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Author Topic: New Regimen-Class based solely on entry inhibitors possible?  (Read 5055 times)

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Offline Customer

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New Regimen-Class based solely on entry inhibitors possible?
« on: August 06, 2006, 08:50:39 AM »

http://www.aidsmap.com/en/docs/BA7BF47D-D8FF-4CC8-8B8F-4FBA8775C32C.asp

In vitro research has suggested that T-20 and other entry inhibitors may produce a synergistic antiviral effect, although this is yet to be demonstrated in clinical studies (Nagashima 2001; Tremblay 2001).

Furthermore, HIV that is resistant to T-20 is less fit that wild type virus, suggesting that people may continue to get clinical benefit from T-20 even after the development of resistance (Reeves 2005).


----

There will soon be a few new entry inhibitors on the market. Combining 3 or so entry inhibitors each having a diffirent target (gp41, CCR5..) could potentially form (an independent) regimen class.

The entry inhibitors do not mess with protein encoding and production process inside the cell, and therefore the side effects are milder, if any.





Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #1 on: August 06, 2006, 10:06:38 AM »

http://cmbi.bjmu.edu.cn/cmbidata/SARS/pdf/86.pdf


...These findings suggest that there may be good prospects for potent combinations of entry
inhibitors,just as HIV-1 protease inhibitors or reverse-transcriptase inhibitors are administered together today.

Tremblay C,Kollman C,Giguel F,ChouTC,Hirsch MS.Strong in vitro synergy observed between the fusion inhibitor T-20 and a CXCR4 blocker,AMD3100.cell fusion.J Infect Dis 2001;183:1121-5.

Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #2 on: August 06, 2006, 03:07:08 PM »
http://www.aidsmap.com/en/docs/41FC5E2A-7CCC-482E-AC20-137D77F93229.asp

Researchers from Progenics have tested a combination of T-20, PRO 542 and PRO 140 individually and in combination against test tube samples of HIV to see whether the drugs could boost each otherís effects (synergy). T-20 (Fuzeon) and PRO 542 were found to be synergistic, to such an extent that when used together, concentrations of the drugs required to inhibit HIV replication could be reduced 30-fold in comparison with the concentrations required when used individually.  

http://jac.oxfordjournals.org/cgi/content/full/54/2/333

Combining bicyclams (CXCR4 antagonists) with fusion blockers such as T-20 is also a developing area of research. Such a combination would target several sites of fusion, potentially creating a potent anti-HIV treatment. Strong synergy between AMD3100 and T-20 was observed in test-tube studies, but AMD3100 has now been discontinued due to cardiac toxicity.

A further strength of enfuvirtide and other entry inhibitors lies in their potential inter-class synergy.27,34,36,39 Enfuvirtide is the fourth drug in treatment options available to antiretroviral-experienced patients, including HAART regimens using NRTIs, NNRTIs and PIs. The development of drugs with different extracellular targets in the future may even lead to the possibility of potent extracellular regimens (E-HAART).53 Synergy has already been seen with enfuvirtide and the other entry inhibitors (i.e. AMD3100 and SCH-C)34,39 and in the future there may be the potential for E-HAART regimens.




« Last Edit: August 19, 2006, 04:37:12 AM by Customer »

Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #3 on: August 06, 2006, 03:44:26 PM »
How i understand the synergetic effect: If the probability of HIV developing a resistant mutant to drug A is 0.05% during one day of drug usage, then the probability of HIV developing a resistant mutant to combination regimen containing three drugs A, B, C (each attacking different protein), is 0.05% * 0.05% *  0.05% = 0.00000001250 %. All mutatations need to occur simultaneously, to generate a surviving species, which reduces the probability exponentially.

As it was mentioned in the texts above, even if mutation occurs, the HIV-species is less fit, not able to multiply rapidly. This also applies to E-HAART (extra-cellular HAART): if a super mutation would take place, the strain that would be able to survive in E-HAART environment would be seriously disabled/handicapped.
« Last Edit: August 06, 2006, 03:50:49 PM by Customer »

Offline HIVworker

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #4 on: August 06, 2006, 04:35:36 PM »
All good stuff customer. What do they say of the potential tropic switch from CCR5 to CXCR4. I know there have been some studies on this and they did see it, but the million dollar question is does this tropic switch speed the progression to AIDS? I have heard second hand of the tropic switch from a conference, but not about AIDS. Any news?

