Posted by jrbecker on August 23, 2004, at 13:04:08
In reply to Re: Nardil Observations » jrbecker, posted by King Vultan on August 23, 2004, at 12:04:00
> > perhaps the selegiline patch (more MAO-B, less MAO-A inhibition) might be a better fit for you if and when it comes out in early 2005.
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> Selegiline would probably be the next thing I would ask to try if the Parnate which I will soon be starting does not work out. I can't say I really have any interest in the patch, however, and would just as soon take the drug in pill form. If I'm not mistaken, I think the patch allows freedom from the MAO dietary restrictions, but these are not a big deal to me personally, and I can easily live with them.
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> Todd
>Todd-
yeah, the initial purpose behind developing the STS [patch form] was indeed to avoid the tyramine dietary restrictions, however, it's now been shown that this medium also limits quite a bit of the other side effects seen with oral ingestion. Most of these bothersome adverse events are due to the amphetamine-like metabolites that build up at higher dosages [see excerpt below]. The patch avoids most of this interaction because of the lack of first-pass metabolism via the transdermal route. I tried oral selegiline myself as an augmentor and found it to be way too "speedy," and actually made my depression worse at times.
I've been in contact with the researchers at Harvard/Penn on the study and they do believe it will have some utility with anergic/atypical types. Some studies have shown fairly good promise with very treatment-resistant depressive types, while some have only had modest results(it should be noted, that these studies only tested with the low dosage level of 20mg. The proposed dosage strengths will now be 20, 30 and 40 mg). Of course, if I've learned anything from all my own research in looking at study trials, it's that the methodology behind these mass-scale studies prove nothing about response for each prospective individual. So until it hits the market I remain skeptical but hopeful.
" This is the first reported clinical trial of transdermally delivered selegiline for the treatment of depression. Several studies have shown selegiline to be an effective and relatively side-effect-free antidepressant when given in high oral doses requiring restriction of dietary tyramine (13–15). We demonstrated that transdermally delivered selegiline, in a dose regimen that appears devoid of clinically significant interaction with dietary tyramine (20, 23–25), offers significantly better therapeutic benefit than placebo in major depression.Transdermal delivery of selegiline provides several pharmacological advantages over oral delivery. First, it sufficiently reduces exposure of the gastrointestinal tract to the drug to limit inhibition of intestinal MAOA activity (21). Thus, adequate gastrointestinal MAOA enzyme is left intact to metabolize dietary tyramine. Second, transdermal administration of selegiline circumvents first-pass hepatic metabolism, which results in sustained high plasma levels of the parent compound with a concomitant decrease in metabolite formation (26). This provides sufficient brain concentrations of selegiline to produce an antidepressant effect, presumably involving substantial MAOA as well as MAOB inhibition. This also may permit the expression of additional pharmacological properties of selegiline other than MAO inhibition previously observed in vitro (27). At the same time, there is less exposure to L-methamphetamine and L-amphetamine metabolites than observed with oral selegiline (26).
Because tyramine restrictions were followed in this initial trial, the risk of a "cheese reaction" could not be assessed. However, oral tyramine challenges in normal subjects after fasting (24) demonstrated that doses of 200 mg or more of oral encapsulated tyramine were required to produce a pressor response. By comparison, when similar tyramine challenges were conducted with tranylcypromine-treated subjects, pressor responses were elicited after 10 mg of oral encapsulated tyramine. The dose of oral tyramine required to produce pressor effects in selegiline patients (200 mg or more) is far in excess of typical dietary intake; a tyramine-rich meal may contain up to 40 mg. Thus, it is unlikely that the selegiline transdermal system will require dietary restrictions.
"As in previous studies of selegiline treatment of major depression, the profile of adverse events differed little between the selegiline transdermal system and placebo. This is notable, given that MAOIs, as a class, are liable to have numerous side effects. Of particular clinical importance, no differences from placebo were observed in adverse events related to cardiovascular function, such as flushing, tachycardia, headache, lightheadedness, blood pressure elevation, or orthostatic hypotension. Only skin reactions at the patch site occurred significantly more frequently with the selegiline transdermal system (36% versus 17%) (p=0.006, Fisher’s exact test). This erythematous, occasionally urticarial local reaction generally persisted for several days after each application. Application site reactions occurred in this study at rates comparable to those reported for nicotine patches (34%) (28). Lower rates have been reported with transdermal estrogen (4%–10%) (29) and nitroglycerin patches (15%) (30). It is notable, however, that only three subjects dropped out of the trial because of application site reactions, indicating this was a generally tolerable side effect.
The favorable side effect profile is likely the basis for the unusually high rate of treatment compliance observed in this study. Both treatment groups used virtually all prescribed patches. In addition, 89% of the subjects receiving active drug (79/89) completed the trial. Given the poor rate of treatment adherence generally observed in depressed patients (31, 32), the high rate seen here may reflect an important therapeutic advantage of the transdermal route of administration.
An intriguing finding was a significant difference between selegiline and placebo at week 1. Although this is not highly unusual in clinical trials of antidepressants, it raises the possibility of an accelerated therapeutic response because of the parenteral drug delivery route, as has recently been demonstrated with intravenous antidepressants (33). Because of the delayed onset of clinical response to oral antidepressant medications, further investigation of the potential for a more rapid antidepressant response to transdermal treatment is warranted.
Three methodologic limitations must be considered in interpreting these results. First, the 6-week duration of active treatment was relatively brief and may have underestimated the treatment effect of the selegiline transdermal system. Second, the fixed-dose design made it impossible to assess dose-response characteristics of the selegiline transdermal system. Finally, subjects in the present study were prescribed a tyramine-restricted diet. Accordingly, additional studies without dietary restrictions will be necessary. "
For more, see....http://www.spahs.umt.edu/DIS/pdf/TransdermalSelegiline.pdf
http://ajp.psychiatryonline.org/cgi/content/full/159/11/1869
http://www.psychiatrist.com/privatepdf/2003/v64n02/v64n0216.pdf
http://www.psychiatrist.com/privatepdf/2003/v64n02/v64n0216.pdf
poster:jrbecker
thread:381095
URL: http://www.dr-bob.org/babble/20040821/msgs/381300.html