Cost-Effectiveness Analysis of COMT-Inhibitors as Adjuvant Treatments to Levodopa in Patients with Advanced Parkinson's Disease.

PURPOSE: We aimed to elicit scientific evidence on the cost-effectiveness of two catechol-O-methyltransferase inhibitors (COMT-i) versus no COMT-i in patients with advanced Parkinson's disease. METHODS: A mixed model of the decision tree and a Markov model with three health states by OFF-time level (<25%, ≥25%, and death) was constructed to compare opicapone (OPC), entacapone (ENT), and no COMT-i over a lifetime. A hypothetical cohort of 10,000 patients was created and simulated based on the characteristics of the BIPARK trial subjects. FINDINGS: Two COMT-i (OPC and ENT) were identified as a cost-effective option compared to no COMT-i. Probabilistic sensitivity analysis showed that over 90% of the simulations proved the robust cost-effectiveness of COMT-i. When the time horizon as the most influential factor decreases to a 5- and 10-year period, COMT-i can be a cost-saving option. Although ENT may be the preferred option over OPC economically because of its lower price, OPC can be acceptable if the drug price is reduced by 17%. IMPLICATIONS: Add-on treatment with COMT-i in patients with PD receiving levodopa/carbidopa appears to be cost-saving compared with not using COMT-i. In the future, it is necessary to evaluate the economic evaluation of COMT-i based on long-term real-world evidence.

Effect of Early Levodopa Treatment on Mortality in People with Parkinson's Disease.

BACKGROUND: The ideal timing for initiating levodopa in newly diagnosed people with Parkinson's disease (PD) is uncertain due to limited data on the long-term effects of levodopa. OBJECTIVE: The aim was to investigate whether early levodopa initiation postpones mortality (primary outcome), the requirement of device-aided therapies, and the incidence of PD-related complications, such as fall-induced injuries. METHODS: Using nationwide claims data from Dutch hospitals (2012-2020), we grouped newly diagnosed PD individuals as "early initiators" (initiating levodopa within 2 years of diagnosis) or "nonearly initiators." We used the national death registry to assess mortality and health-care claims to assess PD-related complications and device-aided therapies. We used marginal structural models to compare mortality and device-aided therapy rates between groups, and a Poisson regression model to compare PD-related complication rates. RESULTS: Among 29,943 newly diagnosed PD individuals (mean age at diagnosis: 71.6, 38.5% female), there were 24,847 early and 5096 nonearly levodopa initiators. Over a median 4.25 years, 8109 (27.1%) died. The causal risk ratio for mortality was 1.04 (95% confidence interval [CI] 0.92-1.19) for early versus nonearly initiators. The risk ratio of receiving any device-aided therapy was 3.19 (95% CI 2.56-5.80). No association was observed with incidence of PD-related complications (incidence rate ratio: 1.00, 95% CI 0.96-1.05). CONCLUSIONS: Early levodopa initiation in PD does neither postpone nor accelerate mortality or PD-related complications, nor does it precipitate earlier occurrence of PD-related complications or mortality. However, we cannot exclude that the results were influenced by residual confounding due to unmeasured risk factors of mortality.

Coadministration of 6-Shogaol and Levodopa Alleviates Parkinson's Disease-Related Pathology in Mice.

Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the nigrostriatal pathway, leading to motor and non-motor dysfunctions, such as depression, olfactory dysfunction, and memory impairment. Although levodopa (L-dopa) has been the gold standard PD treatment for decades, it only relieves motor symptoms and has no effect on non-motor symptoms or disease progression. Prior studies have reported that 6-shogaol, the active ingredient in ginger, exerts a protective effect on dopaminergic neurons by suppressing neuroinflammation in PD mice. This study investigated whether cotreatment with 6-shogaol and L-dopa could attenuate both motor and non-motor symptoms and dopaminergic neuronal damage. Both 6-shogaol (20 mg/kg) and L-dopa (80 mg/kg) were orally administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid- induced PD model mice for 26 days. The experimental results showed that L-dopa alleviated motor symptoms, but had no significant effect on non-motor symptoms, loss of dopaminergic neuron, or neuroinflammation. However, when mice were treated with 6-shogaol alone or in combination L-dopa, an amelioration in both motor and non-motor symptoms such as depression-like behavior, olfactory dysfunction and memory impairment was observed. Moreover, 6-shogaol-only or co-treatment with 6-shogaol and L-dopa protected dopaminergic neurons in the striatum and reduced neuroinflammation in the striatum and substantia nigra. Overall, these results suggest that 6-shogaol can effectively complement L-dopa by improving non-motor dysfunction and restoring dopaminergic neurons via suppressing neuroinflammation.

Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.

BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. OBJECTIVES: Our goal was to investigate the effects of genetic variants on risk and time to LID. METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147). CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinicians' viewpoints on current paradigms of care and research in Parkinson's disease.

Aim of this review is to discuss the value of current ongoing research initiatives in Parkinson's disease from the clinicians' point of view. The repeat, recent failures on progress slowing reflect the drifting apart between initially promising experimental and then disappointing clinical outcomes in the translational trials with well selected Parkinson's disease patients. A similar development concerns the emerging gap between novel developed drugs with improved pharmacokinetic behaviour and their limited use in the clinical practice following approval. Restricted regional different worldwide availability and direct, respectively indirect budget limitations for neurologists in private practice are essential hurdles. They prevent the widespread prescription of these compounds. As a result return of investment for the pharmaceutical industry becomes more and more uncertain. The interest for research on novel treatment approaches for the amelioration of motor and non motor symptoms declines. Clinicians crucially scrutinize the claim for an optimum patient care by payers and regulators.

Remote levodopa challenge test in Parkinson's disease: Feasibility, reliability, validity and economic value.

BACKGROUND AND PURPOSE: The aim was to demonstrate the feasibility, reliability and validity of an in-home remote levodopa challenge test (LCT), as delivered through an online platform, for patients with Parkinson's disease (PwPD). METHODS: Patients with Parkinson's disease eligible for deep brain stimulation surgery screening were enrolled. Participants sequentially received an in-home remote LCT and an in-hospital standard LCT (separated by 2.71 weeks). A modified Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III omitting rigidity and postural stability items was used in the remote LCT. The reliability of the remote LCT was evaluated using the intraclass correlation coefficient and the concurrent validity was evaluated using the Pearson's correlation coefficient r between the levodopa responsiveness of the remote and standard LCT. RESULTS: Out of 106 PwPD screened, 80 (75.5%) completed both the remote and standard LCT. There was a good reliability (intraclass correlation coefficient 0.81, 95% confidence interval 0.69-0.88) and a strong correlation (r = 0.84, 95% confidence interval 0.77-0.90) between the levodopa responsiveness of the remote and standard LCT. The mean cost for PwPD was estimated to be reduced by 91% by using the remote LCT. CONCLUSION: The remote LCT is feasible, reliable and valid and may reduce healthcare-related costs for PwPD and their caregivers.

Highly efficient electrocatalytic oxidation of levodopa as a Parkinson therapeutic drug based on modified screen-printed electrode.

The current study presents the creation of a straightforward and sensitive sensor based on ZnO/Co3O4 nanocomposite modified screen-printed electrode (ZnO/Co3O4NC/SPE) for levodopa determination. At ZnO/Co3O4NC/SPE, an oxidative peak for levodopa solution in pH 6.0 phosphate buffer solution (PBS) were seen that were both more resolved and more enhanced. Levodopa was measured using differential pulse voltammetry (DPV), which showed an excellent linear range (0.001-800.0 µM) and detection limit (0.81 nM). The presence of interference did not affect the electrochemical response of levodopa at ZnO/Co3O4NC/SPE, demonstrating high selectivity. Levodopa in a real samples have been successfully detected using the manufactured sensor.

Opicapone for the treatment of early wearing-off in levodopa-treated Parkinson's disease: pooled analysis of patient level data from two randomized open-label studies.

