Tricompartmental Microcarriers with Controlled Release for Efficient Management of Parkinson's Disease.

Parkinson's is a progressive neurodegenerative disease of the nervous system. It has no cure, but its symptoms can be managed by supplying dopamine artificially to the brain.This work aims to engineer tricompartmental polymeric microcarriers by electrohydrodynamic cojetting technique to encapsulate three PD (Parkinson's disease) drugs incorporated with high encapsulation efficiency (∼100%) in a single carrier at a fixed drug ratio of 4:1:8 (Levodopa (LD): Carbidopa(CD): Entacapone (ENT)). Upon oral administration, the drug ratio needs to be maintained during subsequent release from microparticles to enhance the bioavailability of primary drug LD. This presents a notable challenge, as the three drugs vary in their aqueous solubility (LD > CD > ENT). The equilibrium of therapeutic release was achieved using a combination of FDA-approved polymers (PLA, PLGA, PCL, and PEG) and the disc shape of particles. In vitro studies demonstrated the simultaneous release of all the three therapeutics in a sustained and controlled manner. Additionally, pharmacodynamics and pharmacokinetics studies in Parkinson's disease rats induced by rotenone showed a remarkable improvement in PD conditions for the microparticles-fed rats, thereby showing a great promise toward efficient management of PD.

Effectiveness of Continuous Dopaminergic Therapies in Parkinson's Disease: A Review of L-DOPA Pharmacokinetics/Pharmacodynamics.

Background: Parkinson's disease (PD) is characterized by striatal dopamine deficiency. Since dopamine cannot cross the digestive and blood-brain barriers, its precursor, levodopa (L-DOPA), remains the mainstay of treatment. However, the significant pharmacokinetic (Pk) and pharmacodynamic (Pd) limitations of L-DOPA, combined with the severity of PD, may trigger motor and non-motor complications, for which continuous dopaminergic delivery therapies have been developed. Objective: The aim of this study was to review the literature on the Pk/Pd limitations of L-DOPA and how current treatments of continuous dopaminergic administration ameliorate these problems, in order to identify the need for new therapeutic avenues. Methods: A comprehensive literature search was carried out using PubMed and 75 articles were initially extracted. Following independent screening by two reviewers and consideration of eligibility, 10 articles were chosen for further analysis. Information concerning the Pk/Pd of L-DOPA was classified for each article. Results: Pk/Pd problems notably include: (i) restricted digestive and cerebral absorption; (ii) unnecessary peripheral distribution; (iii) short half-life; (iv) age- and PD-induced decline of central aromatic L-amino acid decarboxylase; (v) misdistribution in many cells; and (vii) pulsatile stimulation of dopaminergic receptors. Current treatments only slightly ameliorate some of these problems. Conclusions: Many Pk/Pd constraints are not resolved by existing continuous dopaminergic delivery therapies. This highlights the significant gap between these treatments and the ideal of continuous dopaminergic stimulation.

Impact of Physical Exercise on Levodopa Therapy Across Parkinson's Disease Stages.

Background: Levodopa is the gold standard of treatment in Parkinson's disease (PD). Its clinical effect changes as the disease progresses. Wearing off is a frequent first manifestation of motor fluctuations. Some patients with advanced PD report faster wearing off after physical exercise. Objective: The aim was to assess if pharmacokinetics of levodopa is influenced by physical exercise in patients with different disease advancement. Methods: 22 patients with PD (12 untreated with levodopa and 10 with motor fluctuations) and 7 healthy controls (HC) were included. Plasma samples were collected at 9 fixed timepoints following administration of levodopa/benserazide 200/50 mg for two days: rest day and standardized physical exercise day. Clinical assessment with Unified Parkinson Disease Rating Scale part III (UPDRS III) was performed in fixed timepoints. Liquid chromatography-tandem mass spectrometry was used to measure levodopa concentrations. Results: No differences between the HC, levodopa naïve and advanced PD groups were observed regarding selected pharmacokinetic parameters. In advanced PD and HC no differences in pharmacokinetic parameters of levodopa with and without effort were observed. In levodopa naïve PD group higher mean residence time after rest than after exercise (168.9±48.3 min vs. 145.5±50.8 min; p = 0.026) was observed. In advanced PD group higher UPDRS III score (14.45±5.5 versus 20.9±6.1 points, p = 0.04) was observed after exercise. Conclusions: The deterioration of motor status of advanced PD patients after physical effort is not reflected by changes in pharmacokinetics but rather mediated by central mechanisms.

[Inhaled levodopa: from evidence to experience]. / Levodopa inhalada: de la evidencia a la experiencia.

