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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 4 of 4. This is the beginning of the thread.
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.
Posted by ed_uk on January 4, 2005, at 12:52:23
In reply to Me thinks this is very interesting indeed (long), posted by Michael Bell on January 3, 2005, at 23:56:23
Hello Michael!
Did you see these.........
Psychopharmacology (Berl). 1992;106 Suppl:S35-6.
Interaction of moclobemide and tricyclic antidepressants with the tyramine pressor effect in rats.
Burkard W, d'Agostini F, Kettler R, Da Prada M.
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Tyramine at high doses (20 mg/kg) increased arterial blood pressure in freely moving rats. This increase was completely prevented by pretreatment with inhibitors of neuronal membrane carriers for noradrenaline (e.g. desipramine or oxaprotiline). Pretreatment with moclobemide induced a mild potentiation of this tyramine-pressor effect which could also be attenuated dose-dependently by co-administration of oxaprotiline.
Acta Psychiatr Scand Suppl. 1990;360:106-7. Related Articles, Links
Hypotensive action and weak potentiation of tyramine effect by moclobemide in rats.Da Prada M, Burkard WP.
Pharmaceutical Research Department, F. Hoffmann-La Roche, Basle, Switzerland.
Moclobemide belongs to a new class of reversible, selective monoamine oxidase-A (MAO-A) inhibitors; it is clinically well tolerated and has little liability to potentiate tyramine pressor effects. Measurement of blood pressure and heart rate in conscious, freely moving rats showed only a slight, nonsignificant decrease in mean arterial pressure in normotensive animals. However, in spontaneously hypertensive rats, moclobemide significantly decreased blood pressure by 20 mmHg within 30 min of oral intake of 30 mg/kg. In the same animals, heart rate was decreased by 20%; normal values returned after 2-3 h. Tyramine alone in oral doses up to 15 mg/kg had no effect on blood pressure in normotensive rats, and after treatment with 30 mg/kg moclobemide, tyramine at 5 mg/kg did not alter mean arterial pressure, whereas there was a significant increase after doses of tranylcypromine, toloxatone and brofaromine. Higher doses of tyramine (10-20 mg/kg) following moclobemide led to a rise of 30-40 mmHg in pressure, but this had disappeared within 20 min. This effect was almost completely eliminated by desipramine, suggesting that coadministration of a norepinephrine uptake inhibitor with a reversible MAO inhibitor is likely to reduce the risk of tyramine-induced hypertensive crisis. Thus, the authors conclude that moclobemide exerts only a slight hypotensive action in hypertensive rats, and differs from other MAO inhibitors in potentiating the pressor effect of tyramine only weakly.
Psychopharmacology (Berl). 1986;88(2):153-7. Related Articles, Links
Moclobemide, a new reversible MAO inhibitor--interaction with tyramine and tricyclic antidepressants in healthy volunteers and depressive patients.Korn A, Eichler HG, Fischbach R, Gasic S.
Moclobemide is a new, short-acting, reversible MAOI, preferentially affecting type A MAO. We have studied the interaction of moclobemide with tyramine and tricyclic antidepressants in healthy volunteers and depressive patients. Neither tyramine capsules (50 mg) nor cheese and wine meals (65 mg tyramine) produced a significant change in blood pressure and heart rate after single or repeated doses of moclobemide in volunteers. In contrast, after 1 weeks' treatment with tranylcypromine pressure response to cheese and wine meals was severe. Blood pressure sensitivity to IV tyramine was slightly increased (1.5-2 fold; P less than 0.05 versus predrug) during moclobemide treatment in patients and volunteers. This increase was neutralised by concomitant administration of desipramine in volunteers. Amitriptyline was well tolerated when given to patients after or together with moclobemide. In conclusion, moclobemide appears relatively safe with respect to tyramine sensitivity and interaction with tricyclics.
J Clin Psychopharmacol. 1982 Dec;2(6):434-5. Related Articles, Links
Amitriptyline protects patients on MAOIs from tyramine reactions.Kline NS, Pare M, Hallstrom C, Cooper TB.
Publication Types:
Letter
Lancet. 1982 Jul 24;2(8291):183-6. Related Articles, Links
Will amitriptyline prevent the "cheese" reaction of monoamine-oxidase inhibitors?Pare CM, Kline N, Hallstrom C, Cooper TB.
Administration of amitriptyline greatly diminished the pressor response to intravenous tyramine in patients receiving monoamine-oxidase inhibitors (MAOIs). Dothiepin and trimipramine, however, produced little change in sensitivity to tyramine. It is suggested that a combination of amitriptyline and an MAOI, started together in a modest dose that is then increased, may protect patients against the potential dangers of eating tyramine-containing foods. However, because MAOIs allow a high proportion of ingested tyramine to be absorbed into the systemic circulation, patients treated with MAOIs, even in combination with amitriptyline, should not be encouraged to eat foods containing tyramine.
NB. amitriptyline inhibits the reuptake of NE and 5-HT, dothiepin is a *weak* dual reuptake inhibitor, trimipramine is not a reuptake inhibitor.
What do you think?
Ed.
Posted by ed_uk on January 4, 2005, at 19:55:01
In reply to Re: Me thinks this is very interesting indeed (long), posted by ed_uk on January 4, 2005, at 12:52:23
Scott (SLS) said.....
The only food that I have ever had a severe hypertensive reaction to is pepperoni. It didn't take much. I ingested no more than a couple of slices on a pizza. The plain cheese pizza from the same restaurant never bothered me. I experienced the classic occipital headache - pounding at the base of the skull in the back. For me, it is a certainty that pepperoni is on my foods to avoid list. I was taking Parnate 60mg + desipramine 150mg at the time.'
....and he was taking desipramine!
Ed.
Posted by Michael Bell on January 6, 2005, at 20:19:49
In reply to Re: Me thinks this is very interesting indeed (long), posted by ed_uk on January 4, 2005, at 12:52:23
It seems that unrelated studies regarding unrelated medications (moclobemide, reboxetine, amitryptiline) have all found that coadministration of a noradrenaline reuptake inhibitor along with an MAOI negates the hypertensive crisis situation. I think reboxetine would be the most effective, since it acts only upon norepinephrine and binds to the NE transporter, blocking tyramine from doing so.
What does this all mean? Well, Reboxetine, AMitriptyline, etc. probably do greatly reduce the risk of hypertensive crisis, but it's not a 100% guarantee and a lot depends on the mixture of meds, length of time on it, etc.
Bottom line: Rebox and the others are probably great antihypertensive preventative meds. Question is, who has the guts to try it?
P.S. By the way, Reboxetine sucks as monotherapy for social phobia.
This is the end of the thread.
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