Rasagiline

RASAGILINE

MTI 11040PURNIMA SINGH

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-

Treatment

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

Taxonomy

Kingdom Organic Compounds

Superclass Benzenoids

Class Indanes

Direct parent Indanes

Structure

Chemical formula-C12H13N

IUPAC name-(1R)-N-prop-2-ynyl-2,3-

dihydro-1H-inden-1-amine

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