Long-term Levodopa Therapy Research Articles

Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson’s disease: A randomized double-blind placebo-controlled trial

BackgroundPatients with Parkinson’s disease (PD) undergoing long-term levodopa therapy are prone to develop levodopa-induced dyskinesia (LID). Amantadine is the main drug recommended for the treatment of LID by current guidelines, but it is far from meeting clinical needs. Tianqi Pingchan Granule (TPG), a compound Chinese herbal medicine, has been developed to relieve symptom of LID. ObjectiveThis randomized controlled trial evaluated the efficacy and safety of the combination of TPG and amantadine for LID. Design, setting, participants and interventionsThis is a randomized double-blind placebo-controlled trial, conducted from January 2020 to August 2021 at 6 sites in Jiangsu, Zhejiang and Shanghai, China. One hundred PD patients with ≥ 0.5 h of LID were randomly assigned to either the TPG plus amantadine group (TPG group) or the placebo plus amantadine group (placebo group), and treated for a period of 12 weeks. To ensure unbiased results, all study participants, investigators and sponsors were unaware of group allocations. Additionally, the data analysts remained blinded until the analysis was finalized. Main outcome measuresThe primary outcome was assessed using the Unified Dyskinesia Rating Scale (UDysRS) (Range 0–104). The key secondary end point was improvement of motor and non-motor symptoms. Safety analyses included all enrolled patients. ResultsOne hundred patients were enrolled and randomized into the two treatment groups. The changes in UDysRS at week 12 were –11.02 for the TPG group and –4.19 for the placebo group (treatment difference –6.83 [–10.53 to –3.12]; P = 0.0004). Adverse events were reported for 2 of 50 patients (4.0%) in each of the groups. ConclusionThis study indicated that a 12-week treatment of amantadine plus TPG effectively reduced UDysRS scores and was well tolerated, demonstrating the efficacy and safety of TPG for the treatment of LID in PD.Trial registration: ClinicalTrials.gov identifier: NCT04173832. Please cite this article asZhang Y, Zhu XB, Zhao Y, Cui GY, Li WT, Yuan CX, Huang JP, Wan Y, Wu N, Song L, Zhao JH, Liang Y, Xu CY, Liu MJ, Gao C, Chen XX, Liu ZG. Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson’s disease: A randomized double-blind placebo-controlled trial. J Integr Med. 2024; 22(5): 545–551.

Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia.

A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson's disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.

A video-atlas of levodopa-induced dyskinesia in Parkinson's disease: terminology matters.

Dyskinesia is a common complication of long-term levodopa therapy in patients with Parkinson's disease (PD), which often worsens the quality of life. It is usually dose-dependent and emerges possibly due to pulsatile stimulation of dopamine receptors. Delineating the pattern of dyskinesia is crucial for determining the most effective therapeutic approach, a task that often presents challenges for numerous neurologists. This article comprehensively describes various patterns of dyskinesia in PD patients and features video demonstration of some of the common forms of dyskinesia. We have used a real case scenario as an example to lead the discussion on the phenomenology, distinguishing features, and management of various types of dyskinesia. A comprehensive literature search was conducted in PubMed using "dyskinesia" as a keyword. The prototype case with videos highlights the differentiating features of dyskinesia along with the treatment strategies. A wide range of descriptive rubrics have been used for certain dyskinesia which are described in detail in this article. The newer types of dyskinesia associated with continuous dopaminergic stimulation in patients with advanced PD and their implications have been described. As there are distinct ways of managing various types of dyskinesia, understanding the phenomenology and chronology of dyskinesia is vital for the optimal management of dyskinetic PD patients. We suggest that dyskinesia should be classified broadly into peak-dose dyskinesia (PDD), biphasic dyskinesia (BD), and OFF-period dystonia. The occurrence of low-dose dyskinesia and complex dyskinesia of continuous dopaminergic treatments should be known to specialists and will require additional studies.

