Levodopa Concentrations Research Articles

Influence of l-Dopa adsorption time and concentration on Au nanorods aggregation for SERS quantitative analysis

Levodopa (l-Dopa) is an important neurotransmitter from the amino acid family and is also associated with the treatment of Parkinson's disease. The obtention of the l-Dopa SERS signal in colloid is a challenge due to the zwitterionic charge promoting repulsion from nanoparticle surface and leading to poor or not active SERS signal. In this work, SERS signal of l-Dopa was successfully obtained using Au nanorods (AuNRs) covered with a cationic lipid bilayer and using the 785 nm laser line. The UV–Vis extinction, dynamic light scattering, and zeta potential results indicated an influence of l-Dopa adsorption time and l-Dopa concentration on AuNRs aggregation. The SERS signal followed this time dependence, being the characteristic l-Dopa band observed only after 30 min. The l-Dopa quantitative analysis using the standard addition method presented a linear SERS signal at 439 cm−1 with a limit of detection of 6.7 × 10−7 mol L−1 for peak intensity, and 7.9 × 10−7 mol L−1 for band integrated area.

Evaluation of haemolymph phenoloxidase activity from the grub of Zophobas morio as a predictor of immune response.

In insects, enzyme phenoloxidase plays a critical role in cuticular sclerotisation and defensive functions. In the present investigation, haemolymph phenoloxidase activity from the grub of Zophobas morio was attempted to evaluate as a reliable predictor of insect's immunological response. Among the various substrates tested, L-DOPA was chosen as an appropriate substrate due to its high oxidation. The optimum pH and temperature for haemolymph PO activity was found to be 8 and 30°C, respectively. The optimum substrate concentration of L-DOPA was found to be 7.5mM for subsequent PO enzymatic characterisation. Among the various chemical inhibitors and copper chelators, PO activity was significantly reduced in the case of PMSF and thiourea. Preincubation of haemolymph with non-self-molecules showed enhancement of PO activity in the case of LPS from Serratia marcescens. In addition, exogenous proteases like α-chymotrypsin enhanced the PO activity of haemolymph and an increase in PO activity was demonstrated when haemolymph was preincubated with the anionic detergent, SDS and cationic detergent, cetyl pyridium chloride. Alteration of PO activity was observed under agonising conditions of starvation, ligation and microplastics injection at different time intervals. Interestingly, there were no correlation between PO and insect defence under live challenge of microbes. SDS protein profile revealed a significant increase in the 85kDa and 55kDa polypeptides in all the experiments over control after 24h, 48h and 96h. Mass spectrophotometric analysis of the polypeptides revealed their homology to antimicrobial peptides for 55kDa protein and 85kDa protein. A significant increase in 85kDa polypeptide was observed in the haemolymph of the grubs after 72h in the case of starved and microplastics injected groups only. These results demonstrated that PO may not be a reliable benchmark of immunological response in this insect.

Smart-Phone-Assisted Optical Biosensors Based on Silk-Fibroin-Decorated Reduced Graphene Oxide Quantum Dots for Fluorescent Turn-On Recognition of l-Dopa

Levodopa (l-dopa) is a gold standard neurological drug for symptomatic medication of Parkinson’s disease. The long-term use of l-dopa therapy frequently leads to l-dopa-induced dyskinesia and several other non-motor flocculants for fluctuating plasma concentration. To alleviate the adverse effect of dopamine replacement therapy, sensitive detection of l-dopa is still challenging. Therefore, this study presents a simple strategy to develop an inexpensive, easy-to-use, smartphone-based fluorescence turn-on sensory system based on the aggregation-induced emission enhancement phenomenon for instant low-level detection of l-dopa in biological samples. The sensor was fabricated using silk-fibroin-decorated reduced graphene oxide quantum dots, which exhibit a progressive increase of fluorescence intensity in the presence of l-dopa. By measuring the turn-on efficiency of the sensor in elevated concentrations of l-dopa, the limit of detection (LOD) was evaluated as 76.18 nM over a linear range of 0–35 μM. We have further designed a smartphone-based electronic device involving a 365 nm light emitting diode attached below the rare camera for capturing the change of fluorescent color of the solution during sensing. From these images, red, green, and blue values are analyzed using a mobile phone application, and the corresponding LOD was found to be 0.29 μM in a similar linear range of concentration. This simple, cost-effective, and rapid screening gadget is very demanding for on-spot detection of the analytes in remote areas where sophisticated instrumentation is not usually available.

