A Roadmap for Future Parkinson's Pharmacogenomics in Asia

Expert Review of Neurotherapeutics, 2015

2017

Title: A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson's disease Authors: Debleena Guin ([email protected]) Manish Mishra ([email protected]) Puneet Talwar ([email protected]) Chitra Rawat ([email protected]) Suman Kushwaha ([email protected]) Shrikant Kukreti ([email protected]) Ritushree Kukreti ([email protected]) Version: 1 Date: 21 Jun 2017 Author’s response to reviews: Response to Reviewers comments: Manuscript # MGNM-D-17-00060 entitled "An integrative approach to decode the common molecular link between levodopa response and Parkinson's disease” We are thankful to the reviewers for their valuable time and efforts in thorough review of the manuscript. We have tried our best to address all the concerns/suggestions raised by the reviewers and believe that the revised version of the manuscript shall meet the journal’s publication requirements.

BMC Medical Genomics

Background: PD is a progressive neurodegenerative disorder commonly treated by levodopa. The findings from genetic studies on adverse effects (ADRs) and levodopa efficacy are mostly inconclusive. Here, we aim to identify predictive genetic biomarkers for levodopa response (LR) and determine common molecular link with disease susceptibility. A systematic review for LR was conducted for ADR, and drug efficacy, independently. All included articles were assessed for methodological quality on 14 parameters. GWAS of PD were also reviewed. Protein-protein interaction (PPI) analysis using STRING and functional enrichment using WebGestalt was performed to explore the common link between LR and PD. Results: From 37 candidate studies on levodopa toxicity, 18 genes were found associated, of which, CA n STR 13, 14 (DRD2) was most significantly associated with dyskinesia, followed by rs1801133 (MTHFR) with hyper-homocysteinemia, and rs474559 (HOMER1) with hallucination. Similarly, 8 studies on efficacy resulted in 4 genes in which rs28363170, rs3836790 (SLC6A3) and rs4680 (COMT), were significant. To establish the molecular connection between LR with PD, we identified 35 genes significantly associated with PD. With 19 proteins associated with LR and 35 with PD, two independent PPI networks were constructed. Among the 67 nodes (263 edges) in LR, and 62 nodes (190 edges) in PD pathophysiology, UBC, SNCA, FYN, SRC, CAMK2A, and SLC6A3 were identified as common potential candidates. Conclusion: Our study revealed the genetically significant polymorphism concerning the ADRs and levodopa efficacy. The six common genes may be used as predictive markers for therapy optimization and as putative drug target candidates.

Journal of the Medical Association of Thailand = Chotmaihet thangphaet, 2006

Long-term levodopa usage in Parkinson's disease (PD) patients is known to cause several motor complications. It may be related to several factors such as levodopa dosage, duration of treatment and severity of disease. To study the prevalence of levodopa motor complications and associated factors in Thai Parkinson's disease patients. The authors prospectively collected baseline characteristics of PD patients, details of treatment and complications from 3 hospitals in various parts of Thailand. These patients were diagnosed by UK PD Brain Bank criteria. A total of 154 patients aged 68.1 +/- 9.5 years were recruited. Age of onset was 61.2 +/- 9.8 years. Most patients were in Hoehn-Yahr stage 1-3. The common clinical features were bradykinesia, rigidity and resting tremor Treatments were levodopa (98.1 per cent), anticholinergic (29.9 per cent), dopamine agonists (26 per cent) and COMT inhibitor (9.1 per cent). Eighty-five per cent of the patients had excellent response to levod...

Neuropsychiatric Disease and Treatment, 2016

Background: In general, a generic drug is considered interchangeable with the original formulated drug. In Parkinson's disease (PD), generic drug use remains debated. This study was aimed to investigate whether the generic drug was as effective as the original in improving the symptoms of PD and the prevalence of motor complications. Methods: This study was a multicenter cohort study of patients with PD enrolled from three northeast hospitals in Thailand between February 2013 and February 2014. The patients were categorized into original and generic levodopa groups. The clinical characteristics, efficacy, and motor complications were compared between the groups. Results: There were 400 eligible patients. Of these, 327 patients (81.75%) met the study criteria and were classified as the original levodopa group (200 patients, 61.16%) and the generic levodopa group (127 patients, 38.84%). The average age of all patients with PD was 65 years. The duration of PD and the modified Hoehn-Yahr stages were not different between the groups. The total doses of original and generic levodopa-equivalent doses were significantly different (199.97±127.08 versus 305.58±138.27 mg; P-value ,0.001) and the actual doses were 198.10±117.92 versus 308.85±139.40 mg (P-value ,0.001). Approximately 80% of patients with PD in both groups had good responses (P-value .0.999), but the development of motor complications was significantly greater in the original than in the generic group. Conclusion: Generic levodopa was effective in improving the symptoms of PD. The prevalence of motor complications in the original compound group, at a lower dose of levodopa equivalent, was higher than in the generic group.

