Antiparkinsonian Drugs Research Articles

Insights of structure-based virtual screening and MPO-based SAR analysis of berberine-benzimidazole derivatives against Parkinson disease

Parkinson's disease (PD) is a progressive neurological condition that causes tremors, rigidity and postural instability. In addition, it can lead to complications such as constipation, orthostatic hypotension, and psychiatric disorders like depression and anxiety. Berberine is a natural alkaloid used in Chinese medicine, extracted from various plants such as Berberis vulgaris and Tinospora cordifolia. The compounds have been reported to possess therapeutic activities, including anti-Alzheimer's, anti-diabetic, anti-inflammatory, antiviral, antibacterial and, in the context of this study, anti-Parkinson's action. This study conducts a structure-based virtual screening of aryl-substituted berberine-benzimidazole derivatives (D1–7). Molecular docking and dynamics simulations are used to predict pharmacodynamics against monoamine oxidase B (MAOB), while multiparametric optimization (MPO) is used to predict pharmacokinetics to the Central Nervous System (CNS). The aim is to propose new alkaloids derived from berberine that can modulate the activity of MAOB receptors in treating PD. The simulations revealed that the D7 compound, which contains a dichlorophenyl group, exhibited a high affinity with MAOB, with an affinity energy of −10 kcal/mol. In contrast, the fluoro- and nitro- substituted compounds showed lower affinity. Structure-activity/property relationship (SAR/SPR) analysis suggest that the chloro‑substituted derivatives are more lipophilic and form essentially hydrophobic interactions with the MAOB. This is corroborated by the dynamics simulations, which show that the MAOB-D7 complex is highly stable and allows for a synergistic effect associated with other anti-Parkinson drugs, further enhancing the inhibition of MAOB. Furthermore, pharmacokinetic predictions indicate that optimal levels of lipophilicity and polarity enhance high passive permeability (Papp = 1.7 × 10−5 cm/s) and metabolic stability of the D7 derivative, leading to increased distribution in the CNS.

Metixene is an incomplete autophagy inducer in preclinical models of metastatic cancer and brain metastases.

A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across different metastatic breast cancer subtypes. This agent significantly reduced mammary tumor size in orthotopic xenograft assays and improved survival in an intracardiac model of multiorgan site metastases. Metixene further extended survival in mice bearing intracranial xenografts and in an intracarotid mouse model of multiple brain metastases. Functional analysis revealed that metixene induced incomplete autophagy through N-Myc downstream regulated 1 (NDRG1) phosphorylation, thereby leading to caspase-mediated apoptosis in both primary and brain-metastatic cells, regardless of cancer subtype or origin. CRISPR/Cas9 KO of NDRG1 led to autophagy completion and reversal of the metixene apoptotic effect. Metixene is a promising therapeutic agent against metastatic brain cancer, with minimal reported side effects in humans, which merits consideration for clinical translation.

Association of anticholinergic drug exposure with the risk of dementia among older adults in Japan: The LIFE Study.

Several studies have investigated that anticholinergic drugs cause cognitive impairment. However, the risk of dementia associated with anticholinergics has not been extensively investigated in the super-aging society of Japan. We conducted this study to assess the association between anticholinergic drugs and the risk of dementia in older adults in Japan. This nested case-control study used data from the Longevity Improvement & Fair Evidence Study, which includes claim data in Japan from 2014 to 2020. We included 66,478 cases of diagnosed dementia and 328,919 matched controls aged ≥65years, matched by age, sex, municipality, and cohort entry year. Primary exposure was the total cumulative anticholinergic drugs prescribed from cohort entry date to event date or matched index date, which was the total standardized daily doses for each patient, calculated by adding the total dose of different types ofanticholinergic drugs in each prescription, divided by the World Health Organization-defined daily dose values. Odds ratios for dementia associated with cumulative exposure to anticholinergic drugs were calculated using conditional logistic regression adjusted for confounding variables. The mean (standard deviation) age at index date was 84.3 (6.9), and the percentage of women was 62.1%. From cohort entry date to event date or matched index date, 18.8% of the case patients and 13.7% of the controls were prescribed at least one anticholinergic drug. In the multivariable-adjusted model, individuals with anticholinergic drugs prescribed had significantly higher odds of being diagnosed with dementia (adjusted odds ratio, 1.50 [95% confidence interval, 1.47-1.54]). Among specific types of anticholinergic drugs, a significant increase in risk was observed with the use of antidepressants, antiparkinsonian drugs, antipsychotics, and bladder antimuscarinics in a fully multivariable-adjusted model. Several types of anticholinergic drugs used by older adults in Japan are associated with an increased risk of dementia. These findings suggest that the underlying risks should be considered alongside the benefits of prescribing anticholinergic drugs to this population.

