Plasma Levodopa Levels Research Articles

Using Spontaneous Eye-blink Rates to Predict the Motor Status of Patients with Parkinson's Disease.

Objective Assessing daily motor fluctuations is an important part of the disease management for patients with Parkinson's disease (PD). However, the frequent recording of subjective and/or objective assessments is not always feasible, and easier monitoring methods have been sought. Previous studies have reported that the spontaneous eye-blink rate (EBR) is correlated with the dopamine levels in the brain. Thus, the continuous monitoring of the EBR may be useful for predicting the motor status in patients with PD. Methods Electrooculograms (EOGs) were recorded for up to 7.5 hours from three PD patients using a wearable device that resembled ordinary glasses. An receiver operating characteristic (ROC) analysis was performed to compare the ability of the EBR estimates at each time-point (Blink Index) and the plasma levodopa levels to predict the motor status. Results The Blink Index was correlated with the plasma levodopa levels. When an indicator for the first hour of the observation period was included in the model, the Blink Index discerned wearing-off and dyskinesia as accurately as the plasma levodopa level. Conclusion Our study provides preliminary evidence regarding the utility of continuous EBR monitoring for the non-invasive evaluation of the motor status in patients with PD.

Plasma catecholamine levels in the early stages of treatment-naïve Parkinson’s disease

Rationale: Parkinson's disease (PD) is a neurodegenerative disorder with predominant involvement of catecholamine-producing neurons of the central and peripheral nervous system. Taking into account the relative availability and low costs of plasma catecholamine measurements, it is worthwhile to study these parameters as biomarkers of the early stages of PD.Aim: To determinate whether plasma levels of dopamine (DA), norepinephrine (NE), L-3,4-dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC) in patients with early stages of PD are related with akinetic-rigid and tremor-dominant variants and to compare the results to healthy volunteers.Materials and methods: This was an observational cross-sectional cohort study performed from 2012 to 2015. The main study group included unselected outpatients who attended the Republican Consultative and Diagnostic Center of Movement Disorders and Botulinotherapy (Kazan, Russia) with newly diagnosed early PD (Hoehn and Yahr stages I and II, 1967), of various ages and both genders, who had not been given any specific antiparkinsonian treatment. The control group included healthy volunteers with no clinical signs of PD (they could have other chronic diseases of the non-extrapyramidal origin). Plasma catecholamine levels were measured by gas liquid chromatography.Results: One hundred and thirty (130) treatment-naïve patients with newly diagnosed PD (mean age 59.34 ± 8.42 years, male gender 45.38%) were enrolled into the main study group. The control group included 56 healthy volunteers matched for age and gender. The distribution of various PD forms and stages was as follows: PD tremor-dominant variant 56.9%, PD akinetic-rigid variant 43.1%; PD stage I 76.9%, PD stage II 23.1%. Irrespective of the variant and stage, the PD patients demonstrated decreased NE levels, compared to the controls (95% confidence intervals 124–216 and 248–428 pg/mL, respectively, р < 0.026). DOPA plasma level was reduced only in the patients with akinetic-rigid PD variant (р = 0.017), while DOPAC level in the patients with PD stage II (р = 0.008). The average DA:NE:DOPA:DOPAC ratio was 1:32:105:64 in the control group, 1:62:238:88 in the patients with PD tremor-dominant variant (the difference is significant for NE and DOPA, р < 0.05), and 1:29:96:32 in those with PD akinetic-rigid variant (p > 0.05). In the healthy controls the changes in DOPA levels account for 84% of the DA and NE variability; no correlation between DOPAC and other catecholamines was found. On the contrary, in the PD patients regardless of the stage and the disease variant, DOPAC levels directly correlated with DA (p < 0.04). The PD tremor-dominant variant patients demonstrated a direct correlation between plasma NE and DOPA levels (p < 0.05).Conclusion: The results obtained on absolute and relative parameters catecholamine turnover in the patients with early PD stages support the hypothesis on different pathophysiology of the tremor-dominant and akinetic-rigid variants of PD.

