Siegfried Muhlack

Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients.

Abstract: 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.

Inhibition of catechol-O-methyltransferase contributes to more stable levodopa plasma levels

The short plasma half‐life limits the antiparkinsonian efficacy of levodopa/carbidopa (LD/CD). Administration of LD/CD with the catechol‐O‐methyltransferase inhibitor entacapone in one tablet (LCE) may extend plasma half‐life of LD and thus its effect on motor symptoms in patients with Parkinsons disease (PD). The objectives of this study were to monitor the motor response to a switch from LD/CD to LCE by a simultaneous performance of an instrumental motor test and rating of motor symptoms and to compare the LD plasma behavior between both conditions in terms of stability. Twenty‐one treated PD patients received LD/CD and then the identical oral LD dosage of LCE within a standardized setting on 2 consecutive days. Rating better reflected the motor improvement after LD application than the instrumental test. Motor symptoms of PD patients decreased significantly more during the LCE than the LD/CD condition, probably due to significantly higher LD plasma levels and a significantly less pronounced fall of the LD concentrations following the second LD intake. Our study shows a more stable LD plasma behavior during LCE intake and accordingly a better effect on motor symptoms according to rating outcomes and motor test results to a lesser extent.

Exercise improves efficacy of levodopa in patients with Parkinson's disease.

The objective was to investigate the impact of exercise on absorption and efficacy of levodopa (LD) in patients with Parkinson‘s disease (PD). A soluble, immediate release LD formulation was given followed by exercise near the aerobic limit on one day to PD patients, who underwent the same procedure only at rest on the second day. LD plasma behavior did not significantly differ between both conditions, but the motor response was significantly better 120 and 150 min after LD intake on the day with exercise than on the day with rest. Moderate exercise increases clinical efficacy of LD.

Pharmacokinetic behaviour of levodopa and 3-O-methyldopa after repeat administration of levodopa/carbidopa with and without entacapone in patients with Parkinson’s disease

Summary.Addition of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) prolongs plasma metabolism of levodopa (LD). Objectives were to determine the clinical response after EN addition and the plasma degradation of LD and 3-O-methyldopa [3-OMD]. Not optimum treated hospitalised patients with Parkinson’s disease received the same LD dosage on the first day only with carbidopa (CD) and on the second day with CD and EN (t.i.d.) within a standardised setting. We scored motor symptoms and measured LD- and 3-OMD levels on both days at fixed moments. Motor impairment significant better improved probably due to significant higher maximum concentrations [Cmax] and computed area under the curve values of LD levels during the LD/CD/EN condition. Time to Cmax of LD was significantly delayed after the first two LD/CD/EN intakes. An impact of EN on 3-OMD levels appeared. A possibly augmented LD absorption and a prolonged LD metabolism after EN supplementation may contribute to a more continuous LD delivery to the brain.

Effect of exercise on reactivity and motor behaviour in patients with Parkinson's disease

Background Following cued levodopa (LD) intake, endurance exercise showed a beneficial effect on scored motor performance in patients with Parkinsons disease (PD) in comparison with rest. This may result from an exercise induced increase in endogenous dopamine synthesis. As a result, beneficial effects on movement and reactivity may occur. Objectives To measure reactivity and motor performance in a repeated fashion with instrumental tasks after cued administration of soluble 200 mg of LD/50 mg of benserazide. Design PD patients consecutively performed paradigms, which assess reactivity and movement performance, after a standardised period of rest or of age-related, heart rate adapted endurance exercise on two consecutive days in a random order. Results Reactivity and execution of simple and complex motion series were significantly better following exercise than after rest. Discussion Endurance exercise has a beneficial effect on reactivity and movement behaviour in PD patients following cued application of LD probably due to an augmented synthesis and release of dopamine and other catecholamines and release in the prefrontal cortex, the nucleus accumbens and the basal ganglia. Small changes in catecholamine modulation of prefrontal cortex cells can have profound effects on the ability of the prefrontal cortex to guide behaviour. Previous exercise may also improve pedunculopontine nucleus function, which is involved in motor-related attention processes.

Chronic levodopa intake increases levodopa plasma bioavailability in patients with Parkinson's disease

Previous pharmacokinetic trials with standard levodopa formulations showed a different behavior of levodopa degradation in plasma of patients with Parkinsons disease (PD) in various advanced stages. The objective of this trial was to compare levodopa plasma metabolism in PD patients with and without previous long-term levodopa intake after oral intake of a dispensable levodopa/benserazide formulation (DLB). The over a 150 min interval computed area under the curve values of levodopa plasma levels after DLB administration were significantly (ANCOVA: F(1,19) = 7.88, P = 0.01) higher in PD patients with chronic levodopa treatment compared to patients without prior levodopa treatment. The maximum plasma levodopa concentration did not differ (ANCOVA: F(1.19) = 1.17, P = 0.29). Long-term levodopa administration results in an increased levodopa plasma bioavailability in PD patients.

Cysteinyl-glycine reduction as marker for levodopa-induced oxidative stress in Parkinson's disease patients.