BACKGROUND: The wearing-off phenomenon is a key driver of medication change for patients with Parkinson's disease (PD) treated with levodopa. Common first-line options include increasing the levodopa dose or adding a catechol-O-methyltransferase (COMT) inhibitor, but there are no trials comparing the efficacy of these approaches. We evaluated the effectiveness of adjunct opicapone versus an additional 100 mg levodopa dose in PD patients with early wearing-off using pooled data from 2 randomized studies. METHODS: The ADOPTION study program included two similarly designed 4-week, open-label studies conducted in South Korea (NCT04821687) and Europe (NCT04990284). Patients with PD, treated with 3-4 daily doses of levodopa therapy and with signs of early wearing-off were randomized (1:1) to adjunct opicapone 50 mg or an additional dose of levodopa 100 mg. Patient-level data from the two studies were pooled. RESULTS: The adjusted mean [SE] change from baseline to week 4 in absolute OFF time (key endpoint) was - 62.8 min [8.8] in the opicapone group and - 33.8 min [9.0] in the levodopa 100 mg group, the difference significantly favoring opicapone (- 29.0 [- 53.8, - 4.2] min, p = 0.02). Significant differences in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III subscore (- 4.1 with opicapone vs - 2.5 with levodopa 100 mg), also favored opicapone (- 1.7 [- 3.3, - 0.04], p < 0.05). Dyskinesia was the most frequently reported adverse event (opicapone 7.2% vs. levodopa 100 mg 4.2%). CONCLUSIONS: In these short-term trials, introducing adjunct opicapone was more effective at reducing OFF time than adding another 100 mg levodopa dose in PD patients with early signs of wearing-off.

Investigating spatiotemporal and kinematic gait parameters in individuals with Parkinson's disease with a history of freezing of gait and exploring the effects of dopaminergic therapy on freezing of gait subtypes.

Introduction: Freezing of Gait (FOG) is a prevalent and debilitating symptom in idiopathic Parkinson's disease (PD). This study evaluated spatiotemporal and kinematic gait parameters in individuals with PD with a history of FOG and explored the effects of dopaminergic therapy on FOG subtypes. Methods: One hundred and nine individuals with PD underwent clinical assessments and quantitative biomechanical measures during walking cycles before and after dopaminergic therapy. Individuals with FOG were classified into levodopa-responsive and levodopa-unresponsive groups. Results: Individuals with FOG displayed longer disease duration and higher Unified Parkinson's Disease Rating Scale (UPDRS) II, III, IV scores, and total scores and levodopa equivalent dose, than those without FOG (all p < 0.0001). Following propensity score matching of 15 pairs based on UPDRS total score and disease duration during the off-medication state, the analysis comparing the FOG and non-FOG groups revealed no significant differences in spatiotemporal and kinematic parameters. In 39 cases of FOG, dopaminergic therapy improved gait performance in individuals with PD, enhancing spatiotemporal parameters (speed, stride length, step length, step variability) and kinematic parameters (shoulder and elbow flexion/extension range of motion (ROM), pelvic rotation, and hip abduction/adduction ROM) regardless of FOG responsiveness to dopaminergic therapy. A significant difference in trunk sway ROM (p = 0.029) remained before and after dopaminergic therapy, even after adjusting for disease duration and clinical severity. Discussion: Dopaminergic therapy had varying effects on PD with FOG, improving several spatiotemporal and kinematic gait parameters but being less effective in levodopa-unresponsive cases. Quantitative biomechanical measures offer detailed insights into gait performance, aiding personalized fall risk assessment and guiding individualized rehabilitation programs.

Parkinson's disease and levodopa-induced dyskinesias: a quantitative analysis through 99mTc-TRODAT-1 SPECT imaging of the brain.

Objective: To compare the dopamine transporter (DAT) density with other risk factors for L-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD), with and without LID. Materials and Methods: We evaluated 67 subjects: 44 patients with idiopathic PD of varying degrees of severity (PD group), and 23 healthy age-matched volunteers (control group). Among the 44 patients in the PD group, 29 were male and the following means were recorded at baseline: age, 59 ± 7 years; disease duration, 10 ± 6 years; Hoehn and Yahr (H&Y) stage, 2.16 ± 0.65; and Unified Parkinson's Disease Rating Scale part III (UPDRS III) score, 29.74 ± 17.79. All subjects underwent 99mTc-TRODAT-1 SPECT. We also calculated specific uptake ratios or binding potentials in the striatum. Results: The DAT density in the ipsilateral and contralateral striata was lower in the PD group. The variables disease duration, L-DOPA dosage, doses per day, L-DOPA effect duration time, H&Y stage, and UPDRS III score explained the occurrence of LID. The DAT density in the ipsilateral striatum, contralateral striatum, and caudate nucleus was lower in the patients with LID than in those without. Conclusion: Our findings suggest that presynaptic dopaminergic denervation is associated with LID in individuals with PD.

