Levodopa Research Articles

Ionic Liquid Facilitated Solvent‐Phase Polymerization of Ultrasmooth Coatings of Polycatecholamines

AbstractMussel‐inspired polycatecholamine coatings and films have proven to be versatile materials for surface modification. However, the progress of chemically modified coatings with tailored properties has been slow due to the lack of definitive evidence of their polymeric structure. Polycatecholamines form aggregates during polymerization, and their formation mechanism has been a subject of debate owing to their insolubility in traditional molecular solvents. Exploiting the capability of ionic liquids (ILs) to exhibit strong electrostatic interactions, herein, the first solution‐phase polymerization approach is reported to achieve polymerization of four catecholamines – dopamine (DA), norepinephrine (NE), L‐3,4‐dihydroxyphenylalanine (L‐DOPA), and adrenaline (AD). Kinetic control over the polymerization process in the solution phase enabled it to follow the process with 1H NMR spectroscopy, revealing the formation of structural features of resulting complex heterogeneous and soluble polymers. The polymers are both covalent and associative in nature. Solution phase polymerization prevented the formation of large aggregates in the solution, thus facilitating the formation of coatings that are ultra‐smooth and have root mean square roughness of the order of sub‐nm to nm scale.

A Sensitive Photoelectrochemical Sensor for Levodopa Detection Using Benzothiadiazole-Based Conjugated Microporous Polymer-Coated Graphene Heterostructures.

Since the 1960s, levodopa (LDA) has been the standard drug for treating of Parkinson's disease. In this study, a novel benzothiadiazole-based conjugated microporous polymer-coated graphene heterostructure (CMP-rGO) was synthesized and used to construct a sensitive photoelectrochemical (PEC) sensor capable of detecting LDA. Under optimal experimental conditions, the intensity of the photocurrent produced by the sensor was linear from 0.005 to 40 μM, and the limit of detection of the sensor was 0.0027 μM. The sensor showed good repeatability, stability, and selectivity for LDA detection. Finally, the constructed sensor was used to detect LDA in levodopa tablets, human serum samples, and urine samples and satisfactory results were obtained. Therefore, the PEC sensor provides a novel platform for the detection of LDA in real samples and broadens the applications of conjugated microporous polymers in PEC sensing.

Development and Validation of a Reversed-Phase HPLC Method with UV Detection for the Determination of L-Dopa in Vicia faba L. Broad Beans.

L-Dopa (LD), a substance used medically in the treatment of Parkinson's disease, is found in several natural products, such as Vicia faba L., also known as broad beans. Due to its low chemical stability, LD analysis in plant matrices requires an appropriate optimization of the chosen analytical method to obtain reliable results. This work proposes an HPLC-UV method, validated according to EURACHEM guidelines as regards linearity, limits of detection and quantification, precision, accuracy, and matrix effect. The LD extraction was studied by evaluating its aqueous stability over 3 months. The best chromatographic conditions were found by systematically testing several C18 stationary phases and acidic mobile phases. In addition, the assessment of the best storage treatment of Vicia faba L. broad beans able to preserve a high LD content was performed. The best LD determination conditions include sun-drying storage, extraction in HCl 0.1 M, chromatographic separation with a Discovery C18 column, 250 × 4.6 mm, 5 µm particle size, and 99% formic acid 0.2% v/v and 1% methanol as the mobile phase. The optimized method proposed here overcomes the problems linked to LD stability and separation, thus contributing to the improvement of its analytical determination.

Efficient Wet Adhesion through Mussel‐Inspired Proto‐Coacervates

AbstractAdhesion underwater is a major challenge. Mussel‐inspired complex coacervates functionalized with L‐3,4‐dihydroxyphenylalanine (L‐DOPA) are proposed for underwater adhesives through versatile chemistry of DOPA, however, simple, efficient, controllable, and nontoxic procedures to harness them are still under investigation. In this study, inspired from the mussel byssus formation process, coacervate adhesives are formed underwater by simple injection of an acidic proto‐coacervate of DOPA functionalized polyelectrolytes on underwater surfaces. The proto‐coacervate is initially an acidic liquid, it increased in pH due to water diffusion, resulting in coacervation driven by electrostatic interaction, without the requirement for pH adjustment or organic solvents. Additionally, the pH of liquid–liquid phase separation is tuned by substituting polyelectrolytes with different pKa, which satisfied different pH requirement in real life. The coacervate‐based adhesives on glass substrates exhibit strengths comparable to commercial glues when dry and to mussel glue when wet, showing high biocompatibility in human epidermis in vitro.

