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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 11 of 11. This is the beginning of the thread.
Posted by Rick on May 30, 2001, at 0:49:14
Of course, this is a manufacturer (Forest Labs) press release, but the results do look intriguing: More robust anti-depression and anti-anxiety effect at lower doses, with side effects comparable to placebo. AS for the "original" Celexa didn't do much for my Social Phobia, but I know it's helped a lot of people in many ways.
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=105&STORY=/www/story/05-09-2001/0001489394
Posted by Rick on May 30, 2001, at 21:16:04
In reply to Studies: New Celexa promising, posted by Rick on May 30, 2001, at 0:49:14
Does anyone know if any other AD's have similarly refined versions in the works? Perhaps Pregabalin and the metabolite of BuSpar (I forget the name) fall into this category, although they are anti-anxiety meds. Also, about a year ago, I read about testing on a new version of Valium without the side effects and dependence or addiction risks.
(Sorry if any of this has already been discussed. I haven't visited P-B a lot lately, and I wouldn't know what search terms to enter to find relevant posts.)
Posted by Mitch on June 1, 2001, at 23:26:59
In reply to Re: Studies: New Celexa promising, posted by Rick on May 30, 2001, at 21:16:04
I saw a Medline abstract months ago talking about the pharmacologically active metabolite of nortiptyline (Pamelelor) 10-hydroxy-nortriptyine as having serotonin down-regulation effect and anxiolytic effects. They mentioned that it ought to be pursued as a possible separate med to develop.
> Does anyone know if any other AD's have similarly refined versions in the works? Perhaps Pregabalin and the metabolite of BuSpar (I forget the name) fall into this category, although they are anti-anxiety meds. Also, about a year ago, I read about testing on a new version of Valium without the side effects and dependence or addiction risks.
>
> (Sorry if any of this has already been discussed. I haven't visited P-B a lot lately, and I wouldn't know what search terms to enter to find relevant posts.)
Posted by Paige on June 2, 2001, at 18:45:04
In reply to Re: Studies: New Celexa promising » Rick, posted by Mitch on June 1, 2001, at 23:26:59
Rick- are you saying there is a new Celexa???
I have not heard anything. Where might I find info?
thanks,
Paige
Posted by SLS on June 2, 2001, at 22:53:59
In reply to Re: Studies: New Celexa promising » Rick, posted by Mitch on June 1, 2001, at 23:26:59
> I saw a Medline abstract months ago talking about the pharmacologically active metabolite of nortiptyline (Pamelelor) 10-hydroxy-nortriptyine as having serotonin down-regulation effect and anxiolytic effects. They mentioned that it ought to be pursued as a possible separate med to develop.
Mitch - can you recall about when the article regarding nortriptyline was published?
> > Does anyone know if any other AD's have similarly refined versions in the works?
A refined version of Prozac, r-fluoxetine, was being developed by Lilly, the manufacturer of Prozac, in conjunction with Sepracor, a company specialized in synthesizing and isolating enantiomers. It was touted as being as effective as Prozac, but with a possibly more benign side effect profile. Unfortunately for the two companies, cardiovascular side effects emerged in phase III trials, and the project was abandoned. Prolonged QTc intervals were observed at the highest dosage tested. They probably should have tested it at half the dosage, as it would seem to me that it would be twice as potent as the racemate (r+s combination). Anyway, Sepracor and other drug manufacturers are pursuing refined versions (called ICEs - Improved Chemical Entities) of currently marketed antidepressants. Escitalopram (s-citalopram) is an example of one. From the URL Rick posted, it looks exciting.
> Also, about a year ago, I read about testing on a new version of Valium without the side effects and dependence or addiction risks.
Did this involve the identification of a benzodiazepine receptor domain subtype?
Thanks.
- Scott
Posted by Rick on June 3, 2001, at 1:59:04
In reply to Re: Studies: New Celexa promising, posted by SLS on June 2, 2001, at 22:53:59
>Anyway, Sepracor and other drug manufacturers are pursuing refined versions (called ICEs - Improved Chemical Entities) of currently marketed antidepressants. Escitalopram (s-citalopram) is an example of one.
Interesting! I hope these trials are harbingers of major improvement in the med arsenal. Good observation re the Prozac trial. It's a shame that this may have been aborted needlessly.
> >Also, about a year ago, I read about testing on a new version of Valium without the side effects and dependence or addiction risks.
> Did this involve the identification of a benzodiazepine receptor domain subtype?I'm not sure what a "receptor domain subtype" is, but the prospects of no-sedation benzos *is* tied to Roche's apparent pinpointing of the key receptor for anxiolytic benefit. I originally read about this in small article in the medical briefs section of a daily newspaper. Immediately below is a more-detailed press release I found on Roche's website. (I simply went to www.roche.com and did a free-text search on Valium.)