Quantitative Colorimetric Sensing of Carbidopa in Anti-Parkinson Drugs Based on Selective Reaction with Indole-3-Carbaldehyde.

The quality of life of patients affected by Parkinson's disease is improved by medications containing levodopa and carbidopa, restoring the dopamine concentration in the brain. Accordingly, the affordable quality control of such pharmaceuticals is very important. Here is reported the simple and inexpensive colorimetric quantification of carbidopa in anti-Parkinson drugs by the selective condensation reaction between the hydrazine group from carbidopa and the formyl functional group of selected aldehydes in acidified hydroalcoholic solution. An optical assay was developed by using indole-3-carbaldehyde (I3A) giving a yellow aldazine in EtOH:H2O 1:1 (λmax~415 nm) at 70 °C for 4 h, as confirmed by LC-MS analysis. A filter-based plate reader was used for colorimetric data acquisition, providing superior results in terms of analytical performances for I3A, with a sensitivity ~50 L g-1 and LOD ~0.1 mg L-1 in comparison to a previous study based on vanillin, giving, for the same figures of merit values, about 13 L g-1 and 0.2-0.3 mg L-1, respectively. The calibration curves for the standard solution and drugs were almost superimposable, therefore excluding interference from the excipients and additives, with very good reproducibility (avRSD% 2-4%) within the linear dynamic range (10 mg L-1-50 mg L-1).

Screening of Crucial Cytosolicproteins Interconnecting the Endoplasmic Reticulum and Mitochondria in Parkinson's Disease and the Impact of Anti-Parkinson Drugs in the Preservation of Organelle Connectivity.

Mitochondrial dysfunction is well-established in Parkinson's disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic reticulum (ER) through a computational approach by constructing an organelle protein network to extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed the influence of anti-parkinsonism drugs (n = 35) on the crucial protein through molecular docking and molecular dynamic simulation and further validated its gene expression in PD participants under, istradefylline (n = 25) and amantadine (n = 25) treatment. Based on our investigation, D-aspartate oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER. Further, molecular docking showed that istradefylline has a high affinity (-9.073 kcal/mol) against DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (-4.53 kcal/mol) shows negligible effects against DDO that contribute to conformational changes in drug binding, Successively, DDO gene expression was downregulated in istradefylline-treated PD participants, which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the recommendation of off-target-free PD treatments.

Medication prescription profile and hospital admission related to medication administration errors in England and Wales: an ecological study

ObjectiveTo explore the correlation between prescribing rate of medications and hospital admissions related to medications administration errors in England and Wales during the time from 1999 to 2020.DesignAn ecological study.SettingA...

Levodopa nanoencapsulation in nanostarch as anti-Parkinsonian drugs candidate

Levodopa nanoencapsulation in nanostarch as anti-Parkinsonian drugs candidate

In silico Investigation of Identified Major Metabolites from Coffea Arabica Leaves against Parkinson’s Disease Target Proteins for Neuroprotective Drug Development

