines affinity at L-type calcium channels with 5-HT2b and melatonin (MT1) receptor binding.

Gut function is controlled by both the enteric (intestinal) nervous system (ENS) and CNS, in which the neurotransmitter serotonin (5-HT) plays a fundamental role. Serotonin is present in large amounts in the ENS where it is involved in sensory, motor and secretory processes within the gut. It modulates gut motility and the perception of pain and also mediates intestinal secretion. Minor disturbances in serotonergic function can lead to symptoms of IBS described above."

Irritable bowel syndrome (IBS) is a common comorbidity of autism.

According to the Mayo Clinic:-


l-syndrome/symptoms-causes/syc-20360016

IBS is a chronic condition that you'll need to manage long term.
Only a small number of people with IBS have severe signs and symptoms. Some people can control their symptoms by managing diet, lifestyle and stress. More-severe symptoms can be treated with medication”

The precise cause of IBS isn't known. Factors that appear to play a role include:
·       Muscle contractions in the intestine. The walls of the intestines are lined with layers of muscle that contract as they move food through your digestive tract. Contractions that are stronger and last longer than normal can cause gas, bloating and diarrhea. Weak intestinal contractions can slow food passage and lead to hard, dry stools.
  • Nervous system. Abnormalities in the nerves in your digestive system may cause you to experience greater than normal discomfort when your abdomen stretches from gas or stool. Poorly coordinated signals between the brain and the intestines can cause your body to overreact to changes that normally occur in the digestive process, resulting in pain, diarrhea or constipation.
  • Inflammation in the intestines. Some people with IBS have an increased number of immune-system cells in their intestines. This immune-system response is associated with pain and diarrhea.
  • Severe infection. IBS can develop after a severe bout of diarrhea (gastroenteritis) caused by bacteria or a virus. IBS might also be associated with a surplus of bacteria in the intestines (bacterial overgrowth).
  • Changes in bacteria in the gut (microflora). Microflora are the "good" bacteria that reside in the intestines and play a key role in health. Research indicates that microflora in people with IBS might differ from microflora in healthy people.

Triggers
Symptoms of IBS can be triggered by:
  • Food. The role of food allergy or intolerance in IBS isn't fully understood. A true food allergy rarely causes IBS. But many people have worse IBS symptoms when they eat or drink certain foods or beverages, including wheat, dairy products, citrus fruits, beans, cabbage, milk and carbonated drinks.
  • Stress. Most people with IBS experience worse or more frequent signs and symptoms during periods of increased stress. But while stress may aggravate symptoms, it doesn't cause them.
  • Hormones. Women are twice as likely to have IBS, which might indicate that hormonal changes play a role. Many women find that signs and symptoms are worse during or around their menstrual periods.
Research shows that some people with IBS report improvement in diarrhea symptoms if they stop eating gluten (wheat, barley and rye) even if they don't have celiac disease.



Rezular – Patent for Oral Treatment for IBS

http://www.google.com.na/patents/WO2009090453A2?cl=ko


  
Conclusion

I guess we may never know why some people’s IBS responds to Verapamil. It is likely because of one of the following:-

The experts suggested:-
     ·      Cav1.2
·      Melatonin MT1
·      Serotonin 5-HT2b

I earlier proposed (in addition to Cav1.2)

  •   ·      Kv1.3

R-Verapamil failed in its trial for IBS-D (IBS that causes increased diarrhoea is often called IBS-D).

But Verapamil clearly does help some types of IBS, you would just have to try it. I did try it on myself and it worked for me.

This post again shows the limitations of clinical trials, because we actually do know Verapamil does resolves the GI problems of some people.

Perhaps they got it all wrong and should have trialed S-Verapamil, or indeed just the regular mixture of Verapamil. They did not do the latter because how do you patent/make money out of an existing ultra-cheap generic drug? One pack costs $1.

It looks strange to me that people with Type-2 diabetes are not prescribed Verapamil, it might save a lot of insulin injections later in their lives. 








21 comments:

  1. Dear Peter, we're from the Netherlands and avid readers of your blog for a couple of years since we found out our son of now almost 13 has ASD (avg. IQ, NVLD, PPD-NOS) paired with severe behavioural issues (tantrums), which forced us to have him in hospitals and institutions. Now he's back home, because the 'peer' environment in institutions is not great.

    At te start we selected the best ASD hospital in NL specifically for the reason that they're leading the Bumetanide research, which we read about in your blog. Unfortunately we couldn't take part in the program and at the moment Bumetanide is still not approved, so also the instituation where our son stayed wouldn't start with it.