Study on Levodopa Sensor Modified by Ti3C2 MXene

The dosage management of levodopa is of great significance in the treatment of Parkinson’s disease. Measuring the patient’s levodopa concentration helps the physician to adjust the dose in time, so as to avoid complications. In this paper, we report an electrochemical sensor based on titanium carbide (Ti3C2) MXene nanomaterials, which can sensitively reflect the change of levodopa concentration. In the study, Ti3C2/GCE electrode was prepared by a simple drop-coating method, and then the Ti3C2/Pt/GCE electrode was prepared by modifying Pt nanoparticles on the electrode surface by impregnation adsorption method. After modification, the response of the GCE electrode to levodopa before and after Ti3C2 decoration was compared by cyclic voltammetry (CV), and the diffusion control process on the electrode surface was also investigated. Then, differential pulse voltammetry (DPV) was used to explore the relationship between the peak current of the oxidation anode and the concentration of levodopa. Finally, the relationship between current and concentration at a certain time point was explored by chronoamperometry (CA), and the time charge curves were plotted to explore the functional relationship between the amount of charge exchanged in the reaction and the concentration of levodopa (Coulomb analysis method). The research shows that the coulomb analysis method has a higher detection sensitivity and linear range, and this technology is expected to be applied to the in vivo monitoring of levodopa in our future research.

Foslevodopa/foscarbidopa Subcutaneous Infusion Maintains Similar Levodopa Exposure to Levodopa-Carbidopa Intestinal Gel Delivered to the Jejunum when Infused for 24-hours (P1-11.003)

<h3>Objective:</h3> To compare levodopa pharmacokinetics (PK) following subcutaneous (SC) infusion of foslevodopa/foscarbidopa and jejunal delivery of Levodopa-Carbidopa Intestinal Gel (LCIG) both administered for 24 hours in healthy volunteers. <h3>Background:</h3> Treatment with LCIG offers improved symptomatic control compared to oral levodopa/carbidopa in patients with advanced Parkinson’s disease (aPD); however, it requires percutaneous endoscopic gastrostomy tube placement for jejunal delivery. Foslevodopa/foscarbidopa is an investigational drug able to provide 24-hour therapeutic levels of levodopa following SC delivery. While a previous study compared the PK of levodopa between foslevodopa/foscarbidopa and LCIG, when LCIG was administered during waking hours, the current work characterizes the levodopa PK when both the SC infusion and intestinal gel are delivered continuously for 24 hours. <h3>Design/Methods:</h3> This study was a randomized, open-label, 2-way crossover study in 20 healthy volunteers. In each period, subjects received either 24-hour foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 hours to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected to assay for levodopa concentrations. PK parameters such as area under the curve (AUC) and degree of fluctuation (DOF) were determined and compared between the two regimens. <h3>Results:</h3> Foslevodopa/foscarbidopa SC infusion provided comparable levodopa levels to LCIG over the 24-hour delivery period as assessed by the AUC and DOF parameters. From the different AUC intervals explored, the differences of the mean ranged from 1 to 8% between the foslevodopa/foscarbidopa and the LCIG regimens. Additionally, the degree of fluctuation of levodopa was similar but lower for foslevodopa/foscarbidopa compared to LCIG (mean 0.32 vs 0.50). <h3>Conclusions:</h3> Foslevodopa/foscarbidopa SC infusion delivers comparable levodopa exposure to LCIG when delivered for 24 hours. The low variability of the levodopa PK profiles supports the strategy of maintaining levodopa exposure within a narrow therapeutic window when treating motor symptoms in aPD. <b>Disclosure:</b> Dr. Rosebraugh has received personal compensation for serving as an employee of AbbVie Inc. Dr. Rosebraugh has stock in AbbVie Inc.. Dr. Facheris has received personal compensation for serving as an employee of AbbVie Inc.. Dr. Facheris has stock in AbbVie Inc..