Real-world considerations regarding the use of the combination of levodopa, carbidopa, and entacapone (Stalevo® ) in Parkinson's disease.

An important aim in long-term levodopa therapy is to prolong the duration of symptomatic efficacy of each dose without increasing peak plasma concentrations above the threshold for the emergence of dyskinesias. One strategy is to enhance levodopa delivery to the brain by co-administering it with inhibitors of peripheral dopa-decarboxylase and catechol-O-methyltransferase (COMT). Levodopa, carbidopa and entacapone (LCE), available in a range of fixed-dose combinations as the branded formulation Stalevo® (Orion Pharma), has been developed to address this requirement and has been in general use for 20 years, having first been evaluated in randomized controlled trials. Experience with LCE has established that improved levodopa pharmacokinetics achieved with dual-enzyme inhibition are translated into improved clinical efficacy, including the possibility of reducing total levodopa dosage with no loss of therapeutic effect. The ease and tolerability of switching to LCE has been affirmed in the SIMCOM trial and by personal experience detailed in this review. Some 300,000 patient-years of safety data are available for LCE, including trial data for up to 5 years. Most adverse effects associated with LCE are attributable to the levodopa component rather than the enzyme inhibitors. The hepatotoxicity observed with the class comparator tolcapone has not been observed with entacapone, the COMT inhibitor in LCE, and there is no formal requirement to monitor liver function during LCE therapy. Other common side effects include diarrhoea, which is one of the more prominent non-dopaminergic adverse events, and urine discolouration, which is harmless but about which patients may require reassurance.

Amphiregulin blockade decreases the levodopa-induced dyskinesia in a 6-hydroxydopamine Parkinson's disease mouse model.

Levodopa (L-DOPA) is considered the most reliable drug for treating Parkinson's disease (PD) clinical symptoms. Regrettably, long-term L-DOPA therapy results in the emergence of drug-induced abnormal involuntary movements (AIMs) in most PD patients. The mechanisms underlying motor fluctuations and dyskinesia induced by L-DOPA (LID) are still perplexing. Here, we first performed the analysis on the microarray data set (GSE55096) from the gene expression omnibus (GEO) repository and identified the differentially expressed genes (DEGs) using linear models for microarray analysis (Limma) R packages from the Bioconductor project. 12 genes (Nr4a2, Areg, Tinf2, Ptgs2, Pdlim1, Tes, Irf6, Tgfb1, Serpinb2, Lipg, Creb3l1, Lypd1) were found to be upregulated. Six genes were validated on quantitative polymerase chain reaction and subsequently, Amphiregulin (Areg) was selected (based on log2 fold change) for further experiments to unravel its involvement in LID. Areg LV_shRNA was used to knock down Areg to explore its therapeutic role in the LID model. Western blotting and immunofluorescence results show that AREG is significantly expressed in the LID group relative to the control. Dyskinetic movements in LID mice were alleviated by Areg knockdown, and the protein expression of delta FOSB, the commonly attributable protein in LID, was decreased. Moreover, Areg knockdown reduced the protein expression of P-ERK. In order to ascertain whether the inhibition of the ERK pathway (a common pathway known to mediate levodopa-induced dyskinesia) could also impede Areg, the animals were injected with an ERK inhibitor (PD98059). Afterward, the AIMs, AREG, and ERK protein expression were measured relative to the control group. A group treated with ERK inhibitor had a significant decrease of AREG and phosphorylated ERK protein expression relative to the control group. Taken together, our results indicate unequivocal involvement of Areg in levodopa-induced dyskinesia, thus a target for therapy development.

Istradefylline for OFF Episodes in Parkinson's Disease: A US Perspective of Common Clinical Scenarios.

The effective management of OFF episodes remains an important unmet need for patients with Parkinson’s disease (PD) who develop motor complications with long-term levodopa therapy. Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with PD experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Originally approved in Japan, istradefylline was recently approved in the USA. In this article, we provide a specific review of the four clinical studies that the FDA included in the approval of istradefylline in the USA, and discuss common clinical scenarios, based on our experience, where treatment with istradefylline may benefit patients experiencing motor fluctuations.

