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

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

[merryBe]

There's far more to this than we might think.

Another good idea would be to double check your vitamins, especially you body builders.

Make sure you are not taking supplements containing ISONINE, which inhibits riba absorption as well.

Meats, and brewer's yeast also are high in isonine.

mb.

[Bali05]

thanks merrybe , very interesting.
Not being able to test Riba  serum concentrations I have been using my HgB as an
indicator for absorption.

[spectda]

"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."

Or you could take a higher dosage of ribavirin, it seems to have worked for several others after not having success the first time.

Good Luck- Dave

[merryBe]

good point Dave, and good idea Bali (although marrow's respond differently so its not a perfect correlation and as the body wears down from the tx I wouldn't count on that being a good indicator. If the marrow gets fried, like from Epo it sometimes will, then the HGB level wouldn't be telling you much at all as regards Riba levels.)

I'm thinking that sice Riba is the most problematic drug, it doesn't absorb well at all, that extra care should be excersised to get it into the blood.

The sooner the riba levels get to optimum, the better the chance of SVR, which is why they are working on several drugs now, to help the riba get into the system.

Since those drugs are still a couple years from approval, I think the best approach would be to take the riba in a meal or snack that does not include prines or isonine, but does include fat....and yes, upping the dose would help, the only problem is very few docs will give you that option since going beyond SOC means they would be liable should your kidneys give out.

I'm recalling Karen Lindahl's study, where higher Riba levels all SVR'd, but 20% had kidney issues or failures at the higher doseage levels.
Since plasma is not tested in the USA for riba levels, (boy would that help), no docs are tailoring the meds to the patient's life style or eating habits. Were they to test, they could then up the dose for just the patients that need that.
Again, I think they should, but will they ever...don't hold your breath.

Isomine has been shown to inhibit Riba absorption in the intestines as well as purines,
but I'm thinking that most docs will not inform patients of any of this either.
Just like they don't inform as to Iron overload, or the other stuff.

My clinic has a 2 hr class for newbies, and it included none of this info.
Dietary adjuncts are just not thought to be very important, evidently.

In my case, the moment I found out about fat adding, and too much roughage harming Riba absorption I altered my diet, and went UND within 2 weeks of doing so, but prior to that I had not been able to get a good log drop, and had in fact had my VL rise again at week 16.  

Ergo diet really does effect outcome, much more than medicine is letting on.

Ideally, we will get an approval of a good drug to get Riba to optimal levels in days, not weeks or months, but until then there are some things the educated patient can do to help them succeed in tx.

I just hope folks will begin to share their experience with their doctors so that the good research that has been done, even though limited, might begin to be taken seriously.

mb

[Susan_1a_CC]

"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."

I read your post yesterday morning and didn't have time to respond until now.  First off, I am relatively new to the battle - shot #9 of 24 yesterday, on Lambda INF and Riba.

I read your caution about limiting high purine foods.  Beans are a significant part of my heart healthy diet (HDL of 99) and I thought this is awful...  This morning in rereading your post I had to wonder what the cited study considered to be "a high purine meal."  After finding this list of foods and purine amounts, I not only feel okay with eating beans, I was also surprised to see that there's even some beef in the "low" purine list:  

http://www.acumedico.com/purine.htm

Other confusing issues:  I had read on this board to increase fat consumption and started out trying that.  Was getting nauseas and the study RN said the Riba dose had already been determined to be consumed with normal healthy eating.  Okay, I'll let that concern go.  

I'm also a bit concerned that I am on iron per doctors orders - low ferritin level before starting - and all of the cautionary posts that I've read about iron inhibiting SVR outcome and being toxic to the liver.  So, I stopped my iron for a period and felt better that my hgb had dropped on next test.  But, I could feel loss of energy and restarted fe.  Hgb holding as of yesterday's blood work.

Oh, and fiber.  I take psyllium and gluccomannan.  Along with a number of supplements - all of which were given the okay by the sponsoring drug company.  

I guess that part of my post is a rant but this gets so damnable frustrating that I would love to see a list put together of important points that might not be covered by your doctor.  As it is, I'll be having my primary doing a number of blood tests when I see him next week, just so I can try to keep an eye out for myself.

And so, that's my addition to the discussion.

[merryBe]

I agree, it gets confusing.

The best we can hope for it to put into practice the things that have been onserved however, as until they bust the riba absoption riddle it is the most risky item in the SOC.
The longer it takes to get to steady state, the more chance of mutation and resistant strains.

Some folks are even predosing their riba to compensate, some studies include predose arms, so its really an importent issue.

THANK YOU so much for the purine food list, I looked that night before starting the thread and couldn't find a good one, so I want to thank you for that.

You'll notice BREWERS YEAST is very high.

That means to everyone this:  WE SHOULD NOT TAKE A MULTIVITAMIN at the same TIME we take our riba.

Basically, inosine follows the same sort of numbers as the purine list, meaning you can avaoid high inosine by simply avoiding high purine foods.
The EXCEPTION to this would be those who are taking MUSCLE BUILDING supplements or body building drinks. Many of them contain inosine.
It is expensive so they don't all contain it...but reading labels is a good thing here.

Here's a link by the way, showing how inosine stops dead the riba absorption in the bowel tissue....it's in the conclusion and you have to ZOOM IN to be able to read it.

http://resources.metapress.com/pdf-preview.axd?code=t37258642421271g&size=largest

Susan, I appreciate your concern...I'm bummed I had to change my diet so much to accomodate this drug...but as I said, before I did the alterations I was not even going down in VL....and that's probably why, I probably was knocking out the riba by including the proteins in every meal.
I had included the proteins because a doctor said eating protein in small quantity several times a day was better for a sick liver...which it IS.
The only problem was, it turns out that it is not going to allow for optimum riba absorption.

Karen Lindhal's study showed that everyone with high plasma riba SVR'd, so to me its important for treater to know how to keep that drug absorbing.

mb

[merryBe]

sorry for my mispelling...my bad....inosine   I no seein"...if they give out awards in medhelp I'll get the worst speller one hands down!!

maybe I'll stop transposing when my brain fog lifts...in the after life.

[merryBe]

I finally found a list of grains and their purine content.

oatmeal = 92

wheat and barley = 51

I guess this means I'd be better off to have cracked wheat for my breakfast with riba that to choose oatmeal.

[merryBe]

please take note that inosine almost completely interfered with riba absorption in the presence of NA+ gradient in the link I gave.

that's med speak for if you salt your meat or eggs, it inhibits the riba more.
So basically the higher the complete protein, the higher the salt with it, the less riba will be absorbed.

Good information....can I get an amen??

[Susan_1a_CC]

First let me say that I think it was a tough break for you to tx as long as you did and then relapse.  Maybe all of your research will not only help get you through and maintain SVR next go round but some of your research may prove instrumental in a better approach to diet during tx.  

I do wonder though just how many variables there are to the riba absorption.  For example, I take phosphatidylserine (PS) which has been found to make the cell membranes more "porous" and better able to pump nutrients in and waste out.  (From there it goes on to having other beneficial effects.)   Diet and nutrition often spark such hot debate that I imagine this may be one reason the researchers aren't focusing on it.  From what I've read here, many on SOC are doing their best when they get any food in - let alone recommended foods.

I'm a few weeks from my 12 week bloods after which point my study is no longer blinded.  I am curious to see the outcome of course - but mostly because of all the fiber, supplements, and a diet that is limited to avoiding trans fats, HFCS, white foods, and foods with a label.  My roll of the dice :).

[Bali05]

The thing I have been wondering is why only take Riba twice a day instead for example
three times a day. If we are going for even plasma concentration isn`t three x 400
thruout the day better than two times 600 when total dose is 1200 ?

I bet the only reason why we have the two time dosing is because more people
were adhering to taking their meds on time in the original trials.

Anyway if you can take enough Riba to max out your HgB than absorption is no longer
an issue since if you get any more into your systems you will become too anemic
requiring dose reduction or EPO.

Still waiting to see someone to come up with a good thought out meal plan for tx.

[merryBe]

yes you are right its darn hard to eat, and I hate to add to that EXCEPT that the more we learn the more will SVR. It made no sense to me that my VL went up 200,000 went I was So compliant, but when I changed my diet it went to UND, and even doctor are telling patients now to include fats with the riba, so at least they've come around on that score.

I don't know Bali, I think given the facts I'd stick with something lower protein for breakfast, a bowl of wheat cereal would be low fiber, of some sort would be better than oats. I like the idea of the bulgar or cream of wheat because you can add fat to that, and add some agave or stevia, or just cook some raisins in it for sweetness...that is sort of a comfort food, and I found that warm cereal was the easiest thing for me to tolerate, kept my stomach calmer.

Then at lunchtime get at least 3 ounces of protein, and lots of veggies and some fruit,

At dinner, I'd again go light on proteins, and light on fibers, cream soups, things like pastas, things like these can accomodate fat again and help the riba absorb. A little protein in a soup or pasta dish is ok but keep it to an ounce or less if you can manage.

then towards bedtime have a little protein/fiber snack.

This way you are getting your protein and fiber, but not at the time you take your ria, then you stick with things that help rather than hinder absorption.

BTW, a snack at night tend to lower morning blood sugars, so this type diet will help keep the INF from being canceled out.

I'll try to work out a more comprehensive plan when I get time.

[Bali05]

Thanks MerryBe , I think a lot of people can benfit from that.
What I have been doing is trying to take my Riba about 1-2 hrs
before the main meal. That way I can take Riba with a preferred
"functional" food item (high fat ect....) and have for a main meal what pleases
my palet which I find very important since it is a looooong treatment.

We all have different issues during tx nausea , change of taste ect....
I just found out that I am serum iron deficient so I will start eating
more red meat ect....
Also I suffer from chronic gastritis so I have to watch my diet for that.
When I take my Riba with a fat containing food ( slice of pumpernickel bread with
butter) I will get a gnawing stomach 2 hrs later and if I don`t eat again it will
burn like hell all day.

My HgB is currently stable around 10 so getting more Riba into my system is asking for trouble.

I can see your point for someone on standard dosing whose HgB does not drop.
That could mean absorption problem and if upping dosage is not an option than
optimizing diet for absorption could possibly help.

[RobertBeWell]

This thread is quite interesting, and scared me for a moment.

You see, breakfast is my biggest meal of the day, and also the one I happen to take my morning dose with. I typically eat two eggs, over medium, a meat, which varies - sausage, chicken breast, ham steak, etc, a bagel with butter.

Imagine my surprise when I consulted several sites and found EGGS - yes EGGS - to be very low in purine and high in protein. I knew about the protein being high, but never thought about "purines".

Oddly enough, according to wikipedia, the Riba molecule is very similar to a purine in structure.

I was quite relieved to find out I hadn't been sabotaging myself all along.

Thanks for the info Merry!

[Junebug812]

Thanks for posting this info MB. At first, I didn't even know I was supposed to take the Riba with food, let alone be careful what I eat before taking it. My doctor never mentioned that I needed to take it with food, but I read the info that came with the drug so I at least learned that fact soon enough.

Thank you very much.

