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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 12 of 12. This is the beginning of the thread.
Posted by tecknohed on October 16, 2005, at 7:44:19
Anyone know anything about New River Pharmaceuticals' new NRP104 drug (D-amphetamine bonded with Lysine), targeted for the treatment of ADHD? Its said to have less abuse potential than other stims - "Because it is inactive until metabolized in the GI tract, it may offer the advantage of reduced potential for abuse or overdose and may have a unique safety profile versus traditional stimulants"
http://www.medicalnewstoday.com/medicalnews.php?newsid=18555
How exactly would this reduce abuse and overdose potential? Sounds to good to be true! It was in phase 3 in Jan this year. Anyone know its current situation?
Posted by Shawn. T. on October 17, 2005, at 11:53:08
In reply to NRP104 - D-amphetamine bonded with Lysine?, posted by tecknohed on October 16, 2005, at 7:44:19
Taking it intranasally or intravenously will not result in a sudden, large increase in the concentration of d-amphetamine in the blood. This is because the breakdown of NRP104 to d-amphetamine will be limited by the availability of gastrointestinal enzymes.
On New River's website (http://www.nrpharma.com/products/NRP104.htm), they state that "We reported the results from our first Phase 3 trial on May 23, 2005. A second Phase 3 efficacy trial, as well as clinical abuse liability studies, are underway. We anticipate filing an NDA on NRP104 for the treatment of pediatric populations diagnosed with ADHD by the end of 2005."
Shawn
Posted by gromit on October 18, 2005, at 1:22:20
In reply to Re: NRP104 - D-amphetamine bonded with Lysine?, posted by Shawn. T. on October 17, 2005, at 11:53:08
Posted by med_empowered on October 18, 2005, at 3:38:11
In reply to Re: NRP104 - D-amphetamine bonded with Lysine?, posted by Shawn. T. on October 17, 2005, at 11:53:08
this company is trying to achieve the holy grail of ADHD treatment: effiacy and proven track record of the old-school stims, with less abuse potential and re-fillable prescriptions (improves public perception, reduces problems and paperwork). My wild guess would be that, if it is proven to be less addictive than usual dextroamphetamine, they may be able to get schedule IV status, maybe with a situation like what happened with Ultram (it was and is schedul V, uncontrolled; the company set up and paid for a monitoring program, which reported to the FDA, to investigate and analyze post-marketing abuse/misuse problems). I'm kind of wondering...do you think this will mean that this version of dextroamphetamine will be less affected by the presence/absence of foods (especially fatty ones) and other substances (acidifying agents) ? That's be **great**.
Posted by tecknohed on October 18, 2005, at 8:29:49
In reply to Re: NRP104 - D-amphetamine bonded with Lysine?, posted by Shawn. T. on October 17, 2005, at 11:53:08
> Taking it intranasally or intravenously will not result in a sudden, large increase in the concentration of d-amphetamine in the blood. This is because the breakdown of NRP104 to d-amphetamine will be limited by the availability of gastrointestinal enzymes.
> ShawnThanks Shawn, but this sounds no different than what 'sustained release' would do. And I dont see how it would mean less abuse potential when, at the end of the day, D-amphetamine is still the active ingredient working on brain chemistry in the same way. (right?)
What am I missing?
Posted by med_empowered on October 18, 2005, at 9:49:22
In reply to Re: NRP104 - D-amphetamine bonded with Lysine? » Shawn. T., posted by tecknohed on October 18, 2005, at 8:29:49
Delayed-onset can reduce abuse potential **alot**...look the barbiturates. Seconal--fast onset, highly abusable...Phenobarbital--slooooow onset, sloooooow course of action--schedule IV, still kinda popular. Benzos--xanax vs klonopin. Until they run trials in people (especially people with histories of illcit drug use), no one will know for sure but...it would *appear* that they may be able to make amphetamines considerably less abusable.
Posted by tecknohed on October 18, 2005, at 19:49:33
In reply to Re: NRP104 - D-amphetamine bonded with Lysine?, posted by med_empowered on October 18, 2005, at 9:49:22
> Delayed-onset can reduce abuse potential **alot**...look the barbiturates. Seconal--fast onset, highly abusable...Phenobarbital--slooooow onset, sloooooow course of action--schedule IV, still kinda popular. Benzos--xanax vs klonopin. Until they run trials in people (especially people with histories of illcit drug use), no one will know for sure but...it would *appear* that they may be able to make amphetamines considerably less abusable.
I see what you mean. I guess I'm just looking at it from a different angle. For someone with no history of drug abuse, the delayed onset would avoid the (almost) instantanious high and so less likely to create an 'instant reward syndrome'. However I do feel that, for those who already abuse/have abused, NRP104 would be no less abusable than normal amphetamine. More convenient even, removing the need to keep 'topping up' - a nice even high throughout the day, just a bit of patience required!
Could it be though, that with such a slow onset of action (assuming it has a 'slow' onset and not just a 'delayed' onset), it wouldn't trigger such a marked effect on DA - an effect yes, but with a more steady re-uptake mechanism without the sudden DA boost/release that occures with standard faster acting amphetamine which instead hits the brain all at once? If so, I can see how this might avoid any downregulation which normally leads to 'crash', craving and tolerence.