    Now he's home we can start the experiment with Bumetanide ourselves under guidance from a GP. However in the meantime, at one of the institutions we started with Concerta, which seems to help quite a bit (but not enough). Now we're in doubt whether to switch to Bumetanide (trial period) for which we didn't get the chance before.

    Nowhere on your blog I can find concerta (or generic MPH) as an applicable medication, but we do know a lot of parents of ASD children (PDD-NOS with behavioural issues) who claim they benefit enormously from it. Probably (or obviously) the concerta eases the often comorbid ADHD, but you don't seem to recommend it.

    Question 1: Don't you believe in some positive effects of concerta (MPH) for ASD?

    Question 2: Could we try the Bumetanide while continuing the concerta (MPH) or should we stop first and then try Bumetanide?

    Question 3: From one of the leading researchers that observed our son we also got the hint (if all else fails) to try 'escilatopram' based on new research in this field of ASD and brain elasticity. Do you have experience or knowledge about this perspective and maybe an opinion?

    Dear Peter, thanks for all the knowledge and experiences that you share with all of us and my wife and me we're educated and experienced by now, so we don't take your word as the 'holy grail', but we're very interested in your opinion on our questions, so if you have the opportunity to answer that would be much appreciated!

    Kind regards,
    Helma & Walter

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    1. Helma & Walter, Lexapro (Escitalopram) is an SSRI antidepressant. It is supposed to have milder side effects than other SSRIs. Some people take this type of drug long term without any problems and find them helpful, but some other people use them for a few months and stop either because they find little benefit or they suffer side effects. You will find some people with Asperger’s very anti SSRIs and some pro.

      Concerta/Ritalin increases the amount of dopamine and norepinephrine and so helps some people diagnosed with ADHD.

      You do have to be aware which psychiatric drugs may lead to tardive dyskinesia, which is very hard to reverse, as our reader from Uruguay has discovered.

      I personally think psychiatric drugs are over used, but your son clearly has some serious issues, so if they help him, why not continue.

      To your questions,

      1. ADHD does overlap genetically with ASD, so it is very likely that some people diagnosed with ASD might respond to Concerta. In many people with ASD I think their “AD” is caused by an excitatory/inhibitory imbalance and Concerta will not help this. I used to know a boy at our school who was diagnosed with ADHD, but it appeared to me that he had ASD. These diagnostic labels have great limitations.

      2. You should always ask your doctor about drug interactions. They are well documented, for example Escitalopram does have some interactions. If your doctor agrees, there does not seem to be any reason why you should stop Concerta when you trial bumetanide.

      3. I doubt Escitalopram will have a profoundly beneficial effect. I think you would need to find the cause of your son’s problems to have a big effect. I would look for clues in any comorbid medical conditions he has, or are present in the extended family, even seemingly trivial but odd things.

      If you have a helpful GP, I would ask him about a trial of Daxas/ Roflumilast 100 mcg for a week or two. You do not want your son to start smoking, but a α7 nAChR agonist might also be worth considering.

      Delete
  2. Hi Tyler, yesterday I was looking for an old comment from december, I think it was from AJ, about glucosamine and its effect on electrical activity, I wanted to know wich form was used in the study. I didn´t find it, but what I did find was a funny comment from you that I have missed in the vastness of the blog.Incredibly,I had just recently talked with Tanya about this not so nice situation that happens with some comments, I spoke about mine. Anyway,better late than never, my son got the message and finally met Al.W. Yankovik. He really made him laugh, specially with some characters,as he said,¨the fake K.Cobain¨. He also couldn´t stop laughing with Beat it/Eat it, when in the end Al Weird takes a digestive pill!.I tell you that a few nights ago, we had our Final Countdown without knowing, when my son woke up at 4 o´clock ,closed night,and decided that was time to make himself an omelette. He took 10 or 12 eggs from the refrigerator,a pack of oregano and a bottle of olive oil. It was a sticky mess when we waked up early in the morning, as you can imagine, but the omelette was prepared, he broke all the eggs and I don´t know how he managed to beat them, of course with tons of olive oil and tons of oregano.I think it was a kind of Hypomanic episode.All was ok for him,he was energetic and excited,no depression at all. He said: Yes, it is a mess but I was hungry.Apart from that, I found a chocolate carton box, that was already empty ,cut into thousands of small pieces that he did it with his hands, as if it was the result of an euphoric moment.What do you think?
    Valentina

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    1. All I can say is I hope he shared the omelette with you. That is a lot if eggs.

