Plasma Levodopa Levels Research Articles

Biosensor Strip for Rapid On-site Assessment of Levodopa Pharmacokinetics along with Motor Performance in Parkinson's Disease.

While levodopa (L-Dopa) is the primary treatment for alleviating Parkinson's disease (PD), its efficacy is hindered by challenges such as a short half-life and inconsistent plasma levels. As PD progresses, the rising need for increased and more frequent L-Dopa doses coupled with symptom fluctuations and dyskinesias underscores the urgency for improved comprehension of the interplay between L-Dopa levels and PD motor symptoms. Addressing this critical need, we present a decentralized testing method using a disposable biosensor strip and a universal slope (U-slope) calibration-free approach. This enables reliable, rapid, simple, and cost-effective decentralized L-Dopa measurements from capillary blood. A pilot study with PD persons demonstrates the ability to monitor real-time L-Dopa pharmacokinetics from fingerstick blood after oral L-Dopa-Carbidopa (C-Dopa) tablet administration. Correlating capillary blood L-Dopa levels with PD motor scores revealed a well-defined inverse correlation with temporal motor fluctuations. We compared the resulting dynamic capillary blood L-Dopa levels with plasma L-Dopa levels using the traditional but clinically impractical high-performance liquid chromatography technique. By providing timely feedback on a proper L-Dopa dosing regimen in a decentralized and rapid fashion, this new biosensing platform will facilitate tailored optimal L-Dopa dosing, towards improving symptom management and enhancing health-related quality of life.

Sublingual apomorphine in the treatment of Parkinson's disease.

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials.

Continuous Levodopa Delivery with an Intraoral Micropump System: An Open-Label Pharmacokinetics and Clinical Study.

Double-blind studies have demonstrated that motor complications in Parkinson's disease (PD) can be reduced with continuous delivery of levodopa. The DopaFuse system is a novel, intraoral micropump that attaches to a retainer and uses a propellant to deliver levodopa/carbidopa (LD/CD) continuously into the mouth. Evaluate the safety, pharmacokinetics, and efficacy of LD/CD delivered via the DopaFuse system compared to treatment with intermittent doses of standard oral LD/CD in PD patients with motor fluctuations. This was a 2-week, open-label study (NCT04778176) in 16 PD patients treated with ≥4 levodopa doses/day and experiencing motor fluctuations. On Day 1 (clinic setting) patients received their usual dose of standard LD/CD; DopaFuse therapy was initiated on Day 2, and on Day 3 patients received DopaFuse plus a morning oral LD/CD dose. Patients returned home on Days 4-14 and returned for in-clinic assessment on Day 15. Continuous DopaFuse delivery of LD/CD was associated with reduced variability in plasma levodopa levels compared to oral LD/CD (mean ± SD levodopa Fluctuation Index reduced from 2.15 ± 0.59 on Day1 to 1.50 ± 0.55 on Day 2 (P = 0.0129) and to 1.03 ± 0.53 on Day 3 (P < 0.0001)). This pharmacokinetic improvement translated into significantly reduced OFF time with DopaFuse therapy (reduction of -1.72 ± 0.37 h at Day 15; P = 0.0004) and increased ON time without severe dyskinesias (increase of 1.72 ± 0.37 h at Day 15; P = 0.0004) versus oral LD/CD administration. DopaFuse therapy was not associated with any clinically significant adverse events. Continuous delivery of LD/CD using the DopaFuse system was associated with significantly less variability in plasma levodopa concentrations and reductions in OFF time compared to treatment with standard oral LD/CD therapy and was well tolerated. © 2024 International Parkinson and Movement Disorder Society.

Satisfaction with videoconferencing support for levodopa-carbidopa intestinal gel: An observational study.