Profile of inhaled levodopa and its potential in the treatment of Parkinson's disease: evidence to date.

Inhaled levodopa is a newly emerging therapeutic option in the treatment of “off ” symptoms associated with Parkinson’s disease (PD). Its mode of delivery offers more rapid absorption of levodopa and shorter onset of clinical benefit compared to oral formulations, and has been shown to be feasible for use in patients with PD experiencing worse motor function due to declining plasma levodopa levels. Clinical development of this compound is supported by preclinical, Phase I–III, long-term-safety studies and studies in special populations, including otherwise-healthy asthmatics and smokers. These investigations demonstrated that the drug is well tolerated without risk of long-term (up to 1 year) changes in pulmonary function or spirometry measures. The most common side effects among PD patients were a mild cough, upper respiratory tract infection, nausea, sputum discoloration, and dyskinesia. Inhaled levodopa offers a different administration method and side-effect profile from the currently available options for rescue therapy for Off periods in PD, though comparative studies have not been performed. The drug is presently under review by the US Food and Drug Administration.

Animal models of l-dopa-induced dyskinesia in Parkinson's disease.

Understanding the biological mechanisms of l-dopa-induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing-off fluctuations and abnormal involuntary movements appearing when plasma levels of l-dopa are high, commonly referred to as peak-dose l-dopa-induced dyskinesia. Parkinsonian models exhibiting these features have been well-characterized in both rodent and nonhuman primate species. The first animal models of peak-dose l-dopa-induced dyskinesia were produced in monkeys lesioned with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated chronically with l-dopa to elicit choreic movements and dystonic postures. Seminal studies were performed in these models using both metabolic mapping and electrophysiological techniques, providing fundamental pathophysiological insights that have stood the test of time. A decade later, it was shown possible to reproduce peak-dose l-dopa-induced dyskinesia in rats and mice rendered parkinsonian with nigrostriatal 6-hydroxydopamine lesions. When treated with l-dopa, these animals exhibit abnormal involuntary movements having both hyperkinetic and dystonic components. These models have enabled molecular- and cellular-level investigations into the mechanisms of l-dopa-induced dyskinesia. A flourishing literature using genetically engineered mice is now unraveling the role of specific genes and neural circuits in the development of l-dopa-induced motor complications. Both non-human primate and rodent models of peak-dose l-dopa-induced dyskinesia have excellent construct validity and provide valuable tools for discovering therapeutic targets and evaluating potential treatments. © 2018 International Parkinson and Movement Disorder Society.

Levodopa: A new look at an old friend

Levodopa is the most effective antiparkinsonian agent, but chronic treatment is associated with the development of motor complications in the majority of patients with PD. Recent scientific and clinical advances are improving this situation. Long-term, double-blind studies demonstrate that dose is an important risk factor for the development of both motor fluctuations and dyskinesia, and suggest that it is best to use low doses of l-dopa when possible. Inhaled l-dopa and sublingual apomorphine are now being developed as rescue therapies that permit rapid and predictable reversal of off periods. Finally, substantial evidence suggests that motor complications are related to the nonphysiological restoration of brain dopamine with intermittent oral doses of standard l-dopa. Double-blind studies demonstrate significant clinical benefits with continuous intraintestinal infusion of l-dopa. New approaches that provide continuous plasma l-dopa levels without the need for a surgical procedure are currently being investigated. Finally, the development of an oral long-acting form of l-dopa that provides continuous plasma l-dopa levels is actively being pursued. Collectively, these approaches offer the potential to considerably reduce and even prevent the disability associated with l-dopa-induced motor complications. © 2017 International Parkinson and Movement Disorder Society.

ND0612, a novel liquid formulation of levodopa/carbidopa for subcutaneous infusion in patients with Parkinson’s disease achieves stable levodopa plasma levels when administered in low and high doses (S4.002)

ND0612, a novel liquid formulation of levodopa/carbidopa for subcutaneous infusion in patients with Parkinson’s disease achieves stable levodopa plasma levels when administered in low and high doses (S4.002)

Helicobacter pylori cytotoxin-associated gene A genotype in Egyptian patients with Parkinson’s disease: could eradication benefit?