      Delete
    2. Valentina oh wow! What a meal ! And all things that stimulate dopamine - eggs chocolate and even the oregano. I’d say maybe it was a little manic moment. Hopefully it doesn’t get too out of hand - maybe you could try taurine if he needs to be reined in? Or lecithin? My son had those euphoric moments - he was actually a lot of fun at these moments, but now I see them for what they really are and what it can lead to. During those episodes he talked a lot, and very loudly. He sang a lot too. He started having these episodes when he was younger beginning in puberty then the depressed and increased anxiety episodes started a few years ago when he was 15. Then last year started the intense manic episodes..
      it is amazing what they can do in those euphoric/hypomanic moments .

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    3. Tanya,as if you had guessed my son doesn´t stop talking and singing, it is almost a week since he is unstoppable for at least 1 or 2 hours a day.Today he added dancing. His birthday is on april 6,soon will be 12. I know that the pattern of evolving to manic depression is unpredictable,but could be preventable? I can´t believe that I will have to return to valproate.Can not take lithium orotate with bumetanide wich it is a shame.How is your son?
      Valentina

      Delete
  3. Hello. Not straightly related to topic, but I think neurotensin could be a worth of investigation. I suggest this to you, Peter and folks, as you are able to do this type of synthesis from the scientific literature. So far what I have been reading, neurotensin is elevated in autism spectrum disorders and playing a key role in mast cell activation. Besides, neurotensin has connection to dopamine, NMDA signalling, GABA, calcium channels, gut and whoknows what else. I did not found you writing anything about it, so I suggest here the topic.

    Keep up the good work!

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  4. I have been reading personal accounts on bipolar websites of people being able to manage things and preventing going in to manic states by knowing their triggers, avoiding stress, and doing whatever it takes to get to sleep. From what I am reading so far it varies as to what supplements can help. I don’t have any experience yet with using supplements to avoid going in to full manic state because my son still is on his medication regimen and will continue for about 8 more weeks. He is doing so well! We are very pleased. The prescribing doctor is wonderful - very caring, positive, and a brilliant man. He has of course his MD but also quite a few PhDs in neuroscience and pharmacogenomics. My son is not on an anticonvulsant- but he is taking a very low dose of olanzapine, low dose lithium and a low dose of SNRI. I also give melatonin because I read some studies that it protects against induced metabolic side effects from having to use an antipsychotic. His doctor also prescribed a pharmaceutical grade B complex with minerals and he takes an Omega 3 with higher EPA to DHA ration every day. All of this has really helped him. But we start to wean off in 8 weeks and we will see how things go then. I really think for my son, knowing his triggers and avoiding stress will really help with prevention.

    ReplyDelete
  5. Reading this blog you get the impression that the GABA system is the main malfunctioning one and that in some cases you might also have a hypo- or hyperfunctioning NMDA/glutamate system on top of that. This can very well be the case.
    But as I have recently dived into the world of malfunctioning glutamate receptors and signalling I see a very strong pattern of this being the primary cause of excitotoxicity, making GABA a secondary dysfunction. Maybe I am blinded by the things I am reading and not seeing the whole picture. But even NAC, here mostly mentioned as a treatment for oxidative stress, does things with glutamate receptors.

    What do you think Peter? There is nothing in Monthys PolyPill targeting glutamate signalling, but I think I remember that you tried something for hypofunction with some positive result (cinnamon?)

    /Ling

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    1. Ling, I will soon add Agmatine to the Polypill list, it does have some effect on glutamate signaling according to research, but I think the benefit to Monty relates to nitric oxide.

      There is research showing that an NMDA dysfunction could be treated via GABAb using Baclofen. So things are inter-related.

      Glutamate excitotoxicity is very important. I made a graphic to show this:-

      https://epiphanyasd.blogspot.com/search/label/Excitotoxicity

      Delete
  6. Peter,

    Is there a way of getting back to an older comment? I was looking for Agneizkas comment which she had posted yesterday, referring to a paper mentioning reaction to drug excepients in individuals with mast cell disorders.

    Thanks

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    1. Kritika, here is a link to that comment:

      https://epiphanyasd.blogspot.com/2017/04/different-types-of-excitatoryinhibitory.html?showComment=1519724714707#c3882505729877411958

      Delete
  7. Peter finally got my hands on some verapamil — compounded in a suspension so I can easily tórrate... I have give my son the equivalent of 1.75 mg a day .... a very tiny amount... and his gut has been amazing... it’s quite incredible. I’m not sure we are seeing theanxiety or allergy relief at the tiny dose, but the GI relief at such a tiny dose was quite astounding!!!

