Re: R5 inhibitor caution

[Guest guest]

I can understand how difficult it can be to accept the idea that lipodystrophy is caused by AZT and d4T, and to some extent other chain-terminating drugs, but not HIV.

Many would like to blame HIV. In an indirect way HIV does cause lipodystrophy, because without HIV no one would have used AZT or d4T. But beyond this connection, there is no evidence that HIV directly causes lipodystrophy or mitochondrial problems. Developing an unhealthy belief in this possibility merely misdirects the focus from the need to stop using AZT and d4T. Its incredible that there are some who still find it relevant whether someone should use AZT or d4T. Its like arguing the difference in benefits between taking Cyanide or Arsenic - or which vitamins might help minimize the effects of taking cyanide or arsenic. In the final analysis, its just not a conversation sane people would engage in. The only correct answer is to take neither.

Because these drugs are so toxic and minimally effective, the manufacturers are providing these older drugs almost for free to lesser developed nations - and this is certainly a tragedy. Just horrible.

By contrast, Integrase inhibitors are a really wonderful drug target as our bodies don't make or use Integrase. Since our bodies make and use proteases and DNA chains, protease inhibitors and chain-terminators were both strategies which were more likely to create unintended negative consequences. This is the reason I agree with your original comment that fusion inhibitors which target gp41 (HIV itself) rather than blocking human receptors (like CCR5) are simply safer and more sensible. It brings back memories of the drugs which tried to block CD4 - a really bad idea if there ever was one, an approach which provided side-effects without benefits.

There are also those who won't use successful treatments, without trials showing a proven survival advantage. As AZT is the only HIV antiviral to have proven a survival advantage, some backward types have stuck to AZT refusing to use the newer HIV antivirals until studies are done which brings the level of proof up to their arbitrary standards. Yet the survival advantage conferred by AZT was proven only for a very short period of time. Failing to see the bigger picture can have catastrophic results. But there's little that can be done about this. In some ways HIV is a Darwinian challenge - people who adopt unsuccessful theories and treatment strategies become debilitated and die. Those who are good guessers thrive.

I was lucky that I couldn't tolerate even one AZT capsule without projectile vomiting and a number of years later had to discontinue d4T use after six weeks due to neuropathy - in my case I woke up one morning with no feeling in my legs from my knees on down. It took several months to go away, with the help of every therapy we could think of. Ironically, viral sensitivity tests in later years showed I am now resistant to d4T - after only six weeks of use many years ago. When I stopping using ddI, after several years of use, it took me more than a year to recover my normal stamina. These drugs were simply a bad idea. I was very grateful for the availability of interferon-alpha and interleukin-2.

I think 's interview with Nolan last year adequately covers this topic of the role HIV doesn't play, and the role bad drugs do play, in lipodystrophy and related topics like mitochondria.

http://www.aegis.com/pubs/gmhc/2005/GM190301.html

In Toronto Don Kotler released results from one of his studies comparing lipodystrophy in people with HIV and those who are HIV negative. He found similar patterns of lipodystrophy in the arms and legs (loss of fat) and trunk (gain of visceral fat) in both HIV+ and HIV negative people as they age. He himself was on the study participants. This study excluded those using AZT or d4T. Obviously Kotler's work supports what Nolan's group has published.

In the lab you can do abnormal things, like injecting salt or foreign proteins into yeast cells. Of course the cell will kill itself -aka apoptosis. This is a protective device designed to eliminate cells infected by pathogens, or which have become otherwise compromised. In this process of self-suicide most cell structures are devastated. Ascribing a special significance to the damage in one cell structure or another, without acknowledging this is simply part of the process by which the cell kills itself, is a useless obsession. There is no psychiatric ward for suicidal cells - they do their duty to their body and kill themselves when their continued existence may pose a risk to the collective of cells called you.

As I mentioned in passing, before there were better antivirals available I used Interferon-alpha to great effect to help control HIV. Interferon-alpha makes cells more likely to kill themselves through apoptosis when they are infiltrated by HIV or another virus - and that's a good thing. When I used interferon-alpha, my T4 count was somewhat lower but my viral load was much lower. Interleukin-2 also causes the death of many cells, those cell infected by HIV. If the apoptosis process had been more aggressive originally, this wouldn't be needed.