Oxidative stress is influenced by the thiol homeostasis, which determines the redox milieu. One of its components is Cysteinyl‐glycine (Cys‐Gly) generation, as its metabolic precursor is the free radicals scavenging glutathione. Levodopa is under suspicion to promote oxidative stress via the turnover of its metabolite dopamine in abundant mitochondria. Objective was to investigate the impact of levodopa on Cys‐Gly plasma metabolism. Fifteen patients with Parkinsons disease orally took one 200‐mg levodopa/50‐mg carbidopa (CD) containing tablet. Levodopa, its derivative 3‐O‐methyldopa (3‐OMD), and free Cys‐Gly were measured at baseline, 60 and 120 min following levodopa/CD administration. Cys‐gly concentrations decreased, levodopa and 3‐OMD levels increased. Inverse relationships appeared between computed differences of Cys‐gly and 3‐OMD bioavailability. We conclude that Cys‐Gly decline is related to levodopa metabolism to 3‐OMD. Cys‐Gly decay may result from the alternative transformation of glutathione to its oxidized form glutathione dissulfide as consequence of free radical scavenging.

Cysteine decrease following acute Levodopa intake in patients with Parkinson's disease

The thiol homeostasis determines the redox milieu and thus scavenging of free radicals by antioxidants like glutathione (GSH). GSH is formed out of cysteine in combination with l-glycine and glutamine acid. An up regulation of free radical occurrence is looked upon as one key feature of chronic neurodegeneration. Levodopa (LD) is under suspicion to support synthesis of free radicals via the degradation of its derivative dopamine in abundant mitochondria. Objectives were to investigate the impact of LD on free cysteine turnover in plasma. 200mg LD/50mg carbidopa (CD) were administered to 13 patients with Parkinsons disease under standardised conditions. Plasma levels of LD and free cysteine were measured before, 60- and 80-min after the LD/CD application. Cysteine concentrations decayed, expectedly LD levels increased. Cysteine decrease may result from an up regulation of GSH synthesis to encounter augmented appearance of free radicals associated with LD turnover via mitochondrial monoaminooxidase.

Acute homocysteine rise after repeated levodopa application in patients with Parkinson’s disease

Elevated plasma levels of total homocysteine (thcys) are an independent risk factor for occurrence of cardiovascular disease and stroke. The incidence of these atherosclerosis related disorders is higher in treated PD patients, probably as a consequence of chronic LD intake in associationwith a dopadecarboxylase inhibitor (DDI), i.e. carbidopa (CD), only [1]. Additionally, associations between thcys rise and an elevated risk for onset of neuropsychiatric symptoms, like depression or deteriorated cognitive function, were shown in treated PD patients (for review: [1]). In particular the homozygote methylenetetrahydrofolate reductase (MTHFR) gene T/T allele predisposes for occurrence of elevated homocysteine levels [1]. Nearly all investigators performed an overnight withdrawal of PD drugs before blood sampling for thcys determination. However, acute one time LD/benserazide intake increases thcys plasma levels dependent on the gastrointestinal absorption and subsequent plasma appearance of LD [2]. But in clinical practice, LD/DDI is often administered several times per day in PD patients in particular of more advanced stages. This is necessary, since the short plasma half life of LD/DDI limits its efficacy onmotor symptoms of PD patients. In contrast thcys has a long plasma half life. Therefore it may accumulate following repeated LD/DDI application. Objective was to investigate plasma levels of thcys and LD during repeated LD/CD administration. The participating 40 PD patients (age: 59.1 11.3 years [mean SD]); Hoehn and Yahr Stage: 2.5 0.4; Unified Parkinson’s Disease Rating Scale (UPDRS) mental behavior: 3.6 1.5; UPDRS activities of daily living: 13.8 2.7; UPDRS motor examination: 32.47 18.88; UPDRS motor complications: 0.7 0.9; gender: men 75%; women 25% fulfilled the UK Brain bank criteria for PD. Exclusion criteria were metabolic disturbances, i.e., diabetes, abnormal vitamin values (i.e., B6, B12, folic acid) or vitamin supplementation, clinical signs of dementia, any electrophysiological or morphological evidence (cranial CT or MRI scan) of additional CNS pathology exceeding PD. No participant was previously exposed to neuroleptic drugs, to any treatment known to affect

Comparison of 200 mg retarded release levodopa/carbidopa – with 150 mg levodopa/carbidopa/entacapone application: pharmacokinetics and efficacy in patients with Parkinson’s disease

Summary.The interval of line tracing performance is more associated to basal ganglia function due to the dependence on bradykinesia and rigidity. The other component of this task, the precision of execution of complex movement sequences, is more related to attention. We compared the motor response after once dosing of 200 mg retarded release LD (levodopa)/CD (carbidopa) and of 150 mg LD/CD/EN (entacapone) by rating of motor symptoms, by measurement of LD- and 3-O-methyldopa (3-OMD) plasma concentrations and by the outcomes of a line tracing task. Thirteen treated patients with Parkinson’s disease (PD) took one of the two tested LD formulations on two consecutive days under randomised, double blind, identical standardised conditions. No significant differences appeared regarding rated motor response and LD plasma concentrations, but 3-OMD only significantly went up after LD/CD intake. LD/CD/EN was superior to LD/CD regarding the attention related components of line tracing probably due to a hypothetically increased dopamine occurrence at the prefrontal cortex, which guides human behaviour.