Association of Catechol-O-Methyltransferase Gene rs4680 Polymorphism and Levodopa Induced Dyskinesia in Parkinson's Disease: A Meta-Analysis and Systematic Review.

Long-term levodopa therapy for Parkinson's disease (PD) can cause levodopa induced dyskinesia (LID). Genetic predisposition has a significant role to play in inter-individual heterogeneity in the clinical manifestation of LID. Despite accumulating evidence for the role of COMT gene polymorphism (rs4680) as a genetic basis for LID, to date results have been inconsistent. Early assessment of the Catechol-O-Methyltransferase (COMT) genotype might be helpful to stratify PD patients concerning their individual risk for LID. In this meta-analysis, we have used 9 studies, which were selected through online databases. Statistical analysis was performed using R (v-3.6) software. 5 genetic models have been used in the present study: Allele model (A vs. G), Dominant model (AA+AG vs. GG), Homozygote model (AA vs. GG), Co-dominant/heterozygote model (AG vs. GG), and Recessive model (AA vs. AG + GG). The results indicated a significant association between COMT rs4680 (Val158Met) polymorphism and LID risk. The genotype AA of COMT rs4680 is a risk factor for LID in PD patients under the recessive model (AA vs GG+AG) in the random-effect model. Analysis based on ethnicity showed that COMT rs4680 SNP allele A is a risk factor for LID development in Asian PD patients, while GG genotype is a risk factor for LID development in non-Asian PD patients using different genetic models. The results of the present meta-analysis support that the COMT Val158Met polymorphism is a risk factor for the development of LID in PD patients having ethnic variations.

Opicapone: Once-Daily COMT Inhibitor for the Treatment of Wearing Off in Parkinson's Disease.

Objective To provide a review of opicapone as a treatment for end-of-dose wearing off associated with long-term levodopa therapy in patients with Parkinson's disease (PD). Data Sources PubMed, Web of Science, and Google Scholar were searched for relevant literature using the following terms: management, treatment, opicapone, BIA 9-1067, entacapone, and tolcapone. Current guidelines and the manufacturer's package inserts were also reviewed. Study Selection/Data Extraction Recent literature and published studies of opicapone in the management of wearing off. Data Synthesis Long-term use of levodopa is associated with known complications of motor fluctuations and dyskinesia. The addition of a drug with fewer daily administrations may reduce the complexity of the current medication regimen, improve adherence, and reduce the risk of adverse events in older people with PD. The Food and Drug Administration (FDA) approved a new catechol-O-methyltransferase (COMT) inhibitor opicapone in combination with levodopa/carbidopa to treat wearing off in PD patients on April 24, 2020. Conclusion Opicapone offers patients with PD a once-daily option with a favorable side effect profile, increased exposure to levodopa, and reduction in "off" time. It may be an appropriate second line option in patients who are intolerant or do not respond with entacapone.

Continuous Subcutaneous Apomorphine Infusion in Advanced Parkinson's Disease: A Systematic Review.

