Nicorandil.....A role in treating CFS

kangaSue

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In light of my personal experience, I think there is a case for further evaluation of Nicorandil as a potential treatment in ME/CFS.

To give a brief overview of my situation, I do not have CFS, my issue is chronic idiopathic Gastroparesis (GP). I have been enteral tube feeding for 10 years, had increasing gut pain over the last 5 years, had low resting blood pressure and bradycardia but no other cardiac defect. Recently found to have bowel ischemia from lack of blood flow to the bowel, diagnosed as Non-occlusive Mesenteric Ischemia (NOMI) as no physical obstruction or artery defect was evident in the Mesentery arteries.

I have not been able to tolerate analgesics in any form due to the GP and was desperate enough to trial Nicorandil on the strength of a brief mention in the only citation I could find that referred to its pain reliever effect outside of a cardiac setting: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2778114 (refer to NOMI under heading Chronic Splanchnic Syndrome)

My U.K. Trained motility specialist has since endorsed my use of Nicorandil and was aware of it being used in Europe in cases of bowel ischemia (but didn't mention it when I sought her help 3 months earlier. I discovered it myself when trying to prove to this specialist my self-diagnosis of Mesenteric Ischemia as CT Angiogram showed no blockage or impediment of blood flow).

The result of taking Nicorandil has been somewhat remarkable;
    1. I had a better than 90% reduction in pain overnight.

    2. Within a week my resting blood pressure was up.

    3. Within 2 weeks I was tolerating oral nutrition supplements.

    4. Within 4 weeks I ceased tube feeding altogether as I could eat 3 small meals a day with a calorie top up from the liquid supplements.

    5. This was the first newly introduced medication, vitamin or supplement that I have been able to tolerate for over 7 years.
I am now 20 months into using Nicorandil and continue to maintain the improvement in symptoms. I don't call it a cure but it makes my life a hell of a lot more bearable.

In the absence of any documented human trials or clinical studies that I can find (I am not particularly accomplished with technology and have no medical or scientific training), my improvement might just be an isolated case but if a drug to treat ischemia in cardiac smooth muscle cells also relieves ischemia in gastric smooth muscle cells then I think its fair to assume that ischemia in other smooth muscle cells in other parts of the body has a good chance of responding similarly.

If I also make the assumption that CFS symptoms in some cases is due, in part, to low blood pressure resulting in poor blood flow to smooth muscle cells resulting in ischemic pain and or reperfusion injury, then it may be concluded that Nicorandil could have a role in treating CFS.

My (limited) understanding of the technical aspect of Nicorandil is that it is a Pyridal nitrate, classed as a potassium channel opener, whose intrinsic mechanism is the selective activation of K+ ATP channels at the sarcolemmal and mitochondrial level, effecting the relaxation of smooth muscle cells and vasodilation of both coronary and peripheral arteries.

It has been demonstrated to have cardio-protective action against ischemia/reperfusion injury, protecting mitochondria from further injury. Not sure if I saw that in relation to human trials or just animal models but as I understand it, it is generally accepted that ischemia/reperfusion injury disrupts mitochondrial energy metabolism, a common belief I often see expressed among those in the CFS community.

All I really know for certain is that as a human guinea pig, Nicorandil works for me in treating bowel ischemia

As per normal, this drug is not available in many countries but it is reported that the majority of potassium channel opener drugs have a similar vasorelaxant action. There are a lot of new PCO's in the development pipeline such as Iptakalim, Aprakalim and Rimakilim but the likes of Flupirtine, a non-opiate, non-nsaid, non-steroidal analgesic drug has been in use in Europe for over 30 years and its biosostere, Ezogabine (also called Retigabine in some markets) has recently entered the American market, albeit as an anti-seizure drug with a reduced analgesic effect. These are not recommendations, only other options to further evalue.

http://ncbi.nlm.nih.gov/pubmed/18221232
http://ncbi.nlm.nih.gov/pubmed/15464034
http://ncbi.nlm.nih.gov/pubmed/11919514
http://ncbi.nlm.nih.gov/pubmed/20839897
 

Hip

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@kangaSue
Congratulations in accomplishing such a major improvement in health. Your story is quite spectacular. Thanks for posting it.

Nicorandil and potassium channel opener drugs sound interesting. One area they might conceivably help in ME/CFS is in the low blood flow to the brain (cerebral hypoperfusion). This study found that Nicorandil improved brain blow flow in patients with chronic cerebral infarction. So perhaps Nicorandil might conceivably help improve the blood circulation to the brain in ME/CFS patients.