Introduction: Parkinson’s disease (PD) is a prevalent neurological disease characterized by the gradual degeneration of dopaminergic neurons leading to a dysfunctional central nervous system. Recently, major metabolites of Coffea arabica leaves were revealed to exhibit good electronshuttling potential in Microbial Fuel Cells (MFCs), similar to neurotransmitters dopamine and epinephrine. Objective: This In silico study aimed to identify the neuroprotective potentials of plant metabolites from coffee leaves and to determine their physicochemical and pharmacokinetic properties for developing viable anti-parkinsonian drug design. Methodology: Molecular docking was performed to evaluate the affinity of identified major compounds in C. arabica against PD-target proteins and compare the results with the binding activity of existing drugs and natural ligands of the identified protein targets via LibDock scores. The druglikeness and ADMET profiles of each ligand were also evaluated using bioinformatics tools. Results: C. arabica metabolites exhibited various degrees of binding activity against PD targets. LibDock scores of test compounds showed that catechin, mangiferin, and chlorogenic acid exhibited higher docking scores than dopamine and levodopa. Physicochemical and pharmacokinetics analysis of the selected molecules revealed caffeine, catechin, and chlorogenic acid as promising candidates for drug development with a low risk of drug toxicity. Conclusion: The present study indicates that Coffea arabica leaves contain promising neuroprotective active compounds against Parkinson’s disease.

Perioperative Use of Intravenous Levodopa as an Anti-Parkinsonian Drug: A Propensity Score Analysis.

Perioperative discontinuation of oral anti-parkinsonian medication can negatively impact the prognosis of abdominal surgery in patients with Parkinson's disease. Although intravenous levodopa may be an alternative, its efficacy has not yet been investigated. To determine the efficacy of intravenous levodopa as an alternative to oral anti-Parkinsonian drugs during gastric or colorectal cancer surgery. We identified patients with Parkinson's disease who underwent surgery for gastric or colorectal cancer between April 2010 and March 2020, using the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan. Patients were divided into two groups: those who received intravenous levodopa during the perioperative period and those who did not. We compared in-hospital mortalities, major complications, and postoperative length of stay between the groups after adjusting for background characteristics with overlap weights based on propensity scores. We identified 648 patients who received intravenous levodopa and 1207 who did not receive levodopa during the perioperative period. In the adjusted cohort, the mean postoperative length of stay was 24.7 and 29.0 days (percent difference, -7.7%; 95% confidence interval, -13.1 to -1.5); in-hospital death was 3.2% and 3.3% (adjusted odds ratio, 0.95; 95% CI: 0.54-1.67); and incidence of major complications were 21.4% and 19.3% (adjusted odds ratio, 0.89; 95% confidence interval, 0.70-1.13) in those with and without intravenous levodopa, respectively. Intravenous levodopa was associated with a shorter postoperative length of stay, but not with mortality or morbidity. Intravenous levodopa may improve perioperative care in patients with Parkinson's disease.

Hydrogen bonding patterns and C-H...π interactions in the structure of the antiparkinsonian drug (R)-rasagiline mesylate determined using laboratory and synchrotron X-ray powder diffraction data.

The structure of (R)-rasagiline mesylate [(R)-RasH+·Mes-], an active pharmaceutical ingredient used to treat Parkinson's disease, is presented. The structure was determined from laboratory and synchrotron powder diffraction data, refined using the Rietveld method, and validated and optimized using dispersion-corrected DFT calculations. The unit-cell parameters obtained in both experiments are in good agreement and the refinement with both datasets converged to good agreement factors. The final parameters obtained from laboratory data were a = 5.4905 (8), b = 6.536 (2), c = 38.953 (3) Å, V = 1398.0 (4) Å3 and from synchrotron powder data were a = 5.487530 (10) Å, b = 6.528939 (12) Å, c = 38.94313 (9) Å, V = 1395.245 (5) Å3 with Z = 4 and space group P212121. Preferred orientation was properly accounted for using the synchrotron radiation data, leading to a March-Dollase parameter of 1.140 (1) instead of the 0.642 (1) value obtained from laboratory data. In the structure, (R)-RasH+ moieties form layers parallel to the ab plane connected by mesylate ions through N-H...O and C-H...O hydrogen bonds. These layers stack along the c axis and are further connected by C-H...π interactions. Hirshfeld surface analysis and fingerprint plot calculations indicate that the main interactions are: H...H (50.9%), H...C/C...H (27.1%) and H...O/O...H (21.1%).

