Effects of linaclotide and lubiprostone on restitution of epithelial cell barrier

[Waverunner]

Has anyone tried Lubiprostone?

http://www.biomedcentral.com/1471-2210/12/3/

Abstract

Background

Linaclotide has been proposed as a treatment for the same gastrointestinal indications for which lubiprostone has been approved, chronic idiopathic constipation and irritable bowel syndrome with constipation. Stressors damage the epithelial cell barrier and cellular homeostasis leading to loss of these functions. Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined. Comparison with effects of lubiprostone, known to promote repair of barrier function was carried out.
Results

In ischemia-damaged pig jejunum, using measurements of transepithelial resistance, 3H-mannitol fluxes, short-circuit current (Cl− secretion) and occludin localization, active linaclotide failed to effectively promote repair of the epithelial barrier or recovery of short-circuit current, whereas lubiprostone promoted barrier repair and increased short-circuit current. In control pig jejunum, 1 μM linaclotide and 1 μM lubiprostone both caused similar increases in short-circuit current (Cl−secretion). In T84 cells, using measurements of transepithelial resistance, fluxes of fluorescent macromolecules, occludin and mitochondrial membrane potential, active linaclotide was virtually ineffective against damage caused by interferon-γ and tumor necrosis factor-α, while lubiprostone protected or promoted repair of epithelial barrier and cell function. Barrier protection/repair by lubiprostone was inhibited by methadone, a ClC-2 inhibitor. Linaclotide, but not lubiprostone increased [cGMP]i as expected and [Ca2+]i and linaclotide depolarized while lubiprostone hyperpolarized the T84 plasma membrane potential suggesting that lubiprostone may lead to greater cellular stability compared to linaclotide. In T84 cells, as found with linaclotide but not with lubiprostone, transepithelial resistance was slightly but significantly decreased by guanylin, STa and 8-bromo cGMP and fluorescent dextran fluxes were increased by guanylin. However the physiological implications of these small but statistically significant changes remain unclear.
Conclusions

Considering the physiological importance of epithelial barrier function and cell integrity and the known impact of stressors, the finding that lubiprostone, but not active linaclotide, exhibits the additional distinct property of effective protection or repair of the epithelial barrier and cell function after stress suggests potential clinical importance for patients with impaired or compromised barrier function such as might occur in IBS.

 

[xchocoholic]

Thanks. I have this problem but I'm not sure I want to try meds for this. Between eating
the wahls way (mostly raw fruits and veggies) and taking natural calm (nc) at night my constipation is under control. I can't
change either my diet or stop the nc tho. Oh and bentonite clay sure throws this off. I needed extra nc to counteract
the constipating effects.

I'm going to run this past my doctor tho.

Tc .. X

 

[Waverunner]

The thing is, many people are still waiting for Linaclotide. Lubiprostone however, seems to be a worthwhile alternative for women and is already available.

 

[xchocoholic]

Thanks again. You're always coming up with some great info.

Drug name = amitiza

I googled this and really couldn't decide if it was right
for me so I'll have to leave it up to my doctor. I was questioning whether someone with chronic dehydration
despite plenty of fluid would benefit or
be harmed by this since it works by pulling water into the bowels. This is what I use the nc / mag citrate for too.

My diet hasn't compensated for this like I'd hoped it would. Anything I eat that's slightly dry, like dehydrated foods or even cooked beans (no longer trying these), cause constipation. The fluid just isn't there without mag citrate.

I also read that this drug crosses the bbb. But I didn't get any further. Tx.. X

 

[MonkeyMan]

Hi Waverunner--

This is fascinating! I don't know whether it's good news (about lubiprostone) or bad news (about linaclotide). Just as I was getting my hopes up about linaclotide, along comes this study saying that "linaclotide failed to effectively repair or protect the epithelial barrier and cell function, whereas lubiprostone repaired or protected the barrier, cell function and homeostasis."

Wow!! Can you imagine if a product that has been under our noses for so many years is actually effective for leaky gut?!!! Anyway, I'm seeing my doctor on Tuesday and will do my best to get a prescription from him for lubiprostone. Thanks again for posting this!!

Drew

 

[Waverunner]

Hi Drew, yes, that study was very interesting. I thought about talking to my doc as well. Moreover I read that the FDA could already decide about Linaclotide in September, so maybe we can test both soon.

 

[August59]

Thanks again. You're always coming up with some great info.

Drug name = amitiza

I googled this and really couldn't decide if it was right
for me so I'll have to leave it up to my doctor. I was questioning whether someone with chronic dehydration
despite plenty of fluid would benefit or
be harmed by this since it works by pulling water into the bowels. This is what I use the nc / mag citrate for too.