A DFT approach to the adsorption of the Levodopa anti-neurodegenerative drug on pristine and Al-doped boron nitride nanotubes as a drug delivery vehicle

The adsorption behavior of the anti-neurodegenerative drug Levodopa (LD) on pristine and aluminum-doped (Al-doped) boron nitride nanotubes (BNNTs) has been investigated in the current study using the density functional theory (DFT) approach at the B3LYP/6-31G** level of theory. The aim was to improve and expand boron nitride nanotubes drug carriers used in biomedical systems, i.e., drug delivery systems. The binding qualities of pure and doped BNNT complexes as adsorbents with LD were explored using the natural bond orbitals (NBO) analysis, density of state (DOS), electrical and structural characteristics, and atoms in molecules (AIM) properties. Due to doping heteroatoms in the adsorbent's molecular structure, the obtained data reveal a gradual shift in LD adsorption, with a significant rise in negative adsorption energy values. The electronic perturbation caused by doped atoms, particularly Al, improves boron nitride nanotube sensitivity to adsorbed Levodopa, and the electronic properties of the nanotubes are altered following Levodopa adsorption in the complex. As the frontier molecular orbital distributions were transferred from LD to BNNTs in the complex of BNNT–LD, it was also shown that LD drugs could be loaded on pristine and Al-doped BNNTs while remaining safe from interactions with other substances. Furthermore, AIM analysis based investigations revealed that O–Al interaction in LD adsorbed on Al-doped boron nitride nanotube and O–N interaction in the BNNT–LD complex are partially covalent. Finally, the findings showed that pristine and Al-doped BNNT could be used in drug delivery processes by controlling the loaded LD contribution to future interactions.

Development of N,N-Dimethylglycine-Amantadine for Adjunctive Dopaminergic Application: Synthesis, Structure and Biological Activity

N-methyl-D-aspartate (NMDA) receptor blockade can improve L-DOPA (l-3,4-dihydroxyphenylalanine)-induced dyskinesias in Parkinson’s disease (PD) patients. Amantadine is a well-tolerated and effective antiparkinsonian agent, recently found to possess NMDA antagonistic properties. Oxidative damage may contribute to dopaminergic (DAergic) neurodegeneration in the substantia nigra of patients with PD. N,N-dimethylglycine (DMG) (also known as vitamin B15 or pangamic acid) acts as an antioxidant, extending the lifespan of animal cells through protection from oxidation. In this study, we synthesized and tested in vivo the newly obtained compound N,N-dimethylglycine-amantadine (DMG-Am) for antiparkinsonian activity. MPTP (1-methyl-4–phenyl-1, 2, 3, 6-tetrahydropyridine) is a widely used neurotoxin to induce an experimental model which mimics Parkinson disease-like symptoms. The neuroprotective capacity of the new amantadine derivative DMG-Am was evaluated by its potential to ameliorate the neuromuscular coordination and behavioral changes worsened by the toxin. Our experimental results showed that DMG-Am applied for 12 consecutive days, 5 days simultaneously and 7 days after MPTP, restored motor and memory performance of the animals to the control level, indication of beneficial protective effect of this compound. In summary, our results reveal the potential of newly synthesized DMG-Am as promising antiparkinsonian agent.