Safety of opicapone use in Parkinson’s disease: review of literature and real-world safety data

Parkinson's disease (PD) presents a significant global health concern with increasing prevalence and burden. This review article examines the safety data of drug Opicapone from literature and real-world sources of safety data, highlighting the need for vigilance over anti-parkinsonian drugs. For literature review, the PubMed database was mined which concluded that Opicapone, a selective COMT inhibitor for PD, demonstrated ADR like dyskinesia, nausea, vomiting, headache, and constipation where on the other hand real-world evidence showed no safety alerts or recalls initiated by regulatory authorities for Opicapone, but known risks like dyskinesia and hallucination were identified. However, clinical trial statistics revealed hypertension as the most probable ADR, alongside constipation, dizziness, dyskinesia, headache, somnolence, and hyperhidrosis. Whereas, unlisted events, such as somnolence, hyperhidrosis, pulmonary embolism, and abdominal pain, were also observed. Most ADRs belonged to the nervous system disorders and gastrointestinal disorders class which can be attributed to the pharmacological effect of Opicapone. It was concluded from this review that there is need for continuous safety vigilance for Opicapone use as despite the presence of well-structured safety guidance, new risks can emerge.

Poisonous substances and geographical distribution of poisoning in hospitalized children based on data from 25 hospitals in China from 2016 to 2020

Objective: To investigate the poisonous substances and geographical distribution of poisoning in children in China. Methods: A cross-sectional study. The clinical data of 8 385 hospitalized children from January 2016 to December 2020 were extracted from the FUTang Updating Medical Records database. These children aged 0 to 18 years and were admitted due to poisoning. They were grouped according to age (newborns and infants, toddlers, preschoolers, school-age children, adolescents), place of residence (Northeast China, North China, Central China, East China, South China, Southwest China, Northwest China), and mode of discharge (discharge under medical advice, transfer to another hospital under medical advice, discharge without medical advice, death, other). The poisonous substance and causes of poisoning in different groups were analyzed. Results: Among these 8 385 children, 4 734 (56.5%) were male and 3 651 (43.5%) female, with a male-to-female ratio of 1.3∶1. The age was 3 (2, 7) years. The prevalence of poisoning was 51.8% (4 343/8 385) in toddlers, 16.5% (1 380/8 385) in adolescents, 14.8% (1 242/8 385) in preschoolers, 14.4% (1 206/8 385) in school-age children, and 2.5% (214/8 385) in newborns and infants. Drug poisoning accounted for 43.5% (3 649/8 385) and pesticide accounted for 26.8% (2 249/8 385). Drug poisoning was more common in adolescents (684/1 380, 49.6%) and toddlers (2 041/4 343, 47.0%); non-drug poisoning was more common in school-age children (891/1 206, 73.9%), of which carbon monoxide was mainly in newborns and infants (41/214, 19.2%) and food poisoning in children of school age (241/1 206, 20.0%). Regarding regional characteristics, drug poisoning was more frequent in South China (188/246, 64.2%) and non-drug poisoning was more frequent in Southwest China (815/1 123, 72.5%). For drugs, anti-epileptic drugs, sedative-hypnotic drugs and anti-Parkinson's disease drugs had a higher proportion of poisoning in North China (138/1 034, 13.0%) than that in other regions. For non-drug poisoning, pesticides (375/1 123, 33.3%), food poisoning (209/1 123, 18.6%) and contact with poisonous animals (86/1 123, 7.7%) were more common in Southwest China than in other regions; carbon monoxide poisoning was more common in North China (81/1 034, 7.6%) and Northwest China (65/1 064, 6.3%). In Central China, poisoning happened more in toddlers (792/1 295, 61.2%) and less in adolescents (115/1 295, 8.8%) than in other regions. Regarding different age groups, poisoning in adolescent happened more in Northeast China (121/457, 26.5%), North China (240/1 034, 23.2%), and Northwest China (245/1 064, 23.0%). The rate of discharge under medical advice, discharge without medical advice, and mortality rate within the 5 years were 77.0% (6 458/8 385), 20.8% (1 743/8 385), 0.5% (40/8 385), respectively. Conclusions: Poisoning is more common in male and toddlers. Poisonous substances show a regional characteristic and vary in different age groups, with drugs and insecticides as the most common substances.

