From

THE GOODDRUG GUIDE

"..... Selegiline, also known as l-deprenyl, is an irreversible and
(relatively) selective MAO-B inhibitor. Meta-analysis of published
clinical trials confirms it offers a cheap, safe and effective
symptomatic treatment of early Parkinson's disease. Selegiline may
also be neuroprotective and act as an antidepressant.
The enzyme monoamine oxidase has two main forms, type A
and type B. They are coded by separate genes. MAO may be
inhibited with agents that act reversibly or irreversibly; and
selectively or unselectively. These categories are not absolute. MAO
type-A preferentially deaminates serotonin and noradrenaline, and
also non-selectively dopamine. Type B metabolises dopamine,
phenylethylamine (the chocolate amphetamine) and various trace
amines.
At dosages up to around 10 mg or so daily, selegiline retains
its selectivity for the type-B MAO iso-enzyme; but it is also a weak
reversible inhibitor of the type-A MAO iso-enzyme. In contrast to
unselective and irreversible MAO inhibitors such as tranylcypromine
(Parnate) and phenelzine (Nardil), both of which strongly potentiate
the catecholamine-releasing effect of tyramine, selegiline inhibits it.
This ensures that low-dosage selegiline does not induce the
hypertensive "cheese effect". A regimen of 2 x 5 mg daily of
selegiline irreversibly inhibits over 90% of MAO-B in the basal ganglia,
the location of over 80% of dopamine in the human brain. This level
of MAO-B inhibition leads to a 40%-70% increase in synaptic
dopamine.
Selegiline has immune-system-boosting and anti-
neurodegenerative effects. Its use increases the level of tyrosine
hydroxylase, growth hormone, cerebral nitric oxide and the
production of key interleukins. Selegiline offers protection against
DNA damage and oxidative stress by hydroxyl and peroxyl radical
trapping; and against excitotoxic damage from glutamate. In
addition, selegiline stimulates the release of superoxide dismutase
(SOD). SOD is a key enzyme which helps to quench the production
of damaging free-radicals. Potentially, selegiline may prevent or
reverse iron-induced memory impairment. The deposition of excess
iron in the brain is implicated several neurodegenerative diseases.
Selegiline protects the mitochondria via its effects on
mitochondrial membrane permeability: it directly interacts with the
mitochondrial membrane permeability: it directly interacts with the
pore-forming structures. Mitochondria are the energy powerhouses
of the eukaryotic cell where oxygen respiration occurs. If the
mitochondrial theory of aging is correct, then the root cause of
aging is damage to mitochondrial DNA by free radical leakage from
adjacent respiratory proteins. Alas selegiline itself is not an elixir of
eternal youth. But its current "off-label" use by life-extensionists
prefigures the longevity-enhancing mitochondrial medicine of
decades to come.
Taken consistently at low dosage, selegiline tends to extend
the life-expectancy of rats by some 20%; enhances drive, libido and
endurance; and independently improves cognitive performance in
Alzheimer's patients and in some healthy normals. Its protective role
against age-related memory decline derives at least in part from its
protection of hippocampal neurons in the aging brain. Aging drug-
free rats have poorer spatial memories and fewer hippocampal
neurons than their counterparts on selegiline. Selegiline is already
used successfully to treat canine cognitive dysfunction syndrome
(CDS) in dogs.
Selegiline retards the metabolism not just of dopamine but also
of phenylethylamine, a trace amine also found in chocolate and
released when we're in love.
Selegiline protects the brain's dopamine cells from oxidative
stress. The brain has only about 30-40 thousand dopaminergic
neurons in all. We tend to lose perhaps 13% a decade in adult life.
An eventual 70%-80% loss leads to the dopamine-deficiency
disorder Parkinson's disease, frequently foreshadowed by depression.
Selegiline in pill form was approved by the FDA as an adjunct in the
treatment of Parkinson's disease in 1989. In June 2006, the FDA
approved once-daily orally disintegrating tablets of selegiline HCl
branded as Zelapar from Valeant Pharmaceuticals. Zelapar is used as
an adjunct therapy for Parkinsonians on levodopa/carbidopa
(Sinemet) whose response is deteriorating. The cocktail allegedly
reduces "off" time by an average of 2.2 hours per day.
