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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 14 of 14. This is the beginning of the thread.
Posted by Janelle on June 13, 2003, at 20:23:12
Okay, I did a Google search like you mentioned on that r-enantiomer word and yep, it brought up tons of hits. However, as I began clicking on them they also mentioned an "s-enantiomer"!!
Now I am thoroughly confused about these two things and if you could explain them in PLAIN ENGLISH (the hits do not; they're very technical), I sure would appreciate it!
I'm determined to be able to understand the difference between Lexapro and Celexa, the latter of which I'm on, and I just know it boils down in large part to the "enantiomer" differences between the two meds, but I can't get a grip on what the r and s enantiomers are! Thanks.
Posted by zeugma on June 13, 2003, at 21:11:22
In reply to St.JAMES: HELP! Need some DEFINITION assistance!, posted by Janelle on June 13, 2003, at 20:23:12
> Okay, I did a Google search like you mentioned on that r-enantiomer word and yep, it brought up tons of hits. However, as I began clicking on them they also mentioned an "s-enantiomer"!!
>
> Now I am thoroughly confused about these two things and if you could explain them in PLAIN ENGLISH (the hits do not; they're very technical), I sure would appreciate it!
>
> I'm determined to be able to understand the difference between Lexapro and Celexa, the latter of which I'm on, and I just know it boils down in large part to the "enantiomer" differences between the two meds, but I can't get a grip on what the r and s enantiomers are! Thanks.
R-enantiomer- right enantiomer. S-enantiomer- sinister (left) enantiomer.Enantiomer- the two gloves that make a pair are enantiomers. Basically they're mirror images of each other, but they're not reversible. Supposedly the left-hand enantiomer (of the Celexa molecule) is more selective for serotonin reuptake inhibition than the right-hand one. The practical effect of this seems to be that Lexapro is effective in lower dosages than Celexa.
Posted by avid abulia on June 13, 2003, at 21:37:05
In reply to Re: St.JAMES: HELP! Need some DEFINITION assistance!, posted by zeugma on June 13, 2003, at 21:11:22
it is like the difference between your right and left hand.
in the case of celexa, it is a racemic mixture meaning it has both the r- and s- enantiomer present. for some reason, probably just for marketing purposes, they took the r- enantiomer out of citalopram (celexa) and marketed just the s- enantiomer by itself as a new drug, escitalopram (lexapro) because the s- enantiomer is a stronger serotonin re-uptake inhibitor in-vitro.
long and short of it--you need about twice as much celexa to get the same effect as lexapro. i believe, but am not certain, that lexapro comes in an injectable form to get higher blood levels faster, and i am not sure if celexa does or not.
~AA
Posted by Larry Hoover on June 13, 2003, at 22:20:42
In reply to St.JAMES: HELP! Need some DEFINITION assistance!, posted by Janelle on June 13, 2003, at 20:23:12
> Okay, I did a Google search like you mentioned on that r-enantiomer word and yep, it brought up tons of hits. However, as I began clicking on them they also mentioned an "s-enantiomer"!!
>
> Now I am thoroughly confused about these two things and if you could explain them in PLAIN ENGLISH (the hits do not; they're very technical), I sure would appreciate it!
>
> I'm determined to be able to understand the difference between Lexapro and Celexa, the latter of which I'm on, and I just know it boils down in large part to the "enantiomer" differences between the two meds, but I can't get a grip on what the r and s enantiomers are! Thanks.Other posters have mentioned the right and left hand gloves that make up a pair. They're identical to each other if you hold one up to a mirror, and compare it to one not viewed through the mirror.
What may help make good sense of that difference is an application you're familiar with.
When you shake hands with someone, you both hold out your right hands. In that example, one right hand is a properly shaped receptor for another right hand. A left hand doesn't fit a right hand during a hand-shake, even though it has all the parts arranged in a similar way, just arranged with the opposite orientation.
The receptors in our brains which receive neurotransmitters have handedness, which is called chirality. The drugs that best fit a chiral receptor have to have the proper handedness. Chemists call the left and right handed versions of molecules s- (for sinestra) and r- (for recta) enantiomers. If we've figured out that the s-enantiomer is the one doing the major work in blocking e.g. serotonin-reuptake, providing the purified drug (s-enantiomer) at lower concentrations is as effective as providing mixtures of r- and s-enantiomers at higher total concentration. Theoretically, less chance of side effects, at the same potency of treatment.