Strong growing evidence supports a link between Helicobacter pylori (HP) infections and Parkinson’s disease (PD). The purpose of this study was to explore the association between infection with HP cytotoxin-associated gene A (cagA) genotype and PD in Egyptian patients and the influence of its eradication on pharmacokinetic and clinical response to l-dopa. This study was performed on 87 idiopathic PD patients and 45 age- and sex-matched controls. HP infection was diagnosed with HP stool antigen test and HP cagA genotype was detected by PCR. PD patients were subjected to UCLA parkinsonism scale, Hoehn and Yahr staging, and l-dopa plasma level detection by high-performance liquid chromatography. HP PD patients were divided into eradicated group (received standard anti-HP therapy) and placebo group (received antioxidant therapy). Four weeks after therapy, patients were reevaluated. Among PD patients, frequency of HP infection was significantly higher than controls (55.2 vs 33.3%, P = 0.02), especially with HP cagA strain (81.2 vs 40%, P = 0.002). PD was more severe in HP infected (P < 0.001), especially in HP cagA-positive patients (P = 0.04) with significant lower l-dopa plasma levels (P < 0.001). cagA strains were associated with higher risk of increased PD severity (OR, 2.139; P = 0.029). Opposing antioxidant therapy, HP eradication treatment improved PD severity (UCLA score decreases by 30%) and increased l-dopa level by 40%. There is a proved link between PD and infection with virulent HP cagA strains. HP could affect l-dopa level by mechanisms other than reactive oxygen radical’s production which need further evaluation.

Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l-DOPA delivery in the 6-OHDA model of Parkinson's disease

Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. l-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any l-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic l-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.

Advances in levodopa therapy for Parkinson disease.

This supplement describes a recent development in the use of a drug very familiar to neurologists. The drug is levodopa, which half a century after its introduction is still widely considered the most effective oral agent for treating the motor symptoms of Parkinson disease (PD).1 The recent development is an oral formulation of levodopa plus carbidopa (RYTARY [carbidopa and levodopa] extended-release capsules), a combination of immediate- and extended-release beads with pharmacokinetic properties that produce an initial peak in levodopa plasma levels in about an hour after administration, and maintains them for 4–5 hours before declining.2

Novel Approaches to Optimization of Levodopa Therapy for Parkinson's Disease.

Levodopa (LD) is the most effective medication to treat Parkinson's disease (PD). However, motor fluctuations and drug-induced dyskinesia compromise the long-term success of levodopa therapy in PD. These response complications are due, at least in part, to fluctuating LD plasma levels (as a result of erratic gastric emptying, variable jejunal absorption, and most importantly, the short half-life of LD) with standard levodopa formulations. Keeping levodopa concentrations as constant as possible is the target for improving the pharmacokinetics and developing new ways of LD administration. In this article, we review novel oral and non-oral LD formulations including the ones that have successfully completed phase 3 clinical trials and have come to market and ones that are still in earlier phases of clinical development.

Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice.

High-level fetal (γ) globin expression ameliorates clinical severity of the beta (β) hemoglobinopathies, and safe, orally-bioavailable γ-globin inducing agents would benefit many patients. We adapted a LCR-γ-globin promoter-GFP reporter assay to a high-throughput robotic system to evaluate five diverse chemical libraries for this activity. Multiple structurally- and functionally-diverse compounds were identified which activate the γ-globin gene promoter at nanomolar concentrations, including some therapeutics approved for other conditions. Three candidates with established safety profiles were further evaluated in erythroid progenitors, anemic baboons and transgenic mice, with significant induction of γ-globin expression observed in vivo. A lead candidate, Benserazide, emerged which demonstrated > 20-fold induction of γ-globin mRNA expression in anemic baboons and increased F-cell proportions by 3.5-fold in transgenic mice. Benserazide has been used chronically to inhibit amino acid decarboxylase to enhance plasma levels of L-dopa. These studies confirm the utility of high-throughput screening and identify previously unrecognized fetal globin inducing candidates which can be developed expediently for treatment of hemoglobinopathies.

