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 as drug targets in CNS disorders

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.

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms.

The L-type calcium channels (LTCCs) Ca_v1.2 and Ca_v1.3, 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 Ca_v1.2 and Ca_v1.3. 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 Ca_v1.2- and Ca_v1.3-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.

Toxins Targeting the KV1.3Channel: Potential Immunomodulators for Autoimmune Diseases

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

  

https://www.drugdevelopment-technology.com/projects/rezular/

"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-HT_2b 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:-

https://www.mayoclinic.org/diseases-conditions/irritable-bowe

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.