Ribavirin absorption-fats and PURINEs?!?!?!?

[merryBe]

Been working on my ideal strategy for next round of tx. and came across this little study of how high purine foods lower Riba absorption.
Since all we've ever discussed in here is how FAT helps riba to absorb,
I thought knowing what might hinder it's absorption was worth knowing also.

Ribavirin is found to be absorbed in the intestine through the human concentrative nucleoside transporter 2 (hCNT2). Cellular uptake of ribavirin was strongly inhibited by purine nucleoside in an in vitro study. This study aims to examine the effects of dietary purine on the pharmacokinetics of orally administered ribavirin in vivo. Twenty healthy participants were enrolled in a randomized, 2-period crossover study. Participants were administered a single 600-mg oral dose of ribavirin after either a high-purine meal or a low-purine meal. Serial blood samples were collected predose and over 144 hours after dosing. Ribavirin concentrations were measured by liquid chromatography/tandem mass spectrometry. In comparison with corresponding plasma values of ribavirin following a high-purine meal, Cmax, AUC0-144 and AUC0-∞ of ribavirin following a low-purine meal were 136% (90% confidence internal [CI]: 120%-155%), 134% (90% CI: 118%-153%), and 139% (90% CI: 120%-159%), respectively. This study indicates that dietary purines have an effect on ribavirin absorption. Dosage regimens of ribavirin might need to be adjusted according to the purine content of the meal.

SO I guess we can kiss our meat, fish and legumes goodbye....or at the very least limit them, as HR once suggested purely for liver health.

Now those treating have extra incentive to limit thier intake, or to at least plan their high protein meal to be at a different time than when they ingest their Ribavirin.

Discussion is welcomed.

mb

[lynda607]

"Uric Acid: During the INCIVEK combination treatment period, 73% of subjects had elevated uric acid levels compared to 29% for those treated with peginterferon alfa and ribavirin alone. Shifts to greater than or equal to 12.1 mg/dL from baseline in uric acid levels were also more frequent among subjects treated with INCIVEK (7%) compared to peginterferon alfa and ribavirin (1%). Less than 1% of subjects had clinical events of gout/gouty arthritis; none were serious and none resulted in treatment discontinuation

[CoWriter]

Purines are a normal part of all human tissue.  Therefore, conditions in which there is tissue breakdown can also result in an elevation of purine levels.  Being overweight makes it even worse because there is more tissue available for breakdown.

There are many other things that elevate purines....hypertension, kidney problems (because it interferes with the elimination of purines) , hypothyroidism, taking diuretics, alcohol use.  

Why do I recommend protein?  Because during tx, interferon gets rid of some protein and because protein helps controls blood sugar/ IR.  

During tx people tend to loose weight, if on top of that they don't have enough protein they will loose muscle...which will cause weakness and that's no way to get to the finish line.

However, high uric acid and high bile acids (which you talked about) do interfere with treatment.

http://jvi.asm.org/cgi/content/full/81/18/9633

http://www.ncbi.nlm.nih.gov/pubmed/18297716?ordinalpos=118&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

CS ate lots of sardines during tx....I know, gross....LOL.  We knew that if we maintained a 3 gram drop in hemoglobin then he would most likely have a good level of Riba.  So I let him have the sardines.  I was nice...ha.

Co
P.S.  I wouldn't worry about the nasty comments.  They'll make for a great chapter in somebody's book.

[Mari5116]

You've put a great deal of time and energy into this reseach and then broken it down so it can be assimilated.  Thanks for sharing it.

[ellen1960]

Good comment, you make a lot of sense.

[spectda]

Good luck with your treatment. I hope your plan works well for you. I think it's important to question things and think out of the box. I also believe that Vertex needs their patients too be successful and their three times daily dosing schedule and fat intake recommendations should be taken seriously if one wants the best chance of svr.

I truly believe that you are way over complicating it and for many people 12 weeks of high fat is well worth the potential for success. Also Victrelis is available for those who are uncomfortable with the fat content, possibility of rash, and still want a similar chance of success.  

If you are able to figure out a better way and you want to experiment on yourself than that's great. The good thing is that the medication is powerful and may work well regardless.  

You can't sell medication without results and I don't think they are counting on selling extra pills by having people do this twice. Maybe they are in bed with the companies selling high fat foods or have stock in McDonalds :)
-Dave

[lynda607]

'I'll have my riba/PI at about 10 am with a warm wheat cereal, cream of wheat or bulgar..and some butter for saturated fat (preferred for leaving virons with more permeable lipid coatings))

have a snack/lunch with  a bit of protein around 2 PM

have a normal dinner around 6 PM, with meat veggies and a carb.
don't overeat as stomach emptying is reduced)

then take my riba/ PI around 10 PM."



