RESUMEN
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 (â¼100%) 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.
Asunto(s)
Carbidopa , Catecoles , Preparaciones de Acción Retardada , Portadores de Fármacos , Levodopa , Enfermedad de Parkinson , Carbidopa/farmacocinética , Carbidopa/administración & dosificación , Carbidopa/uso terapéutico , Carbidopa/farmacología , Animales , Levodopa/farmacocinética , Levodopa/administración & dosificación , Levodopa/uso terapéutico , Levodopa/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Preparaciones de Acción Retardada/química , Catecoles/química , Catecoles/uso terapéutico , Catecoles/farmacología , Catecoles/farmacocinética , Portadores de Fármacos/química , Ratas , Masculino , Nitrilos/farmacocinética , Nitrilos/uso terapéutico , Nitrilos/farmacología , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Liberación de Fármacos , Ratas Sprague-Dawley , Rotenona/farmacologíaRESUMEN
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.
Asunto(s)
Antiparkinsonianos , Levodopa , Enfermedad de Parkinson , Humanos , Levodopa/administración & dosificación , Levodopa/farmacocinética , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapéutico , Administración por Inhalación , Apomorfina/administración & dosificación , Apomorfina/farmacocinética , Apomorfina/uso terapéuticoRESUMEN
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.
Asunto(s)
Antiparkinsonianos , Levodopa , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Levodopa/administración & dosificación , Levodopa/farmacocinética , Levodopa/farmacología , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Dopaminérgicos/administración & dosificación , Dopaminérgicos/farmacocinética , Dopaminérgicos/farmacologíaRESUMEN
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 200/50âmg 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±48.3âmin vs. 145.5±50.8âmin; pâ=â0.026) was observed. In advanced PD group higher UPDRS III score (14.45±5.5 versus 20.9±6.1 points, pâ=â0.04) 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.
Asunto(s)
Antiparkinsonianos , Ejercicio Físico , Levodopa , Enfermedad de Parkinson , Humanos , Levodopa/administración & dosificación , Levodopa/farmacocinética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/sangre , Masculino , Femenino , Anciano , Persona de Mediana Edad , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/sangre , Ejercicio Físico/fisiología , Benserazida/administración & dosificación , Benserazida/farmacología , Combinación de Medicamentos , Progresión de la Enfermedad , Índice de Severidad de la EnfermedadRESUMEN
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.
Asunto(s)
Antiparkinsonianos , Carbidopa , Levodopa , Enfermedad de Parkinson , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/administración & dosificación , Carbidopa/farmacocinética , Carbidopa/administración & dosificación , Combinación de Medicamentos , Levodopa/farmacocinética , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Técnicas Biosensibles , Levodopa , Enfermedad de Parkinson , Levodopa/farmacocinética , Levodopa/uso terapéutico , Levodopa/sangre , Levodopa/química , Enfermedad de Parkinson/tratamiento farmacológico , Humanos , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/sangre , Carbidopa/farmacocinética , Carbidopa/uso terapéutico , Carbidopa/administración & dosificación , Proyectos Piloto , MasculinoRESUMEN
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.
Asunto(s)
Carbidopa , Enfermedad de Parkinson , Humanos , Carbidopa/farmacocinética , Levodopa/farmacocinética , Antiparkinsonianos/farmacocinética , Estudios Cruzados , Voluntarios Sanos , Enfermedad de Parkinson/tratamiento farmacológico , Geles/uso terapéutico , Agonistas de DopaminaRESUMEN
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.
Asunto(s)
Levodopa , Enfermedad de Parkinson , Humanos , Levodopa/uso terapéutico , Levodopa/farmacocinética , Carbidopa , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/farmacocinética , Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-MetiltransferasaRESUMEN
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.