June

[merryBe]

read this

VERY CAREFULLY !!!!!!!!!!!!!!!!!!!!!!!!!!!!!

this is an example of how science can reach conclusions that mislead patients and even doctors.

It is obviously why inosine in the system would protect against anemia, because it prevent ribavirin absorption, so NATURALLY with less riba getting in, anemia would be less,
but this study fails to mention that INOSINE effectly blocks most of the ribavirin from being absorbed in the bowel, especially in the presence of salt ions.

Since most proteins contain salt, and since folks very infrequently eat fish or meats etc without adding salt, this means we can sabotage our chances of a cure by ignoring how purines effect riba absorption.

remember, SVR plasma levels have been proven to directly effect tx outcome.

here's that study, I'm just grateful I read the other studies first, otherwise we might have been lead to an incorrect conclusion.

Inosine triphosphate protects against ribavirin-induced ATP loss by restoring adenylosuccinate synthase function


Yuki Hitomi1, Elizabeth T. Cirulli1, Jacques Fellay1, John G. McHutchison2, Alexander J. Thompson2, Curtis E. Gumbs1, Kevin V. Shianna1, Thomas J. Urban1 and David B. Goldstein1, ,

1 Center for Human Genome Variation, School of Medicine, Duke University, Durham, North Carolina 27708, USA

2 Duke Clinical Research Institute and Division of Gastroenterology, School of Medicine, Division of Gastroenterology, Duke University, Durham, North Carolina 27705, USA

Received 27 August 2010; revised 9 November 2010; accepted 14 December 2010. Available online 1 January 2011.

Abstract
Background & Aims:
Genetic variation of inosine triphosphatase ( ITPA) causing an accumulation of inosine triphosphate (ITP) has been shown to protect patients against ribavirin (RBV)-induced anemia during treatment for chronic hepatitis C infection by genome-wide association study (GWAS). However, the biological mechanism by which this occurs is unknown.

Methods:
We examined whether ITP can be used by adenosine triphosphatase (ATPase) in human erythrocyte or recombinant human adenylosuccinate synthase (ADSS). RBV-induced adenosine triphosphate (ATP) reduction in erythrocyte was compared with the genetically determined low or normal activity of ITPA, leading respectively to high or normal ITP levels.

Results:
Although ITP is not used directly by human erythrocyte ATPase, it can be used for ATP biosynthesis via ADSS in place of guanosine triphosphate (GTP). With RBV challenge, erythrocyte ATP reduction was more severe in the wildtype ITPA genotype than in the hemolysis protective ITPA genotype. This difference also remains by inhibiting adenosine uptake using nitrobenzylmercaptopurine riboside (NBMPR). Interestingly, the alleviation of ATP reduction by the hemolysis protective ITPA genotype was canceled by the ADSS inhibitor 6-Mercaptoethanol (6-MP).

Conclusions:
ITP confers protection against RBV-induced ATP reduction by substituting for erythrocyte GTP, which is depleted by ribavirin, in the biosynthesis of ATP. Since patients with excess ITP appear largely protected against anemia, these results confirm that RBV-induced anemia is due primarily to the effect of the drug on GTP and consequently ATP levels in erythrocyte.

YES< THERE will be less ANEMIA because less riba will absorb in inosines presense.

DO NOT TAKE INOSINE WHILE TREATING !!!!!!!!!!!!!!

truth is as follows:

Brush border membrane vessels (BBMV) obtained from human intestines, in the presense of NA gradient (salt ions) inhibited riba absorption.
That is to say, in the presense of inosine and salt jujenal tissue BBMV lost it's ability to absorb ribavirin. Inosine, unlike the other purines studied was responsible for almost a complete inhibition (93% plus or minus 8%).

http://resources.metapress.com/pdf-preview.axd?code=t37258642421271g&size=largest

I would post the whole study here, but the resource page won't allow me to copy and paste.

mb

mb

[merryBe]

it's good to have both in vivo and in vitro studies so here's the human study proof:

part 1

Hepatitis C virus (HCV) infection is a serious global public health problem affecting more than 170 million people worldwide. It has been estimated that the infection becomes chronic in approximately 70% of these cases. The treatment options for HCV infection are unfortunately limited. Pegylated interferon and ribavirin are currently the most effective and standard first-line combination therapy for this disease. However, only approximately 55% of HCV patients respond to this therapy.

The complete mechanism of antiviral activity of ribavirin is unknown, and intracellular phosphorylation of ribavirin is believed to be required to exert its antiviral activity. Marked improvements in the sustained viral response (SVR) were achieved when peg-interferon was combined with ribavirin. It has been found that higher rates of SVR could be achieved with higher ribavirin concentrations in genotype 1-infected patients. Unfortunately, the incidence of toxicity also increases with ribavirin plasma concentration. Because plasma concentrations of ribavirin are important for both efficacy and toxicity, factors that influence the pharmacokinetic profile of ribavirin are thus of great clinical significance as they affect the drug disposition and, consequently, therapeutic outcome and disease progression of the patient.

As a consequence of its poor oral absorption profile (bioavailability 50%), ribavirin absorption is particularly prone to interference by food. A number of studies have assessed the effect of food (high-fat breakfast) on the bioavailability of a single oral dose of ribavirin. Food has been consistently found to increase the plasma exposure of ribavirin, albeit to varying degrees. The mechanism is unknown but may be related to better dissolution of ribavirin. Although the extent to which food affected ribavirin pharmacokinetics differed widely among studies, ribavirin has been recommended to be taken with food according to the manufacturers' package inserts.

The human concentrative nucleoside transporter 2 (hCNT2, SLC28A2) is a member of the solute carrier 28 family. hCNT2 has a very extensive tissue distribution throughout the body and mediates the transport for endogenous nucleosides as well as a class of nucleoside analog drugs. Its particularly high expression level in the intestine suggests hCNT2 to be an important transporter in the absorption of its substrates, which eventually affects their disposition in the body. In vitro studies conducted by Patil et al have shown that ribavirin is actively transported by the hCNT2 across the intestinal mucosa, and it has been proposed that the saturable uptake of ribavirin in the human intestine is the most likely explanation for the observed lack of proportionality in the peak plasma concentration above a single dose of 800 mg. Variability in the absorption of ribavirin was also believed to be one of the most important reasons for the wide range of bioavailability observed both in healthy volunteers and patient pharmacokinetic studies. From our in vitro studies, we have confirmed ribavirin as a substrate of hCNT2 and demonstrated that purine nucleosides strongly inhibit the uptake of ribavirin into hCNT2-rich expressed U-251 cells. The reported Kms of inosine and adenosine were 4.5 ± 1.0 µM16 and 8 µM,17 respectively, and were much lower compared to the Km of ribavirin (35.6 ± 9.27 µM). It is therefore reasonable to postulate that the concurrent presence of dietary purine nucleosides at the site of absorption will compete with and reduce the absorption of ribavirin. The purpose of this study is to assess the effects of purine content in the meal on oral single-dose pharmacokinetics of ribavirin in healthy participants.

Participants
Healthy male participants between ages 21 and 50 years (inclusive) were considered eligible for this study. This study was conducted in the Clinical Trials and Research Unit, Changi General Hospital (CGH), Singapore, in accordance with the protocol that was approved by the Institutional Review Board, CGH, Singapore. Informed consent was obtained from each participant prior to entry into the study. Participants were healthy without any clinically relevant conditions that could jeopardize participant safety or study validity, as determined through their medical history, physical examination, and results from clinical laboratory tests. Participants were excluded if they (1) had a hemoglobin value <12.5 g/dL or had donated blood within the preceding 30 days; (2) had persistent diarrhea or malabsorption that would interfere with the participant's ability to absorb drugs; (3) had participated in another clinical study within 30 days before day 1, 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication; (4) refused to abstain from the consumption of alcohol, caffeine, or grapefruit-containing products 1 week prior to and throughout the study; (5) had poor peripheral venous access; (6) had significant or suspected personal history of adverse drug reaction (hypersensitivity) to antiviral drugs with a similar chemical structure to ribavirin; and (7) had a pregnant female partner. All participants were required to practice barrier contraception (2 reliable forms such as condom and spermicide) from the first dose of ribavirin through the duration of the study and 6 months after the last dose of ribavirin in the study.

Study Design
The study was carried out in a 2-period, randomized, crossover manner. Participants underwent screening assessment within 14 days of the first dosing with study medication. Twenty participants who met all the inclusion/exclusion criteria were randomized and divided into 2 groups, A and B (n = 10 each). In period 1, participants consumed either a high-purine (group A) or low-purine meal (group B) following an overnight fast of about 10 hours. Thirty minutes later, they were administered a single 600-mg oral dose of ribavirin (Copegus, Roche Pharmaceutical, Nutley, New Jersey) in the form of 3 film-coated tablets with 240 mL of water. No meal was allowed until 4 hours after the dosing. Based on the published elimination half-life of ribavirin following single oral dose administration of 120 to 170 hours, a 4-week washout period was inserted between the period 1 and period 2. After the washout period, the 2 groups were crossed over in period 2. The components and their corresponding nutrient composition and energy contribution of the test meals are listed in Table I. The fat content for both types of meals is approximately 22 g, which is very close to the expected fat content (22.7 g) in a typical Chinese breakfast.

Blood Sample Collection
Blood samples were collected at predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 48, 72, and 144 hours after dosing. Then, 10 mL blood was collected into a heparinized Vacutainer tube at each time point. To minimize the possibility of hemolysis, ribavirin samples were drawn using a large bore catheter collected into a syringe. The needle was removed, and the contents of the syringe were gently released into an uncapped heparinized Vacutainer. The blood tubes were capped. The contents were mixed by gentle inversion, and the tubes were kept in an ice water mixture immediately after collection until centrifugation. The blood (10 mL) in sodium heparin tubes was centrifuged at 2000 g for 15 minutes at 4°C. The plasma was aliquoted into a cryotube and stored at -70°C until assayed 2 months later. Ribavirin is light sensitive; therefore, ribavirin-containing samples were protected from both sunlight and fluorescent light during processing and storage.

[merryBe]

part 2

Bioanalytical Procedures
Liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of plasma concentration of ribavirin. Acetonitrile-containing internal standard bamethane (Sigma-Aldrich, St Louis, Missouri) was added to 50 µL of plasma sample for protein precipitation. The supernatant was collected and evaporated to dryness. The residue was reconstituted in 200 µL of a 90% acetonitrile/10% MilliQ water mix prior to a 5-µL injection. The UPLC separation was performed on a gradient elution using a BEH HILIC column (2.1 x 100 mm, 1.7 µm), and the mobile phase was composed of MilliQ water containing 100 mM ammonium formate (pH adjusted to 3.7 by formic acid) and acetonitrile. Positive ionization mode of electron spray ionization was used for the multiple-reaction monitoring of transitions with a mass-to-charge ratio (m/z) of 245 ->112.9 for ribavirin and 210 ->90.9 for bamethane, respectively. The calibration curve for ribavirin (concentration range of 5.0-2000.0 ng/mL) was linear with the correlation coefficient of 0.996. The lower limit of quantitation for ribavirin was 5.0 ng/mL, which was determined with acceptable precision (% coefficient of variation [CV] <15%) and accuracy (accuracy ±15%). The limit of detection (LOD) of the method was found to be 1.0 1 ng/mL, where the signal-to-noise ratio was 5. The interday precision and accuracy were in the range of 2.0% to 5.3% and 98.0% to 105.6%, respectively, whereas the intraday precision and accuracy were in the range of 3.9% to 10.0% and 96.1% to 110.0%, respectively.