The combination of levodopa with levodopa-metabolizing enzyme inhibitors prevents severe fever with thrombocytopenia syndrome virus infection in vitro more effectively than single levodopa

Severe fever with thrombocytopenia syndrome is a hemorrhagic fever caused by a tick-borne infection. The causative agent, Dabie bandavirus, is also called the severe fever with thrombocytopenia syndrome virus (SFTSV). Ogawa et al. (2022) reported that levodopa, an antiparkinsonian drug with an o-dihydroxybenzene backbone, which is important for anti-SFTSV activity, inhibited SFTSV infection. Levodopa is metabolized by dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) in vivo. We evaluated the anti-SFTSV efficacy of two DDC inhibitors, benserazide hydrochloride and carbidopa, and two COMT inhibitors, entacapone and nitecapone, which also have an o-dihydroxybenzene backbone. Only DDC inhibitors inhibited SFTSV infection with pretreatment of the virus (half-maximal inhibitory concentration [IC50]: 9.0–23.6 μM), whereas all the drugs inhibited SFTSV infection when infected cells were treated (IC50: 21.3–94.2 μM). Levodopa combined with carbidopa and/or entacapone inhibited SFTSV infection in both conditions: pretreatment of the virus (IC50: 2.9–5.8 μM) and treatment of infected cells (IC50: 10.7–15.4 μM). The IC50 of levodopa in the above-mentioned study for pretreatment of the virus and treatment of infected cells were 4.5 and 21.4 μM, respectively. This suggests that a synergistic effect was observed, especially for treatment of infected cells, although the effect is unclear for pretreatment of the virus. This study demonstrates the anti-SFTSV efficacy of levodopa-metabolizing enzyme inhibitors in vitro. These drugs may increase the time for which the levodopa concentration is maintained in vivo. The combination of levodopa and levodopa-metabolizing enzyme inhibitors might be a candidate for drug repurposing.

Catecholamine concentrations in duck eggs are impacted by hen exposure to heat stress.

Rapid "fight-or-flight" responses to stress are largely orchestrated by the catecholamines. Moreover, catecholamines and catecholamine precursors are widely recognized to act as interkingdom signaling molecules among host and microbiota, as well as to serve as chemotactic signals for bacterial foodborne pathogens. While albumen and yolk concentrations of glucocorticoids have received extensive attention as non-invasive indicators of hen response to stress, little is known regarding the impact of the hen's stress response on in ovo catecholamine and catecholamine precursor concentrations. The aim of the present study was to determine norepinephrine and L-dopa concentrations in albumen and yolk of eggs laid by hens maintained under normal or heat stress conditions. Norepinephrine and L-dopa concentrations were also measured in oviductal tissue. Breeder ducks (∼35weeks/age) were kept under normal (22°C) conditions or subjected to cyclical heat stress (35°C day/29.5°C night) for 3weeks. Eggs (n = 12 per timepoint/group) were collected on a weekly basis. Hens were sacrificed at baseline or after 3weeks of heat stress for oviductal tissue collection. Albumen, yolk, and oviduct concentrations of norepinephrine and L-dopa were determined using ultra high-performance liquid chromatography with electrochemical detection. Norepinephrine and L-dopa were detected in oviductal tissue as well as egg albumen and yolk. Norepinephrine concentrations were elevated (p < 0.05) in the yolk of eggs laid by the heat stress group compared to those of the control group. Norepinephrine concentrations in albumen were elevated (p < 0.05) in the heat stress group compared to control group at week 2. L-dopa concentrations were not significantly affected (p > 0.05) by heat stress in albumen, yolk, or oviductal tissue. Together, the present study provides the first evidence of the stress neurohormone, norepinephrine, in duck eggs and identifies that hen exposure to heat stress can affect in ovo norepinephrine concentrations. These data highlight the potential utility of in ovo catecholamine concentrations as non-invasive measures of the hen's response to stress, as well as warrants future research into whether hen deposition of stress-related neurochemicals into the egg could serve as a chemotactic signal in the vertical transmission of foodborne pathogens.