Objetivo: Comparar a densidade do transportador de dopamina (DAT) com outros fatores de risco para discinesia induzida pela L-DOPA em pacientes com doença de Parkinson, com e sem discinesias. Materiais e Métodos: Sessenta e sete sujeitos, 23 voluntários saudáveis e 44 pacientes pareados por idade com diferentes graus de gravidade da doença de Parkinson idiopática (29 homens; idade média ± desvio-padrão (DP), 59 ± 7 anos; duração média ± DP dos sintomas, 10 ± 6 anos; H&Y: média ± DP, 2,16 ± 0,65; UPDRS III: média ± DP, 29,74 ± 17,79). Todos os sujeitos realizaram SPECT cerebral com 99mTc-TRODAT-1. Além disso, foram calculadas as taxas de captação específica ou potenciais de ligação no estriado. Resultados: A densidade de DAT do estriado ipsilateral ou contralateral foi menor no grupo doença de Parkinson. As variáveis duração da doença, dosagem de L-DOPA, doses por dia, tempo de duração do efeito da L-DOPA, H&Y e UPDRS III explicaram a ocorrência de discinesia. Adicionalmente, pacientes com discinesia exibiram menor densidade de DAT no estriado ipsilateral ou contralateral e no núcleo caudado do que os pacientes sem discinesia. Conclusão: O presente estudo sugere que a denervação dopaminérgica pré-sináptica na doença de Parkinson está associada ao desenvolvimento de discinesia induzida pela L-DOPA.

Quantum-level machine learning calculations of Levodopa.

Many drug molecules contain functional groups, resulting in a torsional barrier corresponding to rotation around the bond linking the fragments. In medicinal chemistry and pharmaceutical sciences, inclusive of drug design studies, the exact calculation of the potential energy surface (PES) of these molecular torsions is extremely important and precious. Machine learning (ML), including deep learning (DL), is currently one of the most rapidly evolving tools in computer-aided drug discovery and molecular simulations. In this work, we used ANI-1x neural network potential as a quantum-level ML to predict the PESs of the L-3,4-dihydroxyphenylalanine (Levodopa) antiparkinsonian drug molecule. The electronic energies and structural parameters calculated by density functional theory (DFT) using the wB97X method and all possible Pople's basis sets indicated the 6-31G(d) basis set, when used with the wB97X functional, exhibits behavior similar to that of the ANI-1x model. The vibrational frequencies investigation showed a linear correlation between DFT and ML data. All ANI-1x calculations were completed quickly in a very short computing time. From this perspective, we expect the ANI-1x dataset applied in this work to be appreciably efficient and effective in computational structure-based drug design studies.

The recovery of sympathetic skin responses with levodopa in a patient with multiple system atrophy-parkinsonian type.

Herein, we report a 62-year-old female patient with Multiple system atrophy (MSA) at whom the sympathetic skin responses (SSRs) were absent at initial investigations. However, the levodopa therapy provided normalization of SSRs and moderately improvement in orthostatic hypotension-related symptoms. Based on this rare illustration, we discuss the possible mechanisms underlying the pathophysiology of autonomic dysfunction in MSA. We remark on the need for future clinical and experimental studies in this field.

A Patient with Multiple System Atrophy-Parkinsonian Type Presenting with Progressive Micrographia.

Herein, we present the case of a 57-year-old male patient who was admitted to our center due to progressive writing difficulty and slowness of his right hand over the last 3 years. In conclusion of the clinical and laboratory workup, a diagnosis of multiple system atrophy (MSA) was established. Our report on progressive micrographia (PM) constitutes a crucial sample remarking on this intriguing manifestation in another disease subtype of MSA, which differs from Parkinson's disease in terms of the clinical and pathophysiological processes. We think that further studies are warranted to clarify the significance of this entity in movement disorder in clinical practice and to reveal the underlying neural mechanisms.