Levodopa-carbidopa intestinal gel (LCIG) is a continuously delivered Parkinson's disease therapy intended to stabilize plasma levodopa levels. Patients receiving LCIG require education and follow-up. Some LCIG support programs use video-assisted telenursing. To examine how videoconferencing impacts satisfaction with LCIG support programs. FACILITATE CARE (Feasibility of video-Assisted Care for Intestinal Levodopa Infusion with Telenursing - observAtional Trial Evaluating patient and Caregiver Acceptance in REal life) was a 12-week, prospective, open-label, 2-arm, parallel-group, observational study assessing satisfaction with LCIG support in patients who self-assigned to video or audio-only arms. Patients aged 18-85 years had completed LCIG titration and owned a videoconferencing device (video arm only). A visual analog scale measured satisfaction (1-10, 10 being most satisfied). Patients' mean (standard deviation) ages were 67.9 (7.4, n = 26) and 71.1 (6.2, n = 15) years in the video and audio arms, respectively. Patients, caregivers, and physicians in both groups reported satisfaction scores of 8-10 with LCIG support personnel, communication access, and assistance with becoming independent. At week 12, the Modified Caregiver Strain Index least square means change from baseline was lower in the video vs. audio arm (-2.3 [1.0] vs. 1.6 [1.2]). LCIG support personnel travel time was lower in the video vs. audio arm (125.7 [70.2] vs. 203.0 [70.0] minutes). LCIG support programs are associated with high patient, caregiver, and physician satisfaction; video and audioconferencing satisfaction are similarly high. Video-assisted telenursing may be a convenient communication avenue and may reduce caregiver burden. ClinicalTrials.gov; NCT04500106.

An Amperometric Biosensor Based on a Bilayer of Electrodeposited Graphene Oxide and Co-Crosslinked Tyrosinase for L-Dopa Detection in Untreated Human Plasma.

L-Dopa, a bioactive compound naturally occurring in some Leguminosae plants, is the most effective symptomatic drug treatment for Parkinson's disease. During disease progression, fluctuations in L-DOPA plasma levels occur, causing motor complications. Sensing devices capable of rapidly monitoring drug levels would allow adjusting L-Dopa dosing, improving therapeutic outcomes. A novel amperometric biosensor for L-Dopa detection is described, based on tyrosinase co-crosslinked onto a graphene oxide layer produced through electrodeposition. Careful optimization of the enzyme immobilization procedure permitted to improve the long-term stability while substantially shortening and simplifying the biosensor fabrication. The effectiveness of the immobilization protocol combined with the enhanced performances of electrodeposited graphene oxide allowed to achieve high sensitivity, wide linear range, and a detection limit of 0.84 μM, suitable for L-Dopa detection within its therapeutic window. Interference from endogenous compounds, tested at concentrations levels typically found in drug-treated patients, was not significant. Ascorbic acid exhibited a tyrosinase inhibitory behavior and was therefore rejected from the enzymatic layer by casting an outer Nafion membrane. The proposed device was applied for L-Dopa detection in human plasma, showing good recoveries.

In situ continuous Dopa supply by responsive artificial enzyme for the treatment of Parkinson’s disease

Oral dihydroxyphenylalanine (Dopa) administration to replenish neuronal dopamine remains the most effective treatment for Parkinson’s disease (PD). However, unlike the continuous and steady dopamine signaling in normal neurons, oral Dopa induces dramatic fluctuations in plasma Dopa levels, leading to Dopa-induced dyskinesia. Herein, we report a functional nucleic acid-based responsive artificial enzyme (FNA-Fe3O4) for in situ continuous Dopa production. FNA-Fe3O4 can cross the blood-brain barrier and target diseased neurons relying on transferrin receptor aptamer. Then, FNA-Fe3O4 responds to overexpressed α-synuclein mRNA in diseased neurons for antisense oligonucleotide treatment and fluorescence imaging, while converting to tyrosine aptamer-based artificial enzyme (Apt-Fe3O4) that mimics tyrosine hydroxylase for in situ continuous Dopa production. In vivo FNA-Fe3O4 treatment results in recovery of Dopa and dopamine levels and decrease of pathological overexpressed α-synuclein in PD mice model, thus ameliorating motor symptoms and memory deficits. The presented functional nucleic acid-based responsive artificial enzyme strategy provides a more neuron friendly approach for the diagnosis and treatment of PD.

