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ezetimibe peg add on trial on hcv
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ezetimibe peg add on trial on hcv

very interesting trial, although on hbv ezetimibe might be weaker.for those not aware of ezetimibe studies

Ezetimibe blocks hepatitis B virus infection after virus uptake into
hepatocytes.

http://www.medhelp.org/posts/Hepatitis-B/Ezetimibe-blocks-hepatitis-B-virus-infection-after-virus-uptake-into-hepatocytes-/show/1868002


The efficacy of ezetimibe add-on with combination peginterferon plus ribavirin therapy in patients with HVC

http://astp.jst.go.jp/modules/search/DocumentDetail/0451-4203_51_11_The%2Befficacy%2Bof%2Bezetimibe%2Badd-on%2Bwith%2Bcombination%2Bpeginterferon%2Bplus%2Bribavirin%2Btherapy%2Bin%2Bpatients%2Bwith%2Bchronic%2Bhepatitis%2BC_N%252FA


Title: The efficacy of ezetimibe add-on with combination peginterferon plus ribavirin therapy in patients with chronic hepatitis C
Author: Kazuo Notsumata; Masataka Kanno; Hisato Matsuda; Taku Sanada; Koichi Shin; Shotaro Kosaka; Hiroyuki Watanabe; Daishu Toya; Nobuyoshi Tanaka; Yoshiko Sudo; Shiro Miyayama (Department of Internal Medicine, Fukui-ken Saiseikai Hospital; Department of Pathology, Fukui-ken Saiseikai Hospital; Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital)
Source: Kanzo; ISSN:0451-4203; VOL.51; NO.11; PAGE.607-614; (2010)
Pub.Country: Japan
Language: Japanese
Abstract: The efficacy of the administration of ezetimibe, a cholesterol transporter inhibitor, concomitantly with combination peginterferon alfa-2b (PEG-IFN) plus ribavirin (RBV) therapy was retrospectively examined in patients with chronic hepatitis C (CHC). The subjects examined were 334 HCV genotype 1 high titer patients (44 receiving ezetimibe, 290 not receiving ezetimibe) treated with PEG-IFN/RBV in our hospital for whom conducting assessment of HCV RNA-negativity from the start of treatment to Week 12 in treatment (EVR: less than 50 IU/ml by Amplicore method) was performed. The EVR rate was 65.9% in the group receiving ezetimibe, which was significantly higher (p=0.002) compared to 45.2% in the group not receiving ezetimibe. In multivariate analysis, concomitant administration of ezetimibe was selected as a factor contributing to EVR (odds ratio: 2.993, p=0.004). The cumulative HCV RNA negativity rate was also significantly higher in the group receiving ezetimibe (p=0.0035). However, a tendency of higher EVR rate was observed with the group receiving ezetimibe than with the group not receiving ezetimibe regardless of the presence or absence of hepatic steatosis in pretreatment liver biopsy.
The results suggest the possibility that the concomitant administration of ezetimibe might be useful for improving the results of PEG-IFN/RBV treatment in CHC.
15 Comments Post a Comment
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Avatar_m_tn
here s a link to full study in japanese, i dont know how to translate it

https://www.jstage.jst.go.jp/article/kanzo/51/11/51_11_607/_pdf

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Avatar_m_tn
Trust you to find the article! To read it, you use Google Translate (translate.google.com) to translate block by block of text.

Ezetimibe was used to test the hypothesis that lipid mechanism affects the effectiveness of PegIFN + Ribavirin, in the sense that if you are lower in cholesterol, you respond better to treatment.

This is my understanding after a quick translate.
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Avatar_m_tn
doesn t work on google translate, pdf doesn t keep format

no the point is not cholesterol but to block viral entry, hbv, hcv and hdv share ntcp receptor which is blocked by ezetimibe, i wanted to know the doses used on these trials

i also found another in vivo testing to mice with human livers.they blocked hcv infection by ezetimibe only but also there i could not find full text or ezetimibe doses used
http://www.nature.com/nm/journal/v18/n2/full/nm.2581.html

i have used ezetimibe in 2013 combo with tdf+etv for about 3-4 months, of course not the best combo to see results because pegintf is best.hbsag decreased very little about 500-800iu/ml impossible to say if it was ezetimibe

i was just interested to see the doses used on these trials.ezetimibe has been used to the max dose of 120mg/day without sides for months, no study on toxicity at higher doses because 10mg is more than enough for cholesterol but for ntcp much higher doses are needed for sure
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Avatar_m_tn
you are right the copy piece by piece works on google translate, thanks
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Avatar_m_tn
http://www.merck.ca/assets/en/pdf/products/EZETROL-PM_E.pdf

there s new data about toxicity, i didnt see it in jan 2013 when i tried ezetimibe, toxicity is extremely low:
http://www.merck.ca/assets/en/pdf/products/EZETROL-PM_E.pdf

acute toxicity
In animals, no toxicity was observed after single oral doses of 5000 mg/kg of ezetimibe in rats
and mice and 3000 mg/kg in dogs.

