Antiparkinsonian Agents Research Articles

Potential of Cellular and Animal Models Based on a Prion-Like Propagation of α-Synuclein for Assessing Antiparkinson Agents.

The pathological hallmark of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies (LBs). LBs are intracellular inclusions typically found in these neurons and in noradrenergic neurons of the locus coeruleus in patients with PD. However, LBs can be found more widely in neurons of the olfactory bulb, cerebral cortex, and spinal cord. Additionally, LBs appear in neurons of the cardiac, cutaneous, and intestinal autonomic nervous systems. LBs are composed of fibrillar aggregates of α-synuclein (α-syn). The widespread distribution of LBs indicates that α-syn aggregation occurs in neurons in various areas, supporting the concept that PD is not only a simple movement disorder but also a complex one with nonmotor impairments. However, it is unclear how α-syn pathology spreads in the nervous system. Postmortem analyses of patients with PD who received transplants of fetal mesencephalic dopaminergic neurons revealed LB formation in surviving grafts, providing a crucial clue regarding the host-to-graft disease propagation. Recent experiments demonstrated that fibrillar α-syn is transferred from neurons to neurons in cellular and animal models, suggesting that fibrillar α-syn is repeatedly generated in cells by triggering the continuous conversion of normal soluble species into fibrillar ones. These findings suggest a "prion-like" mechanism for α-syn propagation in the pathogenesis of PD. This review summarizes the experimental findings on the prion-like propagation of α-syn and discusses the potential of cellular and animal models for testing the protective effects of chemical agents against neurodegeneration in PD.

Anti-parkinsonian efficacy of target-specific GSK3β inhibitors demonstrated in Caenorhabditis elegans

Parkinson's disease (PD) is the second most common form of neurodegeneration among elderly individuals. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. Glycogen synthase kinase (GSK)-3β, a multifunctional protein has been implicated in the pathological characteristics of PD, including the heightened levels of α-synuclein, aberrant phosphorylated tau, and neurodegeneration. Hence, Gsk3β has been nominated as prime target for the development of new anti-parkinsonian agents. We have previously reported several series of target-specific inhibitors with the strong affinity toward GSK3β. In the present study, anti-parkinsonian efficacy of these inhibitors was evaluated in Caenorhabditis elegans model of PD. The inhibitors displayed low micromolar rescue potency when administered post-symptomatically, indicating both prevention and reversal of the dopaminergic deficit. The results indicate that GSK3β inhibitors rescued the behavioral deficit characteristic of dopaminergic impairment in transgenic C. elegans expressing human α-synuclein. In addition, GSK3β inhibition led to long-lasting prevention and rescue of neurodegeneration. Our findings indicate that the GSK3β activity is critical for neurodegeneration caused by α-synuclein accumulation, suggesting that kinase inhibition of GSK3β may represent a promising therapeutic strategy for PD.

A Comparative Study Between Spray-Drying and Fluidized Bed Coating Processes for the Preparation of Pramipexole Controlled-Release Microparticles for Orally Disintegrating Tablets

In the present study, controlled-release microparticles for orally disintegrating tablets (ODT) were prepared using two different processes, spray drying and fluidized bed coating processes. Pramipexole dihydrochloride monohydrate (PRM), an anti-Parkinson's disease agent, was selected as a model drug. The in vitro release rate and morphology of microparticles were evaluated and compared. The size of microparticles prepared by spray drying (SD microparticles) and fluidized bed coating (FC microparticles) was around 10 and 200 µm, respectively. The latter size was defined by the size of an inert core bead. The release behavior of SD microparticles was characterized by a large initial burst release prior to slow release. In the case of FC microparticles, the initial burst release was smaller than that of SD microparticles and the compression process damaged the release-controlling layer, which led to a change in release rate. The results indicated the importance of carefully considering the manufacturing process for microparticles during the design of controlled-release ODT.

Toxicity and metabolism of layered double hydroxide intercalated with levodopa in a Parkinson's disease model.

Layered hydroxide nanoparticles are generally biocompatible, and less toxic than most inorganic nanoparticles, making them an acceptable alternative drug delivery system. Due to growing concern over animal welfare and the expense of in vivo experiments both the public and the government are interested to find alternatives to animal testing. The toxicity potential of zinc aluminum layered hydroxide (ZAL) nanocomposite containing anti-Parkinsonian agent may be determined using a PC 12 cell model. ZAL nanocomposite demonstrated a decreased cytotoxic effect when compared to levodopa on PC12 cells with more than 80% cell viability at 100 μg/mL compared to less than 20% cell viability in a direct levodopa exposure. Neither levodopa-loaded nanocomposite nor the un-intercalated nanocomposite disturbed the cytoskeletal structure of the neurogenic cells at their IC50 concentration. Levodopa metabolite (HVA) released from the nanocomposite demonstrated the slow sustained and controlled release character of layered hydroxide nanoparticles unlike the burst uptake and release system shown with pure levodopa treatment.