The same cerebral hypoperfusion is also found in postural orthostatic tachycardia syndrome (POTS), a comorbid condition that many ME/CFS patients have, so perhaps Nicorandil might be helpful here too.


What I would like to know is how potassium channel opener drugs like Nicorandil affect potassium levels inside the cell. ME/CFS patients have reduced intracellular potassium (and reduced intracellular magnesium), and if Nicorandil improved this, it would be great. It has been suggested that ME/CFS patients might have a potassium ion channel dysfunction causing this low level of potassium inside the cell.


Anyway, I'll have to look into this drug further...
 

kangaSue

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How did you become interested in chronic fatigue syndrome, by the way @kangaSue ?
G'day Hip,

I found that a lot of things I was googling to do with my condition kept bringing up links to this forum and after a bit of time poring over the posts here, I come to realize that some aspects of our conditions are similar.

I recognized the same desperation expressed in some of the posts that I have been through myself and really just wanted to share here something that has worked for me because (1) I don't know where else the info would be best disseminated and (2) I couldn't see anywhere on this site where Nicorandil or potassium channel openers had been discussed before so figured it was relatively unknown and (3) this is a great site for in depth info on a wide variety of issues so I guess a big part of the reason why I'm here is self interest.
 

Hip

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Well I hope you find being on this site of benefit to you.

I have to admit that I had not heard of gastroparesis before, but it's interesting that this condition involves a lack of normal muscular stomach contractions which move food down into the small intestine for digestion. The vagus nerve controls these contractions, and I read that gastroparesis may occur when the vagus nerve is damaged or dysfunctional.

As you may be aware, the vagus is part of the autonomic nervous system (ANS). The ANS has two branches: sympathetic nerves (activated during "fight or flight"), and the parasympathetic nerves (activated activated "resting and digesting"). The vagus nerve forms a major part of the parasympathetic nerves.

I wonder whether supplements that stimulate this vagus nerve may further improve your digestion and gastroparesis.

Ginger stimulates the vagus, and in this way is a gastric stimulant. Ginger activates the muscarinic M3 receptors on the vagus nerve.

I believe the herb Epimedium (horny goat weed) also stimulates the vagus in the same way.

A list of drugs that stimulate the parasympathetic nervous system are given here:
Parasympathomimetic drug - Wikipedia

I read once that potassium supplementation stimulates the vagus, but I cannot find any scientific references to this.

Practices like yoga have been shown to improve vagus/parasympathetic function.



I read that gastroparesis may be an autoimmune condition. Often in autoimmunity, the immune system will make antibodies that attack and incapacitate the receptors on nerve cells, which might then cause dysfunction of the nerve, because the nerve cells cannot receive the nerve signal if the receptors are out of action. In ME/CFS it has been found that there are autoimmune antibodies attacking various receptor types on the vagus nerve. I posted a thread about this here:

Could autoantibodies to muscarinic acetylcholine receptors underpin ME/CFS?

It might be that autoimmune antibodies are attacking the receptors of the vagus nerve in gastroparesis also.

There are many supplements and diets that may reduce autoimmunity, and these might be worth looking into, as they may reduce this autoimmune attack.
 

kangaSue

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Well I hope you find being on this site of benefit to you.

I have to admit that I had not heard of gastroparesis before, but it's interesting that this condition involves a lack of normal muscular stomach contractions which move food down into the small intestine for digestion. The vagus nerve controls these contractions, and I read that gastroparesis may occur when the vagus nerve is damaged or dysfunctional.

As you may be aware, the vagus is part of the autonomic nervous system (ANS). The ANS has two branches: sympathetic nerves (activated during "fight or flight"), and the parasympathetic nerves (activated activated "resting and digesting"). The vagus nerve forms a major part of the parasympathetic nerves.

I wonder whether supplements that stimulate this vagus nerve may further improve your digestion and gastroparesis.

Ginger stimulates the vagus, and in this way is a gastric stimulant. Ginger activates the muscarinic M3 receptors on the vagus nerve.

I believe the herb Epimedium (horny goat weed) also stimulates the vagus in the same way.

A list of drugs that stimulate the parasympathetic nervous system are given here:
Parasympathomimetic drug - Wikipedia

I read once that potassium supplementation stimulates the vagus, but I cannot find any scientific references to this.

Practices like yoga have been shown to improve vagus/parasympathetic function.