Disulfide bridge-targeted metabolome mining unravels an antiparkinsonian peptide

Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics, thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials. However, the success rate is decreasing, presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely ‘overlooked’ during the characterization effort. Here, we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP (ribosomally synthesized and post-translationally modified peptide), named acalitide, by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules. Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease (AcaB)-catalyzed lactamization of AcaA, an unprecedented precursor peptide. Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy. Taken together, the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson's disease that is globally prevailing in an alarming manner.

Real-world use of Safinamide in motor fluctuating Parkinson’s disease patients in Italy

IntroductionSafinamide is a recent antiparkinsonian drug that modulates both dopaminergic and glutamatergic systems with positive effects on motor and nonmotor symptoms of Parkinson’s disease (PD). Here, we aimed to describe the efficacy and safety of safinamide in the Italian PD patients in real-life conditions.MethodsWe performed a sub-analysis of the Italian cohort of the SYNAPSES study, a multi-country, multi-center, retrospective-prospective cohort observational study, designed to investigate the use of safinamide in routine clinical practice. Patients received for the first time a treatment with safinamide and were followed up for 12 months. The analysis was conducted on the overall population and in subgroups of interest: i) patients > 75 years, ii) patients with relevant comorbidities and iii) patients affected by psychiatric symptoms.ResultsItaly enrolled 616/1610 patients in 52 centers, accounting for 38% of the entire SYNAPSES cohort. Of the patients enrolled, 86.0% were evaluable at 12 months, with 23.3% being > 75 years, 42.4% with psychiatric conditions and 67.7% with relevant comorbidities.Safinamide was effective on motor symptoms and fluctuations as measured through the Unified PD rating scale III and IV scores, and on the total score, without safety issues in none of the subgroups considered.ConclusionThe SYNAPSES data related to Italian patients confirms the good safety profile of safinamide even in special groups of patients. Motor fluctuations and motor impairment improved at the follow-up suggesting the significant role of safinamide in managing motor symptoms in PD patients.

Abstract 6 Combined Umbilical Cord Mesenchymal Stromal/Stem Cell Application For Primary Torsion Dystonia Treatment (Case Report)

Abstract Introduction Primary torsion dystonia (PTD) is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and/or postures with severe disability of young patients. Traditional therapies for PTD include oral anti-parkinsonism drugs, botulinum neurotoxin, pallidotomy and deep brain stimulation. Stem cell therapy is another promising treatment option, due to its neuroregenerative properties. Objectives The objective of the study was to investigate the effect of combined (intrathecal and intravenous) administration of umbilical cord derive stromal/stem cells (UC-MCS) on PTD reduction. Methods Patient M, born on 25.06.2004, fell ill gradually, 8 years ago developed signs of muscle dystonia, especially in right hand. Genetic tests were carried out, which revealed mutations in the DYT-1 gene. The diagnosis of primary torsion dystonia was established. Conservative treatment was not effective. The patient was offered treatment in the frame of research scientific program "To investigate the effectiveness of regenerative cell technologies in the neurosurgical treatment of patients with demyelinating diseases of the CNS and cerebral palsy. № 0119U000112" UC-MSCs for this study were isolated from healthy human umbilical cord and prepared due to the minimal criteria established by the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy. 3 injections of UC-MSC were performed with time interval of 6 month (intravenously and intrathecally in a dose of 6 × 107at each injection). Intrathecal administration was performed according to the typical method of performing lumbar puncture in compliance with the rules of asepsis and antiseptics in the operation room using local anesthesia. Results Prior to stem cells injection, the patient's Unified Dystonia Rating Scale (UDRS) dystonia movement score was 15, which progressively decreased after procedure to 13, 10, 7 and 4 after 6, 12, 18 and 24 months respectively. There was a significant improvement in the patient's quality of life. Discussion UC-MSC significantly reduce dystonia in patient. This result is probably achieved due to the neuroregenerative and neurotrophic effects of UC-MSCs. Study results suggest the need to provide larger multicenter randomized studies with more sophisticated methods of investigations.

