Antiparkinsonian Drugs Research Articles

Respiratory dysfunction in Parkinson's disease: a narrative review

The presence of respiratory symptoms in Parkinson's disease (PD) has been known since the first description of the disease, even though the prevalence and incidence of these disturbances are not well defined. Several causes have been reported, comprising obstructive and restrictive pulmonary disease and changes in the central ventilatory control, and different pathogenetic mechanisms have been postulated accordingly. In our review, we encompass the current knowledge about respiratory abnormalities in PD, as well as the impact of anti-Parkinsonian drugs as either risk or protective factors. A description of putative pathogenetic mechanisms is also provided, and possible treatments are discussed, focusing on the importance of recognising and treating respiratory symptoms as a key manifestation of the disease itself. A brief description of respiratory dysfunctions in atypical Parkinsonism, especially α-synucleinopathies, is also provided.

Study of Monoamine Oxidase-B and Indole Derivatives Using Two Molecular Docking Programs: Molegro and MOE

Inhibition of the enzyme Monoamine oxidase (MAO) is an important approach in the treatment of Parkinson’s disease. A series of indole derivatives were synthesised and evaluated as inhibitors of MAO-B may give insight to develop new ways of antiparkinson drug, In general, the derivatives were found to be selective MAO-B inhibitors with IC50 values . MAO-B inhibitors, are considered useful in the therapy of Parkinson’s disease since oxidation by MAO-B represents a major catabolic pathway of dopamine in the central nervous system . 
 Our goal of research is to study the inhibition of MAO-B by molecular modeling methods. Different molecular modeling tools are used to perform this work (molecular mechanics, molecular dynamics and molecular docking by two programms MDV ( molegro virtual docker) and MOE (modelling Opering Environment. The results obtained from this work, into which the inhibition of MAO-B by molecular modeling methods was elucidated, allow us to conclude that indole derivatives are promising reversible MAO-B inhibitors with a possible role in the treatment of neurodegenerative diseases such as Parkinson’s disease (PD).

A modern view on potential biomarkers of Parkinson’s disease (review)

Parkinson’s disease (PD) is one of the most widespread neurodegenerative diseases. In spite of the large number of researches, the problem of earlier diagnosis and targeted pathogenetic therapy remains relevant. For more than 20 years, scientists have been continuing to study potential diagnostic and prognostic PD biomarkers. An accurate diagnostic biomarker can help identify PD before motor symptoms occur, or when motor and non-motor symptoms are insufficient to diagnose, and also can be used to differentiate between idiopathic PD and other forms of parkinsonism.The aim of the research is to analyze the last studies of potential PD biomarkers in human biological fluids.Conclusions. Most studies of recent years indicate that the level of total α-synuclein, its oligomers in blood plasma and its formed elements is elevated in patients at the early stages of PD, and it can be a valuable prognostic biomarker for disease progression, in particular its motor symptoms. Studies of the level of this potential biomarker not only in blood plasma and its formed elements, but also in neuronal exosomes, are promising. The negative impact of oxidative stress in PD is a significant trigger for irreversible pathogenetic processes that affect the development of neurodegenerative changes. Perspectives of further researches may lay not only in identifying the concentrations of nitrotyrosine and oxidative stress components and antioxidants in the blood of PD patients, but also in determining of the effect of antiparkinsonian and neuroprotective drugs on the antioxidant system in order to pathogenetically justify their use for reducing of oxidative stress. It is promising to study the activity of melatonin in the context of its relationship with the components of oxidative stress and antioxidants by determining their concentrations in blood of PD patients.