Lar
Posted by stjames on June 13, 2003, at 23:48:08
In reply to St.JAMES: HELP! Need some DEFINITION assistance!, posted by Janelle on June 13, 2003, at 20:23:12
as simple as I can make it is that they are mirror images of each other
Posted by avid abulia on June 14, 2003, at 12:47:55
In reply to Re: St.JAMES: HELP! Need some DEFINITION assistanc, posted by stjames on June 13, 2003, at 23:48:08
to take the hand analogy further, you could, say, be left-handed. then, you could shake hands with your right hand pretty well with someone, provided that they extend the right hand to shake, and you would pass an evaluation at handshaking as having your right hand being a better fit... but if you were never tested for writing skills, no one would notice that your right hand was not all that good at signing your name for you. quite simply, tests are not done to evaluate all measures of chemical activity; you might compare it to preliterate scientists doing the testing on your communication ability, wherein they may understand that your right hand is good at communicating a greeting, but they have no context for which to understand why signing the proper name may be important as well.
the biogenic amine theory may have a use in treatment of depression and the like, but we know relatively little of most other neurotransmitters and less still of second-messenger systems, neurotrophic factors, neurohormones, gene expression, and the like, so it is difficult to say if a given enantiomer is inactive if we only have a limited schema in which to test effectiveness...
and in addition to all of this, one may consider a very good friend of mine who has a very rare variant of dwarfism. one might say, my friend has wet his pants because his legs are too short and have no knees to carry him fast enough to the bathroom, or because he has lost the tool he must use to unbutton his pants and acheive proper aim, or because he has had a seizure and lost urinary control, or because he always antagonizes rednecks and they prevent him from entering a bathroom, or any combination or variation of the above, but the end result is still the same, and some magic-bullet effect to find just what it was in that situation may not work in all other scenarios unless a very specialized and broad-spectrum system is developed.
reductionist psychopharmacology: see how well it works for us!
~AA
Posted by stjames on June 14, 2003, at 12:57:46
In reply to St.JAMES: HELP! Need some DEFINITION assistance!, posted by Janelle on June 13, 2003, at 20:23:12
In my opinion, the only thing unique here
between an s or r enantiomer, is that
one can hold seperate patents for s & r
enantiomer (Celexra) and single enantiomer
(Lexpro). This is the so called "least patentable
difference" & many use it to extend their patents
and we fall for this and for a while are sure
Lexpro will solve everything. Just like the hype
of any new drug.
Posted by Janelle on June 14, 2003, at 16:31:56
In reply to Re: St.JAMES: HELP! Need some DEFINITION assistance! » Janelle, posted by Larry Hoover on June 13, 2003, at 22:20:42
Posted by Janelle on June 14, 2003, at 16:49:39
In reply to Re: St.JAMES: HELP! Need some DEFINITION assistance! » Janelle, posted by Larry Hoover on June 13, 2003, at 22:20:42
Where on earth did you read/learn that great and easy to follow analogy with the gloves and where did you learn/read about chiralty, and s- and r- eantiomers? This is so impressive, I would just love to know where this info is available (on the net?) because my apparently lame-o search did not turn up anything remotely like these great explanations!
However, I do have one question - you said that when you shake hands with someone, you both hold out your right hands but that a left hand doesn't fit a right hand during a hand-shake, even though it has all the parts arranged in a similar way, just arranged with the opposite orientation.
Well, actually when I shake hands with someone my left hand fits perfectly though oppositely with their right hand and vice versa!
Is the r-enantiomer the RIGHT side one and the s-enantiomers the LEFT one? I'm just curious since "r" is the first letter for the "R"ight side? True?
So, it sounds like they removed the WEAKER of the two enantiomers from Celexa and kept it IN Lexapro, because Lexapro has a LOWER dosing level than Celexa (though not by a whole lot!) Is this correct?
Thanks a million for your info. It clarified the whole thing about the enantiomers at least!
Posted by avid abulia on June 14, 2003, at 17:57:42
In reply to LARRY: where did you learn/read that stuff?, more: » Larry Hoover, posted by Janelle on June 14, 2003, at 16:49:39
i know you aren`t asking me this question, but i will answer it cuz i got here first and, lo and behold, but here i was posting in the very same thread! it`s okay, though, cuz i practically didn`t notice me, either.
the r-enantiomer is the equivalent of a right hand, and the s-enantiomer is the equivalent of the left. chirality also occurs in amino acids, and (except for in the cell walls of certain bacteria) the d-isoform (equivalent to the r-enantiomer; d stands for dextro-rotary, dextro- is a prefix denoting the right side of something, hence a person who is ambidextrous is <<doubly-right-handed>>) the d-isoform is not produced and is quite toxic in many cases, whereas the l-isoform (levo-rotary, or left-handed form) occurs naturally in all living cells.
the reason r-enantiomers are not always toxic whereas d-isoforms often are is because the body generally does not attempt to incorporate drugs into its proteins except for purposes of excretion.
if you look for online physiology or microbiology tutorials, you will find this information in an easy-to-understand form. (i learned this stuff from bio courses, myself).
~AA
Posted by Janelle on June 14, 2003, at 18:09:04
In reply to Re: LARRY: where did you learn/read that stuff?, more:, posted by avid abulia on June 14, 2003, at 17:57:42
Posted by Larry Hoover on June 14, 2003, at 18:44:37
In reply to LARRY: where did you learn/read that stuff?, more: » Larry Hoover, posted by Janelle on June 14, 2003, at 16:49:39
> Where on earth did you read/learn that great and easy to follow analogy with the gloves and where did you learn/read about chiralty, and s- and r- eantiomers? This is so impressive, I would just love to know where this info is available (on the net?) because my apparently lame-o search did not turn up anything remotely like these great explanations!