Maybe I just think too much (sigh).
teck.
Posted by Larry Hoover on October 19, 2005, at 6:37:21
In reply to NRP104 - D-amphetamine bonded with Lysine?, posted by tecknohed on October 16, 2005, at 7:44:19
I did a little poking around about this new drug, and yes, it will avoid Schedule 2. The FDA has already determined that NRP104 is not an amphetamine/analog.
This drug is one of a series of investigational drugs, all falling under the registered mark of Conditionally Bioreversible Derivatives, known collectively as Carrierwave technology.
This lysine/amphetamine dimer must have a very simple structure. There's only one possible bond between the two, to form the conjugate, an amide bond at the lysine carboxylic moiety and the amphetamine amine.
The "condition" which would cleave the two would be low pH in the stomach, via acid catalyzed hydrolysis. Unless there is an enzyme specific to removing n-terminal lysine residues, I think that any inference that the release of amphetamine is under enzymatic control is quite specious. Certainly, intravenous or inhaled drug would fail to encounter the acidity required to hydrolyze the dimer at any substantial rate, so abuse potential would simply be via excessive oral intake.
IMHO, the release of amphetamine would be somewhat slower than from amphetamine salts, but not delayed release in any meaningful way.
That's just my brain looking at it, anyway.
Lar
Posted by Shawn. T. on October 22, 2005, at 15:49:40
In reply to Re: NRP104 - D-amphetamine bonded with Lysine?, posted by Larry Hoover on October 19, 2005, at 6:37:21
I didn't just infer that. On New River's website, it is stated that "The binding of the adjuvant renders the active pharmaceutical ingredient essentially inactive until it is broken down into its component parts. We believe that this breakdown only occurs at specifically-targeted sites of enzymatic activity in the body. In the case of our current Carrierwave™ compounds, the site of enzymatic activity is primarily in the gastrointestinal tract. At the target site, enzymes hydrolyze or cleave the adjuvant from the active pharmaceutical ingredient, releasing the active pharmaceutical ingredient into circulation.
While we have not fully established the mechanisms of absorption involved in our Carrierwave™ technology, we believe that the rate of release of the active pharmaceutical ingredient from the CBD is subject to a "saturation effect," which occurs when the CBD is administered in doses greater than that which can be accommodated by the enzymatic processes in the gastrointestinal tract."
I find your claim that NRP104 does not exhibit delayed release in any way to be quite specious. New River has said that "NRP104 demonstrated bioavailability comparable to that of currently-marketed, extended release amphetamine- based products." (http://www.wrhambrecht.com/ind/auctions/openipo/nrph/nrph20040805.pdf)
Posted by Chairman_MAO on October 25, 2005, at 22:31:16
In reply to Re: NRP104 - D-amphetamine bonded with Lysine? » Larry Hoover, posted by Shawn. T. on October 22, 2005, at 15:49:40
to think that it will be anything but laughably easy to cleave that lysine off with some dietary supplement (in the stomach) or other or other research chemical is delusional thinking.
Posted by Larry Hoover on October 27, 2005, at 14:15:11
In reply to Re: NRP104 - D-amphetamine bonded with Lysine? » Larry Hoover, posted by Shawn. T. on October 22, 2005, at 15:49:40
Shawn, I'm sorry. Did I say something to make you feel under criticism?
The manufacturer's claims are not fully consistent with simple physiology. As I suggested, stomach acid would initiate hydrolysis of the dimer. The pancreatic enzyme trypsin, secreted in the duodenum, has some specificity for lysine, and would likely finish the job. However, I do not know of any evidence to support a claim of a "saturation effect", in this instance. If it did come to bear on the kinetics here, I'd have to suggest that it would occur only at doses far above those expected from prescribed amounts.
As Chairman MAO points out, and my comments infer, it would be simple to cleave the amphetamine from the lysine. The prodrug would have little effect if injected or snorted as supplied, but it's not too difficult to defeat the CBD safety feature, and liberate the amphetamine.
It's hard to know just what was observed in their trials, as nothing I can find has been published. As they are also CBD delivery systems for opiate analgesics, we can expect some serious scrutiny. Until we see some data, we will be restricted to opinionated speculation. I'm sorry if my thoughts left anyone feeling unhappy. I purposely posted to the thread, and not to an individual.
Lar
Posted by ADHDdoc on April 10, 2006, at 16:32:49
In reply to Re: NRP104 - D-amphetamine bonded with Lysine? » Larry Hoover, posted by Shawn. T. on October 22, 2005, at 15:49:40
I read with interest the October, 2005 discussion between Shawn T. and Larry Hoover about NRP104 and its possible mechanisms of metabolism. Six months later, is there any more information about how NRP104 is metabolized? Since New River describes the metabolism as being dependent on "GI enzymes," I wondered whether any of the Cytochrome P450 enzymes might need to be called upon to cleave the lysine off of the d-amphetamine molecule. If so, might this not increase the potential for drug-drug interactions, particularly if an ADHD patient were taking something else that were an inhibitor or a substrate of the same enzyme?
This is the end of the thread.
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