Rick
-------
Roche - Media Release
Basel, 5. October 2000
Towards a Better Treatment of Anxiety
Molecular Target for Benzodiazepine Tranquilizers Identified
At a press conference held in Zurich today, a major scientific breakthrough was announced which sets the foundation for the development of improved drugs to treat anxiety disorders. Swiss scientists have identified the molecular target for the anxiolytic effect of benzodiazepine tranquilizers, including diazepam (VALIUM). This finding to which Roche researchers contributed is published in the October 6th issue of Science.The benzodiazepine drug class was discovered by Roche scientists in the late 1950s and benzodiazepines are now widely used to treat anxiety disorders. An estimated 10-15% of the adult population in the Western countries suffers from anxiety disorders. Thus, the discovery and development of novel, improved tranquilizers is addressing an important medical need.
In human and animal brain, inhibitory control of nerve cell activity is primarily mediated by the activation of widespread GABAA (gamma-aminobutyric acidA) receptors. Benzodiazepines act to facilitate the function of these GABAA receptors and thereby ease anxiety. Classical benzodiazepine drugs such as VALIUM interact indiscriminately with all benzodiazepine-sensitive GABAA receptor subtypes (alpha1, alpha2, alpha3 and alpha5). The focus of current investigations is the determination of the relative role of the subtype receptors in the therapeutic actions and side effects of the benzodiazepines.
Swiss scientists have now succeeded in identifying the receptor subtype which is the molecular target that mediates the anxiolytic effect of benzodiazepine tranquilizers. This scientific breakthrough was accomplished within a research programme which has been undertaken to silence each of these a subtype receptors in gene targeted mice generated in a collaborative effort between scientists at Roche, researchers at the Federal Institute of Technology in Zurich (ETHZ) and the University of Zurich. In the present study, two mouse lines were compared in which one GABAA receptor subtype, either the alpha2 or alpha3 GABAA receptor, was rendered insensitive to diazepam. This was done by creating genetically altered mice which carry a variation, or so-called point mutation, in one of the subunits of the GABAA receptor. The results indicate that the anxiolytic action of diazepam in mice is selectively mediated by neurons carrying the alpha2 GABAA receptor localised in the limbic system, a brain area which is implicated in emotional stimulus processing of the anxiety response.
This study, together with previous investigations conducted by the research group of Prof. Hanns Möhler at the Federal Institute of Technology in Zurich (ETHZ) and the University of Zurich together with Roche scientists, points the way to designing selective anxiolytic drugs targeted to alpha2 containing GABAA receptors thereby creating more selective tranquilizers lacking undesired effects such as sedation.
All trademarks used or mentioned in this release are legally protected.
(c) 2000 F. Hoffmann-La Roche Ltd
Posted by Rick on June 3, 2001, at 2:13:23
In reply to Re: Studies: New Celexa ...RICK, posted by Paige on June 2, 2001, at 18:45:04
Paige -
The link I included in my initial post seems to be the most detailed to-date. It summarizes study findings that were presented May 9 at the American Psychiatric Association meeting in New Orleans.
I found it on the following page, which has links to various articles about escitalopram, "original" citalopram (Celexa/Cipramil), plus other current and pipeline meds from Forest Pharmaceuticals:
http://www.frx.com/financial/press_release.shtml
Rick
> Rick- are you saying there is a new Celexa???
> I have not heard anything. Where might I find info?
> thanks,
> Paige
Posted by Mitch on June 3, 2001, at 12:07:00
In reply to Re: Studies: New Celexa promising, posted by SLS on June 2, 2001, at 22:53:59
> Mitch - can you recall about when the article regarding nortriptyline was published?
SLS, It is quite old, but here is the entire
abstract,Mitch
Neuropsychobiology 1996;34(1):44-8
Antidepressant and anxiolytic profiles of E-10-hydroxynortriptyline on electrocorticograms of rats.
Nordin C, Krijzer F.
Department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Huddinge University Hospital, Sweden.
Electrocorticograms of rats were recorded after administration of increasing doses of the major metabolite of nortriptyline (NT), E-10-hydroxynortriptyline (E-10-OH-NT). The results were compared with those of NT administration. In visual as well as computerized evaluations, E-10-OH-NT demonstrated clear antidepressant properties, thus confirming previous experiments in depressed patients. There is some evidence that E-10-OH-NT also has an anxiolytic profile. The results with the parent drug NT were not so pronounced. Since E-10-OH-NT has been shown to be devoid of side effects when previously administered to humans, this substance is clearly to be considered of interest for potential development into a new antidepressant. Whether or not the anxiolytic profile is of clinical interest needs to be investigated further.
PMID: 8884759 [PubMed - indexed for MEDLINE]
Posted by Rick on June 3, 2001, at 15:18:52
In reply to Re: Studies: New Celexa+others promising » SLS, posted by Mitch on June 3, 2001, at 12:07:00
My guess is that business considerations and/or legal technicalities could have quashed any interest in following up on this study. I'm not even sure which pharmaceutical company would have worked on a more benign version of nortryptyline, since both Novartis (Pamelor) and Eli Lilly (Aventyl) make branded versions -- not to mention the long-available generics. Interestingly, Nortryp isn't even referenced on their websites.
