Catechol-O-Methyltransferase Inhibition in the Treatment of Tetrahydrobiopterin Deficiency

The treatment of tetrahydrobiopterin (BH4) deficiency is well established, and directed toward the correction of hyperphenylalaninemia, neurotransmitter (NT) deficiency, and folate depletion in dihydropteridine reductase (DHPR) deficiency. L-dopa substitutive therapy involves major problems, as pharmacological disadvantages or adverse effects encompass both its short-term and long-term outcome. The former are mainly due to the short (1-2 hours) L-dopa plasma half-life, consequent to its rapid absorption and metabolism through decarboxylation and methylation. Diurnal fluctuations of L-dopa plasma concentration, and hence of brain dopamine, wane the clinical benefits, resulting in turn in diskinesia at the onset and in “wearing off” or “end-of-dose” patterns of motor activity at the end of each dose cycle. With time, these clinical disappointments do increase, leaving to a complex syndrome which also includes gastrointestinal and neuropsychiatrie symptoms (1,2). The progress of this condition is chiefly characteristic of Parkinson's disease, as the dopamine deficiency is combined with the worsening of nigrostriatal neurons degeneration, but it may be shared by patients suffering from BH4 deficiency needing chronic L-dopa therapy (3,4).