Pharmacokinetic Analysis
The pharmacokinetic parameters were determined by noncompartmental analysis using WinNonlin Version 5.2 (Pharsight Corp, Mountain View, California). The maximum observed plasma concentration (Cmax) and time to maximum plasma concentration (tmax) were obtained directly from the plasma concentration-time profile of each participant in each treatment. Area under the curve from time 0 to the last quantifiable sampling point (AUC0-t) was calculated by the linear trapezoidal method. The terminal phase rate constant (kel) is the slope of the terminal linear portion of the log concentration versus time curve, and it was used to calculate the terminal phase half-life (t 1/2 = ln(2)/kel) and the area under the curve extrapolated to infinity.

Statistical Analysis
The sample size for this study was estimated based on variability observed in previous ribavirin pharmacokinetic studies. This study has an 84.8% predicted power to detect a 35% difference in Cmax, tmax, and AUC of ribavirin between a high- and low-purine meal at the .05 significance level. Statistical analysis for Cmax, AUC0-144, and AUC0- {infty} between the 2 types of meals was performed using PROC MIXED in SAS (Version 9.1, SAS Institute, Cary, North Carolina). Variables were logarithmically transformed prior to analysis. The analysis of the variance (ANOVA) included sequence, period, and meal type as factors and subjects within sequence as random effects. The ratio of geometric means for Cmax, AUC0-t, and AUC0- {infty} between the low- and high-purine meals was obtained from the antilog of the difference in the least squares means of the natural logarithmically transformed data. The 90% confidence intervals of these ratios were also calculated. Nonparametric methodology (Mann-Whitney test) was used to compare the tmax and t 1/2 between the 2 types of meals.

Tolerability
Adverse event reports, medical examinations, and clinical laboratory data were assessed to evaluate tolerability.

Participant Disposition
Twenty healthy male volunteers participated in this study. The mean ± SD (range) of age, weight, and height of participants was 36 ± 8 (range, 23-49 years) years, 69.1 ± 7.8 (range, 54.1-81.7 kg) kg, and 172 ± 6 (range, 160-179 cm) cm, respectively. Among the study participants, 19 successfully completed both periods (low- and high-purine meals). One participant withdrew after completion of the first period (low-purine meal) for reasons unrelated to the study drug. All participants were compliant with the diet restrictions throughout the study.

[merryBe]

part

Pharmacokinetic Analysis
The mean plasma concentration profiles of a single oral dose of 600 mg ribavirin following low-purine and high-purine meals are illustrated in Figure 1 . Despite a 4-week washout period, measurable concentrations of ribavirin were observed in predose samples in period 2. These indicated carryover effects, which were unexpected from the published half-life of ribavirin, are suggestive of a much more extensive ribavirin distribution into a deeper compartment and a much longer elimination half-life. Pharmacokinetic parameters of ribavirin administered under low-purine and high-purine meals are presented in Table II . ANOVA testing indicated that the Cmax, AUC0-144, and AUC0- {infty} of ribavirin were not influenced by the sequence in which participants received the meal. However, there is a significant difference in Cmax, AUC0-144, and AUC0- {infty} between the 2 periods (P  .05).

Discussion
There was a significant retention of ribavirin after a 4-week washout period between period 1 and period 2, which resulted in a significant carryover effect. This was unexpected given the reported half-life of ribavirin of 120 to 170 hours. This retention of ribavirin may reflect a much deeper compartment for ribavirin with the terminal half-life longer than previously reported. An empirical estimate of the ribavirin half-life in this study-based on the last 3 time points, including the predose value for period 2-yielded half-lives ranging between 209 and 550 hours.

Administration of ribavirin after a low-purine meal caused an increase in exposure of ribavirin compared to a high-purine meal. As we had hypothesized, the presence of purines in the diet will compete with the absorption of ribavirin through hCNT2 across the intestinal mucosa and decrease the plasma exposure to ribavirin. Three previous studies have assessed the effect of food on the bioavailability of a single oral dose of ribavirin. The food effects on these parameters (Cmax, AUC0-t, and tmax) from these 3 studies are outlined in Table III . The results consistently showed that the food slowed the absorption of ribavirin and increased the maximum concentration of ribavirin. However, the extent to which food affected ribavirin bioavailability differed widely. This difference may be attributed to the different composition of the meals, particularly the fat content used for testing. The presence of fat may be associated with a faster degree of dissolution for hydrophobic ribavirin. In this study, we characterized the effects of meals with different purine content but standardized fat content (about 45% of the calories contributed by fat). The findings from the current study indicated that the purine content in food is an important factor influencing ribavirin pharmacokinetics.

Dietary habits vary substantially across different ethnic groups. Generally, the protein content in a typical Western meal is higher compared to a local Chinese meal. This may result in a greater difference in purine content between Western and Chinese meals because purines are often associated with protein-rich food. The purine content for a typical Western and Chinese meal ranges from >300 mg to 50-150 mg, respectively. The findings from this study also suggest that Chinese patients with hepatitis who are undergoing ribavirin treatment may have greater ribavirin exposure, leading to higher efficacy as well as higher risk of toxicity such as hemolytic anemia, when prescribed the standard given dose of ribavirin compared to their Western counterparts. This is also consistent with the results of a few recent clinical trials: Asian patients with HCV showed a significantly greater SVR on interferon and ribavirin treatment compared to white patients.

The effects of food and food composition on ribavirin have not been adequately considered despite evidence showing greater bioavailability during the fed state. This may be related to better dissolution of ribavirin. Our data provide additional evidence that the purine content of food can alter the bioavailability of ribavirin. The complex interactions between lipid and purines in any particular diet need to be clarified further. Clinical dosing regimens will therefore need to take these dietary factors into consideration.

In conclusion, this study has demonstrated that a low-purine meal significantly increased Cmax and AUC0-144 of ribavirin by 36% and 34%, respectively, compared to a high-purine meal. This finding suggests that dosage may need to be adjusted accordingly for different patient groups with different amounts of purine in their diets.

sorry I couldn't post this as one study, medhelp won't take large post : (

THIS IS A VERY IMPORTANT PIECE OF INFO, AND COULD EXPLAIN WHY SO FEW AMERICAN'S CURE....WE EAT THE LARGEST AMOUNTS OF PROTEIN OF ANY CULTURE.

WHAT IF, just what if our low rate of cure is not just because most of us have G1, what if, it's because we are eating protein when we take the RIBA !!!!!!!!!!

In fact both my GI, hepatologist and our own HR all told us to eat protein with every meal, small amounts 2-3 oz more often I was told. Better not to overtax the liver!!!!

BUT if the protein stopped the riba from absorbing....that would explain A LOT!!!!!!

mb

I wish I had known this info when I treated!!!!

mb

[Susan_1a_CC]

Since most proteins contain salt, and since folks very infrequently eat fish or meats etc without adding salt, this means we can sabotage our chances of a cure by ignoring how purines effect riba absorption.
____________________________________________________________________________

Okay, no Inosine, I'm good with that. I do have a question though about absorption rates.


I've read that a high fat meal will increase riba absorbtion by a factor of 1.46.   I looked up another drug (unrelated but that's recommended to take with a meal) and saw that a high fat meal increased its absorption by "177.5% and increased AUC (AUC0-t, AUC∞) by 123.5% and 115.4%, respectively."  Maybe I am mixing apples and oranges but to your knowledge is there any standard absorption rate table that would suggest that increasing riba absorption by 1.46 is truly as beneficial as we'd like to think?  Please understand that I am trying my best to understand and am not knocking your attempt to conquer the virus.  As I've said, this can be frustrating...  

With my appreciation for your research,
Susan

[merryBe]

Great question, and yes, fats do increase absorption significantly, numbers may vary from study to study, but that fats do increase absorption has been known to most forums and most doctors for some time now.

In fact many drugs are aided by fat in the diet, chiefly the drugs that are known for being hydophobic (hydo=water, phobic=fear). hydophobic substance don't mix well with water or digestive juices alone, but they do disolve and become more bioavailable in the presense of lipids (fats).

That said, I am VERY concerned that most patients don't know this.

Let me use myself as as example. I was told by forum members to add fat to my diet.

So, I added butter to my morning breakfast, either oatmeal or eggs.
Then I usually relied on the fat content in my meat in the evening meal.

the studies I cited were not available when I treated.

Now it looks like I was inhibiting riba absorption in both meals. Worse at night because, well who eats meat or fish without some salt.
Breakfast wasn't perfect either since eggs and oatmeal do contain purines, and of course we always cooked our oatmeal with a little pinch of salt (and then I was adding salted butter to get the fat for the riba) or if I had eggs, well who eats those without salting them?

So in other words, I got very little riba absorption.

After I found out to add the fat, my absorption got better, because only then did I go UND.
(my diet used to contain much less fat).

However, in light of these recent studies, I'd bet dollars to donuts my riba level was half what it should have been, maybe less.

So, since our goal IS TO CONQUER this virus, this is extremely important information and I would suggest people print the study and GIVE IT TO THEIR DOCTORS, most of whom are unaware, especially dietary studies seem to get ignored, so it behoves us as patients to tell our providers so that they will better their skills at curing people!!

mb

[merryBe]

Here's another good example:
anemia is predictive of outcomes, WHY, because the greater the anemia, the greater amount of riba got into the system.
Ergo, one has to take the good with the bad...if one's HGB is holding...it means that you probably aren't getting enough riba in there because the folks that did see large drops, known to be caused by the riba, are the ones that SVR'd ar a much higher rate!!

In this study result was NOT linked to DOSE, but it was linked to anemia and EVR,
meaning it wasn't the DOSE that mattered as much as how much riba got in, and how FAST it got in, and if that happened then anemia was much greater but so was SVR.

I think I've made all my points now.

Anemia during Hepatitis C Treatment Predicts Sustained Response to Pegylated Interferon/ribavirin

By Liz Highleyman

SUMMARY: Hepatitis C patients who develop anemia during treatment with pegylated interferon plus ribavirin are more likely to achieve a sustained virological response (SVR), according to data from the IDEAL trial published in the November 2010 issue of Gastroenterology. Both ribavirin dose reduction -- which did not decrease SVR -- and medications that stimulate red blood cell production may be used to manage anemia and help people stay on treatment, the study authors concluded.

Anemia is a common side effect of treatment for chronic hepatitis C virus (HCV) infection, due to red blood cell destruction (hemolytic anemia) caused by ribavirin and bone marrow suppression related to interferon.

Erythropoietin (Procrit) and other erythropoiesis-stimulating agents (ESAs) that boost red blood cell production may be used to manage anemia. Reducing the dose of ribavirin is also done to control anemia, but this may increase the risk of post-treatment relapse, and therefore decrease the likelihood of achieving sustained response.