Pharmacological Profile of Opicapone, a Third Generation Nitrocatechol COMT Inhibitor, in the Rat

In this study opicapone´s pharmacological properties were evaluated as well as its potential cytotoxic effects. The pharmacodynamic effects of opicapone were explored by evaluating rat catechol-O-methyltransferase (COMT) activity and levodopa pharmacokinetics, in periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential. Opicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg/kg up to 6 h post-administration. The effect was sustained over the first 8 h and by 24 h COMT had not recovered control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with concomitant reduction of 3-OMD from 2 h up to 24 h post-administration, while tolcapone produced significant effects only at 2 h post-administration. The effects of opicapone upon brain catecholamines after levodopa administration were sustained up to 24 h post administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period. In conclusion, opicapone is endowed with a prolonged inhibitory profile on peripheral COMT resulting in an extended bioavailability of levodopa without toxicity effects, presenting thus some improved properties over the current available COMT inhibitors.

Dual κ-agonist/μ-antagonist opioid receptor modulation reduces levodopa-induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease.

Effective medical management of levodopa-induced dyskinesia (LID) remains an unmet need for patients with Parkinson disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed agonist/antagonist analgesic nalbuphine in reducing LID and its molecular markers in the nonhuman primate model. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline subcutaneously as: (1) monotherapy, (2) acute coadministration with levodopa, and (3) chronic coadministration for 1 month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma levodopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses. Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-PD effect of levodopa or changing plasma levodopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine coadministered with levodopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine cotherapy blocks several molecular correlates of LID, including overexpression of ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5, and increased phosphorylation of DARPP-32 at threonine-34. Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID.

Pharmacological profile of opicapone, a third-generation nitrocatechol catechol-O-methyl transferase inhibitor, in the rat.

Catechol-O-methyltransferase (COMT) is an important target in the levodopa treatment of Parkinson's disease; however, the inhibitors available have problems, and not all patients benefit from their efficacy. Opicapone was developed to overcome those limitations. In this study, opicapone's pharmacological properties were evaluated as well as its potential cytotoxic effects. The pharmacodynamic effects of opicapone were explored by evaluating rat COMT activity and levodopa pharmacokinetics, in the periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential. Opicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg⋅kg(-1) up to 6 h post-administration. The effect was sustained over the first 8 h and by 24 h COMT had not returned to control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with a concomitant reduction in 3-O-methyldopa from 2 h up to 24 h post-administration, while tolcapone produced significant effects only at 2 h post-administration. The effects of opicapone on brain catecholamines after levodopa administration were sustained up to 24 h post-administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period. Opicapone has a prolonged inhibitory effect on peripheral COMT, which extends the bioavailability of levodopa, without inducing toxicity. Thus, it exhibits some improved properties compared to the currently available COMT inhibitors.

Can levodopa-induced dyskinesias go beyond the motor circuit?

This scientific commentary refers to ‘A network centred on the inferior frontal cortex is critically involved in levodopa-induced dyskinesias’ by Cerasa et al. (doi: 10.1093/brain/awu329). Pioneers of levodopa treatment for Parkinson’s disease in the 1960s quickly realized that the dramatic motor improvement was often clouded by the occurrence of involuntary movements never previously seen in the disorder (Lees et al. , 2015). Levodopa-induced dyskinesias (LIDs) have been a common problem ever since and are one of the main reasons for recommending surgical treatment in advanced cases of Parkinson’s disease. In this issue of Brain , Cerasa and colleagues test the hypothesis that LIDs arise not only from the compromised basal ganglia motor circuit at the heart of Parkinson’s disease but from disturbances in areas of frontal cortex (Cerasa et al. , 2015). LIDs comprise a range of abnormal movements that may be distinguished according to presentation and type. The most common are choreic and sometimes dystonic movements that coincide with high plasma levodopa levels and maximal anti-parkinsonian benefit; hence, these are referred to as ‘peak dose’ or ‘ON’ period dyskinesia (Fahn, 2000). Experimental models are limited to such ‘peak dose’ presentation, which is the most studied type of LID. However, the pathophysiological mechanisms that cause LIDs are still incompletely understood. Classically, it has been proposed that LIDs are related to the degree of nigrostriatal neurodegeneration and striatal changes associated with chronic levodopa therapy (Obeso et al. , 2000). These interact to induce plastic synaptic abnormalities in striatal medium spiny neurons, which has the effect …

Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications.