Our bodies ruthlessly eliminate compromised cells, and it takes few chances. Bystander cell apoptosis caused by contact with HIV gp120 protein demonstrates how cells kill themselves if there is any chance of compromise. The failure of this important system gives rise to problems like cancers. Apoptosis is a good thing, it helps keeps your body healthy. I don't think attempting to interfere with apoptosis is a sound strategy.

*****************************

>> I look forward to your thoughts.>> M.

[Guest guest]

Because these drugs are so toxic and minimally effective, themanufacturers are providing these older drugs almost for free to lesserdeveloped nations - and this is certainly a tragedy. Just horrible.Because these drugs are so toxic and minimally effective, themanufacturers are providing these older drugs almost for free to lesserdeveloped nations - and this is certainly a tragedy. Just horrible.Nobody thought that humans used reverse transcriptase, either, but later, the inhibition of mitochondrial polymerase showed up.  I spent the week in Canada with the doctor who had the largest site in the integrase trials.  Nothing like "inside information," eh?It was very encouraging to hear him say that he was not able to tell who was on integrase, because there were basically no side effects!  A few patients seemed to complain about constipation, which must be a first in an HIV drug trial.It is a tragedy that D4T is being poured onto the world, because it is cheap to make.It would be a bigger shame if people died because they couldn't get Viread.When a government needs to build a school or a road, they use "eminent domain" to purchase land.  The owner is fairly compensated, and the governement gets the land for  the greater good.Rather than the short-sighted frenzy to seize patents, which if extended to other industries would destroy the US economy, it would seem that purchasing rights to the drugs at a fair price, and licensing for cheap manufacture, would be a reasonable solution. Barrowpozbod@...

[Guest guest]

Because these drugs are so toxic and minimally effective, themanufacturers are providing these older drugs almost for free to lesserdeveloped nations - and this is certainly a tragedy. Just horrible.Because these drugs are so toxic and minimally effective, themanufacturers are providing these older drugs almost for free to lesserdeveloped nations - and this is certainly a tragedy. Just horrible.Nobody thought that humans used reverse transcriptase, either, but later, the inhibition of mitochondrial polymerase showed up.  I spent the week in Canada with the doctor who had the largest site in the integrase trials.  Nothing like "inside information," eh?It was very encouraging to hear him say that he was not able to tell who was on integrase, because there were basically no side effects!  A few patients seemed to complain about constipation, which must be a first in an HIV drug trial.It is a tragedy that D4T is being poured onto the world, because it is cheap to make.It would be a bigger shame if people died because they couldn't get Viread.When a government needs to build a school or a road, they use "eminent domain" to purchase land.  The owner is fairly compensated, and the governement gets the land for  the greater good.Rather than the short-sighted frenzy to seize patents, which if extended to other industries would destroy the US economy, it would seem that purchasing rights to the drugs at a fair price, and licensing for cheap manufacture, would be a reasonable solution. Barrowpozbod@...

[Guest guest]

Because these drugs are so toxic and minimally effective, themanufacturers are providing these older drugs almost for free to lesserdeveloped nations - and this is certainly a tragedy. Just horrible.Because these drugs are so toxic and minimally effective, themanufacturers are providing these older drugs almost for free to lesserdeveloped nations - and this is certainly a tragedy. Just horrible.Nobody thought that humans used reverse transcriptase, either, but later, the inhibition of mitochondrial polymerase showed up.  I spent the week in Canada with the doctor who had the largest site in the integrase trials.  Nothing like "inside information," eh?It was very encouraging to hear him say that he was not able to tell who was on integrase, because there were basically no side effects!  A few patients seemed to complain about constipation, which must be a first in an HIV drug trial.It is a tragedy that D4T is being poured onto the world, because it is cheap to make.It would be a bigger shame if people died because they couldn't get Viread.When a government needs to build a school or a road, they use "eminent domain" to purchase land.  The owner is fairly compensated, and the governement gets the land for  the greater good.Rather than the short-sighted frenzy to seize patents, which if extended to other industries would destroy the US economy, it would seem that purchasing rights to the drugs at a fair price, and licensing for cheap manufacture, would be a reasonable solution. Barrowpozbod@...