Mark Sulkowski and fellow investigators looked at the relationship between treatment outcomes, anemia, and use of ribavirin dose reduction and ESAs among participants in the IDEAL trial.

As previously reported, IDEAL compared 180 mcg/week pegylated interferon afa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin versus 1.0 or 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus 800-1400 mg/day ribavirin in more than 3000 previously untreated genotype 1 chronic hepatitis C patients at 118 U.S. sites. Participants who received Pegasys had a higher end-of-treatment response rate, but those taking PegIntron had a lower relapse rate, so SVR rates ended up about the same.

IDEAL participants who developed anemia -- defined as a hemoglobin level  3 g/dL: SVR 43.7%;
Drop of < 3 g/dL: 29.9%.
* Participants who reduced their ribavirin dose were not significantly less likely to achieve SVR.
* Among patients with early-onset anemia (through week 8 of treatment), those who used ESAs had a significantly higher SVR rate than those who did not (45.0% vs 25.9%).
* People with early anemia who used ESAs were also significantly less likely to discontinue treatment due to adverse events (12.6% vs 30.1%, respectively).
* However, ESA use did not affect SVR or treatment discontinuation rates among patients who developed anemia after 8 weeks.

"Among HCV genotype 1-infected patients treated with [pegylated interferon/ribavirin], anemia was associated with higher rates of SVR," the study authors concluded.

"The effect of ESAs varied by time to anemia," they continued. "[P]atients with early-onset anemia had higher rates of SVR with ESA use, whereas no effect was observed in those with late-onset anemia."

Importantly, the likelihood of HCV relapse did not increase among patients who decreased their ribavirin dose, in constrast with some prior research.

These findings "firmly underscore the recommendation for [ribavirin] dose reduction as the primary strategy for management of treatment-related anemia," before using ESAs, the researchers wrote. They added that, "ESAs should not be used solely to avoid [ribavirin] dose reduction in anemic patients."

Investigator affiliations: Johns Hopkins University School of Medicine, Baltimore, MD; Bon Secours Health System, Liver Institute of Virginia, Newport News, VA; Beth Israel Liver Center, Boston, MA; University of Pennsylvania Health System, Philadelphia, PA; Mount Vernon Endoscopy Center, Alexandria, VA; University of Texas Southwestern Medical Center, Dallas, TX; Thomas Jefferson University, Philadelphia, PA; Brooke Army Medical Center, Fort Sam Houston, TX; Cedars-Sinai Medical Center, Los Angeles, CA; Schering-Plough Research Institute (now Merck & Co), Whitehouse Station, NJ; Duke Clinical Research Institute, Durham, NC.

1/11/11

Reference
MS Sulkowski, ML Shiffman, NH Afdhal, and others (IDEAL Study Team). Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate. Gastroenterology 139(5): 1602-11 (Abstract). November 2010.

Other Source
Reuters Health. Anemia in treated-HCV patients bodes well for sustained virological response. December 12, 2010.

mb

[Bali05]

When did you become UND on your first tx and what were your HgBs incl. baseline ?

[it'sallgood]

Hi MerryBe, i'm just a newbie but according to drugs.com  "Ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months." Since riba has such a long half life why not just take it between meals with some fat?  
eric

[scaredycat7]

I was thinking that too -what it'sallgood said -what if I took riba with cake and an apple ? Healthy cake made without chemicals?

This is such interesting information.  I was trying to eat more sardines! Holy smokes. I wonder if you can still eat the sardines etc for lunch between riba doses? How does overall diet affect the riba?  Why don't they just come out with some tasty "fat-pockets" like dog/cat "pill-pockets"?  

non-fat yogurt? forgetaboutit!

hmmm . . . need to print out that list .. . wish docs gave out list of good foods to eat on tx.
I've go a few weeks to work on it . . . before wk 12. Tonight - riba and ice cream! Or, maybe always take riba with snacks -never with breakfast or dinner? Any ideas in this direction?

Wow. This is HUGE!  
Thanks merryBe!
SC7

[Susan_1a_CC]

Your post states:

"anemia is predictive of outcomes, WHY, because the greater the anemia, the greater amount of riba got into the system.
Ergo, one has to take the good with the bad...if one's HGB is holding...it means that you probably aren't getting enough riba in there because the folks that did see large drops, known to be caused by the riba, are the ones that SVR'd ar a much higher rate!!"
_____________________________________________________________________________
To add another perspective for those who may follow:
I was motivated to stop my iron supplements in order to see if I, too, could become anemic and therefore know my riba was working.  Fortunately, I was having weekly blood draws, and yes, my HGB fell within one week.  *However* with the iron supps - which my doctor stared my on - my HGB is holding.  Should I fear lack of absorption - I don't think so but time will tell.

[nygirl7]

Susan

But look at me I had a six point full drop in just ten days at week 2/3 but didn't clear until week 24. AND I was almost double dosing the riba (from docs ordered 800 a day to 1200 - 1400 and sometimes even 1600)......with ice cream and peanut butter and bacon - I'm sure my absorption was tremendous at that point but it really didn't mean alot in the long run.

I should have been called ribagirl at that time in my life. What an idiot I was.

[Susan_1a_CC]

I may be missing the point here.  Is there an actual benefit to clearing the virus by having fewer red blood cells - or is the anemia pointing to riba getting absorbed?  I did observe my HGB drop when I stopped the iron so can I make the leap that without the iron I'd be anemic?  (Somethings working because my brain isn't ;).)

[Trinity4]

If you are familiar with MB and her writings, that is just the tip of the iceberg.  :)

[Fnzol]

Why don't you just post links instead of the entire narrative?  This forum software is hard enough to read.  

[merryBe]

bali, went UND at 6 months, only got down to 300,000 then had a breakthrough at 16 weeks, then went UND when I changed me diet and also this is when my HGB really fell.

it's all good-  yes riba has a long half life and doesn't clear the system for months, but that is NOT what we are addressing here.
We are addressing getting plasma levels high enough to kill virons, This is important throughout treatment and ESPECIALLY at the beginning of treatment.
As I've said, the virus has a window in which most mutaions occur of 48-72 hours, meaning the first few DAYS of treatment one must do EVERYTHING possible to bring the riba into the bloodstream, I would argue at least the first month ot two one should follow closely any and all dietary adjuncts proven to be helpful. Studies have shown the intraveneous riba, or riba levels where dosage was increased to get to high plasma levels had far superior rates of SVR.  I'm saying that getting your plasma up is important and keeping it there is too.  NOw, even if you increased your dose it might not compensate for the inhibitory nature of inosine, ergo you may be walking around thinking how fortunate yo are to be "tolerating" treatment so well, and it may be that the reason is that the one drug is in such low amount that you are hampering your chances of success.

scardycat...yes, high carb high fat low protein sounds best...
I was eating sardines also, good fat source...little did we know eh???
I'm going to have to do more research on fiber, some say it hurts, but then, vegetarians treat with better results and they eat more fiber...so we don't know if it's hurtful...it could be their inosine is naturally low due to being vegetarian.
I'll keep working on this.
Trust me, if I could talk my doctor into intraveneous ribavirin, know what I know now, I'd do it!

Susan
what stage grade are you???  You should only be on iron if your FREE Ferritin number is low, very low...50 is OK, PM me if you need more help with this.

NY girl, you are just one lucky dame lady!!  Of course now a days the dose you took is what's normally given, but you just lucked out...and all those foods had purines!!!

Meso- can't please everybody, some folks need and want to know this stuff.

Trin-  ; )

Frizo,

for one reason, sometimes links disappear....when one returns years from now, a link may not be available. If it is highly pertinent then I'll post it.
Also, that study is only available to subscribers as it was from a medical journal, meaning not everyone would have access to it.
Sometimes I post a link, sometimes a study, depends on the source etc. Just be glad that there is info available which over time you may find more interesting.

peace to all.

mb

[Cory255]

Flaxseed shouldn't be taken with Ribavirin either.    

" The fiber in flaxseed may lower the body's ability to absorb medications that are taken by mouth.  Flaxseed should not be taken at the same time as any conventional oral medications or other dietary supplements. "  

http://nccam.nih.gov/health/flaxseed/ataglance.htm

[merryBe]

I should add that there may be a component effecting some of us more than others.

Some may remember my gall bladder was not functioning and had to be removed during my treatment. But all this inosine info got me thinking....

The gall bladder concentrates the bile, making that aspect of the digestive juices many times more powerful.
The gall bladder secrets this bile in response to the signal that fats and proteins are present in the intestine. The digestive concentrates then have an effect on the breakdown, and influence the absorption of said fats and proteins.

I'm just wondering out loud if the hydrophobia is less pronounced in the presence of more concentrated bile. Were this so, it would mean that folks without gall bladder might benefit from dosage adjustment on their riba since their bile is diluted and not able to do as good of a job in aiding absorption.

I will definitely bring this up next month with my hepatologist and get his take, meanwhile any thoughts or answers would be appreciated.

mb

[Susan_1a_CC]

Ah, you put the cherry on top for me given that I add ground flaxseed into my morning breakfast protein smoothie...  Well, at least my sex hormones are stabilized ;*).

[it'sallgood]

merry - thanks for the clarification and pointing out the importance of diet in riba absorption.
eric

[willing]

useful information - thanks for posting! The pubmed cite for the article is :
http://www.ncbi.nlm.nih.gov/pubmed/19369574

I think this is good information to be aware of, but I'm probably not going to revise my diet quite yet. As spectda points out all bioavailability issues can be handled by simply taking more  or less pills. We've know for  a while that addition of fats can increase absorption. The news here seems to be that you can further improve absorption by cutting down on molecules that look like rbv to hCNT2, the enzyme responsible for moving the drug across the intestinal membrane "  ribavirin is actively transported by the hCNT2 across the intestinal mucosa".  And this  makes good sense - if you want hCNT2 to focus on your rbv, cut down on the decoys.

However absorption is only one of the factors affecting serum concentration,  another documented key factor is kidney function/clearance rate. And short of peeing less there's not much to be done there.

We know auntie riba is crucial to successful function of  the dynamic duo, but why take it and how much to take ? Bill1954 and mikesimon posted interesting links about this a while back. The best current answer to why take it seem to be because it enhances expression of ifn-stimulated genes:

http://www.ncbi.nlm.nih.gov/pubmed/20303352

which implies you want an abundance of rbv molecules in cells where ifn-stimulated genes are busiest.

With regards to how much to take, from Bill's link to the rbv wikipedia article:

"Red blood cells (erythrocytes) concentrate the drug and are unable to excrete it, so this pool is not completely eliminated until all red cells have turned over, a process estimated to take as long as 6 months"

So RBCs act as rbv sponges. Rbv diffuses across the membrane but can't get out, resulting in hemolytic anemia:  the RBCs die off and your Hgb tanks. This is likely why Hgb drop is such a good proxy for whether you're getting enough rbv : if there are enough rbv molecules in circulation (regardless of dosage/absorption/clearance) to kill off  a significant fraction of your RBCs there probably are enough to diffuse into the hcv-infected hepatocytes where expression of ifn stimulated genes is part of the hand-to-hand combat against the virus.  