Administered at low doses, selegiline is neuroprotective against
possible damage to the serotonergic fine axon terminals caused by
overconsumption of the popular drug MDMA (Ecstasy). Several
competing theories exist that purport to explain MDMA-induced
neurotoxicity. One theory blames the deamination by MAO-B of
excessive dopamine taken up by the membrane-bound transporter
into the depleted serotonin terminals. This abnormal uptake follows
MDMA-induced reversal of the serotonin reuptake pump. In the
absence of MAO-B inhibition, deamination by MAO-B of excess
dopamine taken up into the serotonergic axon terminals is liable to
generate a glut of toxic free radicals. These highly reactive
compounds cause membrane lipid peroxidation and consequent fine
compounds cause membrane lipid peroxidation and consequent fine
terminal degeneration. Selegiline prevents such serotonergic
damage, in theory at any rate.
On the other hand, co-administering unselective selegiline
dosages or unselective irreversible MAOIs like tranylcypromine
(Parnate) or phenelzine (Nardil) with MDMA is potentially lethal.
Taken at MAO-B-selective dosages, selegiline is typically less
effective as a mood-brightener than other dopaminergics such as
amineptine (Survector) - though occasionally spectacular remission
of depressive symptoms may occur even with minimal MAO-A
inhibition. Taken at unselective dosages of 20mg a day or more,
selegiline is typically an effective, well-tolerated antidepressant.
Selegiline at higher dosages may also be useful for "atypical"
depressive symptoms of overeating, oversleeping, and
hypersensitivity to rejection. An unselective dosage regimen would
normally call for an MAOI diet (no cheese, red wine, fava beans,
salami, etc).
However, the gastrointestinal tract can be bypassed.
Selegiline can be delivered via a one-a-day transdermal patch. In
December 2004, pharmaceutical firms Bristol-Myers Squibb and
Somerset Pharmaceuticals announced they had entered into an
agreement to distribute and commercialize EMSAM - the first
transdermal treatment for major depression. Better treatment of
depression and dysthymia is sorely needed. A February 2008 meta-
analysis of (published and unpublished) trials of several commonly
prescribed "second generation" antidepressants concluded that they
were scarcely more effective than placebos.
Wrangling over labelling issues delayed EMSAM's product
launch. But in February 2006, the FDA granted EMSAM a product
license for the treatment of major depressive disorder in adults.
EMSAM's pharmacokinetic and pharmacodynamic properties promote
the inhibition of MAO-A and MAO-B in the CNS while avoiding
significant inhibition of intestinal and liver MAO-A enzyme.
Three different strengths of EMSAM patch are currently
marketed: 20mg/20cm
2
, 30mg/30cm
2
, and 40mg/40cm
2
. The three
patch sizes deliver daily doses of selegiline averaging 6mg, 9mg and
12mg respectively. Use of the lowest dosage EMSAM 6 mg/24 hour
patch doesn't call for dietary modification. Certainly at the lower
dosage range, MAO-A in the digestive tract is preserved at levels
more than adequate to break down tyramine, while MAO in the brain
is inhibited at levels adequate to induce an antidepressant effect. A
restricted "MAOI diet" is prudently advised for the higher dosage
EMSAM 9 mg/24 hr patch and the 12 mg/24 hr patch to avoid any
risk of hypertensive crisis. But it's worth noting that (as of 2008) no
hypertensive crises following dietary indiscretions have been
hypertensive crises following dietary indiscretions have been
reported even in users of the high strength patches.
Other prescribing indications for selegiline are in prospect. In
November 2004, Yale University researchers launched a study of
selegiline for smokers who want to quit tobacco.
Unlike selegiline, the novel irreversible selective MAO-B-
inhibitor rasagiline (Azilect) is not metabolised to methamphetamine
or amphetamine. These trace amines are unlikely to contribute to
selegiline's neuroprotective action. Azilect has been licensed in the
EC from mid-2005; but labelling disputes with the FDA delayed the
product launch of rasagiline/Azilect in the USA until May 2006.
Either way, by the standards of posterity we are all little
better than glorified glue-sniffers in the light of the chemicals we put
into our bodies. The impending Post-Darwinian Transition to an era
of paradise-engineering has dreadfully crude origins. But by today's
modest standards, at least, selegiline is a potentially life-enriching
agent...."
Merck Manual CERI Sources Search Medline
Refs
and further reading
Search
Synthesis
rasagiline.com
amineptine.com
Quality Health Inc
Selegiline for Pets
PEA (from PiHKAL)
Product information
Airsealed Marketing
Selegiline: structure
The Good Drug Guide
International Pharmacies
E-mail
Webmaster