[Guest guest]

I should acknowledge that 3TC is considerably less toxic, and more effective, than the other fake aminio acid drugs.

But the reason for this was literally sheer luck - the genius of incompetence.

In making the Cytosine analog 3TC, the "fake part" of the molecule so distorted the shape of the cytosine portion that it was less recognizable as cytosine.

To illustrate how random this was, the toxcitity of the D-isomer of 3TC is much closer in toxcitity to AZT, d4T, ddI, and ddC. The D-isomer of 3TC is also markedly less effective than the L-isomer. Its lack of antiviral effectiveness is very similar to the other fake amino acid drugs. L-3TC was a real fluke.

All of these drugs appear to be very effective for about 12 weeks, then their "effectiveness" drops off sharply - yet viral resistance doesn't typically appear for another fifty weeks.

The reason for this is simple. These fake amino acid drugs act as cellular toxins. For the first 12 weeks they slow down cell metabolism. Infected cells produce less virus and cells in the process of killing themselves take longer to do so. This creates a paradoxical rise in T4 count and a decline in viral load. After 12 weeks the cell systems ramp up enough to overcome the drag of this toxin, and most of the "effectiveness" of these drugs are lost.

The true antiviral effect of AZT, d4T, ddI, and ddC is extremely minimal.

This is a good review which covers this topic. http://www.jbc.org/cgi/content/full/276/26/23832

Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs J. Biol. Chem., Vol. 276, Issue 26, 23832-23837, June 29, 2001

>> Because these drugs are so toxic and minimally effective, the> manufacturers are providing these older drugs almost for free to lesser> developed nations - and this is certainly a tragedy. Just horrible.> > Because these drugs are so toxic and minimally effective, the> manufacturers are providing these older drugs almost for free to lesser> developed nations - and this is certainly a tragedy. Just horrible.> > > Nobody thought that humans used reverse transcriptase, either, but > later, the inhibition of mitochondrial polymerase showed up. I spent > the week in Canada with the doctor who had the largest site in the > integrase trials. Nothing like "inside information," eh?> > It was very encouraging to hear him say that he was not able to tell > who was on integrase, because there were basically no side effects! > A few patients seemed to complain about constipation, which must be a > first in an HIV drug trial.> > > It is a tragedy that D4T is being poured onto the world, because it > is cheap to make.> > It would be a bigger shame if people died because they couldn't get > Viread.> > When a government needs to build a school or a road, they use > "eminent domain" to purchase land. The owner is fairly compensated, > and the governement gets the land for the greater good.> > Rather than the short-sighted frenzy to seize patents, which if > extended to other industries would destroy the US economy, it would > seem that purchasing rights to the drugs at a fair price, and > licensing for cheap manufacture, would be a reasonable solution.> > > Barrow> pozbod@...>

[Guest guest]

I should acknowledge that 3TC is considerably less toxic, and more effective, than the other fake aminio acid drugs.

But the reason for this was literally sheer luck - the genius of incompetence.

In making the Cytosine analog 3TC, the "fake part" of the molecule so distorted the shape of the cytosine portion that it was less recognizable as cytosine.

To illustrate how random this was, the toxcitity of the D-isomer of 3TC is much closer in toxcitity to AZT, d4T, ddI, and ddC. The D-isomer of 3TC is also markedly less effective than the L-isomer. Its lack of antiviral effectiveness is very similar to the other fake amino acid drugs. L-3TC was a real fluke.

All of these drugs appear to be very effective for about 12 weeks, then their "effectiveness" drops off sharply - yet viral resistance doesn't typically appear for another fifty weeks.

The reason for this is simple. These fake amino acid drugs act as cellular toxins. For the first 12 weeks they slow down cell metabolism. Infected cells produce less virus and cells in the process of killing themselves take longer to do so. This creates a paradoxical rise in T4 count and a decline in viral load. After 12 weeks the cell systems ramp up enough to overcome the drag of this toxin, and most of the "effectiveness" of these drugs are lost.

The true antiviral effect of AZT, d4T, ddI, and ddC is extremely minimal.

