Managing treatment fluctuations in Parkinson disease: "On" again-, "off" again

The first truly effective medical therapy for Parkinson disease (PD), levodopa, was introduced in the 1960s. Patients had to take huge doses of levodopa, with treatment limited by peripheral decarboxylation of levodopa to dopamine by dopa decarboxylase (DDC), resulting in substantial peripheral side effects.¹ Benserazide and carbidopa were developed as dopa decarboxylase inhibitors (DDCIs); because they do not cross the blood-brain barrier, they effectively block the peripheral decarboxylation of levodopa to dopamine. The combination of carbidopa and levodopa (Sinemet; Merck, Whitehouse Station, NJ) was marketed in 1975. This allowed for levodopa dose reduction due to increased (brain) bioavailability and a marked reduction of peripheral side effects.² The total daily dose of carbidopa needed to effectively block peripheral decarboxylation of levodopa has been 75 to 100 mg, although some patients require supplemental higher doses of carbidopa (Lodosyn; Aton Pharma, Lawrenceville, NJ). Doses of carbidopa up to 400 mg per day are tolerable and safe.³

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