My best guess for how much rbv to take is as much as you can stand without needing epo.

[Cory255]

" Ah, you put the cherry on top for me given that I add ground flaxseed into my morning breakfast protein smoothie... Well, at least my sex hormones are stabilized ;*). "

... bulk fiber too, such as psyllium, bran, FLAX, clay, etc. will bind and transport other medications out of the body.  

Take the flaxseed either 1 hour before, or even better wait at least 2 hours after any prescription/dietary supplements ;)    

[merryBe]

I think that the transport is where the questions lie for me as well. For instance, the in vitro study did not state it included the digestive enzymes, so it's hard to tell from that model.

However when the in vivo studies also showed similar result then it became of more interest.  Certainly other things may come to bear, like for instance now much peptase may play a role vs. say lactase. I mean it may not be soley the domain of the mere presense of inosine but of how many other chemicals a body secrets. Which brings up all kinds of other things like whether proton pump inhibitors help ot hurt, whether lactase and peptase together hurt (they cancel each other out) so a dairy meat combo would have less enyzmatic activity, sheesh, it's a can of worms isn't it!!

also, even without adding salt the body naturally adds it (within the bile salts) so it's impossible to not have ones proteins be "in the presence of NA gradients, not when the proteins and the bile salts naturally contain them, so there again would be a case for lowering the purines, because there no way around the problem.

Trinity is basically saying until proven it's of little to no value to deliver the riba with the right blend of foods. SHe may have a point, proven may take more than a 20 man study, but unfortunately the big bucks go to researching new drugs to make money, not to little researchers willing to devote time to the actual processes, so waiting for big studies on these kind of things may be a very long wait.
To me the human (in vivo) study confirming the in vitro (lab/petre dish) experiment kind of makes me want to raise and call...since our futures hang in the balance this ups the ante.

The only way this proof might be an issue I think is if methodolgy didn't factor in the chemical landscape provided that landscape changed significantly the outcomes. Meaning if the digestive enzyme canceled out some of the inosine, or altered it so that it didn't do in vivo/humans what it appears to do, but like I said since the in vivo/human study seemed to reflect similar results as produce in laboratory that kind of makes it seem as if there is some validity here.

It's hard to believe they would have done a human study without taking into account that digestive inhibitors might throw the study off. I certainly would factor that in.
So while they probably didn't take everything into consideration I mentioned, the chances are they took some precautions. At least I would have screen out folks on proton pump, antacid type drugs.

As I said, I was just brain storming on what else could have thrown my results so completely when I stumbled onto the purine studies, and then the isonine. (it's not all the purines, only certain ones). The in vitro study demonstrated that while inosine completely inhibited some others did not...unfortunately they didn't test every purine, so there's no way to isolate, and they are grouped in nature anyway, so that information wouldn't be as valuable.

The inosine rich protein drinks and muscle builders being the exception, and since muscle wasting is a problem a  few patients, particularly the co-infected, get sold on these muscle building supplements.
It would be a shame if patients were popping expensive inosine supplements and keeping muscle while failing treatment wouldn't it?

mb

[spectda]

There is a point where compliance if it is overly complicated becomes impossible for the average human being. It's easy to become obsessed with possibilities about why or why not treatment works.

Find the best and most experienced Dr (hopefully a hepatologist) to treat and advise you who will allow your input and individualized treatment. Inform yourself about the disease to the point where you are able to advocate for yourself. Eat a bit of extra fat with your riba and take as much as your body can tolerate and perhaps predose. Adding alinia probably won't hurt and may even help. Keep to a healthy weight, take your meds on time and don't dose reduce unless there are no other options.

The DAAs success seems to be independent of how cerebral a person is. As they evolve  treatment time will continue to become shorter, drugs less toxic and svr rates will be in the 90-100% range, and success will not be dependent on an individual's ability to write a thesis about purine.

[grizwald]

Well spoken.

Griz

[GSDgirl]

I like your approach

[Fnzol]

Some things can simply be over-analyzed, and this is one of them.  

Eat a well-balanced nutritional diet and stay well-hydrated and you've done the best you can, as revealed by your labs.  I haven't changed my diet on treatment.  I eat low amounts of fat and carbs, lean meat protein, lots of fruit and veggies, just as before treatment.  My crit dropped from 46 to 32, so am pretty confident that I'm absorbing ribavirin.  

Quit fretting about it.

[James10500]

+ 1, spectda and Fnzol

You'd get the feeling from this post nobody ever achieved SVR.  And those that didn't had very strange diets.

[nygirl7]

Hey all I ate was ice cream and baby cheeseburgers on treatment....I dont think that was very strange though - who you making fun of James   ;)  (I get what you mean though :) like always.

[mikesimon]

Prunes? Did someone say something about prunes?

[Trinity4]

Must be why I'm feeling quite defecatious at the moment.

[merryBe]

over analysis, my specialty...likely prunes are effecting my verbiage to be sure. ; )

I think the point I was most trying to make though, for what few may appreciate and not ridicule the process, can be summed up in 3 simple thoughts:

1. That there is a window for mutants observed to be 48-72 hours and that low riba in that critical early treatment phase requires some efforts be made to maximize absorption before mutation becomes an issue, and one might argue throughout tx would be best.

2. Human trials have shown the same results as lab experiments, that inosine stops riba absorption almost completely. (93% blocked and thats nothing to sneeze at)

3. That giving up a few hamburgers and such, only in some meals, and especially at the beginning of tx, the first week and perhaps month being key, would give one a better chance of not developing a resistant strain.
AND since currently HALF of all G1's who treat develop mutant strains,
that's 1 out of every 2 people failing treatment.
relapse, we ignore such information at our own peril.

I remind the reader that in Dr. Karen Lindahl's ALL the people at the higher Riba plasma levels SVR'd.....ALL of them.

ALL means ALL.    which do we want, Half cured, or ALL cured....let me think....

ok, now, laugh some more....

mb

[it'sallgood]

have you thought about how long you will pre-dose with riba? sorry if i missed your treatment plan in a previous note.

[merryBe]

NY girl  guess what your purines, NOT IN MILK AND CHEESE!!  very low there, so there you go...now the ice cream didn't do your INF any good, but it didn't stop the riba!!

The riba is roughly twice as important as the INF. I say this because the rate of cure with INF only was 15%, it went up to 45-50% when riba was added, and that means the riba was adding 30-35% to the equation, so roughly double the percentile when it was added.
(although in Lindahl's study everyone SVR'd on the higher riba plasma levels, so it may be much more important than we think.)

Therefore, milk and cheese are fine, but I'd advise folks to nix icecream and all sugary items for the INF to stay at full strength and for IR to not set in.

also, check this out, avacado and nuts are GREAT, they have protein and fat, but are low purines, so at least we don't have to just have tofu!! There are some fun foods also.

http://www.goutpal.com/915/foods-high-in-uric-acid-a-surprising-myth/

I'm getting psyched now, because I think given the PI, and the few things we've discovered that may help, many more will cure.

BTW, Cocksparrow cleared you know....he did get his HOMA down, his IR was very bad...
and he did HR's adjuncts, we'll never know for sure what did it, but after 3 failed attempts it was exciting to see that something worked for him!!

[merryBe]

not sure yet, 4 weeks maybe, gonna have to bone up on that...I'll get back to ya!!!

I'm planning to study the chemistry of the drugs in trials now, some are very close to natural acids. They have a couple now that get plasma quite high in short order, so if I can't get my doc to let me be in a trial for one of those, then I will preload or, alternately like I said, there may be something that would mimic the trial drugs.

I like the HCNC2 factor that Willing mentioned above, so I'll be reading up on that and try to compile a list of decoys to avoid them. It is just like the inosine idea, great to figure out what's hampering absorption.
Probably I'll sound like a broken record but the Lindahl study convinced me that the riba absorption was key, and it convinced a lot of doctors also or else there wouldn't be 12 trials right now to find a drug to help the riba absorb!!

But, I have to say my preference would be to find methodology to make the riba absorb rather than preload, only because a sudden onslaught of everything might weaken the virus beyond all hope of mutation, and ergo that would be the ideal.
I noticed there are some exotic forms of zinc in trials now also, interesting because we've known for years that zinc is an antiviral, but I never would have thought that I'd see trials of a natural product. Of course, they tweaked the isotopes a bit, to produce a form with a patent....to make lots of money of course...and that why it's in trials, but I'm just glad that finally they are looking at EVERYthing, because over a billion people have some form of hepatitis, so it's about time.

mb

[FlGuy]

It's hard to follow your logic here:

"The riba is roughly twice as important as the INF. I say this because the rate of cure with INF only was 15%, it went up to 45-50% when riba was added, and that means the riba was adding 30-35% to the equation, so roughly double the percentile when it was added"

Based on your thought process (Inf alone, =15% combo at 50%) then your logic would dictate that riba alone has some effectivness, which it doesn't.  There is synergy at play here and your logic is flawed. Which means that INF is the more important.

[Bali05]

Instead of relying on Riba absorption alone I would go with a higher dose especially until
first UND is reached.
To many on this forum it is very clear and old news really how important Riba is.
The problem is that a naive person going into tx will have a hard time getting rx for higher
dose.Going into it a second time like you are , you should have no problem convincing
your Hepa. for more Riba. A friend of mine currently retreating got rx for 1600mg.
When you retreat you also have a history on how well your body tolerates it.
Some people become very anemic very quickly on standard dose and I don`t think
that is because they eat less purine but genetics play a role.
Personally I like a good level of Vit B12.as well.
http://www.ncbi.nlm.nih.gov/pubmed/16864957
http://www.ncbi.nlm.nih.gov/pubmed/20196801

[merryBe]

the synergy is a separate issue guy, we knows that synergy is involved but the importance of getting the riba to therapeutic plasma levels quickly cannot be understated.

ok, lets back up the train, if INF alone only gets you to 15% clearance, but adding the riba adds a minimum of 30% to that, then we know that the riba, with synergy obviously, is creating a 3 fold threefold increase in SVR, but since it's addition causes a 30% bump, that's double the 15%. So you could look at it either way.
Simply saying here that even conservatively you have a drug whose addition has given a very healthy bump, too healthy to ignore and one that makes us wonder, what if more were used, or what if more were at least bioavailable quickly when it is most needed, in that 72 hour window where levels are still quite low, and where this gives half of geno 1's virons time to mutate. Karen Lindahl asked that question years ago, and yet here we are still waiting weeks to reach optimum levels in our bloodstreams!!

I don't think however one could conclude that the riba is ONLY twice as important, it's actually higher in my mind because in the Lindahl study the higher plasma people ALL Svr'd, so in that study the riba made up the difference to entirely close the gap.

Put differently, the riba at high dose made up the 85% gap that existed entirely, and allowed all patients to SVR and that's a very impressive snipet of info...So in my mind it's a very important part of the equation. In my mind, it explains how the DoubleDoses of our formum arrived at their conclusions.
It may just be at least twice as important for now, in the sense that at mimimum it give that bump...that we could conservatively say I feel, but remember that where 1.5 people in ten once stood, 5 out of 10 now stand, thanks to the addition of riba.