A New Enantioselective Synthesis of the Anti-Parkinson Agent Safinamide

An alternative highly enantioselective synthesis of the anti-Parkinson agent safinamide from simple, commercially available, starting materials is described. The protocol might also be useful in the synthesis of structural variants of safinamide, such as ralfinamide or related analogues

Chinese culture permeation in the treatment of Parkinson disease: a cross-sectional study in four regions of China

BackgroundLittle is known about the clinical features and treatment of Chinese patients with Parkinson disease (PD).MethodsA large cross-sectional survey of clinical features, medication use, and motor complications was conducted in 901 consecutive PD patients, from 42 randomly selected university-affiliated hospitals in four urban economic regions of China, between December 2006 and May 2007.ResultsThe 901 PD patients had age range 30 to 88, and median disease duration 50 months. Most (737, 81.8%) used L-dopa (median 375 mg/day), and often added low doses of other antiparkinsonian agents. Among L-dopa-treated patients, the prevalence of motor complications was low (dyskinesias: 8.5%; motor fluctuations: 18.6%), even among patients with disease duration ≥11 years (dyskinesias: 18.1%; motor fluctuations: 42.2%). Higher L-dopa use was associated with higher occurrence of dyskinesias (OR 2.44; 95% CI 1.20-5.13) and motor fluctuations (OR 2.48; 95% CI 1.49-4.14). Initiating PD treatment with L-dopa alone (OR 0.46; 95% CI 0.22-0.95) or in combination with other medications (OR 0.41; 95% CI 0.19-0.87) was associated with less dyskinesia than treatment initiated with non-L-dopa medication.ConclusionsMany Chinese PD patients are treated with low-dose L-dopa and added low-dose antiparkinsonian agents, with a low prevalence of motor complications, which might be influenced by Chinese culture.

Medications and Impaired Driving

To describe the association of specific medication classes with driving outcomes and provide clinical recommendations. The MEDLINE and EMBASE databases were searched for articles published from January 1973 to June 2013 on classes of medications associated with driving impairment. The search included outcome terms such as automobile driving, motor vehicle crash, driving simulator, and road tests. Only English-language articles that contained findings from observational or interventional designs with ≥ 10 participants were included in this review. Cross-sectional studies, case series, and case reports were excluded. Driving is an important task and activity for the majority of adults. Some commonly prescribed medications have been associated with driving impairment measured by road performance, driving simulation, and/or motor vehicle crashes. This review of 30 studies identified findings with barbiturates, benzodiazepines, hypnotics, antidepressants, opioid and nonsteroidal analgesics, anticonvulsants, antipsychotics, antiparkinsonian agents, skeletal muscle relaxants, antihistamines, anticholinergic medications, and hypoglycemic agents. Additional studies of medication impact on sedation, sleep latency, and psychomotor function, as well as the role of alcohol, are also discussed. Psychotropic agents and those with central nervous system side effects were associated with measures of impaired driving performance. It is difficult to determine if such associations are actually a result of medication use or the medical diagnosis itself. Regardless, clinicians should be aware of the increased risk of impaired driving with specific classes of medications, educate their patients, and/or consider safer alternatives.

Use of Hyposmia and Other Non-Motor Symptoms to Distinguish between Drug-Induced Parkinsonism and Parkinson's Disease

Drug-induced Parkinsonism (DIP) secondary to antipsychotics and other dopamine antagonists is common and can be clinically indistinguishable from idiopathic Parkinson's disease (PD). Making the correct diagnosis is essential as it has important implications both for management of the underlying psychiatric condition and potentially lifelong therapy with antiparkinsonian agents. Additionally, because Parkinsonism does not always resolve with withdrawal of the offending agent or can recur years later, DIP may sometimes represent unmasking of incipient PD. The problem is increasing in scope as antipsychotic drugs are prescribed for a widening variety of indications, and understanding the factors that distinguish pharmacologic from degenerative Parkinsonism represents a significant unmet need. In this review, we discuss the rationale and evidence for using pre-clinical manifestations of PD, particularly non-motor symptoms, to distinguish between the conditions.

