Prodrug Strategies for Brain Targeted Delivery of Antiparkinson Agents
The brain is one of the least accessible organs for the delivery of drugs. The mechanisms that protect the brain from foreign substances also restrict the entry of many therapeutic agents in the treatment of fatal CNS diseases such as brain tumors, HIV, encephalopathy, epilepsy, cerebro-vascular diseases and neurodegenerative disorders. Despite its relatively high blood flow, blood–brain barrier (BBB) is a strong hurdle that has to be crossed for efficient delivery of any bioactive agent into the brain.
The development of new drugs for the brain has not kept pace with progress in the molecular neurosciences, because the majority of large-molecule drugs and greater than 98% of small-molecule drugs do not cross the BBB. More than 99% of worldwide CNS drug development is devoted to CNS drug discovery with <1% of the efforts devoted to CNS drug delivery.
The available strategies for CNS drug delivery include intra-ventricular drug infusion, intra-cerebral implants, BBB disruption, liposomal delivery, carrier /receptor-mediated transport and prodrugs.
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by bradykinesia, postural instability, rigidity and tremor due to specific loss of dopamine neurons in the substantia nigra pars compacta. Dopamine deficiency appears to be responsible for the motor deficits of the disorder but PD cannot be treated directly with dopamine or related catecholamines due to their extensive first pass metabolism and poor permeability across the BBB. L-dopa, a prodrug of dopamine, still remains the most clinically useful drug for treatment of PD but suffers from many drawbacks. To improve pharmacological and pharmacokinetic properties of dopamine and L-dopa, numerous attempts have been made for their targeted delivery to brain through prodrug approach.
This presentation will highlight current status of antiparkinson therapy, drawbacks of BBB, need for brain targeted delivery, various prodrug strategies and recent trends for efficient delivery of antiparkinson drugs to brain.
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