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A new levodopa‐carbidopa intestinal gel (LCIG) system featuring a higher levodopa/carbidopa (LD/CD) concentration and viscosity, LCIG‐HV, is being developed to reduce the intrajejunal volume of LD/CD that is administered as compared to the current commercial formulation, LCIG‐LV. This study characterizes the LCIG‐HV formulation and compares it to the LCIG‐LV formulation via dissolution testing and a clinical pharmacokinetic bioequivalence study. In vitro release profiles of LD/CD were determined using a USP Dissolution Apparatus 2 with 500 mL of phosphate buffer (pH 4.5) operating at 25 RPM. A single dose, open‐label study was conducted according to a two‐period, randomized, crossover design in 28 healthy subjects. The point estimate (PE) of the levodopa Cmax geometric mean for the LCIG‐HV formulation was 4% higher than that of the LCIG‐LV formulation. PEs of levodopa AUCt and AUCinf geometric means were comparable for both formulations. PEs of carbidopa Cmax, AUCt and AUCinf geometric means for the LCIG‐HV formulation were 3%‐5% higher than those of the LCIG‐LV formulation. For both formulations, the median Tmax for levodopa was 1.0 and 3.0 hours for carbidopa. The levodopa half‐life harmonic mean was 1.6 hour for both formulations. The carbidopa half‐life harmonic mean was 1.9 and 2.0 hour, respectively, for the LCIG‐HV and LCIG‐LV formulations. Cmax, AUCt and AUCinf of LD/CD carbidopa were comparable for both formulations. The current study demonstrates that the LCIG‐LV and LCIG‐HV formulations are clinically bioequivalent for LD/CD according to FDA guidance. However, the dissolution method was over discriminatory of formulation differences.

Background: Parkinson’s disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement therapy, mainly through actual dopamine and its original prodrug l-dopa (LD), faces many challenges such as poor blood brain barrier penetration and decreased response to therapy with time. Methods: The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and made by chemical means, and their bioavailability was studied in animals. Results: A promising ester prodrug for intranasal delivery has been developed. LD methyl ester is currently in Phase III clinical trials. A series of amide prodrugs were synthesized with better stability than ester prodrugs. Both amide and dimeric amide prodrugs offer enhanced blood brain barrier (BBB) penetration and better pharmacokinetics. Attaching LD to sugars has been used to exploit glucose transport mechanisms into the brain. Conclusions: Till now, no DA prodrug has reached the pharmaceutical market, nevertheless, the future of utilizing prodrugs for the treatment of PD seems to be bright. For instance, LD ester prodrugs have demonstrated an adequate intranasal delivery of LD, thus enabling the absorption of therapeutic agents to the brain. Most of the amide, cyclic, peptidyl or chemical delivery systems of DA prodrugs demonstrated enhanced pharmacokinetic properties.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction due to the loss of dopaminergic neurons, with an increasing global prevalence estimated to impact 20 million individuals by 2050. The current standard treatment, L-dopa, loses efficacy over time and often induces dyskinesia, highlighting the need for innovative therapeutic strategies with sustained efficacy and fewer side effects. In this study, we developed mesoporous silica nanoparticles (MSNs) templated with L-dopa amide derivatives, specifically designed as a drug-structure-directing agent (DSDA). This novel templating approach improves L-dopa loading capacity and enhances controlled-release performance. Two MSN formulations were selected for in vivo evaluation in a murine model of PD induced by unilateral injection of 6-hydroxydopamine (6-OHDA) in the striatum. In vitro studies demonstrated that L-dopa derivatives-loaded MSNs lead to a controlled and sustained release of L-dopa DSDA and in vivo assays corroborated this hypothesis. A single intraperitoneal dose of L-dopa-loaded MSNs was able to reduce the spontaneous rotational behavior observed in 6-OHDA damaged mice and outdid free-L-dopa. This novel strategy may represent a promising alternative to conventional treatment, reducing dose frequency and hence minimizing L-dopa side effects. The results herein emphasize the potential of MSN-based drug delivery systems for PD, providing a basis for future translational research of nanotechnology-based formulations for neurodegenerative disorders.

Melanin is a natural pigment present in almost all biological groups, and is composed of indolic polymers and characterized by black-brown colorization. Furthermore, it is one of the pigments produced by extremophiles including those living in the Antarctic desert, and is mainly involved in their protection from high UV radiation, desiccation, salinity and oxidation. Previous studies have shown that melanized species have an increased capability to survive high level of radiation compared with the non-melanized counterpart. Understanding the molecular composition of fungal melanin could help to understand this peculiar capability. Here, we aimed to characterize the melanin pigment extracted from the Antarctic black fungus Cryomyces antarcticus, which is a good test model for radioprotection researches, by studying its chemical properties and spectral data. Our results demonstrated that, in spite of having a specific type of melanin as the majority of fungi, the fungus possesses the ability to produce both 1,8-dihydroxynaphthalene (DHN) and l 3-4 dihydroxyphenylalanine (L-DOPA) melanins, opening interesting scenarios for the protection role against radiation. Researches on fungal melanin have a huge application in different fields, including radioprotection, bioremediation, and biomedical applications.Key Points• Isolation and characterization by multidisciplinary approaches of fungal melanins.• Discovery that pathways for producing DOPA and DHN are both active even in its extreme habitat.• Hypothesis supporting the possibility of using melanin pigment for radioprotection.