And, ten out of every ten stood at the higher dosing.

The cautionary of course is we also know the only reason that highest doses aren't used is because of the anemia and chiefly the kidney problems, including kidney failures, which is why I am not advocating for double dosing, but am advocating for attempts to raise the current SOC to the prescribed needed levels more quickly. Time is the real enemy here, at least in my view.
And as to synergy, while synergy plays a part, it's the antiviral that has made the largest leap in positive outcomes.
Same thing with all the HIV antivirals, they are what really knocks the viral loads down from millions to double digits, and without INF I might add.

Now granted you have a point, without the INF no one does SVR and the goal here is not just to keep the VL low (although one wonders why that could not be a goal as well for the folks that can't tolerate current SOC maintainance would be the humane thing to do) but to look at the stats and see how the riba pushed us forward...well it is impressive.

The problem as you know, and for those who never read Lindahl's work, is that 20% of the high plasma group lost kidney function to some degree, or completely.
Enter the PI class of drugs, they still have the anemia issues, but at least their addition isn't putting the kidneys at such high risk, and they attacking another phase of replication as well makes sense for myriad reasons.

I wish INF weren't so good at working in synergy with other chemos, it would be lovely to eliminate it, but it sniffs out and destroys cells that do manage to replicate even in the worst environment for doing so, so it may be a long while if ever before we see it replaced.

Don't know if that makes my logic clearer to you or ot, but I tried.

mb

[Bill1954]

Oh, my...

[Bali05]

Riba is actually quite safe even at higher  dosage  You keep mentioning kidney problems
what was the dosage administered when that occured in 20% of the participants ?
As a precautionary I monitor my kindney function anyway on tx so it really is no big deal.

[merryBe]

THIS IS AN IMPORTANT POST

yes, you are correct, and that BTW was Lindahl's work as well that proved using kidney function was a good indicator. Actually the bast is blood draw, but it's a VERY hard test, it has to be done with thick bore needles, no shaking, put on ice right away but not frozen...the blood plasma test is too hard in other words, so next best thing is creatine etc.

LISTEN, LINDAHL HAS BEEN THINKING OUTSIDE THE BOX FOR YEARS.

NO ONE SEEMS TO TAKE HER SERIOUSLY BECAUSE SHE IS A WOMAN.

gee, I know that feeling.

Example, ten years ago TEN YEARS AGO she did a study in which 5 out of 6 relaspsers cleared...

how did she do it? by adding AMANTADINE 200 mg to the SOC...
but do we hear of it no...will docotrs allow it, no.

BTW, the only reason the kidney thing happened was because she tried very high dose, like 2500 mg riba.

my point however is, yes I'll dose higher riba, maybe preload, it's going to to depend on whether I can get anyone to listen to me. I know exactly how Lindahl must feel. Here's a little swedish doctor that got 5 out of 6 former relaspsers to clear....roughly 80% and yet all I was offered to retreat was Infergen, at 30%.

You want my opinion, (not you Bali), but many men don't like smart women, they feel threatened by them, and if Lindahl's work being dismissed is not proof of that, tell me what is. The way her work has been ignored is beyong the pale egregious IMHO.

but to confirm your point:
TIEvidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin-induced anaemia.AULindahl K, Schvarcz R, Bruchfeld A, St?hle LSOJ Viral Hepat. 2004;11(1):84-7. Ribavirin in combination with interferon alpha-2 or pegylated interferon is the standard treatment for chronic hepatitis C. The current dosage recommendations for ribavirin are based on body weight (bw). Ribavirin is mainly eliminated by the kidneys and we have recently shown that ribavirin plasma concentrations are determined primarily by renal function. It is therefore reasonable to hypothesize that side-effects of ribavirin, i.e. anaemia, should be more closely related to plasma concentrations of ribavirin than to the dose per kg bw. A total of 108 consecutive patients eligible for treatment of chronic hepatitis C were studied. Ribavirin concentrations in plasma were measured by high-performance liquid chromatography (HPLC)-UV after solid-phase extraction in trough samples taken 4, 8 and 12 weeks after the treatment commenced. A total of 213 samples were obtained and the change in the haemoglobin level and the creatinine concentration was measured in addition to ribavirin. The dose of ribavirin per kg bw did not correlate with the drop in haemoglobin level induced by ribavirin. The concentration of ribavirin was non-linearly related to the drop in the haemoglobin level as revealed by fitting a standard Hill equation type dose-response curve. The half maximal drop in haemoglobin was obtained at 4.4 microm. The results from this study suggest that the anaemia induced by ribavirin depends primarily on the concentration of ribavirin, and not on the dose per kg bw. This lends further support to the idea that ribavirin should be dosed according to renal function.ADDivision of InfectiousDiseases, Department of Medicine, Karolinska Institute and Huddinge University Hospital, Stockholm, Sweden. karin.***@****

if you want to read all her work just google Lindahl K and hcv, and a ton of it will emerge.

mb--let the ridicule commence

[desrt]

mb:
K. Lindahl being ignored has less to do with her gender than with the fact that her 'study' only included 10 patients (hardly enough to be considered a random sampling, let alone a statistical universe) and there was never any followup (that I've heard of) other than a 24 week post-tx PCR.

Bali:
The dosing was at a toxic level. Many if not most of those ten anemic Swedes had to be transfused just to keep them alive.

[desrt]

If ribabsorbtion is a burning issue, I believe ribavirin inhalers can still be obtained in Mexico. They've been using it there for years to treat influenza.

[merryBe]

you are correct,the study was small but there was follow up.

Let me tell you what I think really happened. THe drug company giants already had untold million tied up in their new lines.

why do I think so, because they tried to disprove her work and here's how, they took an inferior interferon, dosed it less than optimally, 3 times a week I think, then used a lower dose of riba, 1000-1200, and then they only treated for 24 weeks...

so they picked the worst possible combo and treatment time so they could say aha we disproved her results!!
that was in 07....PI's were already in development, billions are riding on their approval.


NOw, were I the drug company wanting to get an extra 70K per patient for the PI...would I want little old cheap amantadine to do as well???
and could I hire a doctor at john hopkins to prove Lindahl was wrong, you bet I could, especially if billions of dollars were at stake...you can take that to the bank IMO.
ANyone who thinks payoffs never happen is living in an alternate universe.

yes, high riba, yes at that dose it was toxic, that's my point, we can't do that but we do need to find something to help achieve steady state sooner!!
but assuming you took 1600 or even 1800 just until plasma level got built up and not the whole tx, you might stand a much better chance of halting the mutations.
I guess you'd say I've really bought into the mutation window being the key here, which is why I'm bring up any and everything that might help close that window.

mb

[merryBe]

hey, now we're passing the straw around!! Nebutizer's, who'd a thunk...
you have a wicked mind dude, I like it.
hey did you know that 70% of all the ribavirin you take ends up in your brain!!  
No wonder people get bats in the belfry!!

,b

[Trinity4]

"Let me tell you what I think really happened"

That really says it all.  "I" being the operative word.

[Fnzol]

"NO ONE SEEMS TO TAKE HER SERIOUSLY BECAUSE SHE IS A WOMAN. "

Lol.  That does it for me.  Good luck.  Hope it works out for you.  Buh bye.

[merryBe]

yo, trin, I'm not Agent Smith here, I'm in the boat with you...first go study her Karin's work, then go study the "studies" designed to disprove her work, see if you see a pattern, then tell me where I'm wrong. Opinions backed up by observations have more value than those where no attempt to observe have been made. Besides, I've written the woman, have you??

Do I value those who produce science to contradict me, and value truth as opposed to being right, heck yeah, we are trying to find not ignor cures, or things that help cure...is that not why we all came in here??
.But being contrary without proofs....or accusatory, helps none.
Neo can't get the job done without the crew pulling too.

Wasn't it funny how one guy saw that planets revolved around the sun and no on else would even look through the telescope but was sure he was wrong!!??!!
Maybe it wasn't funny.

So what is your theory if someone tries to disprove a study by below SOC doses and cutting treatment in half....that they are stalwarts on a crusade for truth? What?


mb

hey guys, this has all been lots of fun, much more fun being on your time table than mine, but unfortunately I only slept for 2 hours, been up since midnight and need to go lay it all down.

see yous on the flip side!!

mb

[Trinity4]

Oh merrybe, you poor thing.  I think you're in manic mode.  How often does this happen?
Have you talked to a professional about it?  Would medication help? Perhaps after some sleep you'll feel more in control.  

I have no desire to be another Galileo.  I'm not obsessed with proving or disproving theories.  Your next treatment will more than likely be along the same lines at the last one.  Twist and turns around every corner with most people thinking, "huh, I don't get it"?  I'm sure you'll get where you need to go and with a little luck an SVR.  

Sleep well, it's apparent that you need your rest.

Trinity

[Trinity4]

Oh merrybe, you poor thing.  I think you're in manic mode.  How often does this happen?
Have you talked to a professional about it?  Would medication help? Perhaps after some sleep you'll feel more in control.  

I have no desire to be another Galileo.  I'm not obsessed with proving or disproving theories.  Your next treatment will more than likely be along the same lines at the last one.  Twist and turns around every corner with most people thinking, "huh, I don't get it"?  I'm sure you'll get where you need to go and with a little luck an SVR.  

Sleep well, it's apparent that you need your rest.

Trinity

[willbb]

hey did you know that 70% of all the ribavirin you take ends up in your brain!!  "

Me thingkst  maybe 100 %

[James10500]

What amazes me is how can someone with so much distrust for drug makers use their product in the first place. To say someone who did a study with ten people is reliable and the companies that make the drugs that have cured hundreds of thousands of people if not millions are unrepeatable is a joke.

[Trish77]

MerryBe...do you seriously think that people discounted Lindahl on the sole basis that she is a woman and that people purposely set out to sabotage her research and obfuscate her data...again, because she is a woman???   Because...men can't handle smart women??  

:(  As a woman, I'm really not that thrilled with another woman putting out that kind of notion.

I'm just little ole me but frankly, in my experience, particularly in a scientific or analytical area where men are less likely to care about the gender and more about the data, if a woman really has the stuff and the smarts, she will be respected for that.

And frankly, in general....I've noticed more over time that quality men are rather appreciative of a woman with some substance between the ears.  Men are visual, no doubt about it...but they are a whole lot more besides.

[merryBe]

you made an interesting observation.

in following it up I came across something

http://www.wikigenes.org/e/gene/e/9153.html

which shows the hcnt2 binds with purine AND uridine, so it theory then watching those two the most would allow the most absorption of the riba?

I see your point of using the HGB as the measure, and obviously that's an easier way to gauge thing's than checking riba blood levels.

I think the blood tank may not be as good of a gauge early on as latter due to the spleen storage though, and I think that once you start seeing the tanks yes you've got a good gauge, but what a lot of people see early on is that their blood is "holding up well" because of that extra amount the spleen holds in reserve to compensate for losses.

. It's not like it's hugely going to make a long term difference, but the extra blood saves us in any accident or surgery, so it offsets any tanking for at least those first few days.
Ergo, even if they did some study showing that they could get riba in there, if they base it on the tank alone it will be skewed, albeit you could have better absorption and them not be realizing it, if not compensating in the formula for the reserves.

