Levodopa/carbidopa and entacapone in the treatment of Parkinson’s disease: efficacy, safety and patient preference

Abstract

Levodopa (LD) is the oldest, most efficacious and best-tolerated drug for dopaminergic substitution of patients with Parkinson’s disease (PD). Its main drawback is its short half-life, which supports onset of motor complications in the long term. Therefore well-informed PD patients mostly accept LD therapy as late as possible. Recent LD trials indicate that a combination of LD with carbidopa (CD) and the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) may reduce the onset of these motor complications to a certain extent. This observation is further supported by pharmacokinetic trials and experimental research, but there is still a need to confirm this in a clinical trial, which is under way. Additionally, combined LD/CD/EN was superior to LD/CD administration regarding cognition, muscle behavior and gastrointestinal function in small clinical trials. Moreover there is accumulating evidence that combined COMT inhibition with LD administration reduces homocysteine synthesis. In the long term, homocysteine elevation supports onset of arteriosclerosis-related disorders, which are more frequent in PD patients according to epidemiological studies than in the normal healthy population. The introduction of LD/CD/EN in one tablet supported patients’ preference of COMT inhibition as an essential component of LD/DDI therapy, as this combination reduced number and size of tablets.

Drug therapy in patients with Parkinson’s disease

“…A further non dopaminergic adverse event of COMT inhibition is diarrhoea sometimes occurring even up to two to four months following treatment initiation. This may be due to the inhibition of 5-HT metabolism in the gastrointestinal tract, which causes an increase of gastrointestinal motility in some PD patients [25]. Centrally acting, stronger direct EN competitor tolcapone was temporarily withdrawn due to reports on serious hepatic reactions with development of severe, sometimes even fatal, hepatic disease as well as possible occurrence of rhabdomyolysis and neuroleptic malignant-like syndrome.…”

“…This disadvantage of EN therapy was improved with the introduction of the triple combination LD/CD/EN, which allowed to reduce the number of tablet intake and provided a smaller pill size. This further eased swallowing and favoured patients’ acceptance [25]. …”

Homocysteine in Neurological Disease: A Marker or a Cause?

“…Catechol-O-methyl transferase inhibitors as adjuncts not only enhance levodopa half life and its brain delivery, but also lower levodopa-associated hyperhomocysteinemia. Tolcapone [93] has an edge over entacapone [94] in regards to its central action as well as lack of risk for generation of free radicals and neurotoxic Nmethylated tetrahydroisoquinolines [95].…”

The blood–brain barrier-permeable catechol-O-methyltransferase inhibitor dinitrocatechol suppresses experimental autoimmune encephalomyelitis

“…COMT is expressed in the CNS, predominantly in astrocytes (Muller et al, 1993;Huang et al, 2005) as well as in microglial cells (Helkamaa et al, 2007) and in some neurons (Myohanen et al, 2010). COMT inhibitors have been in use for many years as a co-treatment for Parkinson's disease (Muller, 2009;Nord et al, 2010), to reduce the breakdown of the dopamine precursor levodopa and increase central bioavailability (Muller, 2009). A similar effect is observed with the NA precursor droxidopa, where pretreatment with a COMT inhibitor potentiated and prolonged its effects (Verhagen-Kamerbeek et al, 1993).…”