The Role of Multidrug Interactions in the Safety of Pharmacotherapy for Concomitant Parkinson’s Disease and Arterial Hypertension in Poland

Purpose: Multidrug interactions are amongst to the most frequent problems of pharmacotherapy. Such potentially harmful interactions are likely to occur in Parkinson’s disease (PD) patients treated with concomitant arterial hypertension. The aim of this study was to analyze the prevalence of interactions between selected antiparkinson and hypotensive agents. Methods: The analysis included data on the pharmacotherapy of PD and arterial hypertension, obtained from 80 men and women, diagnosed with Hoehn and Yahr stage II and III. However, the table presented data refer to persondrugs (n=186), as some of the respondents were prescribed more than one antiparkinson and/or hypotensive agent. Results: A total of 53 (28.5%) person-interactions were documented in the study group, among them 20 (10.8%) minor, 28 (25.8%) moderate and 5 (28.5%) major ones. The presence of interactions was documented in 37 (46.3%) patients. The number of different interactions present in a single patient amounted to three (n=3, 3.8%), two (n=10, 12.5%), one (n=24, 30.0%). Conclusions: Currently, we lack any detailed guidelines regarding pharmacotherapy of arterial hypertension and selection of hypotensive agents for patients with PD. Achieving desired hypotensive effect and reduction of adverse events resulting from drug-to-drug interactions constitute prerequisites of efficacious hypotensive treatment in patients with PD.

Community adherence to schizophrenia treatment and safety monitoring guidelines.

The 2003 Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations and the Mount Sinai Conference Safety Monitoring recommendations generated guidelines for pharmacological treatment of schizophrenia and monitoring of antipsychotic side effects. This study examined rate of recommendation adherence and impact of adherence on outcomes of outpatients with schizophrenia or schizoaffective disorder in community mental health centers. Clinical practice was assessed as conformant, nonconformant, or not applicable. Treatment practices were conformant for antipsychotic dose (83%); use of antiparkinsonian (97%), antidepressant (100%), and antianxiety agents (90%) but not clozapine for residual positive symptoms (31%); and monitoring weight gain (48%), glucose dysregulation (53%), hyperlipidemia (34%), or extrapyramidal symptoms (11%). Community mental health center treatment practices were largely conformant with the 2003 Schizophrenia PORT treatment recommendations. There is less evidence that patients who receive treatment in the community are adequately monitored for antipsychotic side effects per the Mount Sinai recommendations.

Patterns of antipsychotic prescription to patients with schizophrenia in Korea: results from the health insurance review & assessment service-national patient sample.

This study aimed to analyze the patterns of antipsychotic prescription to patients with schizophrenia in Korea. Using the Health Insurance Review & Assessment Service-National Patients Sample (HIRA-NPS), which was a stratified sampling from the entire population under the Korean national health security system (2009), descriptive statistics for the patterns of the monopharmacy and polypharmacy, neuropsychiatric co-medications, and prescribed individual antipsychotic for patients with schizophrenia were performed. Comparisons of socioeconomic and clinical factors were performed among patients prescribed only with first- and second-generation antipsychotics. Of 126,961 patients with schizophrenia (age 18-80 yr), 13,369 were prescribed with antipsychotic monopharmacy and the rest 113,592 with polypharmacy. Two or more antipsychotics were prescribed to 31.34% of the patients. Antiparkinson medications (66.60%), anxiolytics (65.42%), mood stabilizers (36.74%), and antidepressants (25.90%) were co-medicated. Patients who were prescribed only with first-generation antipsychotics (n=26,254) were characterized by significantly older age, greater proportion of male, higher proportion of medicaid, higher total medical cost, lower self-payment cost, and higher co-medication rates of antiparkinson agents and anxiolytics than those who were prescribed only with second-generation antipsychotics (n=67,361). In this study, it has been reported substantial prescription rates of first-generation antipsychotics and antipsychotic polypharmacy and relatively small prescription rate of clozapine to patients with schizophrenia. Since this study has firstly presented the patterns of antipsychotic prescription to schizophrenic patients in Korean national population, the findings of this study can be compared with those of later investigations about this theme.