The Clinical Development of Levodopa Inhalation Powder.

Oral levodopa is the most effective treatment for Parkinson disease, but OFF periods emerge over time. Gastrointestinal dysfunction and food effects impact levodopa absorption, contributing to unpredictable control of OFF periods. Inhaled levodopa powder (Inbrija) is approved for on-demand treatment of OFF periods in patients receiving oral levodopa-dopa decarboxylase inhibitors. The 84-mg dose is administered via a breath-actuated inhaler. It provides pulmonary delivery of levodopa to the systemic circulation and is taken when a patient has an OFF period in between doses of regular oral levodopa medication. The pivotal SPAN-PD trial in patients experiencing OFF periods on oral dopaminergic therapy showed that levodopa inhalation powder 84 mg produced significant improvement in Unified Parkinson Disease Rating Scale Part III score, as measured 30 minutes postdose at week 12, and improvement was seen as early as 10 minutes. More patients in the levodopa inhalation powder group turned ON within 60 minutes of treatment and remained ON at 60 minutes than in the placebo group. Levodopa inhalation powder can also be used to treat early-morning OFF periods and, when used for up to 12 months, produced no clinically significant differences in pulmonary function compared with an untreated cohort. Levodopa inhalation powder 84 mg increased plasma levodopa concentration rapidly and with less variability than oral levodopa/carbidopa (25/100 mg). Most common adverse event associated with levodopa inhalation powder is cough, found in ~15% of patients in the SPAN-PD trial; otherwise, reported adverse events were consistent with those known to be associated with oral levodopa.

Concomitant use of magnesium oxide significantly decreases absorption of levodopa preparations in patients with Parkinson’s disease

IntroductionConstipation is one of the most frequent non-motor symptoms of Parkinson's disease (PD), and magnesium oxide (MgO) is a frequently used laxative. This study aimed to investigate the effect of concomitant use of MgO on the pharmacokinetics of levodopa preparations in patients with PD. MethodsWe prospectively enrolled 35 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and motor symptoms with and without MgO. The impact of alterations in pH and the addition of MgO on the solubility of levodopa formulations were also evaluated under in vitro conditions. ResultsConcomitant use of MgO significantly reduced the maximum plasma concentration of levodopa (Cmax) (from 7.66 ± 3.74 μmol/L to 5.82 ± 3.69 μmol/L; p = 0.006) and area under the plasma concentration–time curve 3 h after drug administration (AUC3h, from 9.64 ± 3.23 μmol·h/L to 7.39 ± 3.15 μmol·h/L; p < 0.001), and further decreased carbidopa Cmax (from 64.02 ± 27.02 ng/mL to 38.83 ± 21.94 μmol/L; p < 0.001) and AUC3h (from 130.58 ± 65.64 ng/mL to 76.48 ± 52.24 ng·h/mL; p < 0.001). The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III score also deteriorated significantly (from 30.71 ± 11.34 to 32.06 ± 11.22; p = 0.007). MgO significantly affected the pharmacokinetics of levodopa and carbidopa. This also applied when the findings were analyzed by sex and age. In vitro dissolution experiments revealed a decrease in the relative concentrations of levodopa, carbidopa, and benserazide as the pH increased and in the presence of MgO suspension, with the most prominent impact on benserazide. ConclusionsConcomitant use of MgO and levodopa should be discouraged to improve levodopa absorption.