Longitudinal association between dopamine agonists and weight in Parkinson's disease

ObjectiveTo examine the longitudinal relation of dopamine agonists (DA) use with body mass index (BMI) change and weight gain in Parkinson's disease (PD). MethodsIn a cohort of 356 patients with PD annually followed up to 6 years, BMI, antiparkinsonian drugs use, and impulse control disorders (ICDs) were assessed at each visit. DA dose trajectories were estimated using latent class mixed models. The association of DA use with BMI change and weight gain was examined using latent-process mixed models and time-dependent Cox models respectively, while adjusting for disease severity and levodopa (LD) use. ResultsIn the mixed model, BMI (kg/m2) increased over the follow-up in DA users (betaDA×time = 0.13, 95% CI = 0.02, 0.24) compared to non-users, while it decreased in LD users (betaLD×time = −0.26, 95% CI = −0.38, −0.13). We identified three trajectories of average daily DA dose over the follow-up. Patients in the high trajectory gained more weight than patients who never used DA (P = .001) and in the low (P = .02) or moderate (P = .04) trajectories. The incidence of weight gain of ≥6 kg was 2.10-fold (95% CI = 1.03, 4.28) higher in DA users compared to non-users, while LD users were less likely to gain weight (HR = 0.60, 95% CI = 0.33, 1.11). Associations decreased in analyses adjusted for compulsive eating or ICDs. ConclusionWeight increased in DA users over 6 years, and DA use was associated with increased incidence of weight gain. These associations were partially explained by compulsive eating. Alternatively, weight decreased in LD users. These findings warrant careful monitoring of compulsive eating and weight in PD patients.

Multi-combined 3D-QSAR, docking molecular and ADMET prediction of 5-azaindazole derivatives as LRRK2 tyrosine kinase inhibitors

The enzyme Leucine-rich repeat kinase 2 (LRRK2) has become a target of therapeutic interest in Parkinson research.Athree-dimensional quantitative structure-activity relationships(3D-QSAR) study was performed on twenty six azaindazole derivatives as LRRK2 inhibitorsobtained using rigid body alignment (Distill). CoMFA and CoMSIA model shave achieved high activity-descriptor relationship efficiency of 96% and 93% as shown by the regression-coefficient (R2=0.961 and 0.933) and were found statistically significant with cross validated coefficient (Q2 CV= 0.625 and 0.554), respectively.3D-QSAR models were externally validated by a test set of sixbioactive compounds showing satisfactory predicted correlation coefficient (R2 pred) of 0.865 and 0.853 for CoMFA and CoMSIA models, respectively. Besides, Y-randomization test was also performed to ensure the robustness of the obtained3D-QSAR models. This study provides valuable clues to design new compounds against LRRK2. Docking studies suggested that the ligand (new designed compound C2) has more potential than the ligand of reference 4K4 and confirm the obtained results from 3D-QSAR studies. Furthermore, the newly designed compounds and ligand of reference 4K4 were analyzed for their ADMET properties and drug likeness. These results would be of great help in leading optimization for developing new anti-Parkinson drug. Communicated by Ramaswamy H. Sarma

A Drug Decision Support System for Developing a Successful Drug Candidate Using Machine Learning Techniques.

Virtual screening of candidate drug molecules using machine learning techniques plays a key role in pharmaceutical industry to design and discovery of new drugs. Computational classification methods can determine drug types according to the disease groups and distinguish approved drugs from withdrawn ones. Classification models developed in this study can be used as a simple filter in drug modelling to eliminate potentially inappropriate molecules in the early stages. In this work, we developed a Drug Decision Support System (DDSS) to classify each drug candidate molecule as potentially drug or non-drug and to predict its disease group. Molecular descriptors were identified for the determination of a number of rules in drug molecules. They were derived using ADRIANA.Code program and Lipinski's rule of five. We used Artificial Neural Network (ANN) to classify drug molecules correctly according to the types of diseases. Closed frequent molecular structures in the form of subgraph fragments were also obtained with Gaston algorithm included in ParMol Package to find common molecular fragments for withdrawn drugs. We observed that TPSA, XlogP Natoms, HDon_O and TPSA are the most distinctive features in the pool of the molecular descriptors and evaluated the performances of classifiers on all datasets and found that classification accuracies are very high on all the datasets. Neural network models achieved 84.6% and 83.3% accuracies on test sets including cardiac therapy, anti-epileptics and anti-parkinson drugs with approved and withdrawn drugs for drug classification problems. The experimental evaluation shows that the system is promising at determination of potential drug molecules to classify drug molecules correctly according to the types of diseases.