This is a good review which covers this topic. http://www.jbc.org/cgi/content/full/276/26/23832

Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs J. Biol. Chem., Vol. 276, Issue 26, 23832-23837, June 29, 2001

>> Because these drugs are so toxic and minimally effective, the> manufacturers are providing these older drugs almost for free to lesser> developed nations - and this is certainly a tragedy. Just horrible.> > Because these drugs are so toxic and minimally effective, the> manufacturers are providing these older drugs almost for free to lesser> developed nations - and this is certainly a tragedy. Just horrible.> > > Nobody thought that humans used reverse transcriptase, either, but > later, the inhibition of mitochondrial polymerase showed up. I spent > the week in Canada with the doctor who had the largest site in the > integrase trials. Nothing like "inside information," eh?> > It was very encouraging to hear him say that he was not able to tell > who was on integrase, because there were basically no side effects! > A few patients seemed to complain about constipation, which must be a > first in an HIV drug trial.> > > It is a tragedy that D4T is being poured onto the world, because it > is cheap to make.> > It would be a bigger shame if people died because they couldn't get > Viread.> > When a government needs to build a school or a road, they use > "eminent domain" to purchase land. The owner is fairly compensated, > and the governement gets the land for the greater good.> > Rather than the short-sighted frenzy to seize patents, which if > extended to other industries would destroy the US economy, it would > seem that purchasing rights to the drugs at a fair price, and > licensing for cheap manufacture, would be a reasonable solution.> > > Barrow> pozbod@...>

[Guest guest]

I should acknowledge that 3TC is considerably less toxic, and more effective, than the other fake aminio acid drugs.

But the reason for this was literally sheer luck - the genius of incompetence.

In making the Cytosine analog 3TC, the "fake part" of the molecule so distorted the shape of the cytosine portion that it was less recognizable as cytosine.

To illustrate how random this was, the toxcitity of the D-isomer of 3TC is much closer in toxcitity to AZT, d4T, ddI, and ddC. The D-isomer of 3TC is also markedly less effective than the L-isomer. Its lack of antiviral effectiveness is very similar to the other fake amino acid drugs. L-3TC was a real fluke.

All of these drugs appear to be very effective for about 12 weeks, then their "effectiveness" drops off sharply - yet viral resistance doesn't typically appear for another fifty weeks.

The reason for this is simple. These fake amino acid drugs act as cellular toxins. For the first 12 weeks they slow down cell metabolism. Infected cells produce less virus and cells in the process of killing themselves take longer to do so. This creates a paradoxical rise in T4 count and a decline in viral load. After 12 weeks the cell systems ramp up enough to overcome the drag of this toxin, and most of the "effectiveness" of these drugs are lost.

The true antiviral effect of AZT, d4T, ddI, and ddC is extremely minimal.

This is a good review which covers this topic. http://www.jbc.org/cgi/content/full/276/26/23832

Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs J. Biol. Chem., Vol. 276, Issue 26, 23832-23837, June 29, 2001

>> Because these drugs are so toxic and minimally effective, the> manufacturers are providing these older drugs almost for free to lesser> developed nations - and this is certainly a tragedy. Just horrible.> > Because these drugs are so toxic and minimally effective, the> manufacturers are providing these older drugs almost for free to lesser> developed nations - and this is certainly a tragedy. Just horrible.> > > Nobody thought that humans used reverse transcriptase, either, but > later, the inhibition of mitochondrial polymerase showed up. I spent > the week in Canada with the doctor who had the largest site in the > integrase trials. Nothing like "inside information," eh?> > It was very encouraging to hear him say that he was not able to tell > who was on integrase, because there were basically no side effects! > A few patients seemed to complain about constipation, which must be a > first in an HIV drug trial.> > > It is a tragedy that D4T is being poured onto the world, because it > is cheap to make.> > It would be a bigger shame if people died because they couldn't get > Viread.> > When a government needs to build a school or a road, they use > "eminent domain" to purchase land. The owner is fairly compensated, > and the governement gets the land for the greater good.> > Rather than the short-sighted frenzy to seize patents, which if > extended to other industries would destroy the US economy, it would > seem that purchasing rights to the drugs at a fair price, and > licensing for cheap manufacture, would be a reasonable solution.> > > Barrow> pozbod@...>