DOSAGE AND ADMINISTRATION
2.1 INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment
The recommended dose of INCIVEK tablets is 750 mg (two 375-mg tablets) taken orally 3 times a day (7-9 hours apart) with food (not low fat)

The mean elimination half-life after single-dose oral administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady state, theeffective half-life is about 9 to 11 hours.

You have to take Invivek every 7-9 hours 3 x daily.  Your time frame will not work.

[merryBe]

best solution as I see it.

I'll have my riba/PI at about 10 am with a warm wheat cereal, cream of wheat or bulgar..and some butter for saturated fat (preferred for leaving virons with more permeable lipid coatings))

have a snack/lunch with  a bit of protein around 2 PM

have a normal dinner around 6 PM, with meat veggies and a carb.
don't overeat as stomach emptying is reduced)

then take my riba/ PI around 10 PM.

with any luck this will result in no loss of protein, no interuption to family, no changes to normal mealtimes, AND will increase my riba absortion by at least 30% according to the study.   This increase in absorption will also apply to the PI.

Once i've gone UND, and steady state has reached it's peak, this attention to detail becomes less important but for the first 2-3 months at least this is my plan.

mb

[Trish77]

"plus I just notice what the drug company is doing...they are recommending a meal that is enormously high in fat and protein with the riba. "

"Both AUC and C-MAX increased by seventy percent when Rebetol Capsules were administered with a high fat meal: (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study "

I'm going to say this again, the same as I said in another thread when someone else used this same study information to suggest that taking fat with riba was questionable because  the levels of fat here were unreasonable.

This is a circumstance on a study, NOT a recommendation that these amounts should be taken with riba.  The Lindahl study found a 100% incidence of SVR with very high rates of ribavirin however the trial participants needed transfusions and intervention and experienced hard side effects as a result - nobody is recommending those rates of ribavirin either.  It did serve to illustrate the impact of sufficient ribavirin dosages on SVR though.  And that study clip you're using illustrates the difference between fat and non-fat and it's significant. not only in this study scenario but others that have been done. It is ONLY stating what was used however and is NOT a recommendation.

"plus I just notice what the drug company is doing...they are recommending a meal that is enormously high in fat and protein with the riba. "

Where do you see that the drug company is recommending a meal that is enormously high in fat and protein?  Can you pull out a drug company recommendation for high fat and protein for ribavirin please?  I'm not sure I've seen one for fat even for ribavirin from the drug company.    

[merryBe]

bump

plus I just notice what the drug company is doing...they are recommending a meal that is enormously high in fat and protein with the riba.

if the purines are eliminated there is not need for the gargantuan amounts of fat because you are eliminating the number 1 cause of malabsorption, which is purines (proteins).

you can get by on far less fat...because all you need is enough to stimulate bile and aide in overcoming the ydrophobic nature of Riba...this is far less than what the maufacture suggests.

why was this research ignored...let's see...if I can sell 3 bottles instead of one???


here's what the drug company said:

Both AUC and C-MAX increased by seventy percent when Rebetol Capsules were administered with a high fat meal: (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study

that was in 2001, but they are STILL telling folks to eat tons of fat and protein.

fat and protein both stimulate digestion, one does not interfere with absoption and one does....SO WHY are NONE of the doctors telling people this???

enough already, no one should trade hcv for coronary disease!!
Just nix the protein in the riba meal and far more will absorb...

at higher absorption rates 100% of patients SVR'd and that was on dual, not triple therapy.
Did the drug companies ignor pertinent information regarding how this drug is absorbed to sell more product?
I leave that answer to the readers, but something seems awry to me.

mb

[Trish77]

"When I taught college anatomy I knew this but it's been so long I've forgotten the old adage of remembering the level of the student. "

It might also be better if you didn't look at it as if we are students.  Just saying.

[merryBe]

Yes, I see your points Trish, and perhaps I could have processed this more first, but bringing it here had it's advantages.
For instance, had I not bounced and kicked the ball around, then Willing wouldn't have thought of the hctn2 deocys....and that led to the inosine/uridine addition.

I'll be the first to admit that usually my teaching skills suffer unless I take time to hone down a topic. When I taught college anatomy I knew this but it's been so long I've forgotten the old adage of remembering the level of the student.