The fact that this study came out during a period when SSRI's were mushrooming -- and Lilly had to protect cash cow Prozac -- couldn't have helped. Also, competitors could play up the bad press about tricyclics, even if a refined version lacked the side effects and potential lethal overdose hazards. Etc., etc.
Rick
> > Mitch - can you recall about when the article regarding nortriptyline was published?
>
> SLS, It is quite old, but here is the entire
> abstract,
>
> Mitch
>
> Neuropsychobiology 1996;34(1):44-8
>
> Antidepressant and anxiolytic profiles of E-10-hydroxynortriptyline on electrocorticograms of rats.
>
> Nordin C, Krijzer F.
>
> Department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Huddinge University Hospital, Sweden.
>
> Electrocorticograms of rats were recorded after administration of increasing doses of the major metabolite of nortriptyline (NT), E-10-hydroxynortriptyline (E-10-OH-NT). The results were compared with those of NT administration. In visual as well as computerized evaluations, E-10-OH-NT demonstrated clear antidepressant properties, thus confirming previous experiments in depressed patients. There is some evidence that E-10-OH-NT also has an anxiolytic profile. The results with the parent drug NT were not so pronounced. Since E-10-OH-NT has been shown to be devoid of side effects when previously administered to humans, this substance is clearly to be considered of interest for potential development into a new antidepressant. Whether or not the anxiolytic profile is of clinical interest needs to be investigated further.
>
> PMID: 8884759 [PubMed - indexed for MEDLINE]
Posted by Mitch on June 3, 2001, at 19:18:03
In reply to Re: Studies: New Celexa+others promising » Mitch, posted by Rick on June 3, 2001, at 15:18:52
After I made the post, I did think something along the lines of "Well, noone has any patent on this anymore, so there isn't any money in it and that is why you havent' heard anything. That is a shame because a lot of older meds have pharmacologically active metabolites that have promise-but they have already ran their course financially. Sad, but true.
> My guess is that business considerations and/or legal technicalities could have quashed any interest in following up on this study. I'm not even sure which pharmaceutical company would have worked on a more benign version of nortryptyline, since both Novartis (Pamelor) and Eli Lilly (Aventyl) make branded versions -- not to mention the long-available generics. Interestingly, Nortryp isn't even referenced on their websites.
>
> The fact that this study came out during a period when SSRI's were mushrooming -- and Lilly had to protect cash cow Prozac -- couldn't have helped. Also, competitors could play up the bad press about tricyclics, even if a refined version lacked the side effects and potential lethal overdose hazards. Etc., etc.
>
> Rick
>
> > > Mitch - can you recall about when the article regarding nortriptyline was published?
> >
> > SLS, It is quite old, but here is the entire
> > abstract,
> >
> > Mitch
> >
> > Neuropsychobiology 1996;34(1):44-8
> >
> > Antidepressant and anxiolytic profiles of E-10-hydroxynortriptyline on electrocorticograms of rats.
> >
> > Nordin C, Krijzer F.
> >
> > Department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Huddinge University Hospital, Sweden.
> >
> > Electrocorticograms of rats were recorded after administration of increasing doses of the major metabolite of nortriptyline (NT), E-10-hydroxynortriptyline (E-10-OH-NT). The results were compared with those of NT administration. In visual as well as computerized evaluations, E-10-OH-NT demonstrated clear antidepressant properties, thus confirming previous experiments in depressed patients. There is some evidence that E-10-OH-NT also has an anxiolytic profile. The results with the parent drug NT were not so pronounced. Since E-10-OH-NT has been shown to be devoid of side effects when previously administered to humans, this substance is clearly to be considered of interest for potential development into a new antidepressant. Whether or not the anxiolytic profile is of clinical interest needs to be investigated further.
> >
> > PMID: 8884759 [PubMed - indexed for MEDLINE]
Posted by SLS on June 3, 2001, at 19:50:30
In reply to Re: Studies: New Celexa+others promising » Mitch, posted by Rick on June 3, 2001, at 15:18:52
> > "Since E-10-OH-NT has been shown to be devoid of side effects when previously administered to humans, this substance is clearly to be considered of interest for potential development into a new antidepressant."
> The fact that this study came out during a period when SSRI's were mushrooming -- and Lilly had to protect cash cow Prozac -- couldn't have helped. Also, competitors could play up the bad press about tricyclics, even if a refined version lacked the side effects and potential lethal overdose hazards. Etc., etc.
That really, really, really sucks. Really.Actually, I am quite angry right now. As I think about it, this drug could have ended up being the best of the TCAs. Seeing as how I respond better to nortriptyline than any of the others, I feel particularly cheated. I would be even more pissed were I to discover that E-10-hydroxynortriptyline is without the same finicky therapeutic window that nortriptyline has. Capitalism. Is there a better way?
With regard to the r-fluoxetine ICE Prozac, Lilly could have elected to resubmit it for approval using data from a new set of studies using lower dosages, but that would have set back the project another two to three years. They elected to dump it in favor of investing money into the development of duloxetine. This also sucks.
- Scott
This is the end of the thread.
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