Most patients with Parkinson's disease experience motor fluctuations or 'off' periods, which impact on their daily activities, increase their disability and diminish their quality of life. They suffer from these fluctuations despite multiple adjustments to the schedules, doses and intake of medication. In this context, on-demand or rescue treatments are necessary to attempt to improve 'off' periods, with drugs that have the pharmacokinetic advantage of a much faster onset of action because their routes of administration are not oral. There are currently three on-demand therapies for the treatment of fluctuations: subcutaneous apomorphine, inhaled levodopa and sublingual apomorphine. Of the three alternatives, subcutaneous apomorphine generally has the fastest onset of action, sublingual apomorphine provides the longest clinical effect, and inhaled levodopa has the most favourable side effect profile. Each of these drugs has its own characteristics: the time before onset of action, the duration of action and different side effect profiles. The choice for each patient will depend on their individual needs and circumstances. To mark the first year of the introduction of inhaled levodopa, we review these therapies, focusing on the experience with this new dosage form of levodopa.

TITLE: Levodopa inhalada: de la evidencia a la experiencia.La mayoría de los pacientes con enfermedad de Parkinson sufren fluctuaciones motoras o períodos off, que impactan en sus actividades cotidianas, aumentan su discapacidad y empeoran su calidad de vida. A pesar de realizar múltiples ajustes en los horarios, en las dosis y en las tomas de medicación, no se consigue que estén libres de estas fluctuaciones. Es en este contexto en el que son necesarios los tratamientos a demanda o de rescate para tratar de mejorar los períodos off, con fármacos que tienen la ventaja farmacocinética de un inicio de acción mucho más rápido debido a que sus vías de administración no son orales. En la actualidad existen tres terapias a demanda para el tratamiento de las fluctuaciones: apomorfina subcutánea, levodopa inhalada y apomorfina sublingual. En general, la apomorfina subcutánea tiene un inicio de efecto más rápido, la apomorfina sublingual ofrece el efecto clínico más prolongado y la levodopa inhalada tiene el perfil de efectos secundarios más favorable entre las tres opciones. Cada uno de estos medicamentos tiene características únicas: tiempo de inicio, duración de acción y diferentes perfiles de efectos secundarios. La elección para cada paciente dependerá de sus necesidades y circunstancias individuales. Aprovechando el primer año de la introducción de la levodopa inhalada, revisamos estas terapias, centrándonos en la experiencia acumulada con esta nueva presentación galénica de levodopa.

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

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients.

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues.

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson's disease.

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.

Pharmacokinetics and multi-peak phenomenon analysis of novel anti-Parkinson's drug FLZ after multi-dose in cynomolgus monkeys.

The novel anti-Parkinson disease drug, FLZ, had a complicated drug absorption and metabolise process reported in single-dose studies. A multi-peak absorption peak phenomenon was found.This study focused on the multi-dose pharmacokinetics (PK) characteristics of FLZ, T1, and T2 in cynomolgus monkeys and raised discussion on its multi-peak absorption situation. Different doses of FLZ ranging from 75 to 300 mg/kg were administered orally to 16 cynomolgus monkeys. The whole treatment period lasted for 42 days with FLZ once a day.The primary metabolites of FLZ were Target1 (T1) and Target2 (T2), which had plasma exposure (calculated as AUC0-24, day 42) approximately 2 and 10 times higher than the parent drug. The proportion of plasma exposure increase was lower than the proportion of dose increase in FLZ, T1, and T2.Gender influenced its exposure (AUC0-24) with approximately 3-fold higher in males than females. There was no significant accumulation of T1 and T2. Enterohepatic Circulation (EHC) and gastrointestinal (GI) tract absorption may be involved in the mechanism of multi-peak characteristics.

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.

Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC-HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel.

Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug-related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open-label, 2-period crossover study in 20 healthy participants. Participants received either 24-h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC-MSn was performed using high-resolution mass spectrometry to identify drug-related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3-OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug-related compounds with the exception of the administered foslevodopa. 3-OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC-MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG.