In this work, nano-levodopa-liposomes (L-dopa-Lip) suspension was prepared by rotary-evaporated film-ultrasonic method, and freeze-drying powders of L-dopa-Lip were also obtained to improve the stability. The products were characterized by TEM, DLS, and TG-DSC, and the phase-transition temperature (T m ) and encapsulation efficiency were calculated. The brain-targeting and in vitro release of the drug was also studied. The results showed that L-dopa-Lip were well-formed spherical vesicles, and the sizes were about 100 nm, and the encapsulation efficiency was higher than 90%. The drug release temperature of L-dopa-Lip was 68 °C, and the in vitro release property and mathematical model were also studied. The brain targeting of L-dopa-Lip in vivo was explored by injecting the gold nanoparticles (AuNPs) labeled L-dopa-Lip (AuNPs-L-dopa-Lip) through the tail vein. ICP-MS and TEM showed that L-dopa-Lip had brain targeting, suggesting the potential treatment of L-dopa-Lip on brain dysfunction. The results of this work might be helpful for designing drug-loaded liposomes for the treatment of central nervous system (CNS) diseases and monitoring their distributions in vivo.

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

It is crucial to accurately and rapidly monitor the levodopa (LD) concentration for accurate classification and treatment of dyskinesia in Parkinson’s disease. In this paper, 3D graphene foam (GF) with a highly conductive network is obtained by chemical vapor deposition. 3D GF serves as the substrate for hydrothermal in situ growth of tapered cross-linked ZnO nanowire bundle arrays (ZnO NWBAs), enabling the development of a highly sensitive detection platform for LD. The formation mechanism of a tapered cross-linked ZnO nanowire bundle arrays on 3D GF is put forward. The integration of 3D GF and ZnO NWBAs can accelerate the electron transfer rate and increase the contact area with biomolecules, resulting in high electrochemical properties. The electrode composed of ZnO NWBAs on 3D GF exhibits significant sensitivity (1.66 µA·µM −1 ·cm −2 ) for LD detection in the concentration range 0–60 µM. The electrode is able to rapidly and specifically determine LD in mixed AA or UA solution. The selectivity mechanism of the electrode is also explained by the bandgap model. Furthermore, the successful detection of LD in serum demonstrates the practicality of the electrode and its great potential for clinical application.

This study presents the effects of treating polystyrene (PS) cell culture plastic with oxidoreductase enzyme laccase and the catechol substrates caffeic acid (CA), L-DOPA, and dopamine on the culturing of normal human epidermal melanocytes (NHEMs) and human embryonal carcinoma cells (NTERA-2). The laccase–substrate treatment improved PS hydrophilicity and roughness, increasing NHEM and NTERA-2 adherence, proliferation, and NHEM melanogenesis to a level comparable with conventional plasma treatment. Cell adherence dynamics and proliferation were evaluated. The NHEM endpoint function was quantified by measuring melanin content. PS surfaces treated with laccase and its substrates demonstrated the forming of polymer-like structures. The surface texture roughness gradient and the peak curvature were higher on PS treated with a combination of laccase and substrates than laccase alone. The number of adherent NHEM and NTERA-2 was significantly higher than on the untreated surface. The proliferation of NHEM and NTERA-2 correspondingly increased on treated surfaces. NHEM melanin content was enhanced 6-10-fold on treated surfaces. In summary, laccase- and laccase–substrate-modified PS possess improved PS surface chemistry/hydrophilicity and altered roughness compared to untreated and plasma-treated surfaces, facilitating cellular adherence, subsequent proliferation, and exertion of the melanotic phenotype. The presented technology is easy to apply and creates a promising custom-made, substrate-based, cell-type-specific platform for both 2D and 3D cell culture.

l-3,4-dihydroxyphenylalanine (l-DOPA) is a medically relevant compound in Parkinson’s disease therapy. Several extraction methods of l-DOPA from beans, including velvet and faba beans, have been described in the literature. However, these methods require the use of strong acids, long extraction times, or complex downstream processing, which makes the extraction of l-DOPA expensive and energy-demanding, limiting its industrial application. In addition, the stability of l-DOPA during the extraction process is critical, further complicating the extraction of adequate amounts of this amino acid. This work is the first report on a simple, rapid, greener, and robust extraction method of l-DOPA. The developed method consists of a quick homogenization step followed by a double extraction with 0.2% v/v acetic acid for 20 min and was applied to faba bean at a ratio of 1:25 with respect to the extracting solvent. This study also investigated the stability of l-DOPA during extraction and thermal treatment. The proposed method demonstrated to be robust and extraordinarily efficient for numerous cultivars of faba bean, velvet bean, and food products containing faba beans.

A carbon paste electrode (CPE) was modified with graphite oxide (GrO) and β-cyclodextrin (CD) to obtain a sensor for simultaneous voltammetric determination of levodopa (LD), piroxicam (PRX), ofloxacin (OFX) and methocarbamol (MCB). The morphology, structure and electrochemical properties of the functionalized GrO were characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy, contact angle measurements and cyclic voltammetry. Under the optimal experimental conditions, the sensor is capable of detecting LD, PRX, OFX and MCB by square wave voltammetry (SWV) at working potentials of +0.40, +0.60, +1.03 and + 1.27 V (versus Ag/AgCl), respectively. Response is linear from 1.0 to 20 μM for LD, from 1.0 to 15 μM for PRX, from 1.0 to 20 μM for OFX, and from 1.0 to 50 μM for MCB. The respective limits of detection are 65, 105, 89 and 400 nM. The method was successfully applied to the simultaneous determination of LD, PRX, OFX and MCB in (spiked) real river water and synthetic urine samples, and the results were in agreement with those obtained using a spectrophotometric method, with recoveries close to 100%. Graphical abstract Schematic presentation of a novel electroanalytical method employing a carbon paste electrode modified with graphite oxide and β-cyclodextrin for the simultaneous determination of levodopa, piroxicam, ofloxacin and methocarbamol in urine and river water samples by square wave voltammetry.