A bacterial cellulose-based LiSrVO4:Eu3+ nanosensor platform for smartphone sensing of levodopa and dopamine: point-of-care diagnosis of Parkinson's disease.

Among the catecholamines, dopamine (DA) is essential in regulating multiple aspects of the central nervous system. The level of dopamine in the brain correlates with neurological diseases such as Parkinson's disease (PD). However, dopamine is unable to cross the blood-brain barrier (BBB). Therefore, levodopa (LD) is used to restore normal dopamine levels in the brain by crossing the BBB. Thus, the control of LD and DA levels is critical for PD diagnosis. For this purpose, LiSr0.0985VO4:0.015Eu3+ (LSV:0.015Eu3+) nanoplates were synthesized by the microwave-assisted co-precipitation method, and have been employed as an optical sensor for the sensitive and selective detection of catecholamines. The synthesized LSV:0.015Eu3+ nanoplates emitted red fluorescence with a high quantum yield (QY) of 48%. By increasing the LD and DA concentrations, the fluorescence intensity of LSV:0.015Eu3+ nanoplates gradually decreased. Under optimal conditions, the linear dynamic ranges were 1-40 μM (R2 = 0.9972) and 2-50 μM (R2 = 0.9976), and the detection limits (LOD) were 279 nM, and 390 nM for LD and DA, respectively. Herein, an instrument-free, rapid quantification visual assay was developed using a paper-based analytical device (PAD) with LSV:0.015Eu3+ fixed on the bacterial cellulose nanopaper (LEBN) to determine LD and DA concentrations with ease of operation and low cost. A smartphone was coupled with the PAD device to quantitatively analyze the fluorescence intensity changes of LSV:0.015Eu3+ using the color recognizer application (APP). In addition, the LSV:0.015Eu3+ nanosensor showed acceptable repeatability and was used to analyze real human urine, blood serum, and tap water samples with a recovery of 96-107%.

Improving levodopa delivery: IPX203, a novel extended-release carbidopa-levodopa formulation

IntroductionIPX203 is a novel oral extended-release (ER) formulation of carbidopa (CD) and levodopa (LD) developed to address the short half-life and limited area for absorption of LD in the gastrointestinal tract. This paper presents the formulation strategy of IPX203 and its relationship to the pharmacokinetics (PK) and pharmacodynamic profile of IPX203 in Parkinson’s disease (PD) patients. MethodsIPX203 was developed with an innovative technology containing immediate-release (IR) granules and ER beads that provides rapid LD absorption to achieve desired plasma concentration and maintaining it within the therapeutic range for longer than can be achieved with current oral LD formulations. The PK and pharmacodynamics of IPX203 were compared with IR CD-LD in a Phase 2, open-label, rater-blinded, multicenter, crossover study in patients with advanced PD. ResultsPharmacokinetic data showed that on Day 15, LD concentrations were sustained above 50% of peak for 6.2 h with IPX203 vs. 3.9 h with IR CD-LD (P = 0.0002). Pharmacodynamic analysis demonstrated that mean MDS-UPDRS Part III scores prior to administration of the first daily dose were significantly lower among patients receiving IPX203 than IR CD-LD (LS mean difference –8.1 [25.0], P = 0.0255). In a study conducted in healthy volunteers, a high-fat, high-calorie meal delayed plasma LD Tmax by 2 h, and increased Cmax and AUCtau by approximately 20% compared with a fasted state. Sprinkling capsule contents on applesauce did not affect PK parameters. ConclusionThese data confirm that the unique design of IPX203 addresses some of the limitations of oral LD delivery.

