Corticobasal Degeneration

TREATMENT

Current treatment of parkinsonism centers on administration of levodopa. Despite recent advances in our understanding of the chemical and pathologic changes and development of novel therapies for PD, levodopa continues to be the gold standard (see Plate 7-9). Orally administered levodopa is absorbed into the circulation principally from the proximal small intestine. It may be detected in blood for several hours following its administration, reaching maximum peak levels in 2 to 3 hours after ingestion. Rapidly converted to dopamine by the enzyme dopa decarboxylase (DDC; L-aminoacid decarboxylase), approximately 1% of the oral dose penetrates the cerebral capillaries to diffuse through the brain parenchyma, where it is picked up and converted to dopamine in the remaining dopamineproducing cells. Once secreted into the synaptic cleft, dopamine is rapidly deactivated, principally to homovanillic acid by the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). To increase available levodopa and to diminish unwanted peripheral dopamine side effects (nausea, vomiting, arterial hypotension), dopa decarboxylase is inhibited peripherally with carbidopa. The inhibition markedly reduces the conversion of levodopa to dopamine in the medullary vomiting center or trigger zone, preventing its activation. With long-term levodopa use, coupled with the intrinsic pathologic changes occurring in parkinsonism, late motor complications develop in approximately 75% of patients, particularly after 10 years of illness. Wearing off, freezing of gait, unpredictable responses, and levodopa-induced abnormal involuntary movements or dyskinesias may complicate medical management. Certain agents, namely dopamine agonists (ropinirole, pramipexole, rotigotine, pergolide, cabergoline, and bromocriptine) have been developed in hopes of eliminating or delaying the need for levodopa. These agents stimulate dopamine receptors and thus act like dopamine. A dopamine agonist may provide symptomatic improvement and may delay the development of motor complications, chiefly by delaying the need to introduce levodopa. Nonetheless, most patients will require levodopa at one point in the course of their disease. Another strategy has been the use of catechol-O-methyl transferase (COMT) enzyme inhibitors to block COMT. Consequently, dopamine remains at the synaptic cleft, leading to increased duration of on-time (time during which clinical benefit is obtained from levodopa) by 1 to 2 hours and stable plasma levodopa levels. With progressive loss of neurons and its attendant decline in buffering capacity, plasma levodopa levels become the primary driver of the clinical response and motor complications. Of the two currently available COMT inhibitors, entacapone, a peripheral COMT inhibitor, is the most commonly used. Unfortunately, the use of tolcapone, a peripheral and central COMT inhibitor, has been hampered by concerns of severe and potentially fatal liver failure. The latter is an idiosyncratic reaction that is difficult to predict, complicating tolcapone use.

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