Patient and caregiver experiences with pantothenate kinase-associated neurodegeneration (PKAN): results from a patient community survey

BackgroundPantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive genetic disorder of PANK2, which enables mitochondrial synthesis of coenzyme A. Its loss causes neurodegeneration with iron accumulation primarily in motor-related brain areas. Symptoms include dystonia, parkinsonism, and other disabilities. PKAN has been categorized as classic PKAN, with an age of onset ≤ 10 years, rapid progression, and early disability or death; and atypical PKAN, with later onset, slower progression, generally milder, and more diverse symptom manifestations. Available treatments are mostly palliative. Information on the lived experience of patients with PKAN and their caregivers or on community-level disease burden is limited. It is necessary to engage patients as partners to expand our understanding and improve clinical outcomes. This patient-oriented research study used multiple-choice and free-form question surveys distributed by patient organizations to collect information on the manifestations and disease burden of PKAN. It also assessed respondents’ experiences and preferences with clinical research to inform future clinical trials.ResultsThe analysis included 166 surveys. Most respondents (87%) were parents of a patient with PKAN and 7% were patients, with 80% from Europe and North America. The study cohort included 85 patients with classic PKAN (mean ± SD age of onset 4.4 ± 2.79 years), 65 with atypical PKAN (13.8 ± 4.79 years), and 16 identified as “not sure”. Respondents reported gait disturbances and dystonia most often in both groups, with 44% unable to walk. The classic PKAN group reported more speech, swallowing, and visual difficulties and more severe motor problems than the atypical PKAN group. Dystonia and speech/swallowing difficulties were reported as the most challenging symptoms. Most respondents reported using multiple medications, primarily anticonvulsants and antiparkinsonian drugs, and about half had participated in a clinical research study. Study participants reported the most difficulties with the physical exertion associated with imaging assessments and travel to assessment sites.ConclusionsThe survey results support the dichotomy between classic and atypical PKAN that extends beyond the age of onset. Inclusion of patients as clinical research partners shows promise as a pathway to improving clinical trials and providing more efficacious PKAN therapies.

Exploring the prescribing trends and factors affecting initial anti-parkinsonian drug selection in Korea: A nationwide population-based cohort study

BackgroundParkinson's disease (PD) is a common neurodegenerative disorder typically treated with dopamine replacement therapy and dopamine agonists (DAs) to alleviate symptoms and minimize dyskinesia. Optimal treatment strategies for patients newly diagnosed with PD have been a topic of debate for many years. MethodsWe conducted a 10-year descriptive study of drug prescription trends and factors affecting prescription choices for newly diagnosed drug-naïve PD patients using data from the National Health Insurance program in Korea. To identify statistically significant differences in yearly trends, we employed the Cochran-Armitage trend test. Additionally, we utilized multiple logistic regression analysis to investigate the factors associated with the selection of levodopa and DAs as initial anti-parkinsonian drugs. ResultsA total of 99,118 patients with PD who were prescribed levodopa or DAs alone as initial anti-parkinsonian drugs between 2011 and 2020 were eligible for inclusion in the analysis. The prescription rate of DAs increased until 2012, and then steadily decreased annually. The likelihood of levodopa prescription increased with age and at higher-level hospitals. In terms of comorbidities, patients with Alzheimer's disease and cerebrovascular diseases were more likely to be prescribed levodopa than those with peptic ulcer disease and dyslipidemia. ConclusionThe decline in levodopa prescriptions was reversed in 2012, and the prescription rate has continued to increase until recently. The odds ratio of levodopa prescription increased in elderly patients with Alzheimer’s disease and decreased in patients with Medical aid insurance and peptic ulcer disease.

Assessing the Risk of Developing Delirium on Admission to Inpatient Rehabilitation: A Clinical Prediction Model