Parkinson's disease (PD), a neurodegenerative disorder, is caused due to the loss of dopaminergic neurons in substantia nigra pars compacta, and it mainly affects the motor function of the diseased individual. The most effective treatment for PD to date is levodopa, the precursor molecule for dopamine which ultimately helps overcome the loss of dopamine in the brain. However, long-term levodopa therapy significantly impairs patients' quality of life by causing various disabling motor and non-motor complications. We conducted this study intending to review the available literature that has compared the efficacy and safety of continuous subcutaneous apomorphine infusion (CSAI) with other available treatment options like deep brain stimulation, intestinal levodopa gel, and oral dopaminergic agents. We searched PubMed, Embase, and Scopus databases using the appropriate search strategy. The studies which compared the safety and efficacy of continuous subcutaneous apomorphine infusion to other available treatment options in advanced Parkinson’s disease were included in our study. The bias assessment of the studies was done using Cochrane Risk of Bias 2.0 tool for randomized controlled trials, Risk of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) tool for non-randomized interventional studies, and Joanna Briggs Institute Critical Appraisal tools (JBI) for cohort studies. We included eight articles in our systematic review including a randomized controlled trial. None of the included studies had a high risk of bias. We found that in patients with advanced Parkinson’s, CSAI demonstrated definite improvement in off-time duration. CSAI has also been shown to improve various non-motor functions, including neuropsychiatric problems in these patients. CSAI has demonstrated safety and efficacy in patients with advanced Parkinson’s disease. However, the decision-making is multifactorial. Hence, further studies are required that directly compare the available treatment options with one another and study their overall effects on patients’ quality of life.

Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications.

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient’s quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy.

Transcriptomic approach predicts a major role for transforming growth factor beta type 1 pathway in L-Dopa-induced dyskinesia in parkinsonian rats.

Dyskinesia induced by long-term L-Dopa (LID) therapy in Parkinson disease is associated with altered striatal function whose molecular bases remain unclear. Here, a transcriptomic approach was applied for comprehensive analysis of distinctively regulated genes in striatal tissue, their specific pathways, and functional- and disease-associated networks in a rodent model of LID. This approach has identified transforming growth factor beta type 1 (TGFβ1) as a highly upregulated gene in dyskinetic animals. TGFβ1 pathway is a top aberrantly regulated pathway in the striatum following LID development based on differentially expressed genes (> 1.5 fold change and P < 0.05). The induction of TGFβ1 pathway specific genes, TGFβ1, INHBA, AMHR2 and PMEPA1 was also associated with regulation of NPTX2, PDP1, SCG2, SYNPR, TAC1, TH, TNNT1 genes. Transcriptional network and upstream regulator analyses have identified AKT-centered functional and ERK-centered disease networks revealing the association of TGFβ1, IL-1β and TNFα with LID development. Therefore, results support that TGFβ1 pathway is a major contributor to the pathogenic mechanisms of LID.

A non-linear deterministic model of action selection in the basal ganglia to simulate motor fluctuations in Parkinson's disease.

Motor fluctuations and dyskinesias are severe complications of Parkinson's disease (PD), especially evident at its advanced stage, under long-term levodopa therapy. Despite their strong clinical prevalence, the neural origin of these motor symptoms is still a subject of intense debate. In this work, a non-linear deterministic neurocomputational model of the basal ganglia (BG), inspired by biology, is used to provide more insights into possible neural mechanisms at the basis of motor complications in PD. In particular, the model is used to simulate the finger tapping task. The model describes the main neural pathways involved in the BG to select actions [the direct or Go, the indirect or NoGo, and the hyperdirect pathways via the action of the sub-thalamic nucleus (STN)]. A sensitivity analysis is performed on some crucial model parameters (the dopamine level, the strength of the STN mechanism, and the strength of competition among different actions in the motor cortex) at different levels of synapses, reflecting major or minor motor training. Depending on model parameters, results show that the model can reproduce a variety of clinically relevant motor patterns, including normokinesia, bradykinesia, several attempts before movement, freezing, repetition, and also irregular fluctuations. Motor symptoms are, especially, evident at low or high dopamine levels, with excessive strength of the STN and with weak competition among alternative actions. Moreover, these symptoms worsen if the synapses are subject to insufficient learning. The model may help improve the comprehension of motor complications in PD and, ultimately, may contribute to the treatment design.