Application of net analyte signal and principal component regression for rapid simultaneous determination of Levodopa and carbidopa in commercial pharmaceutical formulation and breast (human) milk sample using spectrophotometric method

In this study, a UV–vis spectrophotometric method coupled with net analyte signal (NAS) and principal component regression (PCR) as multivariate calibration methods were used for the simultaneous determination of levodopa (LEV) and carbidopa (CBD) in prepared mixtures, pharmaceutical formulation, and breast milk sample. The mean recovery of the NAS model was 98.10% and 99.60% for LEV and CBD, respectively. Also, the relative standard deviation (RSD%) values were found to be lower than 5.5% and 4% for LEV and CBD, respectively. On the other hand, the mean recovery of LEV and CBD related to the PCR method was obtained at 96.86% and 92.43%, respectively. K-Fold cross-validation was used to estimate the number of components, which was 7 and 3 with a mean square error prediction (MSEP) of 1.50 and 7.14 for LEV and CBD, respectively. The results revealed that the NAS model was better than the PCR model. Additionally, the proposed NAS-based calibration method was successfully developed for the simultaneous analyses of LEV and CBD in a commercial tablet and breast milk.

Sea grapes powder with the addition of tempe rich in collagen: An anti-aging functional food.

Background: This study aimed to determine the potential anti-aging effects of sea grapes and tempe (fermented soybeans) collagen particle size, by measuring the activities of anti-glycation, antioxidant, and tyrosinase inhibitors. Methods: Collagen was isolated from freeze-dried sea grapes and tempe powder and treated with different NaOH concentrations (0.10 M; 0.20 M; 0.30 M), and CH 3COOH 1 M solution, separately. The collagen particle size was adjusted by stirring at 1000 rpm for 5 and 10 hours. 2,2-diphenyl-1-picrylhydrazyl (DPPH) was used to measure the antioxidant activity, and L-tyrosine and L-DOPA (l-3,4-dihydroxyphenylalanine) was used as a marker of tyrosine inhibition. Results: The collagen treated with 0.10 M NaOH produced the highest collagen yield (11.65%), and the largest particle size (2455 nm). Additionally, this collagen, when treated for 5 hours, exhibited 24.70% antioxidant activity, 62.60% anti-glycation, 8.97% L-tyrosine, and 26.77% L-Dopa inhibition activities. Meanwhile, the collagen treated for 10 hours had a 9.98% antioxidant activity, 41.48% anti-glycation, 7.89% L-tyrosine, and 2.67% L-Dopa inhibition activity. Conclusion: Sea grapes and tempe collagen powder treated with 0.10 M NaOH and stirred for 5 hours, possess the best potential anti-aging properties as a functional food.

A dual dopaminergic therapy with L-3,4-dihydroxyphenylalanine and chlorpromazine for the treatment of blepharospasm, a focal dystonia: Possible implications for striosomal D1 signaling

Impairment of balanced activity between dopamine D1 and D2 receptor functions in the striatum, particularly in striatal functional subdivisions (i.e., striosome and matrix compartments), has been proposed to underlie dystonia genesis. This study was undertaken to examine the therapeutic effect of dual dopaminergic modulation with L-3,4-dihydroxyphenylalanine (L-DOPA) and chlorpromazine (CPZ) in patients with blepharospasm, a focal dystonia. For this purpose, Dopacol tablets™ (L-DOPA 50 mg plus carbidopa 5 mg) and Wintermin™ (CPZ phenolphthalinate 180 mg/g) were used. Clinical evaluations were performed before and after an 8-week drug treatment interval using the Visual Analog Scale (VAS), Blepharospasm Disability Index (BSDI), modified VAS (mVAS), and Jankovic Rating Scale (JRS). The data were analyzed using non-parametric statistics. Results showed that in patients (n = 7) with blepharospasm, dystonia symptoms were significantly alleviated by the administration of both Dopacol tablets™ (one tablet × 3/day) and CPZ (5 mg × 3/day), as determined using the VAS, BSDI, mVAS, and JRS. In contrast, there was no improvement of dystonia symptoms in patients (n = 7) who ingested Dopacol tablets™ (one tablet × 3/day) alone, nor in those (n = 7) who ingested CPZ (5 mg × 3/day) alone. Thus, dual pharmacotherapy with L-DOPA and CPZ can exert a therapeutic effect on blepharospasm, suggesting that dystonia symptoms can be attenuated through dopaminergic modulation with inducing an increase in striatal D1-signals. Since dopamine D1 receptors are heavily enriched in the striosome compartment in the “human” striatum, our results also suggest that striosomal loss of D1-signaling may be important in the pathogenesis of dystonia.