ObjectivesTo develop a clinical model to predict the risk of an individual patient developing delirium during inpatient rehabilitation, based on patient characteristics and clinical data available on admission. DesignRetrospective observational study based on electronic health record data. Setting and ParticipantsWe studied a previously validated data set of inpatients including incident delirium episodes during rehabilitation. These patients were admitted to ZURZACH Care, Rehaklinik Bad Zurzach, a Swiss inpatient rehabilitation clinic, between January 1, 2015, and December 31, 2018. MethodsWe performed logistic regression analysis using backward and forward selection with alpha = 0.01 to remove any noninformative potential predictor. We subsequentially used the Akaike information criterion (AIC) to select the final model among the resulting “intermediate” models. Discrimination of the final prediction model was evaluated using the C-statistic. ResultsOf the 20 candidate predictor variables, 6 were included in the final prediction model: a linear spline of age with 1 knot at 60 years and a linear spline of the functional independence measure (FIM), a measure of the functional degree of patients independency, with 1 knot at 64 points, diagnosis of disorders of fluid, electrolyte, and acid-base balance (E87), use of other analgesic and antipyretics (N02B), use of anti-parkinson drugs (N04B), and an anticholinergic burden score (ACB) of ≥3 points. Conclusions and ImplicationsOur clinical prediction model could, upon validation, identify patients at risk of incident delirium at admission to inpatient rehabilitation, and thus enable targeted prevention strategies.

Incidence of cardiovascular morbidity among Parkinson's disease patients; a large-scale cohort study in a 16-year time window around disease onset

ObjectivesTo examine the risk of any or specific types of cardiovascular diseases (CVDs) in patients with Parkinson's disease (PD), in the 16 years around disease onset, and to compare it to that in the general population. MethodsThis is a large-scale population-based retrospective cohort study of newly diagnosed PD patients, members of Maccabi Health Services (MHS), who started taking anti-parkinsonian drugs (APD) between 1/1/2000-31/12/2019 (study period). We collected information about CVD incidence (Congestive heart failure-CHF, Myocardial infarction-MI, Stroke) from MHS-CVD registry. We applied Cox regression to estimate adjusted-HR and 95%CI of CVD risks. We calculated Standardized-Incidence-Ratio (SIR) comparing CVD risks in the PD cohort to that of MHS population. ResultsThe PD cohort comprised 10,840 patients. During a mean follow up of 16.3 ± 4.3y around disease onset, 20.7% (n = 2241) were diagnosed with any CVD: 7.9% with CHF; 6.7% with MI, and 10.5% with stroke. Risks were higher for men: HR = 1.95 (95%CI 1.58–2.40), and for above age 75y at first APD treatment, HR = 2.00 (95% CI 1.65–2.43). Compared to the MHS population, the PD cohort exhibited a significantly lower risk for CVDs, especially for men: SIRmen = 0.21 (95%CI 0.20–0.22), SIRwomen = 0.29 (95% CI 0.27–0.31). These trends were similar for the specific CVDs. ConclusionsThe findings suggest that the risks that PD patients and particularly men, will develop any type of CVD are lower than those of the general population. Further studies are needed to confirm this finding and examine the underlying mechanisms.

AI molecular property prediction for Parkinson's Disease reveals potential repurposing drug candidates based on the increase of the expression of PINK1

Background and ObjectiveParkinson's Disease (PD), a common neurodegenerative disorder and one of the major current challenges in neuroscience and pharmacology, may potentially be tackled by the modern AI techniques employed in drug discovery based on molecular property prediction. The aim of our study was to explore the application of a machine learning setup for the identification of the best potential drug candidates among FDA approved drugs, based on their predicted PINK1 expression-enhancing activity. MethodsOur study relies on supervised machine learning paradigm exploiting in vitro data and utilizing the scaffold splits methodology in order to assess model's capability to extract molecular patterns and generalize from them to new, unseen molecular representations. Models' predictions are combined in a meta-ensemble setup for finding new pharmacotherapies based on the predicted expression of PINK1. ResultsThe proposed machine learning setup can be used for discovering new drugs for PD based on the predicted increase of expression of PINK1. Our study identified nitazoxanide as well as representatives of imidazolidines, trifluoromethylbenzenes, anilides, nitriles, stilbenes and steroid esters as the best potential drug candidates for PD with PINK1 expression-enhancing activity on or inside the cell's mitochondria. ConclusionsThe applied methodology allows to reveal new potential drug candidates against PD. Next to novel indications, it allows also to confirm the utility of already known antiparkinson drugs, in the new context of PINK1 expression, and indicates the potential for simultaneous utilization of different mechanisms of action.