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #5 on: August 06, 2006, 05:37:45 PM »
Co-receptor inhibitors blocking CXCR4 are being being developed. Whether these attempts will be successful or not, blocking the infection route CCR5 reduces the virus replication rate. And maybe it is anough to block CXCR4 route by Fuzeon or some other virus attacking drug.


http://www.bentham.org/cdtid/samples/cdtid5-1/0002S.pdf

The most potent and specific CXCR4 antagonists are the
bicyclam derivatives (AMD3100 and AMD070). AMD3100
was selected as the clinical candidate, which, after initial
Phase I studies, proceeded to Phase II trials. In these trials it
was demonstrated that AMD3100 was effective in suppressing
X4 HIV-1 replication [168]. However, targeting CXCR4 by
AMD3100 showed significant cardiac side effects, which led
to its withdrawal from further development as an anti-HIV-1
agent [137,169].

The theoretic concern exists that blocking CCR5 could enhance the
AACs and Tat bind to similar cellular targets. The most
emergence of CXCR4-using variants and possibly accelerate
disease. So far, in vitro selection for variants resistant to the
CCR5 antagonist SCH-C in PBMC (which express both
CCR5 and CXCR4) has resulted in mutants that were
resistant to this inhibitor but still used CCR5 (reviewed in
[211]). Alternatively, because many HIV-1 strains have the
capacity to use several other chemokine or orphan receptors
for entry, blocking both CCR5 and CXCR4 could lead to a
variant that uses one of these other molecules in place of the
principal coreceptors. This new class of antiviral drugs offers
great promise but also novel concerns, and careful analysis
of viruses that arise with their use in vivo is essential.


So far, studies of interactions between attachment
or coreceptor inhibitors with fusion inhibitors have shown a
high level of synergy [213-215]. Similarly, targeting gp120
and gp41 with monoclonal antibodies in the presence of
CD4-based molecules also showed synergistic inhibition of
the HIV-1 envelope-mediated cell fusion process [216].



Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #6 on: August 06, 2006, 05:54:26 PM »

BTW, this is taken from the same article.

Other multi-target inhibitors have also been described.
For example, Tannin, a polyphenolic compound extracted
from a Chinese medical herb, inhibits HIV-1 entry into cells
by interfering with the gp41 six-helix bundle formation, thus
blocking HIV-1 fusion [200]. Interestingly, Tannin inhibits
also HIV-1 reverse transcriptase [236], protease [237], and
integrase [238] activities.


Offline blondbeauty

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #7 on: August 06, 2006, 05:57:17 PM »
Is it possible to develop these entry and fusion inhibitors in pill form?
The only member in these forums approved by WINBA: World International Nail and Beauty Association.
Epstein Barr +; CMV +; Toxoplasmosis +; HIV-1 +.
Counts when starting treatment:
V.L.:80.200 copies. CD4: 25%=503
Started Sustiva-Truvada 14/August/2006
Last V.L.count (Oct 2013): Undetectable
Last CD4 count (OCT 2013): 52%= 933

Offline HIVworker

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  • HIV researcher
Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #8 on: August 07, 2006, 07:14:54 AM »
Everything but Fuzeon, yes.
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline Customer

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  • Posts: 98
Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #9 on: August 07, 2006, 12:26:11 PM »
http://greentealovers.com/greenteahealthcatechin.htm


Primarily for those drinking green tea to heal through its active ingredient: Catechin. Tannin in green tea is mostly catechin and forms a key component in its astringent taste.

Catechin - Catechin is a tannin peculiar to green tea because the black tea fermentation process reduces catechins in black tea. Catechin is a powerful, water soluable polyphenol and antioxidant that is easily oxidized.  Several thousand types are available in the plant world. As many as two thousand are known to have a flavon structure and are called flavonoids. Catechin is one of them.