Consistent Effects of Once-Daily Opicapone 50 mg on COMT Activity Across Participants: A Pooled Post Hoc Analysis of Two Phase 1 Studies (P14-11.014)

<h3>Objective:</h3> To assess effects of adjunctive opicapone (OPC) 50 mg on catechol-O-methyltransferase (COMT) activity by participants’ baseline characteristics. <h3>Background:</h3> OPC is a once-daily COMT inhibitor approved as adjunctive treatment to carbidopa/levodopa (CD/LD) in patients with Parkinson’s disease (PD) experiencing “OFF”-episodes. In two Phase 3 trials, OPC reduced daily “OFF”-time in patients with PD and motor fluctuations. Phase 1 trials also showed that adding OPC 50 mg to CD/LD in healthy individuals and patients with PD decreased variability in plasma levodopa (LD) levels and COMT activity. However, the effects of participants’ baseline characteristics on COMT inhibition remain unknown. <h3>Design/Methods:</h3> This post hoc analysis included data from 2 open-label Phase 1 studies (Study 1: 16 patients with PD receiving immediate-release CD/LD; Study 2: 18 healthy participants receiving extended-release CD/LD) assessing the effect of OPC 50 mg on LD pharmacokinetics (PK). Blood samples to assess LD PK and soluble-COMT (S-COMT) activity were collected before and after 14–15 days of once-daily OPC 50 mg. Pooled data on S-COMT inhibition were analyzed by participants’ baseline characteristics: disease state (PD vs healthy), sex (male vs female), ethnicity (Hispanic/Latino vs non-Hispanic/Latino), body mass index (&lt;25 vs ≥25), and baseline S-COMT activity. <h3>Results:</h3> OPC added to CD/LD decreased mean (95% CI) S-COMT activity by ≥80% in patients with PD and healthy participants (Study 1: 83.0% [80.5–85.4%]; Study 2: 80.1% [78.5–81.8%]; Pooled: 81.4% [80.0–82.9%]). Mean percent reduction in S-COMT activity was 79–85% for all subgroups in individual and pooled studies, although some subgroups had small numbers of participants. Variability in S-COMT activity was lower in all participants after OPC compared to baseline. <h3>Conclusions:</h3> Adding once-daily OPC 50 mg to CD/LD resulted in substantial S-COMT inhibition with reduced variability regardless of baseline characteristics. In all participants, COMT inhibition shown by OPC with CD/LD leads to more consistent daily LD exposure. <b>Disclosure:</b> Gordon Loewen has received personal compensation for serving as an employee of Neurocrine. Gordon Loewen has received stock or an ownership interest from Neurocrine. Gordon Loewen has received intellectual property interests from a discovery or technology relating to health care. Kurt Olson has received personal compensation for serving as an employee of Neurocrine Biosciences Inc. Kurt Olson has stock in Neurocrine Biosciences Inc. Dr. Liang has received personal compensation for serving as an employee of Neurocrine Biosciences. Dr. Liang has stock in Neurocrine Biosciences. Dr. Klepitskaya has received personal compensation for serving as an employee of Neurocrine Biosciences, Inc.

Pharmaceutical and pharmacokinetic evaluation of a newly formulated multiparticulate matrix of levodopa and carbidopa.

Levodopa is routinely co-administered with carbidopa in the management of Parkinson's disease. Although the aforementioned combination therapy is effective, there may be fluctuating plasma levels of levodopa after oral administration. We formulated and evaluated the kinetic characteristics of the chitosan-pectin-based multiparticulate matrix of levodopa and carbidopa. Pectin was extracted from the cocoa husk, and the chitosan-pectin-based matrix was prepared by wet granulation. Formulations were evaluated for drug-excipient compatibility, drug content, precompression properties and in vitro release. For pharmacokinetic evaluation, rats were put into groups and administered either chitosan-pectin based matrix of levodopa/carbidopa, Sinemet® CR or levodopa/carbidopa immediate release powder. Rats were administered the different formulations of levodopa/carbidopa (20/5 mg/kg) per os every 12 hours. The pharmacokinetic parameters of levodopa were estimated for the various treatment groups. The percentage content of levodopa and carbidopa in the various formulations was within the acceptance criteria. The AUC0-24 for levodopa/carbidopa multiparticulate matrix (Formulation 3: 484.98 ± 18.70 μg.hr/mL); Formulation 4: 535.60 ± 33.04 μg.hr/mL), and Cmax (Formulation 3: 36.28 ± 1.52 μg/mL; Formulation 4: 34.80 ± 2.19 μg/mL) were higher than Sinemet® CR (AUC0-24 262.84 ± 16.73 μg.hr/mL and Cmax 30.62 ± 3.37 μg/mL). The t 1/2 of the new formulation was longer compared to Sinemet® CR.