My diet hasn't compensated for this like I'd hoped it would. Anything I eat that's slightly dry, like dehydrated foods or even cooked beans (no longer trying these), cause constipation. The fluid just isn't there without mag citrate.

I also read that this drug crosses the bbb. But I didn't get any further. Tx.. X

When I was going to Hunter Hopkins Center a few years ago Dr. Black tried me on this for awhile, but it did not do anything for me that 2 grams of Mag. wouldn't do.

It could have been dosage to cause Dr. Black went by the dosing in Prescribing Information and I may be wrong, but I thought she told me that Amitiza was developed primarily for a woman.

 

[Waverunner]

Hi August,

yeah, that's the problem. It has only been approved for women. I don't know the exact cause but I think I read, that the results for men were mixed and that women are more likely to suffer from IBS-C, so they recruited a majority of women for the studies. In the end, it is safe for men, to take it as well but it might not work as good as it does for women.

 

[MonkeyMan]

Hi Drew, yes, that study was very interesting. I thought about talking to my doc as well. Moreover I read that the FDA could already decide about Linaclotide in September, so maybe we can test both soon.

Hi Waverunner--

After doing some research online, I've changed my mind about trying lubiprostone. It seems it's quite the nasty drug:

"Adverse effects of this drug include dizziness, depression, fatigue, insomnia, hypertension, chest pain, abdominal distension, constipation, diarrhea, dry mouth, dyspepsia, flatulence, gastroenteritis, viral gastroesophageal reflux disease, vomiting, fecal incontinence, fecal urgency, urinary tract infection, chest pain, peripheral edema, influenza, pyrexia, viral infection, back pain, arthralgia, muscle cramps, pain in extremities, bronchitis, cough, dyspnea, nasopharyngitis, sinusitis, and upper respiratory infection."

Uggh. Will wait for linaclotide. Yes it causes diarrhea, but is not absorbed outside the gut and as you point out is hopefully going to be available by end of the year.

I guess my biggest concern is that the study you quote above suggests that linaclotide will NOT repair a leaky gut. Any thoughts on that?

Cheers,
Drew

 

[Waverunner]

Hi Drew,

it's not very easy to give definitive answers but the study above may be biased. Sucampo is the producer of AMTIZA (lubiprostone) and it seems that they funded this study:

Competing interest
John Cuppoletti and Danuta H. Malinowska have financial interests in
Sucampo companies, including research support and consulting fees from
Sucampo AG, Zug, Switzerland and John Cuppoletti has stock options in
Sucampo. Anthony T. Blikslager and Prashant K. Nighot have funding from
Sucampo Pharmaceutical Americas and Anthony T. Blikslager is a consultant
to Sucampo.
Acknowledgements
This work was supported by Sucampo Pharmaceuticals, Inc grants to John
Cuppoletti and Anthony T. Blikslager. Dr. Ralph Gianella (University of
Cincinnati College of Medicine) is thanked for providing STa. Glenn Doerman
(Department of Molecular & Cellular Physiology, University of Cincinnati
College of Medicine) is thanked for his help with the figures in this
manuscript


Edit: Oh and there two more things. First of all I think that there will be many possible side effects of linaclotide as well. Systemic absorption is low but does not say much about the effects. Moreover I'm very scared, that the guanylyl cyclase C signaling is completely screwed in CFS. There are many GC-C receptor agonists including LPS and normal glucose. Linaclotide may be a stronger activator but who knows if this is enough. In my eyes the underlying cause of CFS is an infection, that cannot be cleared by the body and messes up everything over time. GC-C might therefore only be a small step.

 

[MonkeyMan]

Hi Waverunner--

Good catch on the funding of the lubiprostone study! As far as linaclotide, I guess there's only one way to find out if it helps and that's to try it. Meanwhile, I'm trying out the following protocol (the slippery elm 3-day fast ... are you familiar with it?)

http://articles.herballegacy.com/na...emic-yeast-overgrowth-and-leaky-gut-syndrome/

Cheers,
Drew

 

[Waverunner]

Hi Waverunner--

Good catch on the funding of the lubiprostone study! As far as linaclotide, I guess there's only one way to find out if it helps and that's to try it. Meanwhile, I'm trying out the following protocol (the slippery elm 3-day fast ... are you familiar with it?)

http://articles.herballegacy.com/na...emic-yeast-overgrowth-and-leaky-gut-syndrome/

Cheers,
Drew

Hi Drew,

yes, it's worth a try. If lina doesn't work, there still is lubi, it's FDA approved and there should be no higher risks to it, than to other drugs.

Regarding the protocol, if you have a reliable test for candida and are positive, it's probably worth a try. On the other side however, I highly doubt that these protocols are of much use when your test comes back negative. The symptom lists for candida include nearly everything and nearly all the alternative theories about disease have two things in common, they have a clear enemy (candida etc.) but no clear means to test for it. If you look at all chronic diseases, you know, that they are highly complex and we don't know enough to cure them. Therefore if someone comes along and says that for example candida is the culprit for nearly everything, without even testing for it, then I highly doubt that this person knows much about diseases in general.