Research aimed at finding the active compounds in green tea revealed that its protective effects are due chiefly to catechins. Tea contains four main catechin substances: EC, ECg, EGC and EGCg, all of which are inclusively called catechin. Epigallocatechin gallate (EGCG) is the most powerful of these catechins. EGCG as an antioxidant is about 25-100 times more potent than vitamins C and E. One cup of green tea provides 10-40 mg of polyphenols and has antioxidant effects greater than a serving of broccoli, spinach, carrots, or strawberries. The high antioxidant activity of green tea makes it beneficial for protecting the body from oxidative damage due to free radicals. Research shows that green tea may help the arterial wall by reducing lipids. Green tea can protect against experimentally induced DNA damage, and slow or halt the initiation and progression of undesirable cell colonies. Studies show evidence that green tea provides immunoprotective qualities, particularly in the case of patients undergoing radiation or chemotherapy. White blood cell count appear to be maintained more effectively in patients consuming green tea compared to non-supplemented patients.




Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #10 on: August 07, 2006, 04:50:35 PM »
There is synergy between TNX-355  and fuzeon, too.

http://www.aidsmeds.com/news/20060707drgd001.html



Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #11 on: August 07, 2006, 05:04:46 PM »
Fuzeon is synergetic (mutual boosting effect) with:

AMD3100 (discontinued)
PRO 542 (Phase II) a CD4 decoy
TNX-355  (Phase II) blocks CD4

Propable synergy with:

Maraviroc (UK-427) binds to a protein on the membrane of T-cells called CCR5.
Vicriviroc (SCH-D) binds to a protein on the membrane of T-cells called CCR5.


Many of these drugs will emerge to the market in two years. What do you think about the cocktail:

Fuzeon (gp41, gp120)
Maraviroc (CCR5)
TNX 355 (CD4)


A full house...I think that that HIV-guy is not going to have so much fun anymore.... he is gonna have hard time in trying to enter any T-Cell.

« Last Edit: August 19, 2006, 04:50:54 AM by Customer »

Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #12 on: August 13, 2006, 03:53:33 PM »
One promlem with CCR5 and CXCR4 blocking proteins is that normal functionalities of T-cells could be supressed. This came to my mind when reading


"Possibly, the attachment of gp120 to CD4 also inhibits the function of the CD4 T-cell. " (http://www.aidsmap.com/en/docs/47453364-17E9-44B9-9B41-0D4586517718.asp)



Offline john

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #13 on: August 14, 2006, 05:08:47 PM »
These are great posts. I am confused, If you have the x4 variant Would standard therapy still help or are you sunk. My doctor never told me which virus I carry. Also. Even with EI therapy couldn't you still add other drugs. (Integrase, PI or something else)?
Jon be good

Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #14 on: August 18, 2006, 01:47:15 PM »
X4-virus-variant uses CXCR4 for entry.

If your E-HAART cocktail contains TNX-355, i suppose it would be effective against X4-variant as well.


http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/08-03-2006/0004410128&EDATE=

TNX-355 is a humanized monoclonal antibody and part of the viral-entry
inhibitor class of HIV therapies. TNX-355, which is administered
intravenously, is distinct from other entry inhibitors in that it binds to
CD4 receptors -- the primary target of HIV infection. Since TNX-355 blocks
HIV entry at a step prior to the co-receptor interaction, it is
"co-receptor tropism independent," with the ability to block both CCR5- and
CXCR4-tropic viruses
. The blockade presented by TNX-355 also does not
depend on targeting a mutation-prone viral protein. TNX-355 has a Fast
Track designation from the FDA.


Nice vids!:
http://www.tanox.com/TanoxMovie/MovieTNX355.htm


X4-virus variant is as vulnerable to standard HAART as R5-variant, since standard HAART does not operate on entry phase mechanisms.



« Last Edit: August 18, 2006, 03:43:33 PM by Customer »

Offline MitchMiller

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #15 on: August 18, 2006, 10:13:32 PM »
Sounds like a $50,000+ regimen to me!  Highly impractical due to costs.

Fuzeon $24,000 +
TNX355 $18,000 +
Maraviroc $12,000 = $54,000/year!!!!

« Last Edit: August 18, 2006, 10:15:35 PM by MitchMiller »

Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #16 on: August 19, 2006, 02:59:40 AM »
One way to reduce costs is intermittent treatment.

http://www.aidsmeds.com/news/20060816drgd003.html


The next step is to conduct a large, randomized prospective trial to confirm these findings. If this is achieved, she concluded, HAART may "become an intermittent treatment rather than a continuous treatment."