Erratum: Zhao et al., "Histochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala".

<h3>Objective:</h3> Characterize the levodopa pharmacokinetic profile achieved with continuous subcutaneous administration of ND0612. <h3>Background:</h3> Continuous levodopa/carbidopa infusion is the optimal delivery route for patients with advanced Parkinson’s disease (PD), but current delivery systems require invasive surgical interventions. ND0612 is a proprietary liquid formulation of levodopa/carbidopa administrated subcutaneously through a mini-pump delivering a range of levodopa doses from 270mg/day to 720mg/day. <h3>Design/Methods:</h3> Two Phase II studies were performed. The first was a phase IIa study in which 16 PD patients were randomized to low-or high- dose ND0612 for 8-hours administration. The second was a double-blind, placebo-controlled study, in which 30 PD patients received low dose ND0612 or placebo, as adjunct to their current optimized oral treatment for 2-weeks, followed by a 1-week open label extension of ND0612 either with or without oral entacapone. <h3>Results:</h3> In the first study, fluctuations in levodopa plasma levels were markedly reduced (both doses) in comparison to baseline oral levodopa/carbidopa. Levodopa maximal plasma concentrations were dose proportionate; low and high ND0612 doses achieved 487ng/mL and 1454ng/ml respectively. Co-administration of entacapone BID increased levodopa plasma levels to 604ng/mL and 1844ng/mL in the low and high dose arms respectively. In the second study, adjunct treatment with low-dose ND0612 eliminated the levodopa troughs associated with oral levodopa/carbidopa. Furthermore, when oral levodopa was discontinued, peaks and troughs in levodopa plasma levels were abolished, and mean levodopa levels were maintained at 550ng/ml. Co-administered entacapone further increased levodopa levels to 800ng/ml. In addition, the trial met its futility analysis endpoint; adjunct ND0612 reduced mean OFF by 2.42h in clinic and 2.13h in pilot home diaries, (vs. 0.41h and 1.39h with optimized oral therapy and placebo). <h3>Conclusions:</h3> Subcutaneous administration of ND0612 provides steady, therapeutic levodopa plasma concentrations that were associated with clinical improvement, and may provide an effective, non-invasive alternative for continuous levodopa delivery. <b>Study Supported by:</b> NeuroDerm Ltd. <b>Disclosure:</b> Dr. Giladi has received personal compensation for activities with Teva-Lundbeck, Merz Inc., and UCB for activities with the Advisory Boards . f Teva-Lundbeck, Merz Inc. Dr. Giladi has received personal compensation for activities with Teva Israel, Intec Pharma and NeuroDerm Inc. as a consultant. Dr. Caraco has received personal compensation for activities with NeuroDerm Ltd. as a consultant. Dr. Caraco has received research support from NeuroDerm Ltd. Dr. Gurevich has nothing to disclose. Dr. Djaldetti has nothing to disclose. L. Adar has received personal compensation for activities with NeuroDerm Ltd. as an employee. Dr. Cohen has received personal compensation for activities with Neuroderm as an employee. Dr. Rahmilevich has received personal compensation for activities with NeuroDerm Ltd., a an employee. Dr. Oren has received personal compensation for activities with NeuroDerm Ltd.

Opicapone as an Add-on to Levodopa in Patients with Parkinson's Disease Without Motor Fluctuations: Rationale and Design of the PhaseIII, Double-Blind, Randomised, Placebo-Controlled EPSILON Trial.