Desafíos en el manejo farmacoterapéutico del paciente ingresado con enfermedad de Parkinson

Patients with Parkinson's disease (PD) are admitted to hospital more frequently and for a longer time than other patients from the same age group. The reason they are hospitalised is often different from their underlying baseline disease and they are usually attended in services with little knowledge of the disease. Both the errors made when administering levodopa and the inappropriate use of pharmacological agents with a central antidopaminergic action are relatively common during their stay in hospital. This study reports on an analysis of the literature available on the challenges and complications that patients with PD have to deal with when they are admitted to hospital, especially those that have to do with pharmacotherapy. Likewise, the authors also propose a series of strategies that lead to better care of the patients during the time they are in hospital, including aspects such as controlling the supplies of antiparkinsonian medication and establishing protocols for the therapeutic exchange of antiparkinsonian agents, as well as protocols for a suitable management of comorbidities in this kind of patients. Other strategies involve encouraging self-management of the antiparkinsonian treatment by the hospitalised patients, conducting follow-up studies to monitor inappropriate prescriptions or creating the figure of 'specialist in PD'. To do so, it will be necessary to raise the awareness of the healthcare staff at the hospital, as well as that of both patients and their relatives, about the problems derived from an inappropriate management of pharmacotherapy in PD.

Trends in antiparkinsonian medication use in new zealand: 1995-2011.

Prescribing trends for medications are influenced by development of new drugs, changes in knowledge about efficacy and side effects, and priorities set by funding agencies. Changes in the utilization of antiparkinsonian agents in the outpatient community in New Zealand were investigated by using the national prescription database for the period 1995–2011. The dispensed volumes of antiparkinsonian agents were converted into number of defined daily doses per 1000 inhabitants per day for analysis. Increases in the dispensed volumes of levodopa (77%), amantadine (350%), and catechol-o-methyl transferase inhibitors (326%) occurred during the study period. Conversely, decreases in the dispensed volumes of anticholinergics (48%), selegiline (82%), and dopamine agonists (6.2%) were observed. New Zealand has seen a substantial increase of the amount of levodopa dispensed in the past 17 years. This increase appears to be related to an increase in the number of people taking the medication. We are unable to extrapolate this change to an increase in the prevalence of PD, given levodopa is used in the treatment of a number of medical conditions. The changes in other antiparkinsonian medications largely reflect changes in availability (increases in entacapone and ropinirole) and best practice treatment (declines in anticholinergics, selegiline, and tolcapone).

Design, synthesis and biological evaluation of peptide derivatives of l-dopa as anti-parkinsonian agents

A series of dipeptide derivatives of l-dopa were synthesized and investigated for their pharmacological activity using the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat as an experimental model of Parkinson’s disease. Among them, (S)-isopropyl 2-(2-amino-2-methylpropanamido)-3-(3,4-dihydroxyphenyl)propanoate (4g) was found to be the most active compound, with 106% AUC activity and 149% peak activity of l-dopa after oral administration.

Assessment of Therapeutic Potential of Amantadine in Methamphetamine Induced Neurotoxicity

Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti-addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity.

Effects of antiparkinsonian agents on β-amyloid and α-synuclein oligomer formation in vitro

The aggregation of β-amyloid protein (Aβ) and α-synuclein (αS) are hypothesized to be the key pathogenic event in Alzheimer's disease (AD) and Lewy body diseases (LBD), with oligomeric assemblies thought to be the most neurotoxic. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for patients with AD and LBD. Here, we examined the effects of antiparkinsonian agents (dopamine, levodopa, trihexyphenidyl, selegiline, zonisamide, bromocriptine, peroxide, ropinirole, pramipexole, and entacapone) on the in vitro oligomer formation of Aβ40, Aβ42, and αS using a method of photo-induced cross-linking of unmodified proteins (PICUP), electron microscopy, and atomic force microscopy. The antiparkinsonian agents except for trihexyphenidyl inhibited both Aβ and αS oligomer formations, and, among them, dopamine, levodopa, pramipexole, and entacapone had the stronger in vitro activity. Circular dichroism and thioflavin T(S) assays showed that secondary structures of Aβ and αS assemblies inhibited by antiparkinsonian agents were statistical coil state and that their seeding activities had disappeared. The antiparkinsonian agents could be potential therapeutic agents to prevent or delay AD and LBD progression.