There are several possible drug-combinations for E-HAART, for instance


Fuzeon (gp41, gp120)
PRO-542 (CD4 decoy)
Maraviroc (CCR5)

This combination drug, has proven synergy between atleast two components (Fuzeon and PRO-542). And one must remember the following: Fuzeon and PRO-542 do not interfere with normal T-cell operation, specially the intra cellular activities. Fuzeon and PRO-542 are direct attacks on the virus, separating them from all other classes of drugs, separating them also from other entry inhibitors. I suppose Fuzeon and PRO-542 are the safest form of HAART when long-term side effects are concerned.

Two drugs is better than one. And three is better than two. Also two-drug combinations could be tried:

PRO-542 (CD4 decoy) + Fuzeon  (gp41, gp120)
,or
PRO-542 (CD4 decoy) + Maraviroc (CCR5)
, or
TNX335 (CD4) + Maraviroc (CCR5)
,or
TNX335 (CD4) + Fuzeon  (gp41, gp120)


Observe: CD4 blockers such as TNX-335 should not be used in combination with PRO-542 because CD4 blockers will probably also block PRO-542.


I am not medical expert. These are just speculation based on common knowledge. It has disturbed me that so little attention has been paid to E-HAART even if the tools to accomplish it will be in the pharmacies with in few years.

« Last Edit: August 19, 2006, 04:47:19 AM by Customer »

Offline MitchMiller

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #17 on: August 20, 2006, 01:04:36 AM »
Be patient.  The cost of Fuzeon is one of the main reasons why it just can't be considered for any but the most deperate patients.  I would have also thought the side-effects would be minimal, but I've heard from some using it that that isn't the case.  It can cause severe dry skin and egg sized welts at the injection sites.  Recently a poster in a trial involving Fuzeon said he would have reconsidered had he known the side-effects he was in for. 
TNX-355 has to be intravenously administered.  I read it takes about 30 minutes on a IV to get it in... but only once/week.  However, that makes it rather impracticle to use... and it has been tested as a monotherapy and resistance quickly developed.
If Marviroc makes it to approval, I think Pfizer will be smart enough to price it around $1000/year (I say that meaning they could go much higher!)... because they would like it to position it as at least a second line drug and possibly first line drug.  That seems to be where the big $$$ are.  Hopefully others will follow and your speculation will become a reality... but I think it's at least seven years out.
If you're looking for a drug that might have fewer side-effects, look at the integrase inhibitor.  It targets something that is not known to occur naturally in the body, so it seems logical to think side effects would be fewer (or at least that's what I've read)... and it's very potent and in phase III trials (Merck).

Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #18 on: August 20, 2006, 06:21:07 AM »

I can well understand why TNX355 administered as monotherapy developed resistance... it is exactly for the same reason PI- and NRTI monotherapy developed resistance in the begining of HAART era. Combination therapy decreases the risk of resistant mutation dramtically. It is sort of waste of meds to use Fuzeon, TNX 355 or PRO542 as monotherapy - atleast one additional entry inhibitor should always be present.

I hear these injection site reactions are nasty. Lets see whether TNX355 could be formulated so that it can be mixed with Fuzeon and injecting as mixture at the same time... or something. Maybe i got carried away a little bit?



Offline john

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #19 on: August 23, 2006, 02:54:04 PM »
A friend of mine is diabetic and he wears a pump that administers his insulin automatically. Wouldn't it be possable to due the with t20 and any other injectable forms of anti viral. I realize it could be complicated, but wouldn't injection site reactions be a thing of the past. Just my 2 cents
Jon be good

Offline Customer

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Re: New Regimen-Class based solely on entry inhibitors possible?
« Reply #20 on: August 25, 2006, 01:19:22 PM »
Fuzeon injection topics:

http://forums.poz.com/index.php?topic=3125.0
http://forums.poz.com/index.php?topic=2240.0

http://ra.disabilityexpo.com/unique/bioject.htm

The Biojector 2000 Needlefree Injection Management System delivers medications parenterally without a needle. Instead, the Biojector uses compressed carbon dioxide (C02) as a safe power source to eject medication through a micro-orifice within a fraction of a second. This delivery action effectively penetrates the skin and delivers the medication into the patient's tissue.

http://www.inc.com/magazine/20020201/23833.html

A fine spray of medicine in liquid form then shoots out the front of the Biojector 2000 at 520 miles per hour. The medicine travels fast enough to create a minuscule hole -- no wider than one four-thousandth of an inch -- in the skin


« Last Edit: August 25, 2006, 01:26:13 PM by Customer »

 


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