However, I will simply say, this was such an exciting little adjunct I thought hey, this could really help bump someone up who was just starting to treat...especially them.
And so I just kinda let you all see a day in the life of my process.

Carol, and Trish, if it's of any help, I just answer Susan in 2 boxes above, and tried to filter it all down to it's essense. Why this might be important.
Try reading those and see if it improves things...

But remember, what Willing said was right on the money, that once you know the mechanism by which something absorbs it pays to pay attention to that.
You'll have to forgive disjointed conversations sometimes, and 2 or 3 heads are usually better than one, and that's what I wanted was some discussion and brain storming.

anyway see if the 2 answers to susan just above don't shed some light. I am trying.

[carol411]

I posted a link on another thread that came from Clinical Care Options.  For teleprevir, at least they are talking of a four week lead in with interferon and ribaviron because if a body is not responding to these it likely will not reach SVR.  Early response is still the best predictor.  And, I inferred (could be wrong) that if there is not at least a one log drop, the risk of mutants may preclude adding the protease inhibitor because of the risk of mutants.  It's just discussion, but it's what they're telling doctors.  Merry may be ahead of the curve here.  But Merry, can you be more succinct?  

[Trinity4]

The information is out there and it is not an absolute.  The same principal applies to alternative strategies as it does to antiviral therapy -  no guarantee it will work for you.   Never beat yourself up because you didn't incorporate a low purine diet, Alinia, SamE or the host of other adjuncts discussed that seem to enhance treatment for some.  

No one can say with any certainty exactly why they didn't SVR even if they attempt to dissect their entire treatment and when that dissection happens is when you start hearing all those "I" -  "I" - "I"'s and me - me - Me's.  So just remember folks that this principal applies across the board:   I ain't you and you ain't me!

http://www.youtube.com/watch?v=gBzJGckMYO4

Trin

[Trish77]

willing:  "you've hit on one of the main sources of disagreement around here - which can be restated as "is it better to clutch at straws or drown hoping for help?". Not much of a choice, but arguing about it helps pass the time while treading water.

There is *never* unequivocal evidence-based support for  alternative strategies : predosing, tapering, increasing dosage or duration, supplements, anti-fibrotics, etc.etc. If one is lucky there are one or two peer-reviewed studies that at least add plausibility.  For example SAMe and rbv predosing are both in the fairly credible category:  there is  a plausible mechansim and some attempts at validating the benefit but nothing yet unequivocally demonstrating clear benefit. Further out, for example with anti-fibrotics, the evidence gets much skimpier.

It's  easy to ridicule and dismiss the alternative approaches as unfounded wishful thinking. However  the alternatives only come up because the alternative to the alternatives is dismal. I sure hope people keep searching ... "

Well said.  Pretty much sums it up, seems to me.

[Trish77]

I do appreciate you posting studies.  However, to be blunt honest, I could do without the lengthy analysis that nobody could possibly verify without spending ungodly amounts of time to do so.  I hope you don't take that personally, that your own opinions would need verifying - but they do.  You're really asking us to take your word for all the comments you make and I'm not really willing to make that kind of leap for any layperson on this site without them providing supporting data to back up anything that isn't a reasonably already-proven theory.  The amount of supporting data that you would have to provide to back up all the assertions you make in your very lengthy posts is mind-boggling.  Therefore, I'm forced to toss much of it away.  

I would rather see you post the study, perhaps comment on the most significant points in it and leave further analysis up to the individual.  If anyone wants to discuss further, you can be sure that will happen here, correct? :)  

Furthermore, I think you make far too big of a leap in some of your conclusions.  We ARE only laypersons here and you should take caution with making such definitive statements that may or may not apply to anyone but yourself - and sometimes remains to be seen whether they actually apply to yourself.  Your body, your risk.  Just please be careful with how firmly you state your own conclusion whether you are making it out to be fact, whether you're intending that or not.  It may be how it is coming across.  It is your opinion only.  

It cannot be stressed enough on this site.  We are only laypersons here and none of us are doctors or medical researchers with years of education and training.  Because we can spend so much time reading data and attempting to make sense of it and apply it, we can lose sight of that fact but should try and remind ourselves of it regularly.

What we are is all in this together.  We need to be able to discuss the topics here that are relevant to each of us without being ridiculed or shouted down or drowned out.  If the topic is not useful to you, move on.  Leave others to discuss what they like.  Show respect for the different journeys each of us is on to achieve the same goal - to either be cured from our Hep C or survive it as well as we possibly can.  