Asunto(s)
Carbidopa , Enfermedad de Parkinson , Antiparkinsonianos/farmacocinética , Ácido Ascórbico/farmacología , Carbidopa/farmacocinética , Humanos , Levodopa/farmacocinética , Óxido de Magnesio , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismoRESUMEN
Background: Lactoferrin (bLF) is an iron-binding multifunctional protein that is abundant in milk. In mice, it inhibits catechol-O-methyltransferase (COMT) activity and increases blood levodopa levels. However, the clinical effects are unknown.Objective: The objective of this study was to determine the effect of bLF on the kinetics of levodopa in blood.Design: The effects of the concomitant administration of a combined formulation of levodopa and an aromatic amino acid decarboxylase inhibitor and bLF on the concentration of levodopa in blood and its metabolism were assessed in eight healthy subjects. In addition, we analyzed the association with clinical factors and evaluated whether clinical factors affected the COMT inhibitory activity of bLF in vitro.Results: Although not statistically significant, the peak plasma concentration (Cmax) of levodopa increased by 18.5%. From the results of the stratified analysis of total cholesterol, a relationship with ΔCmax was predicted. Therefore, bLF was reacted with cholesterol in the presence of lecithin and sodium deoxycholate in vitro to evaluate COMT inhibitory activity, and an increase in inhibitory activity was observed. By contrast, the ester compound cholesteryl oleate had no effect. The inhibitory activity of free fatty acids, which are known to interact with bLF, was also enhanced.Conclusion: The COMT inhibitory activity of bLF is not effective in elevating blood levodopa levels. However, in humans with high lipid levels, such as cholesterol, interactions may enhance the inhibitory effect, resulting in the enhanced absorption of levodopa.Trial registration: ID, UMIN000026787, registered 30 March 2017; URL, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000030749Trial registration: UMIN Japan identifier: UMIN000026787.
Asunto(s)
Lactoferrina , Levodopa , Animales , Antiparkinsonianos/farmacología , Catecol O-Metiltransferasa/química , Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/farmacología , Voluntarios Sanos , Humanos , Lactoferrina/química , Lactoferrina/metabolismo , Levodopa/farmacocinética , Lípidos , RatonesRESUMEN
INTRODUCTION: Some patients with Parkinson's disease (PD) undergoing levodopaâcarbidopa 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 concentrationâtime 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.
Asunto(s)
Antiparkinsonianos/farmacocinética , Carbidopa/farmacocinética , Ayuno/sangre , Levodopa/sangre , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Antiparkinsonianos/sangre , Combinación de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Geles , Humanos , Intestinos/efectos de los fármacos , Levodopa/farmacocinética , Almuerzo/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/sangreRESUMEN
The aim of this study was to investigate drug interactions of L-dopa/carbidopa with catechin and green tea essence in rabbits following the simultaneous administration via an intramuscular injection of catechin or via an intragastric route for green tea essence with L-dopa/carbidopa. The results indicated that catechin at doses of 10, 20 and 50 mg/kg increased the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t ) of L-dopa by about 69, 78 and 42%, respectively. The metabolic ratios of the AUC0-t for 3-O-methyldopa (3-OMD)/L-dopa significantly decreased by about 56, 68 and 76% (P < 0.05), respectively. In addition, a single dose of 5/1.25 mg/kg L-dopa/carbidopa was co-administrated with 150 mg/kg green tea essence via an intragastric route with an oral-gastric tube. Comparing the related pharmacokinetic parameters of L-dopa, the clearance and metabolic ratio of L-dopa decreased by 20 and 19% (P < 0.05), respectively. In conclusion, catechin and green tea essence can significantly affect the metabolism of L-dopa by the catechol-O-methyltransferase (COMT) metabolic pathway. Catechin can enhance L-dopa bioavailability, and both catechin and green tea essence decreased 3-OMD formation. Therefore, catechin and green tea essence may increase L-dopa efficacy for Parkinson's disease treatment.
Asunto(s)
Catequina , Interacciones de Hierba-Droga , Levodopa , Té/química , Animales , Disponibilidad Biológica , Carbidopa/sangre , Carbidopa/química , Carbidopa/farmacocinética , Catequina/metabolismo , Catequina/farmacocinética , Catecol O-Metiltransferasa , Cromatografía Liquida , Levodopa/sangre , Levodopa/química , Levodopa/farmacocinética , Masculino , Conejos , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Tirosina/análogos & derivados , Tirosina/sangre , Tirosina/química , Tirosina/farmacocinéticaRESUMEN
Levodopa (L-Dopa) is the "gold-standard" medication for symptomatic therapy of Parkinson disease (PD). However, L-Dopa long-term use is associated with the development of motor and non-motor complications, primarily due to its fluctuating plasma levels in combination with the disease progression. Herein, we present the first example of individualized therapeutic drug monitoring for subjects upon intake of standard L-Dopa oral pill, centered on dynamic tracking of the drug concentration in naturally secreted fingertip sweat. The touch-based non-invasive detection method relies on instantaneous collection of fingertip sweat on a highly permeable hydrogel that transports the sweat to a biocatalytic tyrosinase-modified electrode, where sweat L-Dopa is measured by reduction of the dopaquinone enzymatic product. Personalized dose-response relationship is demonstrated within a group of human subjects, along with close pharmacokinetic correlation between the finger touch-based fingertip sweat and capillary blood samples.