Фармакокинетика леводопы и персонифицированная терапия болезни Паркинсона

The article provides a review of the pharmacokinetics of levodopa and personalized therapy for Parkinson’s disease. We analyzed the methods used to prolong the action of levodopa using peripheral inhibitors of DOPA decarboxylase, catechol-O-methyltransferase inhibitors, and monoamine oxidase type B inhibitors. The influence of levodopa metabolites with their own biological activity in the possible progression of the disease is emphasized. The role of determining the concentration of levodopa in blood plasma is discussed, as well as the concept of «continuous dopamine stimulation» for the prevention and treatment of side effects of long-term levodopa therapy, such as drug dyskinesias, motor and non-motor fluctuations. The article also provides an overview of the modern forms of levodopa that are currently being investigated.

Recent Clinical Advances in Pharmacotherapy for Levodopa-Induced Dyskinesia.

Onset of involuntary movement patterns of the face, body and limbs are known as dyskinesia. They mostly appear in association with long-term levodopa (L-dopa) therapy in patients with Parkinson's disease. Consequences include patient distress, caregiver embarrassment and reduced quality of life. A severe intensity of this motor complication may result in troublesome disability; however, patients typically prefer motor behaviour with slight, non-troublesome dyskinesia to 'OFF' states. Pharmacotherapy of dyskinesia is complex. Continuous nigrostriatal postsynaptic dopaminergic receptor stimulation may delay onset of L-dopa-associated dyskinesia, while non-physiological, 'pulsatile' receptor stimulation facilitates appearance of dyskinesia. In the past, there have been many clinical trial failures with compounds that were effective in animal models of dyskinesia. Only the N-methyl-D-aspartate antagonist amantadine has shown moderate antidyskinetic effects in small well-designed clinical studies. Amantadine is an old antiviral compound, which moderately improves impaired motor behaviour. Recently, there has been a resurgence of its use due to the US Food and Drug Administration approval of an extended-release (ER) amantadine formulation for treatment of L-dopa-induced dyskinesia. This pharmacokinetic innovation improved dyskinesia and 'OFF' states in pivotal trials, with a once-daily oral application in the evening. Amantadine ER provides higher and more continuous amantadine plasma bioavailability than conventional immediate-release formulations, which require administration up to three times daily.

Manage motor fluctuations in Parkinson’s disease by taking a hierarchical approach and individualizing treatment

Long-term levodopa therapy for Parkinson’s disease is associated with the development of motor fluctuations and other disabling effects. Adjunctive oral, transdermal and device-aided pharmacological treatments, as well as surgical therapies, may be used to manage motor fluctuations. Treatment should be individualized based on the efficacy and safety profiles of the intervention, as well as the clinical characteristics and preferences of the patient, and be adjusted as necessary to manage treatment-related adverse events.

Enfermedad de Parkinson y parkinsonismos

Parkinson's disease (PD) is the second most common neurodegenerative disorder, with a mean age of approximately 60 years. The cardinal clinical manifestations of PD are rest tremor, rigidity, bradykinesia and gait disorder. Nowadays the evidences support an etiological model resulting from interactions between environmental and genetic factors. In early stages, levodopa and dopaminergic therapies improve motor symptoms. Nevertheless, long-term levodopa therapy is associated to motor fluctuations and dyskinesias; thus in advanced stages, infusion therapies and deep brain stimulation are more effective. Furthermore, as the PD progresses, new symptoms no responding to levodopa treatment appear. Current clinical trials are focused on new strategies that may modify the natural course of PD, either stopping or slowing the progression of the disease.

Spike and Local Field Synchronization Between the Pedunculopontine Nucleus and Primary Motor Cortex in a Rat Model of Parkinson's Disease

The pedunculopontine nucleus (PPN) shows altered electrophysiological and anatomic characteristics in Parkinson's disease (PD), but little is known about the effect of 6-hydroxydopamine (6-OHDA) lesion and levodopa (L-DOPA) therapy on the relationship between spike and local field potential (LFP) activities in the PPN and motor cortex. Aiming to investigate this, synchronous spike and LFP signals in the PPN and primary motor cortex (M1) were recorded. The spike–LFP relationship was evaluated using coherence analysis, phase-lock and spike-field coherence (SFC). The results suggested that 6-OHDA lesion had a significant effect on the spike–LFP relationship between the PPN and M1 in rats under a rest or locomotion state. The significantly altered frequency bands varied across different neuron types and animal activity states. In addition, the altered coherence values between PPN spike and M1 LFP were refractory to long-term L-DOPA therapy although all other changes could be reversed by this drug treatment. All results provided evidence of the spike–LFP relationship between the PPN and M1 in PD, revealing some network mechanisms of the cortico-basal ganglia circuitry and PPN, which might be an underlying candidate for PD pathophysiology and therapy.

Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson's Disease.

Background:Parkinson's disease (PD) patients with long-term levodopa (L-DOPA) treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD.Methods:The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine (6-OHDA), followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus (SCN), liver, and plasma were collected at 6:00, 12:00, 18:00, and 24:00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis.Results:L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test (P < 0.01, P < 0.001, respectively). After L-DOPA treatment, Bmal1 decreased in the SCN compared with 6-OHDA group at 12:00 (P < 0.01) and 24:00 (P < 0.001). In the striatum, the expression of Bmal1, Rorα was lower than that in the 6-OHDA group at 18:00 (P < 0.05) and L-DOPA seemed to delay the peak of Per2 to 24:00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes (P > 0.05). In addition, the cortisol secretion was increased (P > 0.05), but melatonin was further inhibited after L-DOPA treatment at 6:00 (P < 0.01).Conclusions:In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.

The impact of early versus late levodopa administration.

Long-term levodopa therapy in patients with Parkinson's disease (PD) is associated with motor complications including motor fluctuations (MF) and levodopa-induced dyskinesias (LID). The time to appearance of MF and LID is apparently related to both the timing and the duration of levodopa therapy, but is highly variable. We performed a retrospective analysis of all levodopa-treated PD patients to explore the effect of time from PD onset to levodopa initiation on time to MF or LID. We used a Cox multivariate regression model after stratifying patients into four quartiles, according to the time to levodopa initiation. Data from 170 PD patients (117 males, age at onset: 65.1±11.6years, time to levodopa treatment: 23.8±28.4months) was included in the analysis. Early levodopa administration was associated with a shorter time from diagnosis to both MF (p<0.001) and LID (p=0.001). The hazard ratio to develop MF and LID from the time of PD diagnosis was 2.48 (p<0.001) and 2.71 (p=0.002), respectively. In our population, we found that delaying levodopa administration was associated with a longer time to the appearance of motor complications after diagnosis. While disease duration is the most important determinant of the onset of motor complications, delaying levodopa could prolong the 'complication-free' period.

Mucuna pruriens for Parkinson's disease: Low-cost preparation method, laboratory measures and pharmacokinetics profile

BackgroundParkinson's disease (PD) is a progressive neurological condition. Levodopa (LD) is the gold standard therapy for PD patients. Most PD patients in low-income areas cannot afford long-term daily Levodopa therapy. The aim of our study was to investigate if Mucuna pruriens (MP), a legume with high LD content that grows in tropical regions worldwide, might be potential alternative for poor PD patients. MethodsWe analyzed 25 samples of MP from Africa, Latin America and Asia. We measured the content in LD in various MP preparations (dried, roasted, boiled). LD pharmacokinetics and motor response were recorded in four PD patients, comparing MP vs. LD+Dopa-Decarboxylase Inhibitor (DDCI) formulations. ResultsMedian LD concentration in dried MP seeds was 5.29%; similar results were obtained in roasted powder samples (5.3%), while boiling reduced LD content up to 70%. Compared to LD+DDCI, MP extract at similar LD dose provided less clinical benefit, with a 3.5-fold lower median AUC. ConclusionConsidering the lack of a DDCI, MP therapy may provide clinical benefit only when content of LD is at least 3.5-fold the standard LD+DDCI. If long-term MP proves to be safe and effective in controlled clinical trials, it may be a sustainable alternative therapy for PD in low-income countries.