Levodopa u terapiji Parkinsonove bolesti

January 2023 marks the 100th anniversary of the birth of Arvid Carlsson, a Swedish scientist, one of the three winners of the Nobel Prize in Medicine in 2000 "for proving that Dopamine is a brain neurotransmitter whose deficiency leads to the symptoms of Parkinson's disease". Levodopa therapy is one of the main achievements of neurology in the twentieth century, and Parkinson' s disease was the first disease in which a specific neurochemical deficiency was confirmed in defined regions of the brain, which forms the basis for rational, chemically supported therapy. The paper briefly reviews the most important achievements in the discovery of Dopamine and levodopa, as well as their functions in the development of Parkinson's disease. Dopamine synthesis, understanding of levodopa synthesis method, possibility of measuring Dopamine concentration in putamen and caudate and its loss in Parkinson' s disease, along with histochemical visualization of nigrostriatal pathway and animal lesion model, enabled understanding of the role of nigrostriatal Dopamine system in the development of Parkinson's disease symptoms. Part of the work is devoted to the metabolism of Dopamine in healthy dopaminergic neurons, and then to its functioning in dopaminergic neurons of Parkinson's disease patients. It is known that in Parkinson's disease, Dopamine deficiency occurs due to selective degeneration of nigrostriatal dopaminergic neurons. Their suffering is triggered by a cascade of events that included the action of potential toxins, the influence of susceptibility genes on the body's response to them, oxidative stress caused by mitochondrial dysfunction, dysfunction of the ubiquitous proteasomal system that leads to the accumulation of incorrectly "packaged" proteins, the exhaustion of the endoplasmic reticulum system and the activation of mycoglia that follows inflammatory process. These changes can lead to programmed cell death of dopaminergic neurons with consequent Dopamine deficiency and the development of PD. Special attention is paid to the consequences of neuron loss on the functioning of the remaining dopaminergic neurons and Dopamine receptors, with reference to the therapeutic motor complications that may arise on that occasion. The basic assumptions about the occurrence of therapeutic complications are still related to the pharmacokinetics of levodopa and the model of its delivery to the brain, which results in non-physiological, pulsatile stimulation of Dopamine receptors. Today's possibilities in achieving a more stable concentration of levodopa with existing strategies are presented, with an answer to the question of whether continuous stimulation can be achieved under the conditions of standard, regular patients' levodopa therapy. In the short final part, the position of levodopa in the guidelines and recommendations for treatment is commented. It is expected that L-dopa will remain the "gold standard" for the treatment of PD at least until the development of more potent and safer Dopamine agonists or the development of neuroprotective or neurorestorative therapies.

Self-Sufficient In Vitro Multi-Enzyme Cascade for Efficient Synthesis of Danshensu from l-DOPA.

Danshensu (DSS), a traditional Chinese medicine, is widely used for the treatment of cardiovascular and cancer diseases. Here, a one-pot multi-enzyme cascade pathway was designed for DSS synthesis from l-DOPA using tyrosine aminotransferase from Escherichia coli (EcTyrB) and d-isomer-specific 2-hydroxyacid dehydrogenase from Lactobacillus frumenti (LfD2-HDH). Glutamate dehydrogenase from Clostridium difficile (CdgluD) was also introduced for a self-sufficient system of α-ketoglutaric acid and NADH. Under optimal conditions (35 °C, pH 7.0, EcTyrB:LfD2-HDH:CdgluD = 3:2:1, glutamate:NAD+ = 1:1), 98.3% yield (at 20 mM l-DOPA) and space-time yield of 6.61 g L-1 h-1 (at 40 mM l-DOPA) were achieved. Decreased yields of DSS at elevated l-DOPA concentrations (100 mM) could be attributed to an inhibited CdgluD activity caused by NH4+ accumulation. This developed multi-enzyme cascade pathway (including EcTyrB, LfD2-HDH, and CdgluD) provides an efficient and sustainable approach for the production of DSS from l-DOPA.

The pharmacokinetics of continuous subcutaneous levodopa/carbidopa infusion: Findings from the ND0612 clinical development program.