The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson’s disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

Dopa-decarboxylase gene polymorphisms affect the motor response to l-dopa in Parkinson's disease

BackgroundIn Parkinson's disease (PD), the response to l-dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from l-dopa is decarboxylation by aromatic l-amino acid decarboxylase (AAAD, encoded by the DDC gene). ObjectiveTo determine the motor response to l-dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDCT/C) and rs3837091 AGAG del (DDCAGAG/−)). MethodsThirty-three Caucasian PD patients underwent an acute l-dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to l-dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUCΔUPDRS) in the 4 h following l-dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of l-dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study. ResultsWhen adjusted for the l-dopa dose, the AUCΔUPDRS was significantly lower in DDCCC/CT patients (n = 14) than in DDCTT patients (n = 19) and significantly lower in DDC−/− or AGAG/− patients (n = 8) than in DDCAGAG/AGAG patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for l-dopa and dopamine. DiscussionThe rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to l-dopa but do not significantly change peripheral pharmacokinetic parameters for l-dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l-dopa response in Parkinson's disease.

Continuous dopaminergic delivery to minimize motor complications in Parkinson’s disease

Motor fluctuations and dyskinesias are common sequelae of Parkinson’s disease (PD) that may limit function and quality of life. With disease progression, striatal dopamine concentration becomes closely linked to plasma levodopa levels, which vary considerably with standard oral regimens. Exposure of striatal dopamine receptors to wildly fluctuating transmitter levels is thought to contribute to the development of dyskinesias and motor fluctuations. Continuous dopaminergic delivery has been shown to reduce motor complications in advanced PD patients, and has been hypothesized to prevent their incidence when given as early therapy in mild PD. In this article, the authors outline the rationale for continuous dopaminergic delivery and review clinical strategies implementing the concept, including transdermal rotigotine, subcutaneous apomorphine infusion, intraduodenal infusion of levodopa gel and the investigational oral levodopa formulation IPX066.

Effects of L-dopa during auditory instrumental learning in humans.

The dopaminergic neurotransmitter system is critically involved in promoting plasticity in auditory cortex. We combined functional magnetic resonance imaging (fMRI) and a pharmacological manipulation to investigate dopaminergic modulation of neural activity in auditory cortex during instrumental learning. Volunteers either received 100 mg L-dopa (Madopar) or placebo in an appetitive, differential instrumental conditioning paradigm, which involved learning that a specific category of frequency modulated tones predicts a monetary reward when fast responses were made in a subsequent reaction time task. The other category of frequency modulated tones was not related to a reward. Our behavioral data provides evidence that dopaminergic stimulation differentially impacts on the speed of instrumental responding in rewarded and unrewarded trials. L-dopa increased neural BOLD activity in left auditory cortex to tones in rewarded and unrewarded trials. This increase was related to plasma L-dopa levels and learning rate. Our data thus provides evidence for dopaminergic modulation of neural activity in auditory cortex, which occurs for both auditory stimuli related to a later reward and those not related to a reward.

Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson’s Disease Patients

Motor complications of Parkinson's disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa-carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-O-methyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for ≥30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total levodopa and carbidopa doses were 1,580 (403) and 395 (101) mg, respectively. Mean (SD) C(avg) (μg/mL) were 2.9 (0.84) for levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation [defined as (C(max)-C(min))/C(avg)] in levodopa, 3-OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2-16 of infusion. Accordingly, the within-subject coefficients of variation in levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported ≥1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.