Asunto(s)
Técnicas Biosensibles/métodos , Monitoreo de Drogas/métodos , Técnicas Electroquímicas/métodos , Levodopa/farmacocinética , Sudor/química , Administración Oral , Enzimas Inmovilizadas/química , Humanos , Hidrogeles/química , Levodopa/administración & dosificación , Levodopa/química , Monofenol Monooxigenasa/química , Oxidación-Reducción , Comprimidos/administración & dosificación , Comprimidos/química , Comprimidos/farmacocinéticaRESUMEN
Previously, we found that ONO-2160, an ester-type prodrug of levodopa (3-hydroxy-l-tyrosine), was mainly hydrolyzed in human plasma by α1-acid glycoprotein (AGP) with a partial contribution of albumin. In this study, we investigated whether ONO-2160 was hydrolyzed in the plasma of preclinical species (dog, rabbit, rat, and mouse) and humans and whether AGP and albumin are involved in its hydrolysis. ONO-2160 was hydrolyzed to some extent in the plasma of all tested species with the order of magnitude mouse > human > rabbit > rat > dog. Except for dogs, ONO-2160 was partially hydrolyzed by animal AGP and albumin. This indicated that, similar to albumin, AGP possesses esterase-like activity in mice, rats, and rabbits, as well as humans. A comparison of the values of intrinsic clearance per milliliter of plasma demonstrated that AGP was the major contributor to the hydrolysis of ONO-2160 in rabbit plasma, whereas albumin was primarily responsible for the hydrolysis of ONO-2160 in mouse plasma. This was confirmed by experiments using AGP-knockout mouse plasma. This study reports the first evidence for the existence of species differences in the hydrolysis of ONO-2160 in plasma related to the different contributions of AGP and albumin.
Asunto(s)
Levodopa/farmacocinética , Orosomucoide/metabolismo , Animales , Perros , Ésteres/química , Ésteres/farmacocinética , Voluntarios Sanos , Humanos , Hidrólisis , Levodopa/química , Masculino , Ratones , Ratones Noqueados , Orosomucoide/genética , Profármacos/química , Profármacos/farmacocinética , Conejos , Ratas , Especificidad de la EspecieAsunto(s)
Antiparkinsonianos/administración & dosificación , Neuronas Dopaminérgicas/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/farmacocinética , Carbidopa/administración & dosificación , Carbidopa/farmacocinética , Catecol O-Metiltransferasa/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Quimioterapia Combinada , Humanos , Levodopa/administración & dosificación , Levodopa/farmacocinética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/psicologíaRESUMEN
Levodopa is considered the gold standard treatment of Parkinson's disease. Although very effective in alleviating symptoms at their onset, its chronic use with the progressive neuronal denervation in the basal ganglia leads to a decrease in levodopa's effect duration and to the appearance of motor complications. This evolution challenges the establishment of optimal regimens to manage the symptoms as the disease progresses. Based on up-to-date pathophysiological and pharmacological knowledge, we developed an integrative model for Parkinson's disease to evaluate motor function in response to levodopa treatment as the disease progresses. We combined a pharmacokinetic model of levodopa to a model of dopamine's kinetics and a neurocomputational model of basal ganglia. The parameter values were either measured directly or estimated from human and animal data. The concentrations and behaviors predicted by our model were compared to available information and data. Using this model, we were able to predict levodopa plasma concentration, its related dopamine concentration in the brain and the response performance of a motor task for different stages of disease.
Asunto(s)
Ganglios Basales/efectos de los fármacos , Levodopa/farmacocinética , Modelos Neurológicos , Enfermedad de Parkinson/tratamiento farmacológico , Transmisión Sináptica/efectos de los fármacos , Ganglios Basales/metabolismo , Ganglios Basales/fisiopatología , Simulación por Computador , Progresión de la Enfermedad , Dopamina/metabolismo , Humanos , Levodopa/administración & dosificación , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Enfermedad de Parkinson/fisiopatologíaRESUMEN
This study evaluated the effect of a small-tablet formulation of opicapone for use in clinical trials in Japan on the pharmacokinetics of levodopa (l-dopa) and 3-O-methyldopa (3-OMD). In an open-label, 3-period, single-sequence crossover phase 1 study in 80 healthy Japanese males (aged 20-45 years; body mass index, 18.5 to <30.0 kg/m2 ), 10 mg of l-dopa/carbidopa 100 was administered 3 times daily on day 0 (period 1) and day 12 (period 3), and opicapone tablets (5, 10, 25, or 50 mg; n = 20 each group) were administered once daily for 11 days (period 2). During periods 1 and 3, plasma concentrations of l-dopa and 3-OMD were measured and pharmacokinetic parameters (maximum observed plasma concentration, time at which maximum concentration was observed, area under the plasma concentration-time curve from time 0 to 5 hours [AUC5h ] and from time 0 to 24 hours [AUC24h ] following each dose, terminal half-life) of plasma l-dopa and 3-OMD were determined along with the geometric mean ratio (period 3/period 1) of AUC24h for l-dopa and 3-OMD. Maximum concentration of l-dopa for the first, second, or third doses of l-dopa/carbidopa did not significantly increase with increasing opicapone dose. The AUC of l-dopa increased with increasing opicapone dose but tended toward a peak plateau with opicapone doses of 25 mg and higher. Geometric mean ratios (90% confidence intervals) of AUC24h were 5 mg, 1.16 (1.10-1.21); 10 mg, 1.26 (1.23-1.30); 25 mg, 1.51 (1.44-1.57); 50 mg, 1.60 (1.54-1.66). Opicapone tablets were well tolerated. In Japanese healthy subjects, increases in plasma exposure to l-dopa appear to level off with opicapone doses of 25 mg and higher, which may be relevant for optimal dosing among Japanese patients with Parkinson disease.