In silico Target Fishing for the Potential Targets and Molecular Mechanisms of Baicalein as an Antiparkinsonian Agent: Discovery of the Protective Effects on NMDA Receptor‐Mediated Neurotoxicity

The flavonoid baicalein has been proven effective in animal models of parkinson's disease; however, the potential biological targets and molecular mechanisms underlying the antiparkinsonian action of baicalein have not been fully clarified. In the present study, the potential targets of baicalein were predicted by in silico target fishing approaches including database mining, molecular docking, structure-based pharmacophore searching, and chemical similarity searching. A consensus scoring formula has been developed and validated to objectively rank the targets. The top two ranked targets catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) have been proposed as targets of baicalein by literatures. The third-ranked one (N-methyl-d-aspartic acid receptor, NMDAR) with relatively low consensus score was further experimentally tested. Although our results suggested that baicalein significantly attenuated NMDA-induced neurotoxicity including cell death, intracellular nitric oxide (NO) and reactive oxygen species (ROS) generation, extracellular NO reduction in human SH-SY5Y neuroblastoma cells, baicalein exhibited no inhibitory effect on [(3) H]MK-801 binding study, indicating that NMDAR might not be the target of baicalein. In conclusion, the results indicate that in silico target fishing is an effective method for drug target discovery, and the protective role of baicalein against NMDA-induced neurotoxicity supports our previous research that baicalein possesses antiparkinsonian activity.

A Case Study on the Use of Trihexyphenidyl, Korean Medical Treatment for the Control of Sialorrhea in Patients with Amyotrophic Lateral Sclerosis(ALS)※

[Abstract] Objectives : Sialorrhea in amyotrophic lateral sclerosis patients is a cause of death due to aspiration pneumonia as well as reduces the patient's quality of life. We report the changes that appeared in the sialorrhea treated by using trihexyphenidyl and Korean medical treatments. Methods : We treated amyotrophic lateral sclerosis patient with sialorrhea by using trihexyphenidyl a known antiparkinsonian agent and Korean medical treatments such as acupuncture, pharmacopuncture and herbal medicine. The salivation rate was checked with visual analogue scale(VAS). Results : There was a more than 50 % decrease in salivation in this case. Owing to the constipation, trihexyphenidyl was stopped after which only Korean medical treatments were provided. Over which a lasting decrease in salivation could be seen. Conclusions : Existing treatments would cause several considerable side effects and have difficulty in being applied in domestic clinics. In this respect, we suspect that our findings could open up new clinical guideline possibilities. We should solve the limitations of this case study and conduct more studies.

Atorvastatin improves cognitive, emotional and motor impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats, an experimental model of Parkinson's disease

Affective disorders and memory impairments precede the classical motor symptoms seen in Parkinson's disease (PD) and the currently approved antiparkinsonian agents do not alleviate the non-motor symptoms as well as the underlying dopaminergic neuron degeneration. On the other hand, there is increasing evidence that inflammation plays a key role in the pathophysiology of PD and that the anti-inflammatory actions of statins are related to their neuroprotective properties against different insults in the CNS. The present data indicates that the oral treatment with atorvastatin (10mg/kg/day), once a day during 7 consecutive days, was able to prevent short-term memory impairments and depressive-like behavior of rats assessed in the social recognition and forced swimming tests at 7 and 14 days, respectively, after a single intranasal (i.n.) administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1mg/nostril). Importantly, at this time no significant alterations on the locomotor activity of the animals were observed in the open field test. Moreover, atorvastatin was found to protect against the long-lasting motor deficits evaluated in activity chambers and the loss of dopaminergic neurons in the substantia nigra pars compacta observed at 21 days after i.n. MPTP administration. At this time, despite the absence of spatial memory deficits in the water maze and in concentrations of the cytokines TNF-α, IL-1β and IL-10 in striatum and hippocampus following i.n. MPTP administration, atorvastatin treatment resulted in a significant increase in the striatal and hippocampal levels of nerve growth factor (NGF). These findings reinforce and extend the notion of the neuroprotective potential of atorvastatin and suggest that it may represent a new therapeutic tool for the management of motor and non-motor symptoms of PD.

Zonisamide for seizures in Parkinson's disease with dementia

Zonisamide (ZNS) is a sulphonamide antiepileptic drug (AED) used to treat epilepsy around the world. Recent studies suggested that ZNS is an effective treatment for motor and nonmotor symptoms of Parkinson’s disease (PD) (for a review). However, only one randomized, double-blind, multicentre, placebo-controlled study conducted in Japan demonstrated the efficacy of ZNS as add-on administration in treating motor symptoms in PD patients, and most observations relating to the effectiveness of ZNS for PD symptoms have been made in Japan, where the drug was originally synthesized and released in March 2009 as an antiparkinsonian agent. Here we report the case of a Caucasian 78 year-old male patient with longstanding PD and dementia, who came to our attention because he developed nocturnal seizures; ZNS treatment significantly improved both his epilepsy and PD, without affecting cognitive functions.