From: dyer@spdcc.com (Steve Dyer)
Newsgroups: sci.med
Subject: Re: RIMA
Date: 26 Aug 92 15:32:08 GMT
Organization: S.P. Dyer Computer Consulting, Cambridge MA

In article <1992Aug26.020115.24848@dragon.acadiau.ca> 880506s@dragon.acadiau.ca (James R. Skinner) writes:
>	Recently my doctor has been discussing the idea of trying me on
>the new class of antidepressants Reversible Inhibitors of Monoamine-oxidase A.
>or simple RIMAs.  Since these are very new ( and supposedly don't have many
>of the side effects older MOAs had ) I was wondering if anyone has taken 
>this drug or knows any more information about them.

Moclobemide is the best known of this class of compounds.  Existing MAO
inhibitors used for depression are non-specific--they inhibit MAO-A and
MAO-B alike, and they tend to be irreversible (that is, they covalently
bond to the enzyme, permanently knocking it out of commission); new
enzyme activity requires new protein synthesis, which is why you need
to wait 7-14 days after discontinuing a MAOI to see MAO acivity return
to normal.

Moclobemide tends to inhibit MAO-A more than it does MAO-B.  MAO-A
seems to be involved in the degradation of norepinephrine,
serotonin, and intestinal tyramine, whereas MAO-B degrades dopamine.
MAOIs which have little effect on MAO-A (such as the drug relatively
selective for MAO-B, l-deprenyl aka selegiline) make inferior
antidepressants.  Moclobemide is a reversible MAOI, meaning that it
occupies the active site of the enzyme, but does not covalently bond to
it, and it will eventually dissociate from the site.  The drug is also
fairly completely metabolized within a day or so, so MAO inhibition
reverts to normal in a day or so.

As you know, one of the big problems with MAOIs is the fact that many
foods contain tyramine, a sympathomimetic amine produced by the
bacterial decarboxylation of tyrosine--it's a problem primarily
with aged or cured foods, such as most cheeses, hard sausages,
some red wines, and an additional list the length of your arm.
A person on a conventional MAOI eating too much food containing
tyramine will experience a rise in blood pressure, possibly
dangerously so, which in some cases has even led to a stroke
or death.  Also, people taking conventional MAOIs have to be
careful what OTC and Rx drugs they take.  Many drugs, especially
but not only sympathomimetic drugs, can be toxic to individuals
on MAOIs.  Another problem with non-specific, irreversible MAOIs
is the side effect of postural hypotension (low blood pressure,
especially upon rising quickly.)

It's been found that moclobemide in particular, and most RIMAs,
tend not to potentiate the effects of dietary tyramine.  This
doesn't make a lot of sense to me, since MAO-A in the gut is what
protects normal individuals (i.e. not on MAOIs) from the effects of
tyramine in foods.  However, experiments have borne this out.
The "cheese reaction" isn't completely attenuated, but enough
so that individuals need not be so scrupulous with their diet.
The drug is also reported to cause little postural hypotension.

No RIMA is yet approved in the US for depression or any other
indication, though from your comments, it seems to be in Canada.
I'm not sure what the timetable is for any introduction in the US.

-- 
Steve Dyer
dyer@ursa-major.spdcc.com aka {ima,harvard,rayssd,linus,m2c}!spdcc!dyer