I read that gastroparesis may be an autoimmune condition. Often in autoimmunity, the immune system will make antibodies that attack and incapacitate the receptors on nerve cells, which might then cause dysfunction of the nerve, because the nerve cells cannot receive the nerve signal if the receptors are out of action. In ME/CFS it has been found that there are autoimmune antibodies attacking various receptor types on the vagus nerve. I posted a thread about this here:

Could autoantibodies to muscarinic acetylcholine receptors underpin ME/CFS?

It might be that autoimmune antibodies are attacking the receptors of the vagus nerve in gastroparesis also.

There are many supplements and diets that may reduce autoimmunity, and these might be worth looking into, as they may reduce this autoimmune attack.
Wow, like I said, this site does in depth analysis and now service over and above the call of duty.

Thanks for the effort Hip. A lot of those aspects have been well picked over in the last few years with anti-body testing etc. but I've learned to never say never. Even though I can eat again, it is quite a restrictive pool of food I can cope with, low fat and no fibre and herbal supplements continue to be a challenge, something I really don't understand why.

The consensus of medical opinion is that I have gastroparesis as a result of mesenteric ischemia, not the other way around so its been a case of start with the bum now and work backwards. Colonoscopy revealed "a diffuse area of moderately friable mucosa in transverse colon resultant in perforation" which I figure gives rise to a leaky gut.

This study was an interesting finding, http://europepmc.org/abstract/MED/24022230 which may solve part of the puzzle. If you have any input on the subject, I would be open to all suggestions.

Cheers, kangaSue
 

Hip

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Any idea what has caused the mesenteric ischemia in the first place? It says here that atheroscleros is a frequent cause. EDTA chelation may help atherosclerosis, though this is controversial.
 
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kangaSue

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Any idea what has caused the mesenteric ischemia in the first place? It says here that atheroscleros is a frequent cause. EDTA chelation may help atherosclerosis, though this is controversial.
Atherosclerosis is the usual suspect but that generally comes on as an acute attack and can be rectified by surgery. My onset is chronic over the long term and without any sign of obstruction on CT Angiogram so it is thought to be due to a tie in between low blood pressure and episodic spasm in the mesentery microvasculature. My response to nicorandil supports that diagnosis according to the medical team.
 

Hip

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My onset is chronic over the long term and without any sign of obstruction on CT Angiogram so it is thought to be due to a tie in between low blood pressure and episodic spasm in the mesentery microvasculature.
Would blood thinners (ie anticoagulants for blood platelets) help, do you think, in terms of improving blood flow in the mesentery microvasculature?

The following have a blood thinning effect:

Anticoagulant Supplements and Drugs ("blood thinners"):
Warfarin (Coumadin) drug is a vitamin K antagonist
MSM (methylsulfonylmethane)
Eugenol (found in cloves, basil, lemon balm) a potent blood thinner
Trisodium citrate
Vitamin E (weak effect)
Aspirin
Turmeric
Ginger (very mild anticoagulant)
Garlic
Papain (papaya enzyme)
Bromelain
Gamma linolenic acid (GLA)
Omega-3 fatty acids
Ginkgo Biloba
Grape seed extract
Flavonols from chocolate
Red Clover
Chondroitin sulfate


Also, be aware that some supplements can thicken the blood, and so may reduce blood microcirculation:

Pro-coagulants Supplements ("blood thickeners"):
Coenzyme Q10
Ginseng
Green tea
Vitamin K


Another thing to consider at the same time might be vasodilators:

Vasodilator Supplements:

Bacopa monnieri — improves brain blood circulation
Alpha GPC— improves brain blood circulation
Ginkgo biloba
Vitamin B3
Garlic
Ginger — improves peripheral circulation
 

Hip

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It might also be an idea to examine the various mechanisms that produce vasoconstriction in the microcirculation.

This article lists many such mechanisms. Might one of these mechanisms be over-active in your body, leading to constant mesenteric microvasculature vasoconstriction? If you can pin down the mechanism, you may find that there are drugs or supplements to correct it.

More info about the regulation of the microcirculation is found here.


Another other thing that occurred to me was whether you have sufficient density of microvasculature in your gut to deliver adequate blood flow.

The process of growing more blood vessels is called angiogenesis. Now interestingly, the herb Angelica sinensis (dong quai) has been shown to promote angiogenesis in the gut:

"AP [Angelica sinensis] at the doses of 5, 10 and 25 mg/kg significantly increased the blood vessel count per field by 36%, 55% and 64% respectively in gastric mucosa. For duodenal mucosa, only AP 10 and 25 mg/kg had significant effects on blood vessel number (an increase of 40% and 57% respectively). Dose-dependent effect was observed in both gastric and duodenal tissues."