Central Aortic Pressure and Arterial Stiffness in Parkinson's Disease: A Comparative Study.

Background Cardiovascular autonomic dysfunction, which leads to hemodynamic disorders, is commonly observed in patients with Parkinson's disease (PD). Central aortic pressure (CAP) is the systolic blood pressure (SBP) at the root of the aorta. In young people, CAP is lower than peripheral arterial blood pressure. In older people, the difference between CAP and peripheral arterial blood pressure decreases depending on the extent of arterial stiffness (AS). In patients with AS, CAP increases. CAP is thus regarded as an indicator of AS. Objective To compare CAP and other hemodynamic parameters for AS between patients with Parkinson's disease and control group. We also aimed to evaluate changes in these hemodynamic parameters after the levodopa (LD) intake. Methods We included 82 patients with PD and 76 healthy controls. Age, sex, disease duration, disease subtype, Hoehn–Yahr stage (H&Y), and nonmotor symptoms (NMS) were documented. TensioMed Software v.3.0.0.1 was used to measure CAP, peripheral arterial blood pressure, pulse pressure (PP), heart rate (HR), mean arterial pressure (MAP), augmentation index (AI), pulse wave velocity, and ejection time. All patients were being treated with LD, and measurements were performed 1 h before and 1 h after LD intake. Results Baseline peripheral arterial blood pressure and CAP values were significantly higher in the PD group than in the control group (p < 0.001 and p=0.02, respectively). Most cardiac hemodynamic parameters, including peripheral arterial blood pressure and CAP, decreased significantly (p < 0.02 and p < 0.001, respectively) after LD intake in the PD group. Disease subtype, duration, and severity did not affect any of the hemodynamic parameters. When NMS were evaluated, patients with psychosis and dementia showed higher baseline parameters. Conclusion Loss of postganglionic noradrenergic innervation is well-known with PD. Several cardiac hemodynamic parameters were affected, suggesting cardiac autonomic dysfunction in these patients. The data obtained were independent of disease severity, duration, and subtype. After LD intake, most of these parameters decreased, which might have a positive effect on the vascular burden.

Poly (Bromocresol purple) incorporated pencil graphite electrode for concurrent determination of serotonin and levodopa in presence of L-Tryptophan: A voltammetric study

In the present investigation, the new electrochemical sensor was established based on the electropolymerisation of Bromocresol purple on pencil graphite electrode for the sensitive detection of serotonin(5-HT) and Levodopa(LD) in assistance with L- Tryptophan(TRP). The morphological characterisation of developed working electrode was done by Scanning Electron Microscope(SEM). The modified sensor presents admirable electrocatalytic performance towards specific and selective examination of 5-HT, LD and TRP at 0.2 M Phosphate buffer solution of physiological pH having the speed rate of 50 mV/s using cyclic voltammetric(CV) and differential pulse voltammetric(DPV) methods. The distinct experimental conditions like impact of supporting electrolyte, dissimilar concentration and varied sweep rates were optimised to accomplish a better peak current. The designed sensor effectually lowers the detection limits of 5-HT (0.49 μM) and LD (2.3 μM) and it is easy to fabricate, disposable, highly stable and applicable to practical analysis of bioactive molecules.

