This is a run down on what I am talking about, it seems like it is being destroyed in the stomach because of the new formulation. If anyone has any thoughts on what this guy is saying and how I could increase it's effectivness I would appreciate it.
Re: ... Old and New Nardil (warning: very long) » shasling
Posted by Tomatheus on January 28, 2006, at 22:14:49
In reply to What's Different Between the Old and New Nardil?, posted by shasling on January 26, 2006, at 10:05:59
Suzie,
Considering that I'm guilty of having made several references to the "old" and "new" Nardils without really giving much of an explanation, it seems appropriate that I should offer a response to your post.
To answer the first part of your question on the simplest level, Pfizer essentially changed the formulation of the U.S. version of Nardil. Many of the inactive ingredients in the "old" Nardil are no longer in the "new" Nardil, and the coatings of the two formulations look obviously different. The "old" Nardil had a hard, shiny candy-like coating, whereas the coating of the "new" Nardil is softer and has the lettering ("PD 270") engraved into it. Pfizer began distributing the "new" Nardil to pharmacies in the place of the "old" Nardil in the fall of 2003. I've listed the inactive ingredients of the two Pfizer Nardil formulations below:
THE "OLD" PFIZER NARDIL (Parke-Davis Division of Pfizer Inc., 2001)
* Acacia, NF
* Calcium carbonate
* Carnauba wax, NF
* Corn-starch, NF
* FD and C yellow No. 6
* Gelatin, NF
* Kaolin, USP
* Magnesium stearate, NF
* Mannitol, USP
* Pharmaceutical glaze, NF
* Povidone, USP
* Sucrose, NF
* Talc, USP
* White wax, NF
* White wheat flower
THE "NEW" PFIZER NARDIL (Parke-Davis Division of Pfizer Inc., 2003)
* Mannitol, USP
* Croscarmellose sodium, NF
* Povidone, USP
* Edetate disodium, USP
* Magnesium stearate, NF
* Isopropyl alcohol, USP
* Purified water, USP
* Opadry orange Y30-13242A
* Simethicone emulsion, USP
Note: According to a letter sent to Pfizer by the FDA (Katz, 2003), the labeling document that Pfizer submitted as part of its supplemental new drug application (dated March 27, 2003) listed "corn starch, NF" as an inactive ingredient using strikethrough formatting.
With respect to whether the "old" Nardil was better than the "new" Nardil, there is some disagreement, but it is my assessment that the "old" Nardil was clearly superior to the "new" Nardil in some individuals. From the experiences that I've read on this board and on the Anxiety Community's Nardil discussion board (
http://anxietyhelp.org/treatment/medication/nardil.html), it is clear that some "old" Nardil users find the "new" Nardil to be markedly less effective and less tolerable (in terms of side effects) than the old product. There are others, however, who have reported no noticeable differences between the two formulations. I have yet to read an experience from someone who took both formulations and found the new one to be superior to the old one. From the posts I've read on the topic, it seems that among those who took both the "old" and the "new" Nardils, most tend to describe the old formulation as being superior to the new one. What is not entirely clear is whether the posts I've read are representative of the overall group of patients who have taken both the "old" Nardil and the "new" Nardil. It is generally believed that those with positive experiences to meds in general to be underrepresented on online discussion forums, so it's possible that those with negative experiences on the new Nardil might not actually be in the majority; they might just be more likely to report their experiences here. But then again, there is no way to know to what extent certain groups of patients are overrepresented here or underrepresented here, so I guess that only thing I can say for sure (assuming that all the reports are accurate) is that some patients (at least several hundred, based on some reports) noticed a significant difference between the "old" and "new" Nardils (with the "old" Nardil being superior), and others did not notice a difference.
