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Re: Ask a silly question...

Posted by Adam on December 7, 1999, at 0:38:30

In reply to Re: You never know-Nardil vs. Parnate, posted by Elizabeth on December 6, 1999, at 20:14:56

> >...Anyway, I thought it might be connected to b.p. somehow, since orthostasis gave some relief.
> Huh - did you try taking your BP?

Nope. Don't have a b.p.-cuff yet. I should get one. My b.p. connection: Getting up temporarily
alleviated the weird lightheadedness. Then it came back. Dr. B. took my b.p. It was low, both
sitting and after getting up. It didn't change. I have no clue what was going on. Nobody else
does either. File under "must be a bug."

> ...which is terribly interesting given selegiline's pharmacokinetic profile (I tested positive for amphetamines at one point when I was on it). I wonder about the d and l forms too; may look that up later on....

Here's what I found...

"Pharmacol Biochem Behav 1976 May;4(5):575-82

Catecholamines and self-stimulation: evidence suggesting a reinforcing role for
noradrenaline and a motivating role for dopamine.

Herberg LJ, Stephens DN, Franklin KB"

"Eur J Pharmacol 1979 Aug 1;57(2-3):127-33

Norepinephrine elevations in cerebrospinal fluid after d- and l-amphetamine.

Ziegler MG, Lake CR, Ebert MH"

Above two abstracts suggest there is no differential effect btw. amphetamine enantiomers and NE
release. D-amp. is much a much more potent stimulator of DA release.

"Pharmacol Biochem Behav 1976 May;4(5):545-9

Differential actions of d- and 1-amphetamine on the metabolism of 3H-norepinephrine in
rat brain.

Peterson DW, Sparber SB"

Authors demonstrated d- and l-amp. have a stereoselective effect on the production of a certain
metabolite, (methoxyhydroxyphenylethylene-glycol). There seems to be no other info. out there
about this metabolite (none I could find anyway), so I have no idea if this is of any importance.

"J Cardiovasc Pharmacol 1982 Mar-Apr;4(2):326-9

Cardiovascular effects of methamphetamine in dogs treated chronically with the amine.

Vidrio H"

"J Auton Pharmacol 1983 Jun;3(2):79-88

Involvement of presynaptic alpha 2-adrenoreceptors in the depressor response produced
by repeated administration of dextro-methamphetamine."

Both abstracts describe the antihypertensive effects of chronic methamphetamine treatment.
L-methamphetamine is a major metabolite of l-selegiline, so _maybe_ there's the answer.
The first abstract suggests that l-methamp. doesn't give this antipressor effect, however.

"Neurology 1997 Mar;48(3):662-7

Selegiline diminishes cardiovascular autonomic responses in Parkinson's disease.

Turkka J, Suominen K, Tolonen U, Sotaniemi K, Myllyla VV

Department of Neurology, University of Oulu, Finland."

In a nutshell, selegiline, at doses indicated for Parkinsons, has sympatholytic properties.

"Br J Clin Pharmacol 1998 Jun;45(6):551-8

Comparison of the effects of moclobemide and selegiline on tyramine-evoked mydriasis in

Bitsios P, Langley RW, Tavernor S, Pyykko K, Scheinin M, Szabadi E, Bradshaw CM

Department of Psychiatry, University of Nottingham, UK."

This one is cool. They use pupil dilation as a model for MAOI/tyramine interactions.
Found that moc. permits tyramine-induced dilation, while selegiline (at MAO-B specific
dose) does not. This would suggest that MAO-B is not involved in protecting against
the effect of tyramine, which seems to contradict the notion that moc. is safe because it
spares MAO-B. Anyway, both drugs actually cause contraction of the pupil alone, and the
authors interpret this as evidence of sympatholytic properties of both sel. and moc.

"Psychopharmacology (Berl) 1985;86(4):432-7

Tyramine pressor sensitivity changes during deprenyl treatment.

Sunderland T, Mueller EA, Cohen RM, Jimerson DC, Pickar D, Murphy DL"

This one demonstrates selegiline is about as bad as tranylcypromine at non-MAO-B
specific doses in increasing sensitivity to the tyramine pressor effect.

So, it seems that selegilne has some sympatholytic properties, but they are
either insufficient to protect against tyramine, or are lost at higher doses.
Whatever this sympatholytic property is derived from, l-amp. and l-methamp. are
unlikely candidates. It would appear, though, that selegiline can protect
against some of its own amphetamine properties. ???? :-\ ????

> Oh god. Don't go least not in humans!
> > I know, ridiculous idea, probably, but something I figured I'd ask.
> Kids, don't try this at home! :)

I know the combo. is strictly contraindicated in "the literature", but so are a
number of combos which turn out to be relatively safe. What, do you suppose,
would be the problem with low-dose selegiline+tranylcypromine? Still a risk
of serotonin syndrome? Too stimulating? Bad CYP450 stuff?




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