Effect of glycine transporter 1 inhibition with bitopertin on parkinsonism and L-DOPA induced dyskinesia in the 6-OHDA-lesioned rat

Dyskinesia remains an unmet need in Parkinson's disease (PD). We have previously demonstrated that glycine transporter 1 (GlyT1) inhibition with ALX-5407 reduces dyskinesia and slightly improves parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine the effect of bitopertin, a clinically-tested GlyT1 inhibitor, on parkinsonism and dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. To do so, we assessed the effect of bitopertin on parkinsonism as monotherapy and as adjunct to a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA). We then assessed the efficacy of bitopertin on dyskinesia in the context of acute challenge and chronic administration studies. Lastly, we evaluated whether de novo treatment with bitopertin, started concurrently with L-DOPA, would diminish the development of dyskinesia. We discovered that bitopertin (0.3 mg/kg), when administered alone, reduced the severity of parkinsonism by 35% (P < 0.01). As adjunct to a low dose of L-DOPA, bitopertin (3 mg/kg) enhanced the anti-parkinsonian effect of L-DOPA by 36% (P < 0.05). Moreover, the acute addition of bitopertin (0.03 mg/kg) to L-DOPA reduced dyskinesia by 27% (P < 0.001), and there was no tolerance to the anti-dyskinetic benefit after 4 weeks of daily administration. Lastly, bitopertin (0.03 mg/kg) started concurrently with L-DOPA, also attenuated the development of dyskinesia, by 33% (P < 0.01), when compared to L-DOPA alone. Our results suggest that GlyT1 inhibition may simultaneously reduce parkinsonism and L-DOPA-induced dyskinesia and represents a novel approach to treat, possibly prevent, motor complications in PD.

Embelin and levodopa combination therapy for improved Parkinson's disease treatment.

Parkinson’s disease (PD), a progressive neurodegenerative disorder, affects dopaminergic neurons. Oxidative stress and gut damage play critical roles in PD pathogenesis. Inhibition of oxidative stress and gut damage can prevent neuronal death and delay PD progression. The objective of this study was to evaluate the therapeutic effect of embelin or the combination with levodopa (LD) in a rotenone-induced PD mouse model. At the end of experimentation, the mice were sacrificed and the midbrain was used to evaluate various biochemical parameters, such as nitric oxide, peroxynitrite, urea, and lipid peroxidation. In the substantia nigra (midbrain), tyrosine hydroxylase (TH) expression was examined by immunohistochemistry, and Nurr1 expression was evaluated by western blotting. Gut histopathology was evaluated on tissue sections stained with hematoxylin and eosin. In silico molecular docking studies of embelin and α-synuclein (α-syn) fibrils were also performed. Embelin alone or in combination with LD ameliorated oxidative stress and gut damage. TH and Nurr1 protein levels were also significantly restored. Docking studies confirmed the affinity of embelin toward α-syn. Taken together, embelin could be a promising drug for the treatment of PD, especially when combined with LD.

Evaluation of the effects of the mGlu2/3 antagonist LY341495 on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.

We have previously demonstrated that the metabotropic glutamate 2 and 3 (mGlu2/3) antagonist LY341495 reverses the anti-dyskinetic and anti-psychotic benefits conferred by mGlu2 activation and serotonin 2A (5-HT2A) antagonism. Here, we hypothesised that a higher dose of LY341495, associated with a higher antagonistic effect at mGlu3 receptors, would result in a reduction of the reversal of mGlu2 activation and 5-HT2A blockade on dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. After induction of parkinsonism with MPTP, marmosets entered 3 streams of experiments, in which the following treatments were administered, in combination with l-3,4-dihydroxyphenylalanine (L-DOPA), after which dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were rated: 1. vehicle/vehicle, LY354740 (mGlu2/3 orthosteric agonist)/vehicle, LY354740/LY341495 1mg/kg and LY354740/LY341495 3mg/kg; 2. vehicle/vehicle, LY487379 (mGlu2 positive allosteric modulator)/vehicle, LY487379/LY341495 1mg/kg and LY487379/LY341495 3mg/kg; 3. vehicle/vehicle, EMD-281,014 (5-HT2A antagonist)/vehicle, EMD-281,014/LY341495 1mg/kg and EMD-281,014/LY341495 3mg/kg. Each of LY354740, LY487379 and EMD-281,014 reduced the severity of L-DOPA-induced dyskinesia, by 55%, 39% and 40%, respectively (all p < 0.001), as well as the severity of PLBs, by 48%, 36% and 41%, respectively (all p < 0.001). Adding LY341495 1 and 3mg/kg to each of LY354740, LY487379 and EMD-281,014 resulted in a dose-dependent reversal of their anti-dyskinetic and anti-psychotic actions. No effect on the anti-parkinsonian action of L-DOPA was noted with any treatment combination. These results suggest that an antagonistic effect at mGlu3 receptors may not be sufficient to overcome the deleterious effect of mGlu2 blockade on dyskinesia in PD. It remains to be seen whether similar effects would have been obtained with a selective mGlu3 antagonist.