Pharmacological interventions for antisocial personality disorder.

Pharmacological interventions for antisocial personality disorder.

Repurposing Pimavanserin, an Anti-Parkinson Drug for Pancreatic Cancer Therapy

Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. The aggressive and therapy-resistant nature of pancreatic cancer warrants the need for novel treatment options for pancreatic cancer management. Drug repurposing is emerging as an effectual strategy in the treatment of various diseases, including cancer. In the present study, we evaluated the anticancer effects of pimavanserin tartrate (PVT), an antipsychotic drug used for the treatment of Parkinson disease psychosis. PVT significantly suppressed the proliferation and induced apoptosis in various pancreatic cancer cells and gemcitabine-resistant cells with minimal effects on normal pancreatic epithelial cells and lung fibroblasts. Growth-suppressive and apoptotic effects of PVT were mediated by the inhibition of the Akt/Gli1 signaling axis. The oral administration of PVT suppressed subcutaneous and orthotopic pancreatic tumor xenografts by 51%–77%. The chronic administration of PVT did not demonstrate any general signs of toxicity or change in behavioral activity of mice. Our results indicate that pancreatic tumor growth suppression by PVT was orchestrated by the inhibition of Akt/Gli1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer.

Associated co-morbidities in a retrospective cohort of orthostatic tremor.

Orthostatic tremor (OT) is characterized by tremor in orthostatism. Primary OT is characterized by a high-frequency tremor at surface EMG recording and assumed to be idiopathic, whereas slow-frequency OT is classically associated with neurological pathologies. We report here a retrospective monocentric cohort study of primary (fast OT) and pseudo-OT (slow OT) patients to describe associated neurological and non-neurological co-morbidities. Between November 2014 and October 2019, 27 patients with OT were selected from the EMG database of the Department of Clinical Physiology in Lariboisière' s hospital. Patients were classified in primary OT if tremor frequency was ≥ 13Hz and in pseudo-OT if tremor frequency was < 13Hz. Leg tremor on standing represented 10.2% of all tremor recordings. Ten patients were included in the primary and 17 in the pseudo-OT group. Females were predominant (62.9%) (p = 0.04). Mean age at diagnosis was 64.8 ± 1.1years. At the first visit, a movement disorder was associated with 30% of primary OT, among them one CADASIL patient, whereas extrapyramidal or cerebellar disorders were reported in 100% of pseudo-OT, among them three Wilson's disease patients. These pathologies all preceded primary OT and occurred concomitantly with pseudo-OT. Frequency remained unchanged during evolution, except pseudo-OT in two patients that completely resolved following the introduction of antiParkinsonian drugs. Treatment of primary OT was partially effective in 28% and in 50% of pseudo-OT patients. In this monocentric study, movement disorders were present in 30% of primary OT patients. This result questions the term "idiopathic" or "primary" OT, but the small number of patients does not allow answering this issue.

(S)-Pramipexole and Its Enantiomer, Dexpramipexole: A New Chemoenzymatic Synthesis and Crystallographic Investigation of Key Enantiomeric Intermediates

A new chemoenzymatic method has been developed for the synthesis of (S)- and (R)-N-(6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl) acetamide, two key synthons for the preparation of (S)-pramipexole, an anti-Parkinson drug, and its enantiomer dexpramipexole, which is currently under investigation for the treatment of eosinophil-associated disorders. These two building blocks have been obtained in good yields and high enantiomeric excess (30% and &gt;98% ee for the R-enantiomer, and 31% and &gt;99% ee for the S- one) through a careful optimization of the reaction conditions, starting from the corresponding racemic mixture and using two consecutive irreversible transesterifications, catalyzed by Candida antarctica lipase type A. Single crystal X-ray analysis has been carried out to unambiguously define the stereochemistry of the two enantiomers, and to explore in depth their three-dimensional features.

