Posted by Michael Bell on January 3, 2005, at 23:56:23
I know I posted a similar topic before, but I decided to compile various studies to determine if Reboxetine truly negates the tyramine pressor effect responsible for hypertensive crises. I'm very interested in this b/c if this turns out to be true, MAOIs could be made much safer. Needless to say, more research needs to be done, but this is what I found so far:
Study #1
MEDLINEBlockade of the norepinephrine reuptake transporter with a compound such as desipramine or the new selective noradrenergic reuptake blocker reboxetine will decrease firing of noradrenergic neurons by increasing the amount of extracellular norepinephrine to bind to the alpha2 receptors. Experiments done by the authors in rat neurons have shown this decrease in firing after 2 days of treatment with either compound. After more time, there is a leveling off of desipramine's effect, but a progressive effect of reboxetine. One implication of this data is that reboxetine may prove to be effective at considerably smaller doses than those used in its initial clinical studies (50%, or 4 mg rather than 8 mg per day).
When tyrosine, a precursor of norepinephrine, is added to neurons, it is taken up into the cell by the reuptake transporter. This causes norepinephrine to be released and, as a result, there is a transient increase in blood pressure. This is the cause of the hypertensive reaction to tyrosine-rich foods in patients taking monoamine oxidase inhibitors (MAOIs). Since the breakdown of norepinephrine is inhibited by these drugs, when the patient eats a high concentration of tyrosine, more norepinephrine is released and the hypertensive reaction is exaggerated. NORADRENERGIC REUPTAKE BLOCKERS BLOCK THIS REACTION, and there is even some data showing that reuptake blockers such as the noradrenergic tricyclic antidepressants may work as antidotes to this MAOI reaction.[2]
Study #2
FROM REBOXETINE.COM
This study aimed to examine whether the increase in heart radioactivity levels after intravenous injection of 14C-tyramine to rats pretreated with the irreversible MAO inhibitor tranylcypromine could be antagonized by reboxetine, a potent and selective noradrenaline uptake blocker. REBOXETINE WAS FOUND TO TOTALLY ABOLISH THE EFFECT OF TRANYLCYPROMINE. Heart radioactivity levels after reboxetine and tranylcypromine were very similar to those found when tyramine was injected after reboxetine only. THESE RESULTS SUGGEST THAT REBOXETINE MIGHT BE ADVANTAGEEOUSLY COMBINED WITH TRANYLCYPROMINE, OR ANY MAO INHIBITOR, IN DEPRESSED PATIENTS UNRESPONSIVE OF EITHER TREATMENT GIVEN ALONEone.
Study #3
The Pharmacology and Toxicology of Reboxetine
Michael J. Burns, MD
Division of ToxicologyTo date, no clinically significant pharmacodynamic or pharmacokinetic drug-drug or drug-food interactions have been described with reboxetine. (9) No significant additive effect on cognitive or psychomotor function was observed when alcohol or lorazepam was given with therapeutic doses of reboxetine. (9, 32, 33) Althogh not clinically proven, it may be possible to administer a MAOI to a patient taking reboxetine. REBOXETINE DOES NOT ITSELF INHIBIT MAO AND, AS AN NRI SHOULD PROTECT AGAINST TYRAMINE REACTIONS ASSOCIATED WITH MAOI THERAPY; THE BLOCKADE OF THE NE REUPTAKE TRANSPORTER BY REBOXETINE SHOULD PREVENT THE RELEASE OF AN EXPANDED PRESYNAPTIC POOL OF NE. (9, 11, 15, 16) ***Conversely, however, the administration of reboxetine to a patient taking a MAOI may be dangerous and could precipitate a life-threatening sympathomimetic reaction by further increasing the amount of NE in the synapse.*** Until more data is available, the concomitant administration of reboxetine and MAOIs is not recommended.
Study #4
The Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 16, 2003; 10.1124/jpet.103.052233The contractions evoked by tyramine (3 x 10-6-10-3 M) was reduced by reboxetine (3 x 10-8-10-6 M) and by cocaine (10-7-10-5 M). We conclude that reboxetine inhibits the membrane amine pump (uptake-1) in the terminals of postganglionic adrenergic neurons in a cocaine-like manner.
Study #5
Norepinephrine Reuptake
Pierre Blier, MD, PhD, of the Department of Psychiatry at the University of Florida in Gainesville, has used a technique called the tyramine pressor test to assess norepinephrine reuptake capacity of antidepressant medications.[6] Tyramine, the chemical responsible for the dreaded "cheese reaction" associated with the use of monoamine oxidase inhibitors, is taken up into the neuron by the norepinephrine reuptake pump, where it displaces norepinephrine from intracellular stores and causes it to be released. When combined with the intracellular effects of monoamine oxidase, norepinephrine levels at the synapse are dramatically increased, thereby causing hypertension. NOT SURPRISINGLY, PRETREATMENT WITH ANTIDEPRESSANTS WITH EFFECTS PRIMARILY ON BLOCKING THE NOREPINEPHRINE REUPTAKE PUMP, LIKE NORTRIPTYLINE OR REBOXETINE, WILL ABOLISH THE TYRAMINE PRESSOR EFFECT BY PREVENTING IT FROM ENTERING THE NEURON.
Study #6
Effect of the selective noradrenergic reuptake inhibitor reboxetine on the firing activity of noradrenaline and serotonin neurons.
Szabo ST, Blier P.
Neurobiological Psychiatry Unit, McGill University, Montreal, Canada.Reboxetine is a non-tricyclic antidepressant with selective noradrenergic (NA) reuptake-blocking effects. The effects of acute and sustained administration of reboxetine, on the firing activity of locus coeruleus NA neurons and dorsal raphe 5-HT neurons, were assessed using in vivo extracellular unitary recording in rats anaesthetized with chloral hydrate. Reboxetine (0.1-1.25 mg/kg, i.v.) dose-dependently decreased the firing activity of NA neurons (ED50 = 480 +/- 14 microg/kg). A 2-day treatment with reboxetine at 1.25, 2.5, 5, or 10 mg/kg per day (using osmotic minipumps implanted subcutaneously) produced significant decreases of 52%, 68%, 81%, and 83%, respectively, of NA firing activity. When the reboxetine treatment (2.5 mg/kg per day) duration was prolonged to 7 days, a 66% decrease in NA firing activity was observed which further decreased to 80% after 21 days of treatment. In contrast, 5-HT neuron firing rate remained unaltered following short- and long-term reboxetine treatments. The suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of NA neurons was unchanged in long-term reboxetine-treated rats, but its effect on the firing activity of 5-HT neurons was blunted. The enhancement of NA firing activity by the 5-HT1A agonist 8-OH-DPAT was abolished in long-term reboxetine-treated rats, whereas, the inhibitory effect of the 5-HT2 agonist DOI was attenuated by about three-fold. In conclusion, sustained NA reuptake blockade by reboxetine lead to profound alterations in the function of NA neurons and of 5-HT receptors modulating their firing activity.
Interesting stuff so far. Most of the studies outright claim that NARIs (Noradrenaline reuptake inhibitors) such as Reboxetine cancel the tyramine pressor effect (or "cheese effect") caused by MAOIs. One of the studies says that more info is needed, as the combo can actually exacerbate the situation.Bottom line... maybe we're on to something.
Night.
poster:Michael Bell
thread:437493
URL: http://www.dr-bob.org/babble/20050103/msgs/437493.html