I'm just a layman of course but if I know one thing, it's that probiotics are far from being perfect. People don't know if they need the strain, they don't know where the bacteria settle (good bacteria at the wrong place become bad), they don't know if they translocate into the bloodstream, they don't know if they inhibit other good bacteria and they don't know if these bacteria worsen or start a immune reaction. That's just my personal opinion.

 

[MonkeyMan]

Very good points, thank you Waverunner!

Drew

 

[xchocoholic]

I tested positive and treated for candida.. My obvious candida related symptoms were gone within
a year, or so ?, of my initial treatment back in 2007. Never to return.

After that my labs (stool) still showed
that I had an overgrowth but I never could relate any symptoms to it. My last 2 stool tests show that my
candida overgrowth is gone and I can't say that I've noticed any changes. I did however pick up
parasites that may detract from any improvements I could've made.

Most of my neuro symptoms were from food intolerances, esp gluten. And that's been better for 5 years now. So based on my experiences the effects of candida are exagerated.

I was reading about mast cells and wondering if they're involved in constipation. I'm in over my head
still
but I'm trying to understand it.

Tc .. X

 

[Waverunner]

Thanks for the insight, xchocoholic. I hope Lina gets approved soon, so we can test it.

 

[alex3619]

There is a natural substance I am looking at for now, as part of research for a blog, that can improve gut integrity. Its alkaline phosphatase, a substance that is often high in ME and CFS patients and usually attributed to liver stress. One of the triggers for it is LPS. It is thought to inactivate LPS as one of its functions, and in rodents at least it can reduce damage from inflammed colons. What I found interesting is one of the major organs to manufacture it is the colon. Traditional opinion has it as a liver function issue. I am still looking into this, I may have more to say later. In particular there are links between this and gamma delta T cells, which I think can be shown as potentially a factor not only in ME but in MCS. Bye, Alex

 

[xchocoholic]

My concern over using a drug versus a natural remedy is that 9 times out of 10, consequences
if the drug aren't revealed until people using it get sick or die. Neither is acceptible to me anymore..

So i'm looking for something that addresses the root cause of constipation despite what I consider
a healthy diet (wahls) and plenty of fluids. I'll be experimenting more in the next few days
with additional flax and konsyl.

Fwiw, I posted an article here awhile back on how solute transporters are damaged in celiacs. These control
how our intestines absorb fluids. Of course
this can happen to anyone with gut damage. Nsaids produce the same results on the gut as gluten does to celiacs.
And yet they're still promoted as safe ! Supposedly these heal in celiacs on a gf diet but we're seeing that even the gf diet doesn't allow all celiacs to heal.

Tc .. X

 

[August59]

I believe this is one of the medications that is being discussed on this thread.

http://forums.phoenixrising.me/index.php?threads/linzess-approved-by-fda-for-ibs-c.19148/

 

[lansbergen]

There is a natural substance I am looking at for now, as part of research for a blog, that can improve gut integrity. Its alkaline phosphatase, a substance that is often high in ME and CFS patients and usually attributed to liver stress. One of the triggers for it is LPS. It is thought to inactivate LPS as one of its functions, and in rodents at least it can reduce damage from inflammed colons. What I found interesting is one of the major organs to manufacture it is the colon. Traditional opinion has it as a liver function issue. I am still looking into this, I may have more to say later. In particular there are links between this and gamma delta T cells, which I think can be shown as potentially a factor not only in ME but in MCS. Bye, Alex

I have been thinking about the isoform change.. I read that normal the gut contains a mixture of both isoforms.

I think it is logical if the gut producing cells are damaged and the liver keeps dumping it, the liver isoform will become prominent.

 

[alex3619]

Hi lansbergen, you could be right about that (post 19), its worth thinking about. I have also been thinking that if substantial LPS is reaching various organs it will also trigger increased alkaline phosphatase of different forms that will mix in the blood stream. This could cause gut damage, and perpetuate the cycle. Whats worse, is that when substantial damage is occurring the gamma delta T cells will then suppress immune activity - including NK cell activity.

It would be really nice to see a study in which the elevated alk phos in ME patients is analyzed for percentage of isoforms and compared to healthy controls.

One thing is clear though, chylomicrons in the lymph inactivate LPS. Its one of their functions. So if someone is making them (which requires eating) then the lymph should be relatively LPS free. During fasting, or severe stomach upset, that might not be the case however. It is important to keep eating, and to include some fat in the diet even when very sick. This makes it very very hard for those with severe MCS - if they don't eat the immune attack will be more powerful.

Bye, Alex