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    1. Audrey, that is great and thanks for leaving your comment in this specific post. So we can again see that L-type calcium channels blockers really do relieve GI problems in some people.

      A while back a parent revealed that the reason they used Memantine (thought of as an NMDAR blocker) in their child with ASD was that is resolved GI problems. Memantine is also a mild blocker of L-type calcium channels.

      Delete
  8. So, Calvin is clearly a responded to Verapamil— at least in the GI dept. but it seems the very tiny dose I’ve been giving him is now causing night waking... sigh. So it’s as if I’ve traded one problem for another. :(
    Any thoughts on why this is happening— I’m guessing the melatonin receptors have something to do with it?
    What this tells us about the larger picture?
    And what I can do about it? Thank you guys!

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    1. Audrey, sleep issues are listed as a known side effect of Verapamil, affecting less than 1% of Verapamil users.

      Your dose really is tiny, so it is odd you have any side effect.

      It turns out that the calcium channel blocked by Verapamil (Cav1.2) plays a key role in the regulation of sleep. There are two quite recent papers on this.

      CAV1.2 calcium channel is involved in the circadian regulation of sleep
      https://www.sciencedirect.com/science/article/pii/S1389945713016249

      Cacna1c (Cav1.2) Modulates Electroencephalographic Rhythm and Rapid Eye Movement Sleep Recovery
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531405/

      You could try only giving Verapamil at breakfast. Verapamil does not stay in your body very long and it might then not affect sleep.

      You might find melatonin itself might help his GI issues, without the use of verapamil, but then you will make him sleepy. There are studies on the use of melatonin for various GI problems. So this is worth considering.

      It does tell you that has Calvin has unusual calcium channels, or his blood brain barrier may be more permeable than is typical. You have said before that he is very sensitive to any drug.

      Delete
  9. Thanks peter! Yes I’m only giving once a day and he is very sensitive to any drug. Do you think this will be something he adjusts to eventually? It’s so hard because we are seeing relief of one symptom but i hate to create a new issue... Calvin is only 40 lbs— and a slow and sensitive drug metaoblizer... they seem to stay in his system longer ... how much melatonin would be too much do you think? I gave him 2.5 mg at bedtime and then again in the middle of the night? What dose shows GI relief?

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    1. Audrey, there is a French study into the dose related effect of melatonin in autism (MELADOSE) but they appear to have never published the final results.

      They trialed 2, 4 and 10 mg of Melatonin one hour before bedtime. Maybe give Calvin all his melatonin in one go, at bedtime.

      Here is one of my old posts on Melatonin.

      More Melatonin!
      https://epiphanyasd.blogspot.com/2016/05/more-melatonin.htm

      Many people report that Melatonin supplements are highly variable (they contain less melatonin than it says on the label).

      You might see how long the GI effect of Verapamil lasts, maybe you do not need it every day.

      Maybe a weak Cav1.2 blocker would give the GI effect without the sleep effect. Olive leaves are a known natural Cav1.2 blocker and you can buy an extract of them.

      Delete
  10. Hi, Dear Peter.
    Thank you for this blog! My son is 7 years old. Weight 28kg. Last week was his genetic analyses. My son found a mutation in the gene cacna1C rs752000790. My son had a regression after of the virus with hyperthermia. Now he has autism, ADHD, poor sleep and many days not pooping. I'd like to try verapamil, but do not know the dose. What dose is needed for 7years old and 28 kg of weight? Thank you very much!

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    1. Your gene encodes the calcium channel that Verapamil blocks. So if his mutation causes too may of these ion channels to be produced, Verapamil would seem the perfect solution. If his mutation causes too few of these ion channels then Verapamil would have a negative effect.

      I would start with a very small dose, say 10 mg, just once. Then observe what the effect is. If there is any negative effect then you stop.

      I think you are more likely to see a good effect.

      Verapamil only remains in your blood for a few hours. I give it 2 or 3 times a day but there are some delayed release products in some countries.

      In my son who is twice the weight of your son, he is having 80 mg spread across the day (not all in one dose!).

      Because your son has this mutation, his optimal dose may be different. Whoever did the genetic test really should be advising you now about what to do.

      Delete
    2. Peter, thank you very much for the reply.

      Delete

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