Rasagiline
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Transcript of Rasagiline
Parkinson's disease is a degenerative disorder of the central nervous system.
The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain.A defect in dopamine pathway.
In Parkinson’s disease, dopamine deficiency occurs in basal ganglia.
Major pathologic process- neuronal degeneration of pigmented substantia nigra compacta (SNpc) a region of basal ganglia that produces dopamine, intrinsically involved in motor control.
Imbalance primarily between
the excitatory neurotransmitter :Acetylcholine and
the inhibitory neurotransmitter :Dopamine
in the Basal Ganglia
Reduction of dopamine in corpus striatum affects the balance
between 2 neurotransmitters-
RASAGILINE
irreversible inhibitor of
monoamine oxidase
A chemically heterogeneous group of drugs that have in
common the ability to block oxidative deamination of
naturally occurring monoamines.
Drugs intended to prevent damage to the brain or spinal
cord from ischemia, stroke, convulsions,
or trauma
NeuroprotectiveAgents
Monoamineoxidase
catecholamines
indolamines serotonin
dopamine
norepinepherine
norepinephrine
MAO -B DOPAMINE
RASAGILINE DOPAMINE
MAO
MAO-A
MAO-B
MAO
nerve terminals,
brain, liver and
intestinal mucos
regulation of the
metabolic
degradation of
dopamine
Dopamine is a simple organic chemical in the catecholamine family which works as a neurotransmitter
DOPAC is a metabolite of the neurotransmitter dopamine which means that dopamine gets broken down into DOPAC.
AADC :Aromatic L-amino decarboxylaseCOMT :Catechol-O-methyltransferaseMAO B :Monoamine oxidase BDOPAC :3, 4-dihydroxyphenylacetic acid
One mechanism is believed to be related to
its MAO-B inhibitory activity, which causes an increase in extracellular
levels of dopamine in the striatum.
MAO-B is responsible for the breakdown of dopamine after its re-uptake from the synapse
DA is taken up by D1 and D2 receptors and synapses takes
place
Rasagiline shows neuroprotective properties by suppressing mitochondrial apoptosis ,
increasing the expression of
down-regulating the
B-cell lymphoma 2
B-cell lymphoma-extra large
Bcl-2-associated
death promoter
Bcl-2-associated X
protein (Bax).
anti-apoptotic proteins
pro-apoptotic
stopping the translocation of glyceraldehyde-3-phosphate dehydrogenase , and halting nucleosomalDNA fragmentation
stopping the mitochondrial permeability transition (MPT) pore opening by inhibiting caspase activation
Neuronsurvives
Absorption
Rasagiline is rapidly absorbed following oral administration.
The absolute bioavailability of rasagiline is about 36%.
Rasagiline readily crosses the blood-brain barrier.
Distribution
Volume of distribution-87 L
Rasagiline is
88-94% bound to plasma proteins,
61-63% bound to human albumin over the concentration range of 1-100 ng/ml.
Metabolism
The metabolism of rasagiline proceeds through two main pathways:
N-dealkylation
hydroxylation to yield 1-aminoindan (AI), 3-hydroxy-N-propargyl-1
aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI).
RasagilineCYP1A2
HepaticMetabolism
1-aminoindan
Elimination
Rasagiline undergoes almost complete biotransformation in the liver prior to excretion.
Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway.
primarily - urine
secondarily – feces
Half life of 3 hours
Formulations
Oral:
Tablets:
0.5 mg (of rasagiline) Azilect (Teva Neuroscience)
1 mg (of rasagiline) Azilect (Teva Neuroscience)
Storage:
15 C - 30 C
DOSING:
Monotherapy :The recommended dose of rasagiline is 1 mg once daily when used alone
Adjunct therapy :When combined with levodopathe recommended starting dose is 0.5 mg once daily.
Toxicity
drowsiness, dizziness, faintness, irritability,
hyperactivity,
agitation, severe headache, hallucinations,
coma;
rapid and irregular pulse,
hypertension, hypotension
respiratory depression and failure,
hyperpyrexia,
diaphoresis,
and cool, clammy skin.
Precautions
It should not be used by patients with moderate or severe liver disease.
Rasagiline should not be administered with antidepressants that increase serotonin levels -serotonin syndrome.
Rasagiline should be discontinued at least 14 days before initiating treatment with antidepressants that increase serotonin levels.
Recent developments
Rasagiline is being investigated for
the treatment of Restless Legs Syndrome
the treatment of Alzheimer's disease
Because of its melanin binding properties, rasagiline was investigated and found to decrease melanoma growth; it may be candidate for combination therapy for melanoma.
REFERENCE
www.webmd.com
http://journal.frontiersin.org/article/10.3389/fneur.2011.00068/full
www.ncbi.nlm.nih.gov/pubmed
Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of
Parkinson’s Disease with Neuroprotective Potential , John P.M. Finberg, Ph.D.*,
RMMJ|www.rmmj.org.il June 2010, Volume 1, Issue 1, e0003
The role of rasagiline in the treatment of Parkinson’s disease, Clinical Intervention in
Aging, 8 May 2010.
MAO-inhibitors in Parkinson’s Disease, Peter Riederer1* and Gerd Laux2,
Experimental Neurobiology , doi:10.5607/en.2011.20.1.1, Vol. 20, pages 1∼17, March
2011
Rasagiline – a novel MAO B inhibitor in Parkinson’s disease therapy, Shimon Lecht et.
Al, Therapeutics and Clinical Risk Management 2007:3(3) 467–474
The neuroprotective mechanism of 1-R-aminoindan, the major metabolite of the anti-
parkinsonian drug rasagiline, O.Bar-Am et al. ,journal of neurochemistry, Journal
Compilation 2010 International Society for Neurochemistry, J. Neurochem. (2010)
112, 1131–1137