It's also possible that the reason younger people survive the onslaught better, blood wise, is because their marrow is more responsive, and their growth hormone allows for a more stimulated response and more HGB to be made, over time our hgh lowers and the rate we can make blood cells at declines as a result.
It's also possible that since many hcv people have pituitary dysfuction that their bone marrow compromise due to low hgh is as much why their blood is tanking, and it's not strickly then proportional to riba absorption but rather to inability to rebound as well.

for all those reasons I think I'll continue my pursuit.
I think I'll peck around anyway, and see what things contain URIDINE now, because in theory your point is impeccable, stop all the decoys and steady state might be reached in far less time, and that's all I'm after.

So from PuRINES, to ISONINE, to URIDINE, oh my. We aren't in kansas anymore!!
mb

[willing]

good points - later in tx Hgb decline may not be as informative. I'm pretty  sure I underdosed on my last tx but still dropped to 10s towards the end. And yes, *everything* seems to move waaay slower as we get older.

The hCNT2 proteins seem to have the job of moving nucleosides across the gut membrane. No idea why they're specific  for purines (A and G ) and uridine (U) leaving Cs and Ts for someone else. I'm not much of a believer in thinking carefully  about  what I eat, mostly out sheer laziness. At the moment I'm doing well if I can keep the Purina cat chow out of my cereal bowl never mind avoiding purines. These are *very* fundamental building blocks however, so some caution in eliminating them from your  diet seems wise.

Also, re Lindhal, I believe it's a mistake to underestimate the influence her work has had. See for example Roche's ongoing VIRID clinical trial (id NCT00662220). If Roche is OK with plying pts with 23/25kg of rbv I felt safe taking 18.  

However mega rbv is no silver bullet either. Check out Lindhal's most recent study, published as Abstract 814 at last fall's AASLD.  (I posted the full text towards the bottom of a thread started by jmjm last Oct):

http://www.medhelp.org/posts/Hepatitis-C/Hello-and-well-wishes-from-Jim/show/1356108#post_6196601

Note only *1* SVR. Seems to show you can cook non-responders with rbv and coax 'em to respond but not quite shove 'em to SVR.

And yes, most word class hepas do seem to be guys. Holding forth in the manner of a  pompous arse seems a key part of the job and that comes so naturally if you've got a Y chromosome.

[merryBe]

argh...well duh...and maybe 2Y's and extra Y is thrown in, I don't know, maybe we should test em. ; )   ( same as a lot of prison guys ya know)

well because 1 and 3 take care of the rest hctn1 and 3 that is.  But since riba only goes through 2 thats all we need to be concerned with IMO, but just my guess.

yes riba alone doesn;t get there, but did you see the stats on CINF...just posted them to James on the IL28b thread.  They got half the non-resonders to SVR...obviously riba alone sukcs..just needs the synergy...

would value knowing what you think of my theory of eliminating the daily gap with CIFN, ridding ourselves of the 8 hrs with no INF (Half life is 4 hrs) might even improve the CIFN stats...can't imagine why no one thought of this.

for future reference, you might want to read the friskies bag and see how much inosine is in it  : ))))))))))))

[Trinity4]

    **************************************WARNING***********************************************

                      DO NOT ATTEMPT ANYTHING SUGGESTED ON THIS THREAD

This thread may contain information unsuitable for those undergoing or considering antiviral therapy. Suggestions or advice attempted by those unfamiliar with the original poster's views can or may result in serious injury.  The information contained within this thread has not been proven by any medical professionals and is pure speculation.  Please for your own safety DO NOT TRY ANYTHING ON THIS THREAD.

[willing]

Trin: huh ? What brought that on? The study MB originally cited:

http://www.ncbi.nlm.nih.gov/pubmed/19369574

Is a well-documented result in a major peer-reviewed journal. Nothing speculative about the basic result they reported:

"In conclusion, this study has demonstrated that a low-purine meal significantly increased Cmax and AUC0-144 of ribavirin by 36% and 34%, respectively, compared to a high-purine meal. This finding suggests that dosage may need to be adjusted accordingly for different patient groups with different amounts of purine in their diets. "

It's a stock bit of advice here to tell people to take their rbv with avocado, peanut butter, or other high-fat food to enhance absorption. The twist in what MB posted  is that there may be an entirely different approach to increasing bioavailability of rbv. Of course the health consequences of  a year of high-fat food or of a diet consistently low in purines is another issue.

MB: BTW, note that Lindhal's rbv dosing formula in her most recent paper is based not on weight/diet but on kidney function - likely the most significant factor in serum rbv concentration.

[James10500]

They were dosed 1 time with 600 mg's of Ribavirin in the study.  From my understanding Riba concentration builds in your body to the point of saturation, taking six months to get out of your system.

The drug companies say take it with  meal, they don't say high fat, or low purine.  My point is why take the drugs these companies make at all, if you think they don't know anything about bioavailability.  If they can't figure out how much works how can they even develop drugs.  Also this would mean that every person who didn't attain SVR did not because of bioavailabilty due to diet.  Meaning that all those people would have to have a similar high purine diet, highly unlikely.

[Trinity4]

I can disagree with thoughts willing.  It's one study from 2009 and only "indicates" that dietary purines have an effect on ribavirin absorption and that dosage regimens of ribavirin might need to be adjusted according to the purine content of the meal.  We've never heard another thing about that I know of.  

I think it irresponsible to suggest those who are undergoing antiviral therapy "kiss meat, fish and legumes goodbye and increase their carbohydrates.  How well would that bode with a diabetic or someone who is IR?   Oh, and least we forget let's use that low purine diet in conjunction with shooting interferon 3 x daily.  Geez!

Trinity

[nygirl7]

"Damn big pharma what do they know after all!"

Rocker4lilfe circa 2008 prior to getting SVR the second time around after participating in a PI trial and having one of the most strange strict diets I know of. Wonder if blueberries, mushrooms and wild whatever bark are full of purines and that is why he failed the first time? I'm pretty sure he didn't eat meat or coldcuts or anything like that yet he failed the first time too.

:O

[GoofyDad]

"In my case, the moment I found out about fat adding, and too much roughage harming Riba absorption I altered my diet, and went UND within 2 weeks of doing so, but prior to that I had not been able to get a good log drop"

Hmmm, Merry - my experience is quite the opposite. The more roughage I eat, the better my log drops are. Go figure.

----------------------------------------------------------------------------------
"having one of the most strange strict diets I know of."

Three pounds of beets, 2 almonds and a gallon of distilled water? What's strange about that?

[GoofyDad]

I must have ESP! How else did I quote NYgirl 4 hours before she posted her Rocker comments?

[willing]

it's quite a way from "disagreeing with thoughts" to stating "do not attempt anything suggested". On what grounds ?

Fact is, the reported increase in Cmax from a high-fat meal
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1804105/
is on the order of what that study reports for a low-purine meal. The fact that this is relatively new information was MB's point in posting it as I saw it (though there seems to be a pretty extensive literature linking CNT proteins to ribavirin absorption).  Going from one preliminary report to a significant change in diet is a leap I'm not ready to make - but it seems useful information to mull over.

Similarly, everyone on tx knows, up close and personal, the difference between the day after the shot and the day before the next shot ( a relevant point for me since today is shot day,  now 1/3 done!) That graph I copied to my photos shows the virus is also well aware of that difference. Pegylation is convenient but doesn't come close to providing uniform ifn concentration for a week. So there is a case to be made for splitting your shots.

I know a lot of these "home-remedies" border on the lunatic fringe. However, letting the lunatics run the asylum seems a good idea in my opinion.  Management (pharma and standard-of-clinical-care ) has clearly shown they are  incompetent (tx fails for half and no one knows why). There's not much to be lost by leaving us loonies loose to explore  alternatives.

[Trinity4]

2009 does not constitute relatively new information.  You're treating willing and not making much sense which is expected.  I'm sorry you don't like my methods of disagreeing but for as much as certain individuals think their information is irrefutable I have every right to refute it in whatever way I see fit.
Trinity

[mikesimon]

I, for one, certainly do appreciate a woman with some substance between her ears....and I'd like to think of myself as a quality man.

I hope you were talking about me because I'm feeling a tad flushed right about now. I think I might have a case of the vapors.

Oh yeah Trish - I agree with you on your point too....by the way.

Shivering,
Mike

[willing]

>You're treating willing and not making much sense
no argument there!! but you're not, so I tend to assume a cease-and-desist warning in BOLD LETTERS is more than unsubstantiated opinion.  

On the face of it, when one compares
http://www.ncbi.nlm.nih.gov/pubmed/19369574
and
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1804105/

it looks like  someone concerned about increasing available rbv but for whom fats are a problem (eg cardio/diabetic/IR risk) should investigate a lower purine diet. If there are dangers associated with doing that  it would be nice to hear about them.

Re 2009, things do move pretty fast around here, but not that fast. As a comparison point the original IL28B Ge et al Nature paper came out in '09 and that information is just starting to be incorporated in clinical use.

[Trinity4]

You are objecting more to the METHOD I've used to warn people not try this at home as opposed to what I'm actually objecting to and with all do respect I don't care if you think it was unfounded or not.  People are going to try all kinds of cockamamie things if they think it'll give them an edge.  When one considers the source and takes the limited amount of information available perhaps their judgement will not be negatively effected by the limited information we currently have; which by the way has no history of safe and effective use.   When one considers the source and once again the limited amount of information available perhaps their judgement will not be negatively effected or they can roll with it, let the chips fall and hope for the best.  I mean let's face it, there is always more than one cuckoo flying over the cuckoo's nest at any given time.  I don't care if someone eats rocks and injects interferon into their eyeballs.  All I can do is continue to say is BEWARE this MAY be hazardous to your health.  

Yours in Service
Nurse Ratched

[R Glass]

“Wasn't it funny how one guy saw that planets revolved around the sun and no on else would even look through the telescope but was sure he was wrong!!??!! “


It was Galileo and it was denounced because of the Fear of The Roman Inquisition not because they all new he was wrong without looking through the Telescope. If my memory serves me correct, he spent the remaining of his life under house arrest because of this theory. It is irrelevant anyway because his theory was wrong. The Earth Revolves Around Me.

[Bali05]

I predosed and highdosed Riba accompanied by lots of CBCs to monitor my HgB.From that experience I know that standard dosing alone would never have gotten my HgB to drop significantly during the crucial firstweeks of tx. If at the time I would not have had the possibility to increase Riba dosage I 100% would have tried a strict low purine
diet at least for a few weeks to see if it would make a difference.

Thank you Merrybe for making me aware of this study.


b

[merryBe]

Willing,

thank you. It's always refreshing when someone makes their points with the science.
whether someone thinks I'm on to something or not, at least when they make their points with science then we have a basis for further discussion.
It's rather comical when you stop to think that the same folks saying I'm crazy now will be jumping on the band wagon to take the first trial drug to cross the finish line and win approval...of the group aimed at greater riba absorption.