Panic buying or good adherence? Increased pharmacy purchases of drugs from wholesalers in the last week prior to Covid-19 lockdown

AimsThe aim of this study was to examine the development of drug purchases during the corona crisis. MethodsThe evaluations in this retrospective cross-sectional study are based on the IMS RPM® (Regional Pharmaceutical Market) Weekly database, which shows the weekly purchases of public pharmacies from fully-stocked wholesalers at the time the pharmacy purchase is made in Germany. The outcome of this investigation was the development in psychotropic, neurological, and cardiovascular drug purchases by packing unit between Calendar Weeks 6 and 16. ResultsIn analyses, performed for psychotropic and neurological drugs, compared to Week 11, the largest increases in Week 12 were for anti-Parkinson drugs and tranquilizers (both 24%), followed by antiepileptics (23%). Purchases of antidementive drugs increased by 16% between Week 11 and Week 12. The increase was 43% for vitamin k antagonists, 39% for ACE inhibitors, and 37% for betablockers. ConclusionThe results of this retrospective cross-sectional study suggest that the Covid-19 lockdown in Germany was associated with a significant surge in purchasing behavior in pharmacies for different markets including psychotropic, neurological, and cardiovascular drugs. Further studies are needed to investigate the sell-out data and to estimate the differences in panic buying by age and sex.

The antiparkinson drug ropinirole inhibits movement in a Parkinson's disease mouse model with residual dopamine neurons

The dopamine (DA) D2-like receptor (D2R) agonist ropinirole is often used for early and middle stage Parkinson's disease (PD). However, this D2-like agonism-based strategy has a complicating problem: D2-like agonism may activate D2 autoreceptors on the residual DA neurons in the PD brain, potentially inhibiting these residual DA neurons and motor function. We have examined this possibility by using systemic and local drug administration in transcription factor Pitx3 null mutant (Pitx3Null) mice that mimic the DA denervation in early and middle stage PD and in DA neuron tyrosine hydroxylase (TH) gene knockout (KO) mice that mimic the severe DA loss in late stage PD. We found that in Pitx3Null mice with residual DA neurons and normal mice with normal DA system, systemically injected ropinirole inhibited locomotion, whereas bilateral dorsal striatal-microinjected ropinirole stimulated movement in Pitx3Null mice; bilateral microinjection of ropinirole into the ventral tegmental area also inhibited movement in Pitx3Null mice; we further determined that ropinirole inhibited nigral DA neuron spike firing in WT mice. In contrast, both systemically and striatum-locally administered ropinirole increased movements in TH KO mice, but produced relatively more dyskinesia than L-dopa. Although requiring confirmation in non-human primates and PD patients, these data suggest that while activating D2-like receptors in striatal projection neurons and hence stimulating movements, D2-like agonists can inhibit residual DA neurons and cause akinesia when the residual DA neurons and motor functions are still substantial, and this motor-inhibitory effect disappears when almost all DA neurons are lost such as in late stage PD.

Involvement of adenosine A1 and A2A receptors on guanosine-mediated anti-tremor effects in reserpinized mice.

Parkinson's disease (PD) signs and symptoms regularly include tremor. Interestingly, the nucleoside guanosine (GUO) has already proven to be effective in reducing reserpine-induced tremulous jaw movements (TJMs) in rodent models, thus becoming a promising antiparkinsonian drug. Here, we aimed at revealing the mechanism behind GUO antiparkinsonian efficacy by assessing the role of adenosine A1 and A2A receptors (A1R and A2AR) on GUO-mediated anti-tremor effects in the reserpinized mouse model of PD. Reserpinized mice showed elevated reactive oxygen species (ROS) production and cellular membrane damage in striatal slices assessed ex vivo and GUO treatment reversed ROS production. Interestingly, while the simultaneous administration of sub-effective doses of GUO (5mg/kg) and SCH58261 (0.01mg/kg), an A2AR antagonist, precluded reserpine-induced TJMs, these were ineffective on reverting ROS production in ex vivo experiments. Importantly, GUO was able to reduce TJM and ROS production in reserpinized mouse lacking the A2AR, thus suggesting an A2AR-independent mechanism of GUO-mediated effects. Conversely, the administration of DPCPX (0.75mg/kg), an A1R antagonist, completely abolished both GUO-mediated anti-tremor effects and blockade of ROS production. Overall, these results indicated that GUO anti-tremor and antioxidant effects in reserpinized mice were A1R dependent but A2AR independent, thus suggesting a differential participation of adenosine receptors in GUO-mediated effects.