While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery. ND0612 is in development as a combination product providing continuous levodopa/carbidopa via a minimally invasive, subcutaneous delivery system for PD patients experiencing motor response fluctuations. We present pharmacokinetic results from a series of studies that analyzed plasma concentrations after SC levodopa delivery with ND0612 to inform the clinical development program. We performed a series of six Phase I and II studies to characterize the pharmacokinetics of levodopa and carbidopa derived from ND0612 infusion with/without adjunct oral therapy of the same ingredients. These studies were conducted in healthy volunteers and in PD patients experiencing motor response fluctuations while on their current levodopa therapy regimen. Taken together, the results demonstrate dose-proportionality dependent on rate of subcutaneous levodopa infusion leading to stable and sustained plasma concentrations of levodopa. Subcutaneous infusion of ND0612 administered with oral levodopa/carbidopa maintained near-constant, therapeutic levodopa plasma concentrations, thereby avoiding the troughs in levodopa plasma concentrations that are associated with OFF time in PD. The data generated in this series of studies also confirmed that a levodopa/carbidopa dose ratio of 8:1 would be the most reasonable choice for ND0612 development. This series of clinical pharmacokinetic studies have demonstrated that ND0612, administered continuously with a levodopa concentration of 60 mg/ml combined with carbidopa 7.5 mg/ml, and complemented with oral levodopa/carbidopa, is suitable for 24 h continuous administration in patients with PD. The stable plasma concentrations of levodopa achieved predict utility of ND0612 as a parenteral formulation for achieving clinically useful delivery of levodopa for PD patients.

Effect of Carbidopa Dose on Levodopa Pharmacokinetics With and Without Catechol-O-Methyltransferase Inhibition in Healthy Subjects.

The treatment of Parkinson's disease (PD) is still symptomatic since disease-modifying treatments for PD are not available. Oral levodopa is the gold standard for the treatment of PD motor symptoms. However, incomplete and fluctuating plasma exposure of levodopa leads to suboptimal treatment of the symptoms. The main objective of this study was to investigate to what extent increased carbidopa doses (50 and 100mg) increase the plasma levels of 100-mg immediate-release (IR) levodopa compared to a 25-mg carbidopa dose with and without co-administration of 200mg entacapone. A double-blind, placebo-controlled, randomized, crossover, phase I, pharmacokinetic study with 25 healthy volunteers was conducted. In addition, a semi-mechanistic pharmacokinetic model was built to theoretically evaluate the effect of inhibiting aromatic amino acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) mediated metabolism of levodopa on the exposure of levodopa. The effect of increased carbidopa doses 50 and 100mg on the total exposure (AUC) of 100mg IR levodopa was +29% and +36%, respectively, when entacapone was co-administered. Without entacapone, the corresponding increases were +13% and +17%. With entacapone co-administration, the increased carbidopa dose also clearly increased levodopa trough concentration. There was no significant effect on the peak concentrations of levodopa. Increasing carbidopa doses significantly increased the exposure and reduced the fluctuation of IR levodopa in plasma during simultaneous COMT inhibition with entacapone. Theoretical pharmacokinetic simulations suggested that the plasma profile of oral IR levodopa can be even further improved by optimizing AADC and COMT inhibition.

How resistant are levodopa-resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease.

Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean=2.3 at T1, 1.7 at T2, 1.2 at T3; p= 0.013). Posture and speech features did not show significant changes, whereas stride length (p= 0.049), turn duration (p= 0.001), and turn velocity (p= 0.024) significantly improved on doubling the levodopa infusion rate. In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

Effect of Nitrogen Sources on L-Dopa and Dopamine Production Using Citrobacter freundii (NRRL B-2643)

Microbial production of L-dopa and dopamine which is an important substrance for the treatment of Parkinson's disease were investigated by using Citrobacter freundii (NRRL B-2643). The effects of nitrogen source such as peptone, yeast extract, casein, soy protein, whey, ammonium sulfate on L-dopa and dopamine production were investigated and extracellular L-dopa and dopamine concentrations were determined by usign HPLC. Optimum nitrogen source concentrations were found to be (peptone 12.5 g/L, yeast extract 10.0 g/L, casein 0.1 g/L, soy protein 0.75g/L, whey 5% v/v and ammonium sulfate 1.0 g /L) for the production of L-dopa and dopamine. At this condition L-dopa and dopamine concentrations were found to be 342 and 467 mg/L, respectively. Although the experiments were continued for 60 hours, maximum production of L-dopa and dopamine concentration was reached at around the 30 th hour of the experiments.