[merryBe]

sorry I forgot about your query regarding fat. The fat issue is more complex, the hydophobic nature of certain drugs makes it harder for them to absorb. These drugs are helped often times by the digestive juices which includes various acids and bile salts.

The reason they tell you to eat with the riba is because it is hydrophobic. It doesn't disolve well in water, which is a great solvent and dissolves many drugs, but not the hydrophobic ones.  Some drugs are helped by the presense of these fluids then and so they need food.

Why? because unless there is food present you don't get digestive juices, or bile salts.
The bile salts are highest when either protein or fat are consumed.

Now why is this relavant? Because we now know that the purines (meat/fish proteins mainly) are interferring with with riba absorption based on the studies given.
And especially in the presence of salt.

Well, you can't eat to get digestive juices and not end up with salts (bile salts) so the next best thing would be to add the fat, but not the protein.

Why? because it's protein OR fat that will help make riba less hydophobic, but it's the protein that will interfere...the fat will not. So this way you get the juices flowing that help the drug but you don't get the substance that blocks...hence better absorption.

Willing brought up that the Hctn2 is what, recognizes the purines and that riba mimicks purines, it is chemically similar.

This is a clue, a key hint as to why the riba may not get absorbed.

You see ALL receptors and cells that have a function can be overwhelmed.
They can only do so much.
It is the Hcnt2 transporter where the drug is allowed entrance. The transporter can only accomodate so many people at the door so to speak. The purine and riba look alike, so it's like 2 people with a key to a door both trying to push their key into the lock at the same time...it's competition.
This is why he suggested that if we eliminated the decoys, that being the purines, that the receptor would gladly take the riba, especially given that it isn't the fat or the salt themselves stopping the process, it's the fact that the transporter recognizes the purine, highly bioavailable in a salty state, as it's natural food, and let's it in the door rather than the riba.

It's kinda like going to a night club, the pretty one we know gets in first, but if they don't show up, then the ugly Betty can come on in. They both look like girls....in other words that neucleotide thinks the riba might be food (a purine).
So the concept is to eliminate the decoys.

I hope this helps you. I have been reading up on the drugs to help riba absorb, and they have some serious issues, but this approach is all we have for now and it is safe.

I would insist people do eat protein in their non riba meals, we do need protein in our diets.
If one did not want to eliminate proteins from the riba meals, there are some choices not as high as others and that would be a good approach in my mind. Although I think for myself the first few weeks I'll choose the least purines.

Of course all this issue would go away if docs would dose us more to start with, but even though there have been studies and been effort in that direction, and even lead-ins that showed great promise, few docs are ready to do that yet.
That doesn't mean it's wrong thinking though.
I am reminded of what happened to me. I prezented my doc with all the research on Alinia, and he still didn't want to try it for the first few months, when it might have done more good.  Afterwards they told me "we will base what we do with others on what happens to you"  In other words, even though 10% more cleared with Alinia on board, they were going to base their opinion on the outcome of ONE patient.
Now maybe you get why I do my own research...even I can figure out that reasoning is whacked...so onward and upward...
mb

[merryBe]

I totally get what you are saying and second the thought...all that would be required of the detractors was to look at the studies and read them, was to have looked at the links I gave, and Willing also gave. Some did not even do that IMO.

As I said to begin with, I was not convinced entirely by the in vitro study. Getting 93% less absorption in a petre dish does not mean that one would see the same thing in humans.

And, added to that you have the rolls of the bile salts. bacterium etc....as it turns out, the NA gradient was part of the equation, meaning the more salt the worse the absorption...
in my mind this meant that one had to factor in the bile load...

after much thought I have concluded that the weaker bile is better, less salts, equals greater absorption but not by much because even weak bile has pleanty of salt and besides it gets reused about 5 or 6 times before it is used up...so the question became did any in vivo studies duplicate the result, and in fact they did show a marked drop in absorption rates as well.
My point was missed, that we couldn't take the in vitro unless we knew if all the gradients were factored in.

However when the in vitro is backed up by in vivo then you have to give this serious consideration. Then the landscape gets less dismal eh?

furthermore so much factors into successful tx no one is ever going to be able to say anything was the definite factor, ever, but we still keep hoping that the more things get tweaked the closer to the goal post we will find ourselves.
Yes we know sam-e's role, we know and accept lots of things now that were at one time JUST LIKE these studies, new and unfamiliar ground,
we need to explore the unfamiliar though...and without fear...explore new worlds as Rodenberry might say.

