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Biotech / Medical : Celgene-CELG -- Ignore unavailable to you. Want to Upgrade?

To: A.J. Mullen who wrote (357)	9/10/1999 11:22:00 AM
From: Biomaven	Read Replies (1) \| Respond to of 804

AJM, The duration of 5mg of the single isomer is indeed longer than that of 10mg of the original - see the preceding posts for details. I'm not sure if the reason for this is fully understood. For an example of how this can happen, one model is SEPR's single isomer albuterol, Xopenex. There the "evil twin" not only has a longer half-life than the good guy, but also interferes with its effectiveness. There it turns out that you can give the single isomer in a quarter of the dose of the racemic mixture and get equivalent efficacy and a longer duration of action. My guess is that something similar is happening with Ritalin, although I don't think here there is any suggestion that the discarded isomer is actually harmful, just that it plugs up the works in some way, maybe by binding to the relevant receptor(s) or otherwise competing with the good isomer. The plasma concentration of the good isomer is approximately the same as when you give double the dose of the racemic, so it's probably not an absorption issue. Peter

To: A.J. Mullen who wrote (357)	9/10/1999 8:23:00 PM
From: Miljenko Zuanic	Read Replies (2) \| Respond to of 804

AJM: I am not neuro-guy and certainly not qualified to give you professional opinion. However, FWIW, here is my thinking. Attenade will probably have better side effects profile than Ritalin, however this will not be of magnitude (because Ritalin is already good and tolerable drug at mild dose, some more side effects at 20 mg dose) to force DRs and HMOs to subscribe premium priced drug. IF DURATION AND RESPONSE RATE ARE BETTER, STORY IS DIFFERENT. Can you image frustrated parents and kids listening comments during their line-up at school nursing office? Investigators expected (to be honest I was bit suspicious about IMMEDIATE release (+)-R formulation results in PIII, even having in front of me data from CELG patent) that Attenade (at half R dose) will have comparable results with some IMPROVEMENT. They didn't expect statistical significance for therapeutic effects duration, the most important issue here, imo. After learned for early completion of this trial I immediate drooped my skepticism. Few calls at that time worked very well for me. Methilphenidate (Ritalin) has good bioaveability and fast response (fast and good cns penetration), however it is also metabolized (to ritalinic acid) fast. (+)-Enantiomer is metabolized at slower rate than (-)-one and there are indication that it is ~10 times more potent than (-)-isomers. CELG and other researchers will probably look on this difference (enatiomers versus racemate) in (+)-isomer plasma level and response duration (this will be important for pulse-release formulation). What is known that there is certain trash hold drug plasma level and further increase in dose (over 20 mg) does not increase therapeutic benefit proportionally. Also, many tried in past (and are trying today) to develop extended release formulation with longer single dose drug therapeutic duration. So far, mixed bag, not so good results. So far, it appears that Attenade will break this barrier and for first time be drug of choice for many DRs/kids. Miljenko