Source: here.
 

kangaSue

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Would blood thinners (ie anticoagulants for blood platelets) help, do you think, in terms of improving blood flow in the mesentery microvasculature?

The following have a blood thinning effect:

Anticoagulant Supplements and Drugs ("blood thinners"):
Warfarin (Coumadin) drug is a vitamin K antagonist
MSM (methylsulfonylmethane)
Eugenol (found in cloves, basil, lemon balm) a potent blood thinner
Trisodium citrate
Vitamin E (weak effect)
Aspirin
Turmeric
Ginger (very mild anticoagulant)
Garlic
Papain (papaya enzyme)
Bromelain
Gamma linolenic acid (GLA)
Omega-3 fatty acids
Ginkgo Biloba
Grape seed extract
Flavonols from chocolate
Red Clover
Chondroitin sulfate


Also, be aware that some supplements can thicken the blood, and so may reduce blood microcirculation:

Pro-coagulants Supplements ("blood thickeners"):
Coenzyme Q10
Ginseng
Green tea
Vitamin K


Another thing to consider at the same time might be vasodilators:

Vasodilator Supplements:

Bacopa monnieri — improves brain blood circulation
Alpha GPC— improves brain blood circulation
Ginkgo biloba
Vitamin B3
Garlic
Ginger — improves peripheral circulation
Thanks Hip. I'll have to get back to you down the track a bit.

Because of the compromised bowel, I've been advised not to experiment any more without medical advice and only consider things where there is proven clinical benefit demonstrated, so have to run everything by my doctor first.

Cheers, kangaSue.
 

Hip

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Thanks Hip. I'll have to get back to you down the track a bit.

Because of the compromised bowel, I've been advised not to experiment any more without medical advice and only consider things where there is proven clinical benefit demonstrated, so have to run everything by my doctor first.
Fair enough. By the way, since you said you often have trouble with digesting supplements due to bowel sensitivities: note that you can often take supplements transdermally, by opening up a capsule and rubbing the powder onto your skin, and then dampening the skin with a few drops of water. For example, many ME/CFS patients take magnesium transdermally (since oral magnesium causes diarrhea in high doses, but transdermal magnesium does not).
 

kangaSue

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Fair enough. By the way, since you said you often have trouble with digesting supplements due to bowel sensitivities: note that you can often take supplements transdermally, by opening up a capsule and rubbing the powder onto your skin, and then dampening the skin with a few drops of water. For example, many ME/CFS patients take magnesium transdermally (since oral magnesium causes diarrhea in high doses, but transdermal magnesium does not).
I saw on another thread where you mentioned transdermal magnesium helped in tolerance to opiods. Any idea on whether the same would apply to nicorandil.

I had to increase the dose for pain after my bowel was perforated 12 months ago but have been unable to return to the lower dose since the bowel settled so am a bit apprehensive of a possible tolerance issue looming. There's not much of me so 20mg twice daily is getting close to the limit.
 

Hip

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I saw on another thread where you mentioned transdermal magnesium helped in tolerance to opiods. Any idea on whether the same would apply to nicorandil.
I think it just applies to opioids. Does tolerance build up to nicorandil?
 

kangaSue

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@kangaSue
One thing you might want to try is removing chloramine (NH2Cl) from you drinking water. About one fifth of the county's supply has chloramine in it, in addition to chlorine.

Chloramine can cause bad effects in the gut. More info here.
Thanks for that, I'll give a try. I assumed that my activated carbon filter removed all the harmful stuff so would never had figured this out by myself.
 

Hip

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It's easy to do: just 10 mg of vitamin C is enough to remove all the chloramine in 1 liter of drinking water. The interesting thing was that, for my severe IBS, I started getting big improvements within a few days.
 

maryb

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@Hip
so the vitamin C absorbs the chloramine? does it work for chlorine and fluoride?
I use a carbon filter but think it takes out all the minerals as well - I struggle to take oral minerals so a double whammy for me.
 

Hip

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@maryb
Vitamin C does not absorb chloramine as such, but changes into different chemicals which are safe, or safer. See this post.

I am not sure what vitamin C will do to the fluoride in water. It would depend on the form of fluoride in the water. Only a few regions in the UK are fluoridated though; see this UK fluoridation map.
 
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