In terms of hard data that show a difference in terms of the ways in which the two formulations exert their effects on the body, I have only been able to find one clearly measurable difference. This is not to say that there are not more differences. The problem for me with respect to finding hard data has been twofold: one, I've only had so much time so far to research the Nardil formulations; and two, the amount of hard data regarding the differences between the formulations is likely limited. In terms of my research, I plan to do more, and it's quite possible (and I would even say likely) that I will find more data suggesting that the two formulations affect the body differently. But for now, the only thing I have is that the peak plasma concentration of the "old" Nardil occurred between two and four hours postdose (Robinson et al., 1985, as cited in Mallinger & Smith, 1991), but the peak plasma concentration of the "new" Nardil occurs approximately 43 minutes after the administration of a single 30 mg dose (Parke-Davis Division of Pfizer Inc., 2003). Because I currently only have the abstract of the original article reporting the peak plasma concentration of the "old" Nardil (Robinson et al., 1985), I don't know what dose of Nardil was given to the patients whose peak plasma concentrations of phenelzine (the active ingredient) averaged between two and four hours postdose. So, I can't really make a direct comparison between the two statistics without knowing whether those who received the "old" Nardil received the same dose as those who took the "new" Nardil. Of course, I will eventually track down the Robinson et al. (1985) article; it's just a matter of me being able to find the time to take a trip down to my nearest med school library. But even though a 100 percent direct comparison cannot be made, it still seems likely that there is a difference between the peak plasma concentrations of the two formulations. If nothing else, such a difference would be consistent with patient reports that the "new" Nardil -- but not the "old" Nardil -- sometimes begins to dissolve in the mouth if not swallowed quickly enough.
Between this board and the Anxiety Community's Nardil discussion board, patients have put forth several different (but sometimes related) hypotheses that have attempted to explain why some patients find the "new" Nardil to be inferior to the old product. Generally, there seems to be a consensus that the "old" Nardil's hard coating (possibly an enteric coating, which is not dissolved until it reaches the small intestine) and/or its relatively slow rate of dissolution and absorption in the body are what cause some patients to find it to be superior to the new formulation.
At this point, I am researching the possibility that too much phenelzine (Nardil's active ingredient) might make its way directly to the liver (where it is metabolized) if it dissolves in the stomach. In accordance with this possibility, I'm also going to be looking into whether or phenelzine is absorbed directly into the bloodstream (without first going through the liver) when it's enterically coated and absorbed in the small intestine. If both of these ideas are true, then I would be able to say with some certainty that at least part of the problem with the "new" Nardil is that it dissolves in the stomach, allowing too much of the phenelzine to go directly to the liver instead of making its way to the small intestine, where it can go directly to the bloodstream and potentially to the brain. The implications of too much phenelzine going directly to the liver would be twofold: one, there would be significantly less phenelzine to enter the bloodstream, reach the brain, and exert its antidepressant effects; two, a relatively large amount of phenelzine would immediately go to the liver and be metabolized to the bioactive amine beta-phenylethylamine, or PEA (Baker et al., 1999). PEA levels would rise to excessively high levels both because more PEA would be created (through the rapid metabolism of phenelzine in the liver) and because less PEA would be destroyed (via the inhibition of MAO-B, the enzyme responsible for the degredation of PEA). Considering that PEA stimulates the release of dopamine and briefly stimulates dopamine receptors (Barroso & Rodriguez, 1996), dopamine levels would also rise to relatively high levels (higher with the "new" Nardil than with the "old" Nardil) -- levels that would likely be excessively high for many traditional MAOI responders suffering from depression and/or anxiety. So, once again, if my mini hypothesis here has any validity, the problem with the "new" Nardil would be a combination of there being not enough MAO-A and MAO-B inhibited in the brain and there being an excessively high level of dopamine, especially in comparison to serotonin and norepinephrine. Raising the dose of the "new" Nardil would raise the level of MAO inhibition in the brain, but it would also allow dopamine to keep rising disproportionately in comparison to the other neurotransmitters. This could, among other things, explain why patients who took both Nardil formulations were more likely to experience insomnia and other side effects on the "new" Nardil, and why some patients reported after the formulation switch that still felt Nardil's antidepressant effect (to a lesser extent than with the "old" Nardil) but not its anti-anxiety effect (high dopamine = generally bad for anxiety). And of course, it could explain why simply raising the dose of the "new" Nardil would not produce the same results as the "old" Nardil.