Ezetimibe (1000 mg/kg) was co-administered with either simvastatin (1000 mg/kg) or lovastatin
(1000 mg/kg) by oral gavage to mice and rats. All animals survived. There were no clinical
observations of toxicity and no effects on body weight parameters. The estimated oral LD50 for
both species was > 1000 mg/kg of each co-administered agent.

Chronic Toxicity (ezetimibe alone)
Ezetimibe was well tolerated by mice, rats and dogs. No target organs of toxicity were
identified in chronic studies at daily doses up to 1500 and 500 mg/kg in male and female rats,
respectively, up to 500 mg/kg in mice, or up to 300 mg/kg in dogs.
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Avatar_m_tn
the link above doesn t work, if so just go to home page and type in search box"ezetimibe peginterferon"

https://www.jstage.jst.go.jp/browse/

this trial used 10mg ezetimibe only, too low since animals in vivo used 10mg/kg to block infection of the liver by hepatitis viruses although use of peginterferon may allow response at lower doses, also to keep in mind that ED50 for hbv was 3-6 times higher than hcv


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Avatar_m_tn

since many of us are in the sequential treatment (3-5years of tdf or etv) and are going to add on pegintf, do you think we can try ezetimibe or Irbesartan again?

what tests can we use to see if they work with pegintf?

hbsag test is not very reliable at start because there is hbsag increase when adding pegintf at first, the response is after 4-6 months, at least lampertico study reported this (i think this is the only study with detailed charts for every single patient)

shall we test bile acids in blood taking the pills 2 hrs before the test?

i think the key is probably ezetimibe dose and of course the use of it with pegintf, my previous trial with ezetimibe+etv+tdf failed or just had little hbsag decrease
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Avatar_m_tn
here is lampertico poster

http://cdn.f1000.com/posters/docs/249857490
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Avatar_m_tn
Acctually noone in this study lost hbsag after the combo sequential treatment.
Is there any study that proves that this sequential treatment works?
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Avatar_m_tn
Ezetimibe might work moderately in ways not related to ntcp blockage, so it is possible that some benefit can be had in adding it to the tdf ifn combo.
We have detailed knowledge now that ntcp blockage has to be very high to achieve a realistic inhibition of HBV entry this way. Myrcludex in doses 20mg or more are needed to block ntcp sufficiently to limit reinfection to the extent needed. At these doses bile acids will rise into the hundreds during the day and their toxicity will be felt as substantial sides. Ntcp is very busy and needed to bring back the bile acids from the portal blood into the hepatocytes to recycle and more importantly to protect the rest of the body from their toxicity. It is unlikely that even the new 5 and 10mg doses used in the new Russian trials will achieve much, maybe in combo with ifn at a high rate of infected cell turnover.
So in summary, ezetimibe or irbesartan are no match to the power of myrcludex to inhibit ntcp, but it needs to be blocked so strongly, that the side effects from impairment of its natural function become the limiting factor.

The experiments with the chimeric mice used a dose of 2mg per kg and the human part of the chimeric liver only contains ntcp and needs to be blocked. The mouse liver has other transporters to clear the bile acids from the portal blood and furthermore, mice do not complain...So it worked well in that system.
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Avatar_m_tn
consider that all had declining hbsag except one and that sides are almost non exsistant.....today i spoke to researchers on these trials and most patients reported very light sides if none, so the point after these first trials will be the use of peg add-on on responders until hbsag is cleared or use staggered schedules like this (which are already clinical practice here on responders):
nucs
peg+nucs
nucs
peg plus nucs again or peg mono until hbsag is cleared

i see there is only one problem to the massive use of these combos, cost for public healthcare...we need soem patents to go and fast.actually i saw soem articles about both entecavir and tenofovir patents to be invalid
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Avatar_m_tn
i think etv already lost it, not very sure if appealed, an israel company should be allowed to make the generic
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Avatar_m_tn
what about 100-200mg ezetimibe daily in the pegintf plus tdf combo?do you think it can have any chance to improve peg response?
of course i dont mean to block reinfection at a great level but just to improve peg response like in the hcv trial

thank you very much
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Avatar_m_tn
That high dose of ezetimibe might have some effect to shift the percentage of responders. It's effects are less likely to show in HBV than in HCV.
A problem might be the high price for the ezetimibe. At least it's toxicity is so low that we are not worried about that. At this dose it still will not inhibit the ntcp to the extent that you have a problem with the bile acids.
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Avatar_f_tn
Glad to see studyforhope again providing hope for hopeless people through his sound scientific knowledge of the subject.
Please folks, we need to develop a way in this community to actually show appreciation to the people that offer the time and skills to others.
May God bless and reward you immensely.
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