Xanthotoxin reverses Parkinson\u2019s disease-like symptoms in zebrafish larvae and mice models: a comparative study

BackgroundThe aim of this study is to preliminary evaluate the antiparkinsonian activity of furanocoumarin—xanthotoxin, in two behavioral animal models, zebrafish larvae treated with 6-hydroxydopamine and mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in order to compare both models.MethodsXanthotoxin was isolated from Pastinaca sativa L. (Apiaceae) fruits. Then, the compound was administered by immersion to zebrafish 5 days after fertilization (dpf) larvae or intraperitoneally to male Swiss mice, as a potential therapeutic agent against locomotor impairments.ResultsAcute xanthotoxin administration at the concentration of 7.5 µM reversed locomotor activity impairments in 5-dpf zebrafish larvae. In mice model, acute xanthotoxin administration alleviated movement impairments at the concentration of 25 mg/kg.ConclusionsThe similar activity of the same substance in two different animal models indicates their compatibility and proves the potential of in vivo bioassays based on zebrafish models. Results of our study indicate that xanthotoxin may be considered as a potential lead compound in the discovery of antiparkinsonian drugs.

Medications associated with development of drug-induced depression

More than 60 % of all depressive syndromes are reactive depression, which occurs in response to internal and external influences. One of the variants of reactive depression is drug-induced (drug-induced) or iatrogenic depression, which is a possible side effect of a number of medications. Depressogenic effect is described in both psychotropic and somatotropic drugs. Depressions that occur when using psychotropic drugs are most often associated with the duration of administration and large doses of the drug. Some antihypertensive, antiarrhythmic, hypolipidemic drugs, antibiotics, hormones, antiparkinsonian drugs and antineoplastic agents are most often mentioned in the series of somatotropic drugs that have a depressogenic effect. Drug-induced depression is one of the most controversial issues. this article presents a systematization of available literature data on depression associated with taking various drugs.

Prescription pattern of anti-Parkinson's disease drugs in Japan based on a nationwide medical claims database

IntroductionParkinson's disease (PD) treatment should follow guidelines and be tailored to each patient. Large database analyses can provide insights into prescribing patterns.MethodsRetrospective, cross-sectional study of patients (≥30 years) with PD diagnosis (ICD-10; schizophrenia/cerebrovascular disease excluded) using health insurance claims data (April 2008–December 2016) from the Japan Medical Data Vision database. Prescription patterns of anti-PD drugs were analysed by patient age and sex, calendar year, and overall.ResultsThe analysis comprised 155,493 PD patient-years (56.1% women, mean 73.4 years). Patient number increased each year, mainly because of database expansion. L-dopa as monotherapy was the most common prescription (22.7% of patient-years); non-ergot dopamine agonists (DAs) were also common (7.6% as monotherapy, 6.8% with L-dopa). Monotherapy was prescribed for ~50% of patient-years, two drugs for 14.1%, and at least three drugs for 18.4%. Consistent with Japanese guidelines, L-dopa was mostly prescribed to older patients (≥60 years), whereas non-ergot DAs were mostly prescribed to middle-aged patients (peak at 50–69 years). Between 2008 and 2011, L-dopa prescription decreased while that of non-ergot DAs increased; this pattern reversed between 2012 and 2016.ConclusionThese results indicate that Japanese clinicians are adhering to Japanese guidelines and tailoring anti-PD treatment to individual patients.