The simple and rapid quantification method for L-3,4-dihydroxyphenylalanine (L-DOPA) from plant sprout using liquid chromatography-mass spectrometry.

L-3,4-dihydroxyphenylalanine (L-DOPA) is one of the important secondary metabolites of plants and has been used for various purposes, such as in clinical treatment for Parkinson's disease and dopamine-responsive dystonia. In plants, L-DOPA is a precursor of many alkaloids, catecholamines, and melanin; the L-DOPA synthesis pathway is similar to that in mammals. L-DOPA acts as an allelochemical, has an important role in several biological processes, such as stress response and metabolism, in plants. L-DOPA is widely used in the clinical treatment as well as a dietary supplement or psychotropic drug, understanding of biosynthesis of L-DOPA in plant could lead to a stable supply of L-DOPA. This paper describes an improved method for simple and rapid quantification of L-DOPA content using liquid chromatography-tandem mass spectrometry. The standard quantitative methods for L-DOPA require multiple purification steps or relatively large amounts of plant material. In our improved method, quantification of L-DOPA was possible with extract of one-two pieces of cotyledon without any partitioning or column for purification. The endogenous L-DOPA (approximately 4,000 µg g-1 FW (fresh weight)) could be detected from the one pieces of cotyledon of the faba bean sprout using this method. This method was also effective for samples with low endogenous amounts of L-DOPA such as broccoli, Japanese white radish, pea, and red cabbage sprouts. Therefore, this improved method will allow to measurement of L-DOPA content easily and accurately from a small amount of plant tissue and contribute to understanding biosynthesis, catabolism, and transport of L-DOPA.

Development and characterization of gastro-floating sustained-release capsule with improved bioavailability of levodopa.

In this study, a new gastro-floating sustained-release capsule (GFC) with levodopa (LD) and benserazide hydrochloride (BH) was successfully developed. GFCs were prepared by filling the LD and BH granules into hard capsules and coated with cellulose acetate (CA) solution as a controlled-release layer. The effects of formulation factors on the release of GFCs were conducted. The AUC0~24 (µgh/mL) of LD were 69.31 ± 3.61 (μgh/mL) and 28.87 ± 2.58 (μgh/mL) and the Cmax were 7.84 ± 0.34 (μg/mL) and 9.21 ± 1.04 (μg/mL) in the GFCs and commercial tablets respectively. The relative bioavailability of LD was 267.55 ± 34.54%. Compared with commercial tablets, the pharmacokinetic study indicated that the developed GFCs provided a better sustained-release effect and higher bioavailability than commercial tablets.

P.022 Prognosis in arm and leg tremor onset Parkinson Disease

Background: There is no biological marker of progression in early Parkinson Disease (PD). Upper limb (UL) tremor is the most common motor symptom at onset. The significance of lower limb (LL) tremor remains unknown. We report on longitudinally followed autopsy-verified PD tremor onset cases. Methods: A chart review of longitudinally followed autopsy-verified PD cases was performed. Age and mode of onset were recorded at initial evaluation. Prognosis was measured by change in Hoehn and Yahr scale while on levodopa (LD). Results: Forty-nine patients were included. Thirty-eight cases had upper limb (UL), four lower limb (LL), and seven upper and lower limb (ULL) onset tremor. UL had 86.8% response to LD, LL 50% and ULL 85.7%. Sub-analysis of UL responders found 20% mild improvement, 53.3% moderate and 26.7% marked. ULL had moderate response in 83.3% and marked in 16.7%. LL responders only had mild improvement with LD. Conclusions: Tremor onset is most common in UL, followed by ULL and then LL. LL onset tremor cases have an inferior response to LD when compared to UL and ULL cases. We plan for further pathophysiologic studies to investigate LL onset in PD.