Levodopa-induced dyskinesia in Parkinson's disease: Insights from cross-cohort prognostic analysis using machine learning.

BACKGROUND: Prolonged levodopa treatment in Parkinson's disease (PD) often leads to motor complications, including levodopa-induced dyskinesia (LID). Despite continuous levodopa treatment, some patients do not develop LID symptoms, even in later stages of the disease. OBJECTIVE: This study explores machine learning (ML) methods using baseline clinical characteristics to predict the development of LID in PD patients over four years, across multiple cohorts. METHODS: Using interpretable ML approaches, we analyzed clinical data from three independent longitudinal PD cohorts (LuxPARK, n = 356; PPMI, n = 484; ICEBERG, n = 113) to develop cross-cohort prognostic models and identify potential predictors for the development of LID. We examined cohort-specific and shared predictive factors, assessing model performance and stability through cross-validation analyses. RESULTS: Consistent cross-validation results for single and multiple cohort analyses highlighted the effectiveness of the ML models and identified baseline clinical characteristics with significant predictive value for the LID prognosis in PD. Predictors positively correlated with LID include axial symptoms, freezing of gait, and rigidity in the lower extremities. Conversely, the risk of developing LID was inversely associated with the occurrence of resting tremors, higher body weight, later onset of PD, and visuospatial abilities. CONCLUSIONS: This study presents interpretable ML models for dyskinesia prognosis with significant predictive power in cross-cohort analyses. The models may pave the way for proactive interventions against dyskinesia in PD by optimizing levodopa dosing regimens and adjunct treatments with dopamine agonists or MAO-B inhibitors, and by employing non-pharmacological interventions such as dietary adjustments affecting levodopa absorption for high-risk LID patients.

Primary familial brain calcification presenting with parkinsonism and motor complications caused by a novel SLC20A2 variant: a case report.

Primary familial brain calcification (PFBC), also known as Fahr's disease, is a central nervous system calcium deposition disorder with symmetrical basal ganglia calcification. Most PFBC cases are caused by SLC20A2 gene variant. We report a Chinese female patient with PFBC and dopamine-responsive parkinsonism who had motor fluctuations and dyskinesia and recovered effectively after symptomatic medication adjustment. A novel heterozygous missense variant was found by whole-exome sequencing and proven harmful by family validation and genetic analysis. This example expands the phenotype of SLC20A2-associated PFBC patients and shows the clinical efficacy of dopaminergic replacement treatment.

Levodopa versus levodopa sparing in early parkinson's disease: can we meet halfway?

Monotherapy is the recommended initial treatment for early Parkinson's disease. The pharmacological options for initial treatment include dopaminergic agonists, monoamine oxidase B inhibitors, and levodopa formulations. Several factors should be considered when selecting the optimal treatment, such as disease severity, disease duration, age, activity level, and the risk of developing motor and non-motor complications. Early evidence on the potential role of levodopa formulations in the risk of dyskinesia led to levodopa aversion in the late 1990s and early 2000s, favoring the use of levodopa-sparing options like dopamine agonists. This shift resulted in an increase in behavioral adverse effects, such as impulse control disorders, leading to a subsequent dopamine agonist aversion in the mid-2000s. This review aims to provide a comprehensive evaluation of the existing literature regarding the benefits and drawbacks of levodopa versus levodopa-sparing strategies in drug-naive early-stage Parkinson's disease.

Improving the Efficiency of Luminescent Zn(II)-Modified N-Doped GOQD Nanomaterials in Parkinson's Disease Treatment: A Theoretical Mechanistic Framework Exploring Doping Effect.

Levodopa, a widely prescribed drug in Parkinson's disease treatment, stands as the foremost prodrug of dopamine. An affordable self-testing kit is utilized to monitor  levodopa content in anti-parkinson drugs in human serum. A photoluminescent trinuclear Zn(II) complex [Zn3(L)2(κ1-OAc)2(κ2-OAc)2] has been synthesized, which cleaves into mononuclear  ZC in aqueous solution. ZC was found to detect L-Dopa in Tris-HCl buffer, exhibiting a moderate decrease in PL-emission. The real-life utility of the ZC probe is limited, for its lower sensitivity (LOD 35.3 µM) and separation challenges. Therefore, an interface between homogeneous and heterogeneous supports has been explored, leading to the strategic development of NGOZC, where ZC was grafted onto NGOQD. This material enables naked- eye detection under both ambient and UV light with color change from bright cyan to green, followed by dark. The nitrogen doping effect was investigated by several comparative investigations involving the synthesis of ZC-grafted GOQD, leading to enhanced quenching performance. Steady-state and time-resolved fluorescence titration study, morphological analysis, and computational calculations have been performed to get insights into the sensing mechanism. To the best of our knowledge, this as-synthesized NGOZC (LOD 1.78 nM) represents a promising strategy and platform for applications in biosensors, especially for Parkinson's and Alzheimer's diseases.