Bali,
I think you hit the mark, I think the early high dose will prove to have been as good a stratgeum over time as any other, and, since you know the stakes and didn't want a repeat of tx I think you did what many patients (and docs who treat as well) have decided is one way around the connundrum. From what I've read of higher dosing of INF that is the worse, harder on the body and less essential thing to up the dose on, but Willings point about the peg is valid and one I alos made recently....but since INF since absoption of that is not an issue like riba,  it's good that if you were going to do one thing to increase your chances you choose higher riba. I salute your efforts.

Goofydad,
that's why I said I wasn't convinced about the fiber part of the equation, because the vegetarians cleared at a higher rate, and they eat lots of fiber. It may be why certain genos have higher clearance, like in asia where the diet contains much less meat.
In any case, I said I was certain about the fat helping, but not whether the fiber hurt as some have said.
At least in some posts I brought this up. However, there is one thing that might be important about fiber, in an american gut, a person who wasn't used to fiber, and didn't have much healthy bacteria could see things move way too quickly through the system... if they statrted adding more...and the quicker things go through the less time for absorption to occur, so from that standpoint, I think maybe a smooth calming type food with the riba would be a better choice for optimal absorption.
Moving even an hour or 2 more slowly through the intestines would allow more riba to get through the lining. Again, the first few days and weeks are when this might help folks the most.

Trin,
you make none of your counterpoints with any science, ergo I'll play the cuckoo to your nurse rachet and consider it a priveledge. Nurse Rachet only wanted to dope folks up, dumb them down, shut them up and/or lobotomize them. I'd rather see them well, and set them free!!


to all

I am not suggesting anyone eliminate proteins, any one who READS my posts will realize that.  I AM suggesting that low protein at the 2 times one takes the riba PARTICULARLY in the beginning weeks of treatment may be wisdom, and eating our proteins at different times may be best just to get the antiviral medication to optimal levels.
The name of the game is to treat successfully, even if that does mean less cheeseburgers at certain times of day for a while for a while. But to each his own.

mb

Is it just me...or is this the same kind of reception that greeted Cowriter with her insulin information?  Are we wanting to help people get well in here, or just too afraid of dietary changes to have an honest discourse??

[GoofyDad]

I fear we're talking different log drops. One woman's logarithms are another man's Charmin busters.

FWIW, I'm pleased to see this info hit the light of day.

[merryBe]

thanks for the levity!!

Rglass...yeah, and he also muttered 'AND YET IT MOVES' ...did he not...truth is truth?

Goofy dad...well you can squeeze my charmin anytime dad!!
FWIW so am I, sigh.  We need to see more folks succeed with treatment!!!

[Trinity4]

"Nurse Rachet only wanted to dope folks up, dumb them down, shut them up and/or lobotomize them."

Nothing wrong with that.  :)

[Trish77]

"I, for one, certainly do appreciate a woman with some substance between her ears....and I'd like to think of myself as a quality man.

I hope you were talking about me because I'm feeling a tad flushed right about now. I think I might have a case of the vapors.

Oh yeah Trish - I agree with you on your point too....by the way.

Shivering,
Mike"

You should put some clothes on then, Mike.  Running around exposed like that.  And in the middle of winter.   Your comments given the usual due consideration.

[mikesimon]

I wasn't naked Trish. I guess you've never had a case of the vapors.

Mike

[Trish77]

I would imagine one can have a case of the vapors clothed or unclothed. You were shivering, Mike.  Made me wonder.  Hope you've recovered.

[nygirl7]

Boy Michael somebody has the hots for you no wonder you are shivering :D

[nygirl7]

I must have ESP! How else did I quote NYgirl 4 hours before she posted her Rocker comments? "

Goofy once again you totally read my mind I was wondering the exact same thing!

[merryBe]

hey it's been lively, and that's refreshing.

BTW I will try this approach, definitively I will nix the purines at riba times.
Once I saw the science on fat absorption it made infinite sense, and more importantly it did WORK, for me, I had zero fat in my diet, so that may be why I could not get a good drop.

But this info about the presense of purines preventing all absoption are too compelling to be ignored.

For those interested the URIDINE  uridine is high in b bitamins supplements, brewers yeast, organ meats, molasses, and tomatoes.

so basically add the tomatoes and the molassess to the NO LIST for purines above, and you've got it.

mb

[merryBe]

As much as I appreciate folks in here, I have to say that sometimes we are a little knee jerky in our responses.

If I was bringing in info telling you to eat your toe cheese from some quack site I could see the reactions.
However, if the information has peer review, is done within the medical community and using scientific methodology then it seems to me it should receive a fair viewing and hearing before being pronouced as heretical. (I did ask a biologist to review the methodolgy BTW, as I did not assume any of you would take my word for it, and he did approve.)

Fair implys that we study the information for ourselves before jumping to the conclusion that it has no merit. It also implies if we don't understand a topic we don't assume it must be horsestuff. It's OK not to understand a topic, but not ok to diss it when you don't.

Being dismissive on a personal level which also has been employed here doesn't help ones case the next time YOU want to make a salient point, I'd rather take the points of others seriously but it becomes more difficult to take seriously those who regularly accuse others of being crazy and the like.
Toning down such verbiage will assure one of future mutual respect, but continual belittlement only diminishes the verbal abuser, in everyones eyes, and it compromises the integrity of the forum..

I have been helped by many in here, and had my eyes opened by members both with a without medical training; intelligent members who take seriously their responsibility towards the sciences and towards each other.
What I have learned from picking the brains of those who actually read and understand what they read has far exceeded what I could have hoped for, and I will be forever grateful to all who have labored to keep abreast of and bone up on this dread disease.
Without you all, I'm sure I would be far behind the curve and hopefully that is not the case entirely any longer. I'm far from knowledgable compared to some, but hopefully the years spent choking on medical papers is starting to pay off somewhat.

Nevertheless we need to remind ourselves of what happens when folks are not given a fair hearing.
First of all patients are pushed away...they run from here, or they write to say that they only feel comfortable with a couple people on the board. That's sad.
Secondly there have been more than a few professionals who have moved on due to some of the knee jerk reactions in here. More than a few. You older members know the truth of this.
We are one of the very few places that do discuss such things as advances, treatment options and adjuncts, so it just makes no sense to stifle research or thoughts that may help when we really are not familiar with a topic, yet I've seen it happen many times, often to people with far more knowledge than those members who do the most questioning.

Think of whom we have had come in here and try to educate us, microbiologists, chemists, geneticists, radiologists, a dialysis specialist, a diebetic (diabetic) specialist, one of the leading hcv researchers in the world, the list goes on and on.

My thinking is that we need to engage, cherish and not accuse the educated amongst us, the better to learn more. The better to keep them here!!
Also I think the time has come to try and get our minds around WHY something might not work BEFORE we try to debunk it and then, if we must to do so with proofs.

I would rather see us debunk something, like for instance when the "OZONE" lady came in
this month we were able to dissuade her, than to see a thread cencored where we try to debunk we know not what (because the link was bleeped out) and then members tried to debunk it anyway without even knowing of what they spoke.
Doesn't that make us just look foolish and reactionary?? Trying to debunk we know not what only makes it apparent that reactionism has reached a crecendo at times, and it serves no purpose except to make us look like an unimformed herd if we throw mud at something without even knowing what it is we are throwing mud at.

I very much appreciated Willings approach which was to study the info first, and then say why it may or may not have had merit.
Therefore I'll give him the best answer on this thread, because he read the studies I gave, and then discussed, and THAT is what will most help other people which is the whole point.

I could just have easily have kept all this to myself, I've done that a lot this year...or brought it to the few board members who are receptive to new ideas, but because this might help so many more folks to get well I felt it was important to bring it in here to everyone....knowing I might take some heat...and ya'all did not disappoint on that note.

Nevertheless, in my view if this helps even a few folks it was worth the grief.

mb

[Susan_1a_CC]

This thread caught my attention early on and then it caused me frustration.  What I would find helpful is that one avoid making blanket conclusions that are stated as fact when one hasn't yet reached the final steps of the scientific method:

Ask a Question
Do Background Research
Construct a Hypothesis
Test Your Hypothesis by Doing an Experiment
Analyze Your Data and Draw a Conclusion
Communicate Your Results

There are so many variables that I do not think it possible to draw a conclusion as a lay person - which is not to say that I wouldn't suggest that there are "generalizing orientations" that can be pointed to as possibly being indicative of an outcome.

Here's an example, of things most recently written, that I as a reader wouldn't want others to take as "fact":

"Once I saw the science on fat absorption it made infinite sense, and more importantly it did WORK, for me, I had zero fat in my diet, so that may be why I could not get a good drop."

This is not at all helpful to the master controller of the body - the brain.  The brain is largely fat and depriving it of what it needs leads to a number of potential medical problems.  Was the added fat you took and accredit to your success actually r/t riba absorption or possibly your brain finally had the fuel it needed to direct a number of other intricate processes that accounted for or contributed to your success?
___________________________________________________________________________
"But this info about the presense of purines preventing all absoption are too compelling to be ignored."

Are any conclusions yet available?  Purines prevent all absorption???  How did anyone ever SVR if that's the case?
___________________________________________________________________________
"For those interested the URIDINE  uridine is high in b vitamins supplements, brewers yeast, organ meats, molasses, and tomatoes."  

And SAMe has been shown to increase rates of SVR.  SAMe has increased absorption and efficacy when taken with B vitamins.

I'm all for looking outside of the box but not all for drawing conclusions without proper methodology.  

[Trinity4]

Very much my thoughts Susan.  If someone is so hell bent on something they should try it on themselves and report back with the results.  That should prevent the "I'm so misunderstood" theory as well.

Trinity  

[Bill1954]

Susan, I think what you’re talking about is ‘evidence based medicine’:

http://en.wikipedia.org/wiki/Evidence-based_medicine

There are topics that have been touched on in this… ahem… discussion that might have research merit, but guidelines for EBM haven’t been implemented.

-Bill

[willbb]

Fortunately most of us here don"t have C.difficile,..,imagine the debate on how much Sh.t we should eat.

[Trish77]

"And SAMe has been shown to increase rates of SVR.  SAMe has increased absorption and efficacy when taken with B vitamins. "

this is totally aside from this issue...but this is where your comment is.  I think I've seen you state this before.  While I've seen data that shows SAMe contributes to early viral load drop, I haven't seen any data that shows where that has also translated to increased SVR in the same groups.  The studies themselves have stated this, that increased SVR rates were not achieved, only early viral load drops.  Increased early viral load drop is not a bad thing to aim for and I would probably include SAMe myself if treating again - I just haven't seen any data personally that has stretched this into increased SVR rates from SAMe as well.   If you have information that shows a corelation between the early viral load drop from SAMe and increased SVR rates, can you please post this, since you're stating it?  It would be useful information.  

[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.

[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.  

[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 ...

[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!!!

[child24angel]

My eyes hurt, they are not merry at all.

[eureka254]

Purines won't work but Murine might ;).

[child24angel]

:) got it :)

[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.

[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

[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.  

[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.

[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

[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?  

[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.

[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]

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]

"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]

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

[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.

[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

[ellen1960]

Good comment, you make a lot of sense.

[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.

[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.

[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