I'm glad my explanation was useful for you. I'm sure I drew on things I've read elsewhere, but the explanation was one I wrote just for you. Another reason the glove analogy is a good one is that you can't put your right hand in a left glove, even if you know it's from a pair that fits you. Picturing these sorts of fitting in and not fitting in go a long way to understanding chirality of molecules.
I'm trained in organic chemistry, and I can picture molecules in three dimensions in my brain. It just makes sense to me. What can I say?
> However, I do have one question - you said that when you shake hands with someone, you both hold out your right hands but that a left hand doesn't fit a right hand during a hand-shake, even though it has all the parts arranged in a similar way, just arranged with the opposite orientation.
>
> Well, actually when I shake hands with someone my left hand fits perfectly though oppositely with their right hand and vice versa!I'm not sure I understand that. When I shake hands, it's right hand to right hand. Except when I was in Boy Scouts, it was left to left.
> Is the r-enantiomer the RIGHT side one and the s-enantiomers the LEFT one? I'm just curious since "r" is the first letter for the "R"ight side? True?
It's from the Latin, rectus for right, sinister for left. The way that it is right or left is perhaps more complicated than I want to get into here, as it doesn't help the understanding any.
> So, it sounds like they removed the WEAKER of the two enantiomers from Celexa and kept it IN Lexapro, because Lexapro has a LOWER dosing level than Celexa (though not by a whole lot!) Is this correct?That's what they're saying. They've removed the r-enantiomer, blaming it for more side-effects, and little contribution to the antidepressant effect.
> Thanks a million for your info. It clarified the whole thing about the enantiomers at least!
I'm glad.
Lar
Posted by Larry Hoover on June 14, 2003, at 23:05:30
In reply to St.JAMES: HELP! Need some DEFINITION assistance!, posted by Janelle on June 13, 2003, at 20:23:12
> I'm determined to be able to understand the difference between Lexapro and Celexa, the latter of which I'm on, and I just know it boils down in large part to the "enantiomer" differences between the two meds, but I can't get a grip on what the r and s enantiomers are! Thanks.I missed the significance of your question in the context of Celexa and Lexapro, so I'll expand on that a little bit.
When human being synthesize drugs, if a chiral center is involved, you typically get something like a 50-50 mix of the two enantiomers, the r- and s- forms. That's just because we don't have the elegant machinery of living organisms, which don't waste energy making unusable forms, as biological enzymes are designed to produce one enantiomer exclusively. In a chemist's reaction flask, molecules form by random processes, and the products are statistical, like flipping a coin.
Man made mixes of the two enantiomers are called racemates. Many drugs are sold that way, if the clinical trial shows them to be effective and there are reasonable levels of side effects. Sometimes one enantiomer is profoundly toxic, as was found with thalidomide. One enantiomer causes birth defects; the other is perfectly safe during pregnancy. (In any case, it will never again be given to pregnant women, you can be sure. Pharmaceutical companies don't like political suicide moves.) Still, it is an effective drug against leprosy and tuberculosis, and some cancers.
In today's profit driven pharmaceutical industry, any change in the patented molecule permits the registration of a new patent (and the exclusive rights for all those years that go along with the new patent). If you can come up with an argument that an entiomeric purification changes the pharmacology of the drug, then that is considered to be a pharmacological change arising from a chemical change (even though there is no chemical change, in a literal sense). So, clinical trials of the purified s-enantiomer (escitalopram) provided sufficient evidence of different pharmacology (lower dose for same response, and decreased side effects), convincing the FDA to register it as a new drug, with a new patent.
I take the cynic's view. It was never about purifying the drug, and reducing side effects. It was about getting an extended market monopoly on a commercially successful drug, with much reduced development costs (amortized over the combined marketing life-time of the drug racemate and enantiomers).
Another example is the GERD/reflux drug Prilosec/Nexium (omeprazole/esomeprazole). Same drug, racemate and single enantiomer. Major profits on Nexium.(I took part in the clinical trial on Nexium. They violated certain terms of the protocol with me, and I have yet to receive a satisfactory response to my inquiries. On request, they are to unblind the data at conclusion, and provide detailed outcomes for any subject so requesting data.)
If Celexa's working for you, there is no justification to switch to Lexapro. Just because the pharmaceutical company argued that the r-enantiomer was either inert or even toxic, doesn't mean that it is so, for you (or anybody, for that matter). I just don't trust the clinical trial process too much. Clinical trials are not done by independent researchers. The drug companies do their own trials. No vested interest in the outcome there, right?
Lar
Posted by Janelle on June 15, 2003, at 16:41:25
In reply to Re: LARRY: where did you learn/read that stuff?, more: » Janelle, posted by Larry Hoover on June 14, 2003, at 18:44:37
You are CORRECT - what a person shakes hands, it's right hand to right hand (or left to left); it is NOT right/left or left/right! I don't know what my lame brain was (or wasn't!) thinking when I had written that. Sorry.
This is the end of the thread.
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