IntroductionLevodopa remains the cornerstone treatment for Parkinson’s disease (PD) but its use is associated with the development of ‘wearing-off’ fluctuations and other motor and non-motor complications over time. Adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/dopa decarboxylase (DDC) inhibitor therapy reduces fluctuations in the profile of plasma levodopa levels following oral dosing, and can therefore be beneficial for the management of motor complications. The objective of the EPSILON study is to investigate the efficacy of opicapone (OPC; a third-generation, once-daily COMT inhibitor) in enhancing the clinical benefit of levodopa in patients in earlier stages of PD, without end-of-dose motor fluctuations.MethodsEPSILON is a phase III, double-blind, randomised, placebo-controlled and parallel-group study, designed to evaluate the efficacy and safety of OPC as add-on to levodopa/DDC inhibitor therapy in patients with early PD who do not exhibit signs of motor complications. Eligible patients will be randomised (1:1) to receive OPC 50 mg or placebo, in addition to their existing levodopa/DDC inhibitor therapy, over a 24-week, double-blind treatment period, after which they will have the option of entering an additional 1-year, open-label extension period, during which all patients will receive OPC 50 mg.Planned OutcomesThe primary efficacy endpoints are change in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III total score from baseline to the end of the double-blind period (double-blind phase) and change in MDS-UPDRS Part IV total score from open-label baseline to the end of the open-label period (open-label phase). Secondary outcomes during the double-blind phase will include other measures of PD symptoms, including quality of life, non-motor symptoms, and development of motor fluctuations. Safety assessments will include evaluation of treatment-emergent adverse events, laboratory safety parameters, suicidality and impulse control disorders.Trial RegistrationEuropean Union Drug Regulating Authorities Clinical Trials Database (number 2020-005011-52).

P 81 ELEGANCE – A prospective non-interventional study of the long-term effectiveness and safety of levodopa–entacapone–carbidopa intestinal gel (LECIG) in patients with advanced Parkinson's disease in routine care

Background: Levodopa–entacapone–carbidopa intestinal gel (LECIG) is a device-aided therapy option introduced in 2021 that has received marketing authorisation in several European countries for the treatment of patients with advanced Parkinson’s disease (PD) who have motor complications that cannot be adequately controlled by optimised oral/transdermal PD medication. The presence of entacapone in LECIG increases the bioavailability of levodopa compared with standard levodopa–carbidopa intestinal gel, allowing a reduced levodopa dose (by 20–35%) to be given to achieve the same effective plasma levodopa levels. The ELEGANCE study has been established to collect real-world data on the efficacy and safety of LECIG in clinical practice use. Study design: ELEGANCE is an international, prospective, non-interventional, observational study that will be undertaken in ∼16 countries, including Germany and Austria, once marketing authorisation for LECIG is received. Study centres will offer participation in the ELEGANCE study to all adult patients with advanced PD who have severe motor fluctuations and hyperkinesia or dyskinesia despite taking optimised or transdermal PD therapy and who have been prescribed treatment with LECIG as part of routine clinical practice. Subjects can be de novo patients or those who switch from another infusion therapy. The planned total number of patients to be recruited to the study is ∼300 across all countries. In Germany and Austria, it is planned that around 15 centres will participate with the aim of recruiting ∼75 patients. Patients will be followed for 24 months or until study discontinuation. Data collection commenced July 2021, and recruitment is planned until in July 2022 with study completion in Q2 2024. An interim analysis will be performed. Study endpoints: Primary objectives are to evaluate the long-term efficacy and safety of LECIG over 24 months. Efficacy evaluations will include effect on motor symptoms (change from baseline to 24 months in daily OFF time [MDS-UPDRS IV] and motor aspects of experiences of daily living [MDS-UPDRS II] scores), required levodopa dose, use of other PD medication, Clinical and Patient Global Impression, and satisfaction with treatment. Adverse events will be monitored for evaluation of safety. Secondary objectives are to investigate patients‘ non-motor symptoms (change from baseline in Non-Motor Symptom Scale Score, Parkinson's disease sleep scale-2, and MDS-UPDRS lb scores), quality of life (change from baseline in Parkinson's Disease Questionnaire total score [PDQ-8 or PDQ-39]), and healthcare resource utilisation (complications of PD leading to hospitalisation, problems with medication or device). Conclusions: The data generated from ELEGANCE will provide valuable real-world information on the efficacy and safety of LECIG, as well as on patient perspectives of this treatment and its impact on healthcare utilisation that can help inform clinical decisions and policy making.

ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized, placebo-controlled phase 2 study

IntroductionND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations. MethodsThis was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h. ResultsND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC0–10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of −2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H0 of μ0 ≤-1.6). ConclusionLevodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.

Practical aspects of prescribing antiparkinsonian drugs. The place of amantadines in the management of Parkinson’s disease

Treatment of Parkinson’s disease (PD) includes the administration of dopaminergic and occasionally non-dopaminergic drugs, in mono- or in combination therapy. One of the key drug used to treat Parkinson’s disease is levodopa considered a gold standard. In addition levodopa can also be used as a challenge test to confirm the accuracy of diagnosis of PD known as the “Levodopa challenge test”. However many non levodopa class of drugs are also used and consist of dopamine agonists (ADRs), MAO-B and COMT inhibitors, as well as drugs working on glutamate such as a group of drug with NMDA receptor inhibitor activity (amantadines). The successful treatment of PD therefore depends on the correct choice of drugs to initiate treatment and sustainance of such therapy. The main parameters for personolised treatment include the patient’s age, severity and pattern of motor deficit, the state of cognitive function and lifestyle. Levodopa, although the most effective, is almost invariably associated with motor fluctuations and dyskinesias. Before prescribing levodopa, in addition to MAO-B inhibitors and ADRs, amantadines can be used as a monotherapy. Once replacement of therapy is required, then it is necessary to use a coefficient to calculate an equivalent dose of levodopa known as the levodopa equivalent dose. Progression of PD is inevitable inspite of adequate symptomatic therapy and at the advanced stage of PD approaches for the management of motor complications of levodopa need to be considered. For motor fluctuations these strategies require a change in the dosage regimen of levodopa (daily dose and frequency of intake), as well as the addition of an adjunct drug – ADRs, MAO-B inhibitor or COMT inhibitor. When dyskinesias arise, the management depends on correct identification of the type of dyskiensias. The commonest type of dyskinesia is peak dose dyskinesias related to peak plasma levodopa levels after intake. Amantadine provides a quick and long-lasting antidyskinetic effect which has been confirmed in open label as well as double-blind placebo-controlled studies. Compared to аmantadine chloride, amantadine sulfate has more stable pharmacokinetic parameters and a better safety profile. In addition, parenteral administration of amantadine sulfate can be utilized for severely ill patients with akinetic crisis in PD. Amantadine also has a broad spectrum effect and these may include improvement of fatigue and apathy. Some data also suggest that the use of amantadine in patients may increase life expectancy, improve survival and reduce the risk of dementia.

Opicapone enhances the reversal of MPTP-induced Parkinson-like syndrome by levodopa in cynomolgus monkeys

Opicapone is a third generation nitrocatechol catechol-O-methyltransferase inhibitor that has received regional market approval for use as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. This study evaluated the effects of opicapone as adjunct to levodopa in reversing a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson's-like syndrome in cynomolgus monkeys in during opicapone preclinical development program. A Parkinson's-like syndrome was induced in cynomolgus monkeys by daily administrations of MPTP. Evaluation of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity. MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (PPMRS scores of 10–15) and decreased locomotor activity (13% of pre-MPTP values). Opicapone treatment alone, for 14 days, did not change Parkinson's-like symptoms nor decreased subject's locomotor behaviour. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS and improved locomotor behaviour reaching statistical significance for levodopa/benserazide doses of 18/4.5 mg/kg and those effects were enhanced in opicapone treated subjects. Opicapone treated subjects as compared vehicle-treated, had markedly reduced erythrocyte catechol-O-methyltransferase activity, significantly increased plasma levodopa levels (1.8-fold higher AUC) with no statistically significant changes in Cmax and significantly reduced 3-OMD AUC and Cmax values (7.8- and 6.8-fold respectively). Opicapone potentiated the improvements in Parkinson's-like symptoms produced by levodopa/benserazide combinations with concomitant increase in plasma levodopa exposure, reduction of plasma 3-O-methyldopa levels and erythrocyte catechol-O-methyltransferase activity, results that were later demonstrated in 2 large Phase 3 studies in Parkinson's disease patients.

