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| njb35@cantab.net (Nick Bennett) wrote in message news:<d9e7522c.0408221111.331e0ae@posting.google.com>...
> j.umber@ac-nancy-metz.fr (Jean) wrote in message news:<5eb4d562.0408200926.74cff60e@posting.google.com>...
>
Thank's to correct my english!
>
> Heheh, true enough, but you can test and there comes a point where
> several things also have to come into play:
>
> (1) Mechanistic probability (homeopathy makes no sense by atomic
> physics!)
Just look at this publication.
http://perso.wanadoo.fr/jean.umber/Chimie/Modification of water proton
relaxation times in very high diluted aqueous solutions, Prof
Demangeat.pdf
Demangeat JL, Demangeat C, Gries P, Poitevin B, Constantinesco A.
Modification des temps de relaxation à 4 MHz des protons du solvant
dans les très hautes dilutions salines de silice-lactose. J Med Nucl
Biophy. 16, 2: 135-35; 1992
and
http://perso.wanadoo.fr/jean.umber/...in_BHJ_2001.pdf
but it is not the objective of our debate
> (2) You've tested enough and covered enough variables to remove
> reasonable doubt.
>
> Besides, acupuncture is actually proven to work. It is surprisingly
> effective at pain relief, and I've seen it used as such by mainstream
> medical practitioners. One example of looking hard and finding that
> there WAS some truth to it all...
>
> Mechanistically it is likely acting with the "gate theory" of pain
> blockade, so that makes sense with the clinical findings.
>
>
> Okay, fire away!
>
>
> Not always: sometimes it's how you read things, and also I get the
> impression that chemistry is "your thing" whereas it isn't for me.
> You may be explaining things I can't always follow without converting
> them to layman's language.
>
> in
> of
>
> I got the impression the H2O was already in the pocket, and the 3` OH
> could fit in addition to them.
>
> And the size of this group is
>
> Yup, no argument.
I do'nt understand.
>
> I have never said that water
>
> Okay, my mistake.
>
>
>
> Thanks for pulling that up - the dipole and boiling points are
> especially helpful :o)
>
>
> Ok, I can accept that but I'm not sure why. If you can explain why
> that is I'd appreciate it. Is it just that the molecules can align
> better with each other?
Yes. And they are closer. The three nitrogen are good aligned (two pi
bonding between each nitrogen)
>
> So the
>
> Agreed. I can't see an obvious reason otherwise why the boiling point
> should increase. You picked some good examples to explain things
> here. I think I'm right in saying that the dipole due to the C2H5 is
> going to be not much at all, so by extension the majority of the
> effects must be due to the OH group. Therefore OH is going to have
> stronger effects than N3H, despite the similar dipole moment.
Yes
>
>
> True, I think that steric hindrance is quite important in the AZT
> resistance mutations.
>
> Here too, we must have models and I think that
>
> Ok, I think I'm still following you. If O changes from -0.782 to
> -0.680, N therefore cannot be more negative than it's original charge
> of -0.586. Is that right?
Yes
>
>
> Tentatively, I'm still in agreement here...
>
>
> As I see it the simple reason is that the Phe has a larger side chain,
> much larger than threonine. That alone would prevent the 3 H2O from
> getting into the pocket as far as I see it. Threonine also
> contributes an OH bond which Phe doesn't.
Yes, that's why it is more logical to think that thymidine bind better
with threonine (H bond stronger), and that azidothymidine bind better
with phenylalanine (VdW stronger). In apparent contradiction of the
clinical observations.
>
[vbcol=seagreen]
>
> I'm still not convinced: the sidechain changes are pretty drastic:
> anything involving a change to or from a Phe tends to mess things up
> pretty badly from my experience. It's a recurring theme in the
> literature.
I agree
>
> <snip>
>
> I'll have to read the reduction stuff on AZT and get back to you...
>
>
> This doesn't explain why AZT is so effective at controlling virus
> prior to the resistance mutations occuring. It also doesn't explain
> why:
>
> 1. 3TC monotherapy causes reversion of the AZT-resistance mutations
> 2. this correlates with returning sensitivity of the virus to AZT
> 3. Combination therapy delays the appearance of AZT resistance, but
> doesn't completely prevent it (dual resistance can occur).
>
> In contrast the amino-acid substitution theory explains it all nicely.
>
>
> Y'know, Glaxo might well have done this in drug development. Combivir
> after all is AZT plus 3TC.
I know that. But where are the papers?
What do you want to say with "controlling virus" ?
Is it CD4 decrease, and clinical improvement ?
If we look at the reduction of AZT by thiols, (this seems more and
more likely), and why it is well absorbed in the blood, I assume that
it can rapidly decrease the thiols amounts in the opportunistic
microorganisms, which die (clinical improvement).
But, in this article, it is showed that, with AZT+D4T, it is a decline
of CD4 :
http://www.sfaf.org/treatment/beta/b31/b31goodn.html
(with the paper of the french team :
http://www-dsv.cea.fr/content/cea_e.../actu03_azt.htm
it become obvious that AZT + D4T can no more do than AZT alone, which,
clearly, decrease CD4)
Whath with 3TC.
I have previously missed anything. 3TC admit of a 1-oxa 3-thiolane
cycle.
In all my courses in chemistry, I have learned that these compounds
are slowly hydrolysed in a acidic solution. With the help of imidazole
from chymotrypsine, it is perhaps faster. 3TC can be hydrolysed to a
1-cytidyl 1-hydroxy ethane-2-thiol and glycolic aldehyde.
We know now that AZT reacts well with thiols, and I assume that this
reaction, wich gives d4T, aminothymidine and other products from AZT,
and sulfinic acid, sulfonate and sulfate from the thiol -
( http://www.ncbi.nlm.nih.gov/entrez/...8&dopt=Abstract
:
and
http://perso.wanadoo.fr/jean.umber/Chimie/Massive loss of sulfur in
HIV infection.pdf ) -
, prevent the long term action of AZT (CD4 decline, "resistance"). The
amount of glutathion is preserved, because it reacts not with AZT, but
with the SH group from hydrolysed 3TC. Hydrolysed 3TC reacts also with
the other oxidants, and during this time, the natural glutathion
replenishes.
But for all that AZT has been able to kill the opportunistic
microorganisms, because it is rapidly absorbed.
3TC is not totally hydrolysed (slow reaction), therefore one finds the
S-oxy lamivudine.
Dual resistance occurs, perhaps, because many by-products are toxic
(aminothymidine, D4T)
>
> I'll try to get my head around all the reduction/oxidation stuff you
> found. Your explanations of the differences between OH and N3H were
> useful though, although I'm still not convinced they refute why the
> replacement of an OH on a pre-terminal carbon with a terminal benzene
> (!) should prevent a chemical binding.
>
> Cheers
>
> Bennett
Friendly
Jean
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