Asunto(s)
Antiparkinsonianos/farmacocinética , Carbidopa/farmacocinética , Inhibidores de Catecol O-Metiltransferasa/farmacocinética , Levodopa/farmacocinética , Oxadiazoles/farmacología , Adulto , Antiparkinsonianos/administración & dosificación , Área Bajo la Curva , Pueblo Asiatico , Carbidopa/administración & dosificación , Inhibidores de Catecol O-Metiltransferasa/administración & dosificación , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Semivida , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Oxadiazoles/administración & dosificación , Comprimidos , Tirosina/análogos & derivados , Tirosina/farmacocinética , Adulto JovenRESUMEN
Levodopa is widely administered orally in clinical treatment of Parkinson's disease; however, due to levodopa various oral absorption and low bioavailability, intranasal delivery seems to be a suitable alternative route of administration. Pluronic F-127 is a thermosensitive polymer, which can form gel at nasal cavity temperature and increase drug residence time. In this study, a rapid High Performance Liquid Chromatography (HPLC) method was validated in presence of internal standard to determine pharmacokinetic parameters following levodopa administration to rats in three different intravenous solution, intranasal solution and intranasal thermosensitive gel groups. A precised (96.7%) and accurate (95.0%) HPLC method was validated at low UltraViolet (UV) wavelength of 208 nm that showed limit of detection and limit of quantitation of 59 and 177 ng/mL, respectively. Specificity results showed no interference for levodopa with endogenous serum materials, and serum extraction efficacy was 93%. Pharmacokinetic parameters including bioavailability of 75 and 85% with mean residence time of 78 and 94 min were estimated for intranasal solution and thermosensitive gel using the validated HPLC method, which indicated that levodopa nasal gel may be a good alternative with appropriate pharmacokinetic outcome. Therefore, the validated levodopa HPLC analysis method at low UV wavelength was efficiently applied in pharmacokinetic study.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Levodopa/sangre , Levodopa/farmacocinética , Administración Intranasal , Animales , Disponibilidad Biológica , Levodopa/administración & dosificación , Levodopa/química , Límite de Detección , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Infection with Helicobacter pylori seems overrepresented in Parkinson's disease. Clinical observations suggest a suboptimal treatment effect of levodopa in Helicobacter positive patients. OBJECTIVE: Describe and explain the connection between a Helicobacter pylori infection of the upper gut and changes in pharmacokinetics of oral levodopa treatment in Parkinson's disease. METHODS: PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: Bioavailability, drug metabolism, dyskinesia, Helicobacter, L-dopa, levodopa, motor control, pharmacodynamics, pharmacokinetics, prevalence, unified Parkinson's disease rating scale. RESULTS: The prevalence of Helicobacter pylori in Parkinson's disease patients is reported to be about 1.6-fold higher than in a control population in some studies. Helicobacter has therefore been assumed to be linked to Parkinson's disease, but the mechanism is unclear. As regards symptoms and treatment, patients with Parkinson's disease on levodopa therapy and with Helicobacter pylori infection display worse motor control than those without Helicobacter infection. Eradication of the infection improves levodopa response in Parkinson's disease, likely as a consequence of an increased oral pre-systemic bioavailability of levodopa, likely to be explained by reduced Helicobacter-dependent levodopa consumption in the stomach. In addition, small intestinal bacterial overgrowth may also have an impact on the therapeutic setting for levodopa treatment but is less well established. CONCLUSION: Eradication of Helicobacter pylori improves levodopa bioavailability resulting in improved motor control. Eradication of Helicobacter should be considered in patients with poor symptomatic control and considerable motor fluctuations.