Biomimetic synthesis of L-DOPA inspired by tyrosine hydroxylase

L-3,4-dihydroxyphenylalanine (L-DOPA) is in high demand as the cornerstone for treatment of Parkinson's disease. The current production of L-DOPA is associated with poor productivity and long production period. Biomimetic system inspired from tyrosine hydroxylase was developed to achieve the production of L-DOPA from tyrosine with high reactivity, efficiency, and specificity. The biomimetic system owned close resemblance of component and structure in comparison with tyrosine hydroxylase, consisting of tyrosine as substrate, a redox complex of Fe2+ and EDTA as the catalyst to simulate the active center of the natural tyrosine hydroxylase, hydrogen peroxide as the oxidant, and ascorbic acid as the reductant. HPLC, HPLC-MS/MS, 1H NMR, and specific rotation identified L-DOPA was generated. The system showed high catalytic activity and regioselectivity for hydroxylation of tyrosine as equal to tyrosine hydroxylase. FeIVO2+ was formed as the major active species, and NIH shift was observed. EDTA accelerated the reaction by reducing the redox potential of Fe3+/Fe2+ couple. Density functional theory calculation suggested formation of FeIVO2+ was more thermodynamically favorable. The biomimetic system shared analogous catalytic mechanism with TyrH. Process parameters was optimized for maximum production of L-DOPA, namely 6.4 mM tyrosine, 1.6 mM Fe2+, 1.92 mM EDTA, 150 mM H2O2, and 35 mM ascorbic acid in 0.2 M glycine-HCl buffer at pH 4.5 and 60 °C. The yield, titer, and productivity were obtained as 52.01%, 3.22 mM, and 48,210.68 mg L−1 h−1, respectively. The proposed method exhibited an amazing productivity, might provide a promising strategy to industrialize L-DOPA production.

Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease: Observations and Dilemmas after 10 Years of Real-Life Experience.

Advanced Parkinson’s disease (APD) cannot be treated efficiently using the classical medications however, in recent decades invasive therapeutical methods were implemented and confirmed as effective. One of these methods makes it possible to continue the levodopa (LD) supplementation as a gel administered directly into the upper intestine. However, there are a number of unanswered questions regarding this method. Therefore, we retrospectively analyzed a 10-year period of selected patients that were treated with levodopa/carbidopa intestinal gel (LCIG). We included all APD patients with motor fluctuations and dyskinesia at presentation. LCIG treatment was started in 150 patients: on average these patients received LD for 10.6 ± 4.4 years with a frequency of 5.2 ± 1.0/day until the introduction of LCIG. The estimated and the real LCIG dose differed significantly (mean: 1309 ± 321 mg vs. 1877 ± 769 mg). The mean duration of LCIG administration was 19.8 ± 3.6 h, but in a number of 62 patients we had to administer it for 24 h, to maximize the therapeutic benefit. A carefully and individually adjusted LCIG treatment improves the quality of life of APD patients, but questions remain unresolved even after treating a large number of patients. It is important to share the ideas and observations based on the real-life experience related to the optimal timing, the appropriate dose and duration of administration of the LCIG.

Ru‐Catalyzed C−H Hydroxylation of Tyrosine‐Containing Di‐ and Tripeptides toward the Assembly of L‐DOPA Derivatives

AbstractThe development of catalytic tools for the late‐stage modification of amino acids within a peptide framework is a challenging task of capital importance. Herein, we report a Ru‐catalyzed C(sp2)−H hydroxylation of a collection of Tyr‐containing di‐ and tripeptides featuring the use of a carbamate as a removable directing group and PhI(OCOCF3)2 (PIFA) as oxidant. This air‐compatible tagging technique is reliable, scalable and provides access to L‐DOPA (L‐3,4‐dihydroxyphenylalanine) peptidomimetics in a racemization‐free fashion. Density Functional Theory calculations support a Ru(II)/Ru(IV) catalytic cycle.magnified image