To answer your last question, it is my understanding that no version of Nardil produced anywhere in the world is exactly the same as the "old" Pfizer Nardil in terms of the drug's inactive ingredients. Based on information that I have gathered, the inactive ingredients for the Australian Nardil (manufactured by Link Pharmaceuticals) are listed differently than the ingredients for the U.K. Nardil (manufactured by Concord Pharmaceuticals). But considering the fact that Link is the "marketing authorisation holder" of the U.K. Nardil and the fact that the U.K. and Australian versions of Nardil appear to have the same type of coating, it's possible that they might actually be the same (with some of the ingredients in the U.K. Nardil being incorporated under the "coating" ingredient for the Australian Nardil), or at least very similar. Here is a breakdown of the inactive ingredients of both the U.K. and Australian Nardils:
CONCORD (U.K.) NARDIL (James, 2006)
* Mannitol
* Povidone
* Magnesium stearate and maize starch with the tablet coating containing hydroxypropyl cellulose
* Polyvinylacetatephthalate
* Stearic acid
* Sunset yellow (E110)
* Titanium dioxide (E171)
* Erythrosine (E127)
* Hydroxypropylmethylcellulose (E464)
* Talc
According to David James (2006), Concord's product information and technology executive, the company's formulation "has been in use prior to the current Marketing Authorisation Holder acquiring the rights to the product in 1999."
LINK (AUSTRALIA) NARDIL (Link Medical Products Pty Ltd, 2004)
* Mannitol
* Povidone
* Maize starch
* Magnesium stearate
* Coating (Opadry 20A25096 Red)
Finally, with respect to the efficacy of the U.K. and Australian versions of Nardil, I have read mixed reports from those who have posted both here and on the Anxiety Community's Nardil discussion board. Some Nardil users from the U.K. and Australia argue that their versions of Nardil are no different from the "old" Pfizer Nardil. But then again, I don't recall having read a message written by someone from either Australia or the U.K. who took *both* their local Nardil formulation and the "old" Pfizer Nardil. I suspect that the Nardil formulations in both the U.K. and Australia either haven't been changed at all or haven't been changed in significant ways. So, for those who have *only* taken either the Australian Nardil or the U.K. Nardil all along, the new stuff would be just as good as the old stuff because nothing about their versions of Nardil have changed. What I can with respect to the "old" Pfizer Nardil and the various international Nardils is that some former "old" Nardil users on the Anxeity Community's discussion board have tried taking either the U.K. version of the drug, the Australian version, or both, and they generally found the U.K. and Australian Nardil versions to be comparable to the "new" Pfizer in terms of both efficacy and side effects.
Even though I live in the U.S., I have been taking the Australian Nardil with somewhat successful but sometimes frustrating results. What's frustrated me about Nardil is that I usually feel its antidepressant effect for the first two to three weeks after increasing to a higher dose (assuming that my dose is at least 60 mg), but then I experience a sort of negative energy that doesn't completely negate the antidepressant effect, but sort of makes it less noticeable. The best thing that I can compare the "negative energy" to is how I felt on Wellbutrin, which would suggest that my dopamine levels might be disproportionately high in comparison to those of norepinephrine and especially serotonin (remember, this is consistent with what I had hypothesized about earlier). I suspect that if I add something like Lamictal to my Nardil (as some Nardil users tend to do), it might help with the "negative energy" and allow Nardil's antidepressant effect to shine through. I might very well end up going this route. But right now, I've actually just begun a trial of the make-your-own enterically coated Nardil that PsychoBabble member Michael Bell first tried. I've already noticed some improvements, but I'm going to wait a few weeks before making a judgment as to whether or not the make-your-own enterically coated Nardil approach is something that's truly working for me. But anyway, if you would like more information on Michael Bell's approach, check out these links:
http://www.dr-bob.org/babble/20050527/msgs/505052.html
http://www.dr-bob.org/babble/alter/20050510/msgs/506644.html
http://www.dr-bob.org/babble/alter/20050510/msgs/506649.html
Well, I hope you found my post helpful and not too confusing. If you have any questions about anything that I've written, feel free to let me know.
Tomatheus
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http://www.dr-bob.org/babble/20060122/msgs/603926.html