Association between Fecal Bile Acids and Levodopa Response in Patients with Parkinson's Disease.

Levodopa is the mainstay of treatments for Parkinson's disease (PD), but large heterogeneity exists in patient response. Increasing evidence implicates bile acids (BAs) involved in the pathogenesis of PD. Furthermore, BAs have also participated in drug bioavailability. However, the impact of BAs on levodopa response (LR) has not been investigated. This study evaluated the association between fecal BAs and LR. Levodopa challenge test (LCT) was conducted in 92 PD patients to assess LR. A total of 36 fecal BAs and plasma levodopa concentrations were detected using LC-MS/MS. The difference of BAs between subgroups with bottom and top 30% LR were analyzed and fecal samples from the two groups were collected for metagenomic shotgun analysis. No fecal BAs were significantly correlated with LR, except for chenodeoxycholic acid-3-ß-D-glucuronide (CDCA-3-ß-glucuronide, R = -0.228, p-value = 0.039). We found no significant difference in BAs between subgroups with bottom and top 30% LR. What is more, no significant changes in bacterial species composition related to bile acids metabolism or in the proportional representation of genes encoding known bile acids enzymes were observed between the groups. Overall, our data do not support an association between fecal BAs and levodopa response in PD patients. More precise macro-metabolomic approaches are needed to reveal the potential association between gut microbial interactions and the treatment effect of levodopa.

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.

BACKGROUND: Patients 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. OBJECTIVE: This randomized controlled trial evaluated the efficacy and safety of the combination of TPG and amantadine for LID. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This 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 MEASURES: The 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. RESULTS: One 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. CONCLUSION: This 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 AS: Zhang 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; Epub ahead of print.

Levodopa-based device-aided therapies for the treatment of advanced Parkinson's disease: a social return on investment analysis.

Introduction: Parkinson's disease (PD) is an incurable, progressive, neurodegenerative disorder. As PD advances and symptoms progress, patients become increasingly dependent on family and carers. Traditional cost-effectiveness analyses (CEA) only consider patient and payer-related outcomes, failing to acknowledge impacts on families, carers, and broader society. This novel Social Return on Investment (SROI) analysis aimed to evaluate the broader impact created by improving access to levodopa (LD) device-aided therapies (DATs) for people living with advanced PD (aPD) in Australia. Methods: A forecast SROI analysis over a three-year time horizon was conducted. People living with aPD and their families were recruited for qualitative interviews or a quantitative survey. Secondary research and clinical trial data was used to supplement the primary research. Outcomes were valued and assessed in a SROI value map in Microsoft Excel™. Financial proxies were assigned to each final outcome based on willingness-to-pay, economic valuation, and replacement value. Treatment cost inputs were sourced from Pharmaceutical Benefits Schedule (PBS) and Medicare Benefits Scheme (MBS) published prices. Results: Twenty-four interviews were conducted, and 55 survey responses were received. For every $1 invested in access to LD-based DATs in Australia, an estimated $1.79 of social value is created. Over 3 years, it was estimated $277.16 million will be invested and $406.77 million of social return will be created. This value is shared between people living with aPD (27%), their partners (22%), children (36%), and the Australian Government (15%). Most of the value created is social and emotional in nature, including reduced worry, increased connection to family and friends, and increased hope for the future. Discussion: Investment in LD-based DATs is expected to generate a positive social return. Over 50% of the value is created for the partners and children of people living with aPD. This value would not be captured in traditional CEA. The SROI methodology highlights the importance of investing in aPD treatment, capturing the social value created by improved access to LD-based DATs.