Subclinical affective and cognitive fluctuations in Parkinson's disease: a randomized double-blind double-dummy study of Oral vs. Intrajejunal Levodopa.

Chronic levodopa treatment in Parkinson's disease (PD) may promote undesirable motor and non-motor fluctuations. Compared to chronic oral levodopa treatment, continuous infusion of levodopa/carbidopa intestinal gel (LCIG) in advanced PD reduces motor fluctuations. However, differences in their effect on acute non-motor changes were not formally demonstrated. We performed a randomized, double-blind, double-dummy, crossover study to compare acute non-motor changes between intermittent oral immediate-release carbidopa/levodopa(LC-IR) and LCIG. After > 12-h OFF, thirteen PD patients chronically treated with LCIG and without history of non-motor swings, were allocated to receive first, LCIG infusion plus three oral doses of placebo, or placebo infusion plus three oral doses of LC-IR. Over-encapsulated oral medication (LC-IR or placebo) was administered every 2h. We monitored plasmatic levels of levodopa, motor status (UPDRS-III), mood, anxiety, and frontal functions at baseline (0-h) and hourly after each oral challenge. Repeated-measures ANOVAs showed significant group by treatment interaction indicating more fluctuations of levodopa plasma levels with LC-IR. No significant interactions were seen in the temporal profile of motor status, anxiety, mood and cognition. However, point-to-point parametric and nonparametric tests showed a significant more marked and more sustained improvement in anxiety scores under LCIG. A significant improvement of mood and verbal fluency was seen a + 3-h only under LCIG. Our sample of advanced PD patients exhibited moderate but significant non-motor fluctuations. LCIG was associated with a more favorable profile of acute affective and cognitive fluctuations that was particularly expressed at the first part of the infusion curve.

The preclinical discovery and development of opicapone for the treatment of Parkinson’s disease

ABSTRACT Introduction Opicapone (OPC) is a well-established catechol-O-methyltransferase (COMT) inhibitor that is approved for the treatment of Parkinson’s disease (PD) associated with L-DOPA/L-amino acid decarboxylase inhibitor (DDI) therapy allowing for prolonged activity due to a more continuous supply of L-DOPA in the brain. Thus, OPC decreases fluctuation in L-DOPA plasma levels and favors more constant central dopaminergic receptor stimulation, thus improving PD symptomatology. Areas covered This review evaluates the preclinical development, pharmacology, pharmacokinetics and safety profile of OPC. Data was extracted from published preclinical and clinical studies published on PUBMED and SCOPUS (Search period: 2000–2019). Clinical and post-marketing data are also evaluated. Expert opinion OPC is a third generation COMT inhibitor with a novel structure. It has an efficacy and tolerability superior to its predecessors, tolcapone (TOL) and entacapone (ENT). It also provides a safe and simplified drug regimen that allows neurologists to individually adjust the existing daily administration of L-DOPA. OPC is indicated as an adjunctive therapy to L-DOPA/DDI in patients with PD and end-of-dose motor fluctuations who cannot be stabilized on those combinations.

