Posted 22 April 2004 - 03:00 AM
Olav---
As I see it, there are several potential advantages of rasagiline over deprenyl. However, I do not think the metabolism (hydrolysis) issue is particularly important. L-amphetamine and L-methamphetamine have minimal CNS activity and do not cause the kind of catecholaminergic stimulation (speediness, edginess, attentiveness) or letdown (burnout or "crash") that their optical cousins do, i.e., D-amphetamine (dextroamphetamine) and D-methamphetamine (methamphetamine, or "meth"), which are collectively known as "speed." In terms of selectivity of catecholaminergic effect, deprenyl (and presumably rasagiline) selectively upregulates dopaminergic systems (arrousal, drives, motivation, passions, irritability, etc.) and has minimal effects on norepinephrine and epinephrine systems (which involve allertness, attentiveness, etc.). Having taken deprenyl on and off for years, I can attest that there is no "letdown" or rebound effect, and I do not experience significant norepinephrine-mediated effects, even at ten times my "effective" dose.
The hydrolysis issue may be important for legal reasons. Non-chiral methods for detecting drug residues in urine are not able to distinguish between L- and D-isomers of amphetamine. So some people might appreciate it if rasagiline does not cause a "false positive" urine test for D-amphetamine use.
The selectivity issue (MAO-B over MAO-A) is probably more important from clinical perspective, especially for longer-term use (as is the case with both Parkinson's treatment and longevity applications).
One of the issues that I feel should be extremely important for longevists is the possibility that derivatives of deprenyl -- and possibly rasigiline -- might be neurotoxic. There was a contamination problem with deprenyl back in the early 90s that resulted in premature death of Parkinson's patients in the Parkinson's Disease Research Group study, which was the largest and logest-term study of deprenyl ever undertaken. Although the authors of the paper officially blamed deprenyl for the 60% increased mortality in the deprenyl group, their conclusion is not scientifically defensible. All of the mortalities occurred in 6 months, in the middle a 5-6-year study! In other words, the death *rate* during the study was identical to the control group for the first 2.4 years of the study, it increased by a factor of eight within 2 months, and then returned to identical for the last 2.5 years of the study. The erroneous conclusion of the PDRG-study authors is the reason that deprenyl is currently out of favor as a Parkinson's therapy.
Although I admit that it is possible that some non-deprenyl-related contaminant was responsible for these deaths, I think it is more likely that a quaternary ammonium salt derivative of deprenyl was responsible. The dopaminergic toxicity of MPTP is mediated by MPP+, a quaternary salt metabolite of MPTP. Furhtermore, several mitochondrial Complex-I poisons are quaternary ammonium salts. All of these structures can be considered to be quaternary ammonium analogs of nicotinate (vitamin B3), which is the cofactor for coenzyme 1 (NAD, NADH, the substrate for Complex I). So, if the recipe for deprenyl manufacture is accidentally botched by the addition of too much methylating agent (which adds the N-methyl group) or too much propargylating agent (which adds the N-propargyl group), the result would be a quaternary ammonium analog of deprenyl.
The danger to longevists is that the anti-aging, neuroendocrine-sensitizing, drive-enhancing effects of deprenyl might be easily offset by some small chronic, cumulative neurotoxicity from a quaternary deprenyl analog. Since the authors of the PDRG study managed to keep their "dirty laundry" from public, professional and regulatory knowledge, companies making deprenyl may not be aware that this potential problem exists and not take (simple and easy) steps to ensure that quaternary ammonium reaction byproducts do not end up in the final drug product. I've had anecdotal reports from people who reproducibly get headaches from one deprenyl brand and not from 4-fold larger doses of another deprenyl brand. Such reactions could be caused by immediate hypersensitivity reactions to tablet excipients, but it is also possible that the headaches are a reaction to a neurotoxin. Since preservation of the brain and the functionality of the mind are an integral part of any rational longevity program, there is reason to be cautious.
I am particularly interested in learning whether rasagiline has diminished capacity for forming quaternary ammonium salts. This could easily be parallel to its resistance to hydrolysis. If anybody knows or hears anything about this, please post and/or e-mail me at fowkes@ceri.com.