Revue Neurologique, 2020

Althea Medical Journal, 2019

Background: Parkinson's disease (PD) is one of many neurodegenerative diseases with symptomatic management, and with the correct pattern of pharmacological treatment PD may have an improved quality of life for a minimum of three years. This study aimed to illustrate treatment patterns and comorbidities in PD patients at Dr. Hasan Sadikin General Hospital, Bandung. Methods: This study was a cross-sectional descriptive study by using total medical records of the period of 2013 to 2018. PD patients receiving pharmacological treatments such as levodopa, anticholinergics, dopamine agonists, or combined therapy were included. Patients with incomplete data and with the previous history of other neurological diseases before PD were excluded from this study. Results: In total, there were 57 patients with PD, of whom most of them were males (79%). Agewise, PD was most common in 60 to 69-year-olds (32%). The most commonly used treatment pattern was the administration of levodopa (33%). Patients aged younger than 30 years were administered anticholinergics, whereas the older patients (>60 years old) mostly were given levodopa. Comorbidities after PD diagnosis were mostly stroke, dementia, and epilepsy. Conclusions: Males are most affected by PD, and the most commonly used treatment pattern is levodopa monotherapy. PD is most commonly found in patients aged 60 to 69 years. Patients aged below 30 years are administered anticholinergics. The most common comorbidities found are a stroke, followed by dementia and epilepsy. By recognizing the patterns and comorbidities of this disease, the study may provide some insights into choosing the most effective pharmacological therapy for PD.

Movement Disorders, 2004

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the “gold standard” against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy. © 2004 Movement Disorder Society

2010

After more than 40 years of clinical use, levodopa (LD) remains the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Compared with other available dopaminergic therapies, dopamine replacement with LD is associated with the greatest improvement in motor function. Long-term treatment with LD is, however, often complicated by the development of various types of motor response oscillations over the day, as well as drug-induced dyskinesias. Motor fluctuations can be improved by the addition of drugs such as entacapone or monoamine oxidase inhibitors, which extend the half-life of levodopa or dopamine, respectively. However, dyskinesia control still represents a major challenge. As a result, many neurologists have become cautious when prescribing therapy with LD. This review summarizes the available evidence regarding the use of LD to treat PD and will also address the issue of LD delivery as a critical factor for the drug's propensity to induce motor complications.

Neurological Research, 2014

Objectives: Levodopa-induced dyskinesia (LID) is one of the most disabling complications of long-term pharmacotherapy of Parkinson's disease (PD). The objective of our study was to examine the clinical profile and determinants of severity of LID in Indian PD patients on levodopa therapy. Methods: Retrospective analysis of records of PD patients with LID was performed. All patients were on levodopa and carbidopa combination. Records of subjects with complete information about disease profile, drug intake, and dyskinesia were analyzed. Characterization of LID was based on responses to part IV of unified Parkinson's disease rating scale (UPDRS). Results: Records of 42 patients (M : F 5 4.6 : 1) were analyzed. The median Hoehn and Yahr (H&Y) stage was 2.5 while median duration of levodopa therapy was 6.16 years (range: 1.91-14.58). Early morning dystonia was reported by 97.6% of the patients. Patients treated with §2 concomitant PD medication reported a significantly lower median UPDRS IV A score compared to patients treated with ,2 number of concomitant drugs. A trend toward a lower UPDRS IV A score was associated with use of dopamine agonists (DA). Patients with H&Y score §3 had a significantly higher median total UPDRS IV A score than patients with H&Y score ,3. Discussion: Early morning dystonia might be more common among Indian patients of LID. Use of a higher number of concomitant PD medications alongside levodopa is associated with a reduced severity of dyskinesia, even on prolonged use. Levodopa-induced dyskinesia is not only a drug-related phenomenon but the stage of PD itself also affects the dyskinesia severity.