Effects of liraglutide in the treatment of severe obesity in a young patient with parkinson’s disease

The Glucagon-like peptide-1 (GLP-1) analog exert disease-modifying effects in patients with Parkinson’s disease (PD). Nonetheless, the significant improvement in motor performance was paralleled by significant reduction in body weight in exenatide-treated PD, so that it could argued that levodopa pharmacokinetics could have been improved by either body weight loss or by other GLP-1-related. We describe a 42-year-old female Italian PD patient with a 2-year history of PD, who presented a few month after the onset (October 2017) with III class obesity (BMI 47 kg/m2). To assess the effects of body weight loss both on efficacy of pharmacological treatment and on PD symptoms, the GLP-1 analog Liraglutide was prescribed for obesity (according to Italian guidelines) in adjunct to pramipexole PR 1 mg/day and levodopa/benserazide 400mg/day. Plasma Levodopa levels were investigated. The overall body weight loss of 29 kg (-21% , from 138 kg to 129 kg) was associated to a significant improvement in the motor disability was paralleled by a 2-fold increase in the area-under-the curve (AUC from 119 to 235 (ug/ml)*min and the Cmax (from 1.45 to 2.98 ug/mL). The use GLP-1 analog Liraglutide is able to improve PD motor disability in the short-term, likely because of optimized levodopa pharmacokinetics. It remains to be elucidated whether this is a consequence of either body weight loss or greater levodopa intestinal absorption or both.

Bound, free, and total L-dopa measurement in plasma of Parkinson's disease patients.

Peaks and troughs of levodopa in plasma contribute to pulsatile postsynaptic dopamine receptor stimulation in patients with Parkinson's disease. Measurement of levodopa plasma levels mostly only considers the total levodopa plasma concentration. Objectives were to determine bound, free, and total plasma levodopa and to investigate their correlations to each other. We employed reversed-phase high-performance liquid chromatography combined with electrochemical detection. Bound levodopa was computed as difference between total and free L-dopa values. Close correlations between free and total (R = 0.93, p < 0.0001), bound and total (R = 0.91, p < 0.0001) plasma levodopa appeared. A considerable variability of levodopa concentrations occurred. The ratio between bound and free levodopa did not differ in patients with a higher and lower oral daily levodopa dosing. Free, bound, and total levodopa plasma levels are closely related. Estimation of the total levodopa level only seems to be meaningful.

Old Drugs, New Delivery Systems in Parkinson's Disease.

Levodopa is the mainstay of treatment in Parkinson's disease (PD). As the disease progresses, variations in plasma levodopa levels lead to motor fluctuations. The common reasons behind variations in the plasma levels include delayed gastric emptying, small intestinal bacterial overgrowth, protein interaction with levodopa absorption, and limited oral bioavailability of levodopa. Efforts to find newer delivery systems for older drugs to avoid the problems associated with oral delivery of medications are continuing. This review aims to provide up-to-date information about the newer delivery options for drugs used for PD and provides a summary of infusion therapy with apomorphine, modifications to other dopamine agonists, various oral formulations of carbidopa/levodopa, inhaled levodopa, intrajejunal infusion of levodopa, and sublingual apomorphine. The advantages, dose, and adverse effects of each treatment modality are reviewed. We also discuss several drugs under investigation, such as the subcutaneous carbidopa/levodopa infusion and subcutaneous rotigotine.

Design of a ratiometric fluorescence nanoprobe to detect plasma levels of levodopa

Simply obtained by the oxidation of levodopa in alkaline media, polylevodopa nanoparticles are able to quench the fluorescence emission of CdTe quantum dots (QDs) via energy transfer mechanism. The extent of this quenching can be exploited for the quantification of levodopa, as an important therapeutic agent in the treatment of Parkinson's disease. However, to effectively improve the detection performance, in this study, we have designed a ratiometric probe by making use of variations in both the emission of QDs and the intrinsic emission of polylevodopa nanoparticles. The enhanced sensitivity, in particular, arose from the measurement of the ratio of fluorescence intensities at two different wavelengths, by which the resulting signal was totally analyte-dependent and free from environmental effects. The built-in self-calibration in this ratiometric approach led to a remarkable detection limit of 18.3 nmol L−1, without interruption from possible interferences. The proposed ratiometric nanoprobe not only proved to be highly selective, but also showed to be capable of successively detecting levodopa in complex biological fluids such as plasma, in which possible interferences are usually likely to affect the detection results.