Transdermal Delivery of Pramipexole Using Microneedle Technology for the Potential Treatment of Parkinson's Disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disease primarily impacting neurons responsible for dopamine production within the brain. Pramipexole (PRA) is a dopamine agonist that is currently available in tablet form. However, individuals with PD commonly encounter difficulties with swallowing and gastrointestinal motility, making oral formulations less preferable. Microneedle (MN) patches represent innovative transdermal drug delivery devices capable of enhancing skin permeability through the creation of microconduits on the surface of the skin. MNs effectively reduce the barrier function of skin and facilitate the permeation of drugs. The work described here focuses on the development of polymeric MN systems designed to enhance the transdermal delivery of PRA. PRA was formulated into both dissolving MNs (DMNs) and directly compressed tablets (DCTs) to be used in conjunction with hydrogel-forming MNs (HFMNs). In vivo investigations using a Sprague-Dawley rat model examined, for the first time, if it was beneficial to prolong the application of DMNs and HFMNs beyond 24 h. Half of the patches in the MN cohorts were left in place for 24 h, whereas the other half remained in place for 5 days. Throughout the entire 5 day study, PRA plasma levels were monitored for all cohorts. This study confirmed the successful delivery of PRA from DMNs (Cmax = 511.00 ± 277.24 ng/mL, Tmax = 4 h) and HFMNs (Cmax = 328.30 ± 98.04 ng/mL, Tmax = 24 h). Notably, both types of MNs achieved sustained PRA plasma levels over a 5 day period. In contrast, following oral administration, PRA remained detectable in plasma for only 48 h, achieving a Cmax of 159.32 ± 113.43 ng/mL at 2 h. The HFMN that remained in place for 5 days demonstrated the most promising performance among all investigated formulations. Although in the early stages of development, the findings reported here offer a hopeful alternative to orally administered PRA. The sustained plasma profile observed here has the potential to reduce the frequency of PRA administration, potentially enhancing patient compliance and ultimately improving their quality of life. This work provides substantial evidence advocating the development of polymeric MN-mediated drug delivery systems to include sustained plasma levels of hydrophilic pharmaceuticals.

A neoteric annotation on the advances in combination therapy for Parkinson's disease: nanocarrier-based combination approach and future anticipation. Part II: nanocarrier design and development in focus.

INTRODUCTION: The current treatment modalities available for Parkinson's disease (PD) prove inadequate due to the inherent constraints in effectively transporting bioactive compounds across the blood-brain barrier. The utilization of synergistic combinations of multiple drugs in conjunction with advanced nanotechnology, emerges as a promising avenue for the treatment of PD, offering potential breakthroughs in treatment efficacy, targeted therapy, and personalized medicine. AREAS COVERED: This review provides a comprehensive analysis of the efficacy of multifactorial interventions for PD, simultaneously addressing the primary challenges of conventional therapies and highlighting how advanced technologies can help overcome these limitations. Part II focuses on the effectiveness of nanotechnology for improving pharmacokinetics of conventional therapies, through the synergistic use of dual or multiple therapeutic agents into a single nanoformulation. Significant emphasis is laid on the advancements toward innovative integrations, such as CRISPR/Cas9 with neuroprotective agents and stem cells, all effectively synergized with nanocarriers. EXPERT OPINION: By using drug combinations, we can leverage their combined effects to enhance treatment efficacy and mitigate side effects through lower dosages. This article is meant to give nanocarrier-mediated co-delivery of drugs and the strategic incorporation of CRISPR/Cas9, either as an independent intervention or synergized with a neuroprotective agent.

Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease.

KW-6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW-6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration-time data from healthy subjects and patients with PD who were administered KW-6356. Using these data, we developed a population PK model by sequentially fitting the KW-6356 parameters followed by the M6 parameters. A first-order absorption with a 1-compartment model for KW-6356 and a 1-compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first-order absorption rate constant, baseline serum albumin level on apparent clearance of KW-6356, and baseline body weight on apparent volume of distribution of KW-6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW-6356 or M6 exposure.

Opicapone Pharmacokinetics and Effects on Catechol- O -Methyltransferase Activity and Levodopa Pharmacokinetics in Patients With Parkinson Disease Receiving Carbidopa/Levodopa.

OBJECTIVES: Levodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa (3-OMD). Catechol- O -methyltransferase inhibition can improve treatment outcomes by decreasing variability in circulating LD concentrations. Opicapone is a once-daily COMT inhibitor approved in the US adjunctive to carbidopa (CD)/LD in patients with Parkinson disease experiencing "OFF" episodes. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of once-daily opicapone 50 mg adjunctive to CD/LD in patients with stable Parkinson disease. METHODS: Once-daily opicapone 50 mg was administered the evenings of days 1 to 14. Participants were randomized to receive CD/LD (25/100 mg) every 3 or 4 hours (Q3H or Q4H). Participants received Q3H or Q4H CD/LD on days 1, 2, and 15 and their usual CD/LD regimen on other days. Serial blood samples were collected to determine plasma opicapone, LD, and 3-OMD concentrations and erythrocyte soluble COMT (S-COMT) activity. The effects of opicapone on S-COMT, LD, and 3-OMD were assessed. Mean (SD) values are presented. RESULTS: Sixteen participants were enrolled. At steady-state (day 14), opicapone Cmax (peak plasma concentration) and AUC 0-last (area under the curve-time curve) were 459 ± 252 ng/mL and 2022 ± 783 ng/mL·h, respectively. Maximum COMT inhibition was 83.4 ± 4.9% of baseline on day 14. After opicapone administration, LD total AUC, peak concentration, and trough concentration increased; peak-to-trough fluctuation index decreased. Correspondingly, 3-OMD total AUC, peak concentration, and trough concentration decreased. CONCLUSIONS: Adding once-daily opicapone 50 mg to LD resulted in marked and extended COMT inhibition, which increased systemic exposure to LD. These changes translated into higher trough concentrations and decreased peak-to-trough fluctuations for LD.