What we are discussing which is how to get the greatest absorption particularly in early in treatment when the actual mutant strains (that survive throughtout the entire treatment) (that then revert to wild strain when treatment is over) to overwhelm those few mutants that keep HALF the people from ever. Succeeding in tx we need to avail ourselves of every tool at our disposal.

I think part of why there is resistance to these ideas is because the concept of early on mutation is not a popular item of discussion, understandably.
No one really likes the findings, they are scary. No one wants to hear that VEVR is the best predictor because it means there was a wipe out, and beyond that the chances of mutation go up and up. I certainly did not like the information when I first learned about it!!!!
Yet if we accept the science, then we have to look for ways to help ourselves until the docs are able to help us. Obviously they want to...otherwise why are they working on umpteen pills to MAKE the riba absorb quicker...answer: because ALL of them are convinced the mutations happen quickly and that RIBA need to reach steady state much sooner than it does to combat that.

I am going to eat protein, I never suggested people stop, only that they might taylor when they eat it, if not throughout treatment than at least for the first few weeks.

I am not going to eat high fat, I will however eat some fat with my riba as it has been shown to help,
and I will heed these studies, done by doctors, and not comsume purines, inosine or uridine in my riba meal until such time as science disproves the studies I gave.

Will I get 35% more absorption like the people in the study? I don't know, but it could make the difference, and I want to live, I want to succeed at treatment!!!!!!!

I will also look into seriously anything that shows promise.
Honestly there are doctors, researchers working overtime trying to figure out ways to solve this, all I did was bring you all some of their research!!

I just don't get why there is so much objection to these ideas.
I'm like you Susan, I just want to get well, and it makes sense to me to watch the new discoveries. I think the majority of researchers and drug companies are doing good work.
(with a few exceptions as with any profession or corporate environment.)

thanks for your post, you made some good points.

[child24angel]

:) got it :)

[eureka254]

Purines won't work but Murine might ;).

[child24angel]

My eyes hurt, they are not merry at all.

[viaduk]

----"is it better to clutch at straws or drown hoping for help?". Not much of a choice, but arguing about it helps pass the time while treading water. -----

Nice!!!

[willing]

you've hit on one of the main sources of disagreement around here - which can be restated as "is it better to clutch at straws or drown hoping for help?". Not much of a choice, but arguing about it helps pass the time while treading water.

There is *never* unequivocal evidence-based support for  alternative strategies : predosing, tapering, increasing dosage or duration, supplements, anti-fibrotics, etc.etc. If one is lucky there are one or two peer-reviewed studies that at least add plausibility.  For example SAMe and rbv predosing are both in the fairly credible category:  there is  a plausible mechansim and some attempts at validating the benefit but nothing yet unequivocally demonstrating clear benefit. Further out, for example with anti-fibrotics, the evidence gets much skimpier.

It's  easy to ridicule and dismiss the alternative approaches as unfounded wishful thinking. However  the alternatives only come up because the alternative to the alternatives is dismal. I sure hope people keep searching ...

[Trish77]

I understood your point, which is why my comment started out with…"this is totally aside…"  :)

Noted on the benefits of EVR, which is why I'd personally choose to add SAMe if I were treating again, despite the lack of corelation *at this time* to an increase in SVR rates among the SAMe group.  I'd take whatever edge I can get within reason and EVR is desirable.

Like you, I've got a bit of a time constraint at the moment (never mind posting when I shouldn't be) and I apologize as I usually like to post the data I'm referring to.  I'll get to it when I'm somewhere it's available to me, which it isn't at the moment. :)  

Thanks for your response, Susan.  

[Susan_1a_CC]

From: http://www.thebody.com/content/art46371.html

"(Early Virological Response): EVR means that hepatitis C viral load has dropped by 99% (2 logs), or is undetectable after 12 weeks of HCV treatment. An EVR is a good predictor of the ultimate response to HCV treatment. If a person does not have an EVR, their chance of SVR is very low (1-4%). Usually, HCV treatment is discontinued in people who do not have an EVR."

See how easy it is to imply a leap that's not exactly so.  Yes, I said increased SVR rates - and it's actually increased chance of SVR.  My point is in using prudence before implying the answer to an equation.  I'll be happy to post other info re your request when I have a few more minutes but it you yourself have already written "While I've seen data that shows SAMe contributes to early viral load drop" perhaps you'll make your own deduction given that EVR is related to SVR.  HTH.