Adjunction of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) to levodopa/carbidopa (LD/CD) improves motor symptoms in patients with Parkinson disease (PD) by a prolonged elimination of LD. But it is not known whether EN addition influences gastric emptying and thus LD pharmacokinetics and pharmacodynamics. Objectives were to simultaneously determine plasma LD elimination, gastric emptying, and clinical response after a single intake of the same LD dosage as LD/CD-or as (LD/CD/EN) formulation on 2 consecutive days. In both groups, PD patients with delayed gastric emptying had significant lower LD plasma concentrations. Addition of EN did not influence gastric emptying but significantly improved motor response, which was not different for patients with delayed gastric emptying. However, with and without EN adjunction gastric emptying distinctly contributes to the variability of plasma LD bioavailability. This may impact LD delivery to the brain and thus motor response in PD patients. Therefore, fine tuning of LD application, which considers gastric emptying, becomes more and more essential in advanced PD stages with a reduced striatal neuronal dopamine capacity, which is responsible for maintenance of motor response in early PD patients.

In advanced Parkinson's disease (PD) patients, continuous intra-duodenal infusion of levodopa/carbidopa intestinal gel (LCIG) is an established approach in the management of motor complications that cannot be further improved by conventional oral therapy. In general, tolerability of LCIG has resembled that of oral dopaminergic therapy; however, cases of symptomatic peripheral neuropathy (PN), sometimes severe, have been reported in patients receiving LCIG. Cases are generally a sensorimotor polyneuropathy with both subacute and chronic onsets, often associated with vitamin B12 and/or B6 deficiency. Rare cases clinically resemble Guillain-Barré syndrome. In the absence of prospectively collected data on possible associations between LCIG and PN, it is prudent to explore potential mechanisms that may explain a possible relationship. The PN may be linked to use of high-dose levodopa, promoting high levels of homocysteine and methylmalonic acid or reduced absorption of vitamins essential for homocysteine metabolism. Cases of LCIG-associated PN often have responded to vitamin supplementation without need for LCIG cessation, although LCIG cessation is sometimes necessary. It may be advisable to monitor vitamin B12/B6 status before and after patients start LCIG and be vigilant for signs of PN. Prospective, large-scale, long-term studies are needed to clarify whether vitamin supplementation and routine use of a catechol-O-methyltransferase inhibitor may help prevent PN in LCIG recipients and whether these measures should be routine practice in patients with PD on high-dose oral levodopa.

Parkinson`s disease (PD) is a progressive, disabling neurodegenerative disorder with onset of motor and non-motor features. Both reduce quality of life of PD patients and cause caregiver burden. This review aims to provide a survey of possible therapeutic options for treatment of motor and non motor symptoms of PD and to discuss their relation to each other. MAO-B-Inhibitors, NMDA antagonists, dopamine agonists and levodopa with its various application modes mainly improve the dopamine associated motor symptoms in PD. This armentarium of PD drugs only partially influences the onset and occurrence of non motor symptoms. These PD features predominantly result from non dopaminergic neurodegeneration. Autonomic features, such as seborrhea, hyperhidrosis, orthostatic syndrome, salivation, bladder dysfunction, gastrointestinal disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis, cognitive dysfunction with impaired execution and impulse control may appear. Drug therapy of these non motor symptoms complicates long-term PD drug therapy due to possible occurrence of drug interactions, - side effects, and altered pharmacokinetic behaviour of applied compounds. Dopamine substituting compounds themselves may contribute to onset of these non motor symptoms. This complicates the differentiation from the disease process itself and influences therapeutic options, which are often limited because of additional morbidity with necessary concomitant drug therapy.

Ongoing loss of nigral dopaminergic presynaptic neurons is the primary cause of Parkinson disease (PD) with onset of motor symptoms, which mainly result from a 70% to 80% reduction of striatal dopamine levels. One metabolic precursor of dopamine, blood-brain barrier–trespassing levodopa, represents the most effective and initially the best-tolerated dopaminergic antiparkinsonian drug. However, a long debate continues on the putative neurotoxicity of this compound.^1,2 This controversy considers the impact of long-term levodopa application on homocysteine metabolism only to a certain extent.³ Levodopa is administered with dopa decarboxylase inhibitors (DDIs) to prevent its peripheral degradation. This combination increases the conversion of levodopa to 3-O-methyldopa by the ubiquitious enzyme catechol O-methyltransferase (COMT) in blood, peripheral tissues, and nigrostriatal neurons.⁴ Catechol-O-methyltransferase requires magnesium as a cofactor and S-adenosylmethionine (SAM) as the methyl donor. Thus O-methylation of levodopa to 3-O-methyldopa is associated with conversion of SAM to S-adenosylhomocysteine and subsequently homocysteine.^3,4Therefore, long-term levodopa/DDI metabolism via COMT results in elevated total homocysteine (tHcy) levels, decreased methionine levels, and decreased plasma SAM levels in PD patients.^5-7 It has not been clinically proved whether the altered homocysteine, SAM, and S-adenosylhomocysteine metabolism, which is associated with long-term levodopa/DDI application, is neurotoxic in PD patients.⁸However, increased tHcy levels contribute to the incidence of vascular disease, brain atrophy, Alzheimer disease, or all of these.^9-13 A sensitive, clinical, biological surrogate neurotoxin marker could be a primary axonal-accentuated degeneration with secondary demyelination of sural nerves. The objective of the present study was to demonstrate an association between daily oral levodopa/DDI intake, tHcy plasma levels, and electrophysiologic sural nerve conduction findings.