Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of dopaminergic neurons, with consequent reduction in striatal dopamine levels leading to characteristic motor symptoms. The most effective treatment for this disease continues to be the dopamine replacement therapy with levodopa together with an inhibitor of aromatic amino acid decarboxylase (AADC). The efficacy of this therapy, however, decreases with time and most patients develop fluctuating responses and dyskinesias. The last decade showed that the use of catechol-O-methyltransferase inhibitors as adjuvants to the levodopa/AADC inhibitor therapy, significantly improves the clinical benefits of this therapy.



The purpose of this article is to review the current knowledge on the enzyme catechol-O-methyltransferase (COMT) and the role of COMT inhibitors in PD as a new therapeutic approach to PD involving conversion of levodopa to dopamine at the target region in the brain and facilitation of the continuous action of this amine at the receptor sites. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on nebicapone, presently under clinical development, as well as entacapone and tolcapone, which are already approved as adjuncts in the therapy of PD. This article reviews human pharmacokinetic and pharmacodynamic properties of these drugs as well as their clinical efficacy and safety.

/pdf/catechol-o-methyltransferase-and-its-inhibitors-in-parkinson-kgc4ly1lrx.pdf

Catechol-O-methyltransferase and its inhibitors in Parkinson's disease.

Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.

Warriors versus worriers: the role of COMT gene variants

IntroductionDifferences in catechol-O-methyltransferase (COMT) activity and genotype may determine individual variations in the therapeutic response to levodopa or Parkinson's disease (PD) susceptibility. The role of functional COMT haplotypes in PD susceptibility and treatment response has not been

The association of functional catechol-O-methyltransferase haplotypes with risk of Parkinson's disease, levodopa treatment response, and complications.

Objective
In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMTHH), intermediate (Val/Met, COMTHL), or low (Met/Met, COMTLL). The objective of this study was to determine the response to entacapone in COMTHH and COMTLL PD patients.

Methods
Thirty-three PD patients, homozygous for the COMT alleles COMTHH (n = 17) and COMTLL (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells.

Results
The gain in the best ON time was higher in COMTHH than in COMTLL patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMTHH than in COMTLL patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMTHH than in COMTLL patients (−0.54 ± 0.07 vs −0.31 ± 0.06 pmol/min/mg protein, p = 0.02).

Interpretation
The COMTHH genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined. ANN NEUROL 2011;;69:111–118.

The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: a randomized crossover clinical trial.

Two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were developed during the 1990’s to be used as adjuncts to levodopa (LD) – dopa decarboxylase (DDC) inhibitors in the treatment of Parkinson’s disease (PD). Entacapone is currently in wide clinical use, while tolcapone can be used in restricted indications only, due to its hepatotoxicity. COMT inhibitors prolong the elimination of LD, while DDC inhibitors mainly increase its absorption; both mechanisms leading to increased bioavailability of LD. The pharmacokinetic properties of LD, carbidopa and entacapone are quite similar, and entacapone is administered concomitantly with LD plus carbidopa. Entacapone prolongs the clinical effect of each LD dose by 30 to 40 minutes; this effect is seen already after the first entacapone dose. When LD is administered in several frequent daily doses, addition of entacapone reduces the daily fluctuations of plasma LD by 30 to 40%.

Clinical advantages of COMT inhibition with entacapone – a review

Objective: To investigate the relationship between the catechol- O -methyltransferase (COMT) genotype and the therapeutic efficacy of entacapone. Methods: The efficacy of 2 months of entacapone treatment in 65 patients with PD with end-of-dose deterioration was studied. The efficacy of entacapone was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) score, the daily levodopa dosage, and the patients’ diary card. Results: Thirty-six patients (55.4%) had a high-activity COMT gene ( COMT HH ), 22 (33.8%) had an intermediate-activity COMT gene ( COMT HL ), and 7 patients (10.8%) had a low-activity COMT gene ( COMT LL ). Two months of entacapone treatment resulted in a significant increase in “on” time, a reduction in “off” time, and a reduction in the total UPDRS score, but these results were independent of the COMT genotype of the patient. There was no significant difference in the frequency or severity of dyskinesias between the patients with different COMT genotypes. Conclusion: The COMT genotype seems to be a minor factor in judging the beneficial effects of entacapone administration.

H. S. Kim

Papers

COMT genotype and effectiveness of entacapone in patients with fluctuating Parkinson's disease.