The Prescribing Patterns of Antipsychotic Drugs and Antiparkinsonian Drugs in Elderly Patients with Dementia

The Prescribing Patterns of Antipsychotic Drugs and Antiparkinsonian Drugs in Elderly Patients with Dementia

EQUIDopa: A responsive web application for the levodopa equivalent dose calculator

Background and objectiveLevodopa/carbidopa intestinal gel infusion is a treatment option for patients of advanced stage of Parkinson's disease. This treatment requires the time-consuming and error-prone conversion of orally taken antiparkinson drugs into an equivalent replacing dose of levodopa/carbidopa, which is delivered via pump. In order to facilitate and speed up this conversion process, we developed a specific user-friendly application that would be available online or as a standalone mobile application. Such an application has now been written and designed in collaboration with a computer scientist and physician, who is also intended to be the final user. MethodsThe levodopa equivalent dose calculations are based on previous studies and data reported in the literature. Two related on-line conversion applications were analyzed and evaluated. The primary objectives of the application were determined, and basic functionalities were outlined. The application was implemented using modern development tools and frameworks. ResultsThe application has proven to be effective and easy to use in our clinical setting. It can serve as a control for manual calculations made by medical staff. It can also be applied as a useful tool in levodopa/carbidopa intestinal gel infusion courses for the advanced treatment of Parkinson's disease. ConclusionThe presented application could replace the tedious and error-prone levodopa equivalent dose conversion of antiparkinson drugs efficiently. In comparison to related on-line conversion applications, this specific application provides more functionality, reduces the risk of user errors, and can be run on a variety of devices. The conversion value provided by the application is only an estimate. The effect of the drugs is specific for each individual patient, which could not be considered in the calculations. Therefore, the responsibility of using the results of the application rests with the clinical judgment of the user. Nevertheless, the application can give us a good starting point for the initial pump setting, which would be adjusted further during the titration period, according to the patient's response.

“Peptic Esophageal Stricture In A Patient With Parkinson’s Disease”

Benign esophageal strictures are uncommon and their management remains challenging. Herein, we present a rare both functional and organic esophageal stricture in a patient with Parkinson’s disease and reflux esophagitis. The patient was diagnosed with severe complex stricture in the distal part of the esophagus, requiring surgical treatment. We performed subtotal esophageal resection and Ivor-Lewis gastroesophagoplasty. The successful management of antiparkinsonian drug therapy with adequate parenteral substitution in the early postoperative period is of great importance to avoid any further complications.

Guidelines on exercise testing and prescription for patients at different stages of Parkinson's disease.

Exercise is highly recommended in patients with Parkinson's disease (PD). Exercise-induced amelioration of motor, non-motor, and drug-induced symptoms are widely known. However, specific guidelines on exercise testing and prescription in PD are lacking. This study reviews the literature on exercise-based approaches to the management of symptoms at each stage of the disease and evaluate: (1) the most suitable clinical exercise testing; (2) training programs based on testing outcomes and PD stage; (3) the effects of exercise on antiparkinsonian drugs and to suggest the most effective exercise-medication combination. A systematic search was conducted using the databases MEDLINE, Google Scholar and, Cochrane Library using "Parkinson's Disease AND Physical therapy", "Training AND Parkinson", "Exercise", "Exercise AND Drug" as key words. In addition, references list from the included articles were searched and cross-checked to identify any further potentially eligible studies. Of a total of 115 records retrieved, 50 (43%) were included. From these, 23 were included under the rubric "exercise testing"; 20 focused on the effectiveness of different types of exercise in PD motor-functional symptoms and neuroprotective effects, throughout disease progression, were included under the rubric "training protocol prescription"; and 7 concern the rubric "interaction between exercise and medication", although none reported consistent results. Despite the lack of standardized parameters for exercise testing and prescription, all studies agree that PD patients should be encouraged to regularly train according to their severity-related limitations and their personalized treatment plan. In this manuscript, specific guidelines for tailored clinical testing and prescription are provided for each stage of PD.