Ascorbic acid can alleviate the degradation of levodopa and carbidopa induced by magnesium oxide.

INTRODUCTION: Levodopa and carbidopa are reported to be degraded by magnesium oxide (MgO), which is often used as a laxative for patients with Parkinson's disease (PD). Ascorbic acid (AsA) can stabilize levodopa and carbidopa solutions; however, the effect of AsA on the degradation of levodopa and carbidopa induced by MgO has not been fully investigated. METHODS: The effect of AsA was evaluated using in vitro examinations, compared with lemon juice, and by measuring the plasma concentration of levodopa in a patient with PD. RESULTS: In vitro experiments showed that the relative concentrations of levodopa remained almost constant, and the relative concentrations of carbidopa decreased with time with addition of MgO. AsA mitigated this effect in a concentration-dependent manner, whereas the addition of lemon juice caused little change, although the pH decreased to the same extent. The results of levodopa pharmacokinetics of the patient showed that the area under the plasma concentration-time curve values from hour 0 to 8 were 53.00 µmol·h/L with regular administration and 67.27 µmol·h/L with co-administration of AsA. CONCLUSIONS: AsA can mitigate the degradation of carbidopa induced by MgO and may contribute to improving the bioavailability of levodopa in patients with PD.

A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson's disease.

Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson's disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

Novel therapeutic interventions for combating Parkinson's disease and prospects of Nose-to-Brain drug delivery.

Parkinson disease (PD) is a progressive neurodegenerative disorder prevalent mainly in geriatric population. While, L-DOPA remains one of the major choices for the therapeutic management of PD, various motor and non-motor manifestations complicate the management of PD. In the last two decades, exhaustive research has been carried out to explore novel therapeutic approaches for mitigating motor and non-motor symptoms of PD. These approaches majorly include receptor-based, anti-inflammatory, stem-cell and nucleic acid based. The major limitations of existing therapeutic interventions (of commonly oral route) are low efficacy due to low brain bioavailability and associated side effects. Nanotechnology has been exploited and has gained wide attention in the recent years as an approach for enhancement of bioavailability of various small molecule drugs in the brain. To address the challenges associated with PD therapy, nose-to-brain delivery utilizing nanomedicine-based approaches has been found to be encouraging in published evidence. Therefore, the present work summarises the major challenges and limitations with antiparkinsonian drugs, novel therapeutic interventions, and scope of nanomedicine-based nose-to-brain delivery in addressing the current challenges of antiparkinsonian therapy. The manuscript tries to sensitize the researchers for designing brain-targeted nanomedicine loaded with natural/synthetic scaffolds, biosimilars, and nucleic acids that can bypass the first-pass effect for the effective management of PD.

Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

Amantadine Revisited: A Contender for Initial Treatment in Parkinson's Disease?

The best practice for the initiation of symptomatic motor treatment for Parkinson's disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson's disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson's disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.

Fasting state is one of the factors associated with plasma levodopa fluctuations during levodopa‒carbidopa intestinal gel treatment.

INTRODUCTION: Some patients with Parkinson's disease (PD) undergoing levodopa‒carbidopa intestinal gel (LCIG) treatment experience motor fluctuations in the afternoon. The migrating motor complex, a specific periodic migrating contraction pattern occurring in the stomach and small intestine during the fasting state, can affect drug absorption. We aimed to compare the pharmacokinetic parameters between two conditions (with and without lunch) and assessed the influence of the fasting state on the levodopa pharmacokinetics in LCIG treatment. METHODS: We evaluated the levodopa pharmacokinetics from 12:00 p.m. to 6:00 p.m. in 10 LCIG-treated PD patients in the presence and absence of lunch. RESULTS: The maintenance dose of LCIG correlated strongly with the mean plasma concentration of levodopa in the absence (r = 0.94, coefficient of determination (R2) = 0.89, p < 0.001) or presence of lunch (r = 0.96, R2 = 0.93, p < 0.001). Comparison of the pharmacokinetic parameters revealed that the coefficient of variation was significantly greater in the condition without lunch than in the condition with lunch (p = 0.004): 16.73% (4.88%) without lunch and 9.22% (3.80%) with lunch. There were no significant differences in the mean plasma concentration of levodopa (p = 0.49) and area under the plasma concentration‒time curve (p = 0.27) between the two conditions. CONCLUSIONS: Plasma concentrations of levodopa fluctuated more in patients undergoing LCIG treatment without than with lunch. Our results indicate that a small amount of food intake may be a better corrective approach for worsening of symptoms in the fasting state rather than additional levodopa.