O-methyltransferase Inhibitors

Dopamine agonists exert their effect by aedvadng dopamine receptors and bypassing the presynapdc synthesis of 

Pramipexole has been shown to be safe and effective when used as monotherapy early in PD (Parkinson Study Group, 1997, 2000) and in mild to moderate PD (Shannon et al., 1997). Ropinirole has also been shown to be effective in early PD (Rascol et al., 1998 Korczyn et al., 1999). In later stages of PD, dopamine agonists are usually prescribed with levodopa to achieve optimal therapeutic effects and to help moderate the motor fluctuations associated with levodopa (Pinter et al., 1999). Possible side effects of all dopamine agonists include nausea, peripheral edema, somnolence and hallucinations. Pramipexole has also been associated with compulsive behavior (Driver-Dunckley etal., 2003). 

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Nissinen, E. et al. (1997) Entacapone, a novel catechol-O-methyltransferase inhibitor for Parkinson s disease, does not impair mitochondrial energy production. European Journal of Pharmacology,... 

Synthesis of14 C-labelled catechol-O-methyltransferase inhibitors... 

Fig. 1.3 The vinylogy principle applied to the catechol O-methyltransferase inhibitor, tolcapone.

Liljequist R, Haapalinna A, Ahlander M, Li YH, Mannisto PT (1997) Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behavioural Brain Res 82 195-202... 

Use of COMT (catechol-O-methyltransferase) inhibitors, such as tol-capone, which leads to an increase in the transport of L-dopa into the brain. 

Catechol-O-methyltransferase inhibitors (entacapone, tolcapone) reduce the peripheral breakdown of dopamine. 

Bonifati V, Meco G. New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson s disease. Pharmacol. Ther. 1999 8 1-36. 

Ruottinen HM, Rinne UK. Effect of one month s treatment with peripherally acting catechol-O-methyltransferase inhibitor, entacapone, on pharmacokinetics and motor response to levodopa in advanced parkinsonian patients. Clin Neuropharmacol 1996 19(3) 222-33. 

Merello M, Lees AJ, Webster R, Bovingdon M, Gordin A. Effect of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson s disease. J Neurol Neurosurg Psychiatry 1994 57(2) 186-9. 

Drugs that exert their effect indirectly and require a functional background The catechol O-methyltransferase inhibitor entacapone, the effect of which is due to the accumulation of nonmetabolized dopamine... 

Nissinen, E., Linden, I. B. Biochemical and pharmacological properties of a peripherally acing catechol-O-methyltransferase inhibitor entaca-pone. Naunyn Schmiedebergs Arch. Pharmacol. 1992, 346, 262—266. 

D8. Demassieux, S., Corneille, L., Lachance, S., and Carriere, S., Determination of free and conjugated catecholamines and L-3,4-dihydroxyphenyalanine in plasma and urine Evidence for a catechol-O-methyltransferase inhibitor in uraemia. Clin. Chim. Acta 115,377-390(1981). 

Leicht MJ, Mitchell SD Catechol-O-methyltransferase inhibitors New options for Parkinson s disease... 

CATECHOL-O-METHYLTRANSFERASE INHIBITORS Catechol-O-Methyltrans-ferase (COMT) metabolizes levodopa as well as dopamine, producing the pharmacologically inactive compounds 3-O-methyl DOPA (from levodopa) and 3-methoxytyramine (from dopamine) (Figure 20-7). Approximately 99% of an orally administered dose of levodopa does not reach the brain but, rather, is decarboxylated to dopamine, which causes nausea and hypotension. Addition of an AAD inhibitor (e.g., carbidopa) reduces the formation of dopamine but increases the fraction of levodopa that is methylated by COMT. COMT inhibitors will block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma tj j of levodopa as well as the fraction that reaches the CNS. 

Table 3 lists the dose and incidence of the hepatotoxicity for various drugs, some of which have been withdrawn as a result of these findings. Some of the drugs show effects on liver function earlier than the actual onset of liver toxicity, with serum aminotransferase levels raised by threefold the upper limit of normal (ULN). The incidence of this is much higher and can show a classical dose response for instance, tolcapone, a catechol-O-methyltransferase inhibitor used as an adjunct to levodopa in Parkinson s disease, produces threefold the ULN in 1-3% of patients receiving 100 mg TID and 3.7% of patients receiving 200 mg TID (Olanow and Watkins 2007). Tolcapone, an o-nitrocatechol, is metabohzed to reactive intermediates - o-quinone or quinoneimine species - by human fiver microsomes (Smith et al. 2003). 

The metabolism of nitrobenzenes to quinone-imines arises from a six-electron reduction of the nitro group to the corresponding aniline metabolite via the intermediate nitroso and hydroxylamine analogs. Aromatic ring hydroxylation by CYP ortho or para to the aniline nitrogen then generates the aminophenol derivative. The conversion of a nitrobenzene derivative to a quinone-imine is illustrated with the catechol-O-methyltransferase inhibitor tolcapone, an... 

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