Effect of Opicapone on Levodopa Pharmacokinetics in Patients with Fluctuating Parkinson's Disease.

Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations. To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens. A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes. Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P&lt; 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time. Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association Between Microbial Tyrosine Decarboxylase Gene and Levodopa Responsiveness in Patients With Parkinson Disease.

Interindividual variability in levodopa efficacy is a challenge for the personalized treatment of Parkinson disease (PD). Gut microbiota might represent a new approach for personalized medicine. Recently, a novel microbial levodopa metabolism pathway was identified, which is mediated by tyrosine decarboxylase mainly encoded by tyrosine decarboxylase gene (tyrDC) in Enterococcus faecalis. In this study, we aimed to identify whether the abundance of microbial tyrDC gene and E faecalis is associated with levodopa responsiveness and could predict the drug response. This cross-sectional study enrolled patients with PD between December 2019 and January 2022 and evaluated levodopa responsiveness using a levodopa challenge test. Patients were stratified into moderate and good responders based on levodopa responsiveness. The tyrDC gene and E. faecalis abundance in fecal samples were measured using quantitative real-time PCR. Plasma levodopa concentrations were measured using liquid chromatography-tandem mass spectrometry analysis. The predictive models for levodopa responsiveness were constructed and verified through cross-validation and external validation. A total of 101 patients with PD were enrolled in the primary cohort and 43 were enrolled in the external validation cohort. Moderate responders had higher abundances of the tyrDC gene (3.6 [3.1-4.3] vs 2.6 [2.1-2.9], p < 0.001) and E faecalis (3.2 [2.5-4.4] vs 2.6 [2.1-3.6], p = 0.010) than good responders. The tyrDC gene abundance was independently associated with levodopa responsiveness (OR: 5.848; 95% CI: 2.664-12.838; p < 0.001). Notably, tyrDC gene abundance showed certain discriminative power for levodopa responsiveness in primary cohort (sensitivity: 80.0%; specificity: 84.3%; area under the curve [AUC]: 0.85; 95% CI: 0.77-0.93; p < 0.001) and external validation cohort (sensitivity: 85.0%; specificity: 95.7%; AUC: 0.95; 95% CI: 0.89-1.02; p < 0.001). The prediction of levodopa responsiveness based on tyrDC gene abundance had good calibration and discrimination in cross-validation (C-index in training and test sets: 0.856 and 0.851, respectively) and external validation (C-index: 0.952). The microbial tyrDC gene abundance could serve as a potential biomarker of levodopa responsiveness. Novel strategies targeting the tyrDC gene may provide new approaches for personalized levodopa treatment.

Gastrointestinal Motility and Response to Levodopa in Parkinson's Disease: A Proof-of-Concept Study.

Simultaneous measurement of gastrointestinal transit time (GITT) and plasma levodopa concentration (PLC) is crucial to understanding the effect of dysfunctional motility on levodopa response in patients with Parkinson's disease (PwPD). The aim is to determine if altered segmental GITT correlates with clinical response and PLC variability in PwPD. Ten typical and 10 erratic responders ingested the SmartPill (SP) wireless motility capsule. Serial PLC and finger tapping, obtained every 30minutes for 3 hours after SP/levodopa ingestion, evaluated the correlation between GITT, clinical response, and PLC. Glucose breath testing assessed small intestinal bacterial overgrowth (SIBO). GITT was not significantly different in "typical" and "erratic" responders. SIBO was positive in half of the erratic and negative in most typical responders. SP is a feasible technology for assessing GITT in PwPD. A larger study may be able to significantly differentiate/correlate GITT in different segments of the GI tract with response to levodopa. © 2022 International Parkinson and Movement Disorder Society.