Antiparkinsonian Agents Research Articles

2018 New Drug Update.

Five new drugs marketed within the last year, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs include an anticoagulant, an antiparkinson agent, an agent for tardive dyskinesia, an agent for psoriasis, and an agent for constipation. The drugs reviewed are betrixaban, safinamide mesylate, valbenazine tosylate, guselkumab, and plecanatide.

Neuroprotective effect of IDPU (1-(7-imino-3-propyl-2,3-dihydrothiazolo [4,5-d]pyrimidin-6(7H)-yl)urea) in 6-OHDA induced rodent model of hemiparkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative motor disorder characterized by the degeneration of dopaminergic nigrostriatal neurons. Levodopa (l-DOPA) is the most effective therapy for PD, however, PD progression continues with significant side effects in long term, thus necessitating the search for effective therapy that impedes PD progression. PD therapy through non-dopaminergic pathways offers treatment without the risk of extrapyramidal effects. In this regard, earlier, we had reported, a novel compound IDPU with potential adenosine A2A receptor antagonist effect in haloperidol (chronic treatment) induced Parkinson model. In the present study, we extended our investigation towards i) evaluation of IDPU in well-established 6-OHDA induced Parkinson rat model to establish its role in the therapy of PD ii) its function in alleviating the neuronal loss. We carried the IDPU administration (i.p.) in rats for two weeks after establishing 6-OHDA induced unilateral lesions. The behavioral activity, neurochemical alteration, oxidative stress marker and tyrosine hydroxylase positive neurons in substantia nigra were analyzed. The results showed that IDPU significantly reduced motor and non-motor deficits induced by 6-OHDA in the behavioral tasks such as apomorphine, rota rod and force swim test. Furthermore, the results of oxidative stress biomarkers revealed that IDPU successfully modulated oxidative stress associated biomarkers such as MDA, catalase, superoxide dismutase, nitric oxide and reduced glutathione level. Additionally, IDPU significantly elevated intracellular dopamine, decreased glutamate and calcium levels in brain as compared to 6-OHDA alone treated animals which is evocative of its neuroprotective behavior. Thus, the investigations clearly validated IDPU as a potent anti-parkinsonian agent which showed immense capability to protect neurodegeneration.

Synthesis, Biological Evaluation and Molecular Modeling Studies of Propargyl-Containing 2,4,6-Trisubstituted Pyrimidine Derivatives as Potential Anti-Parkinson Agents.

Monoamine oxidase B (MAO-B) inhibitors are potential drug candidates for the treatment of various neurological disorders including Parkinson's disease. A total of 20 new propargyl-containing 2,4,6-trisubstituted pyrimidine derivatives were synthesized and screened for MAO inhibition using Amplex Red assays. All the synthesized compounds were found to be reversible and selective inhibitors of the MAO-B isoform at sub-micromolar concentrations. MVB3 was the most potent MAO-B inhibitor with an IC50 value of 0.38±0.02 μμ, whereas MVB6 (IC50 =0.51±0.04 μμ) and MVB16 (IC50 =0.48±0.06 μμ) were the most selective for MAO-B with a selectivity index of more than 100-fold. In cytotoxic studies, these compounds were found to be nontoxic to human neuroblastoma SH-SY5Y cells at concentrations of 25 μm. MVB6 was found to decrease the intracellular level of reactive oxygen species to 68 % at 10 μm concentration, whereas other compounds did not produce significant changes in reactive oxygen species levels. In molecular modeling studies, MVB3 displayed strong binding affinity for the MAO-B isoform with a dock score of -10.45, in agreement with the observed activity. All the compounds fitted well in the hydrophobic cavity of MAO-B. Thus, propargyl-substituted pyrimidine derivatives can be promising leads in the development of potent, selective and reversible MAO-B inhibitors for the treatment of Parkinson's disease.

Actual Versus Expected Doses of Half Tablets Containing Prescribed Psychoactive Substances: A Systematic Review.

To assess through a systematic review of the literature if the practice of splitting tablets containing psychoactive/psychotropic medications for medical or economic reasons would result in the expected doses. A MEDLINE and PsycInfo comprehensive search of English-language publications from January 1999 to December 2015 was conducted using the terms describing tablet splitting (tablet splitting, split tablets, tablet subdivision, divided tablets, and half tablets) and psychoactive substances (psychoactive medicines, psychotropic medicines, antidepressants, anxiolytics, anticonvulsants, antipsychotics, and antiparkinsonian agents). An additional supplementary search included the references from the articles found. Studies were included if splitting content was directly related to psychoactive medications and examined the effect of tablet splitting on drug uniformity, weight uniformity, and adherence of psychoactive drugs. Articles were systematically reviewed and examined regarding the study design, methodology, and results of the study. A total of 125 articles were screened, and 13 were selected. Tablet splitting implications are extensive, yet substantial deviations from the ideal weight, potency, and dose uniformity are more prone to be important to patient safety. The uneven division of tablets might result in the administration of different doses than what was prescribed, causing under- or overdosing, which might be relevant depending on the drug. In 55% of the cases, splitting psychoactive drugs was satisfactory. It cannot be generalized that splitting psychoactive drugs compromises dose accuracy, thus tablet splitting might still be employed in cases in which the advantages outweigh the disadvantages. It is recommended that alternatives be adopted to prevent the disadvantages related to tablet splitting.

272 - A Case Series of Trihexyphenidyl Abuse for Recreational Purpose in Thai Children and Adolescents

Purpose: To demonstrate clinical presentation of children and adolescents who took trihexyphenidyl (street name is B5) for recreational purpose and psychosocial impact among them. Trihexyphenidyl is an antimuscarinic antiparkinsonian agent which is used for the adjunctive treatment of all forms of parkinsonian syndrome and also for the relief of parkinsonian signs and symptoms of antipsychotic agent-induced (e.g., butyrophenones, phenothiazines, thioxanthenes) extrapyramidal effects. Until now, there has not been a documented report of trihexyphenidyl abuse in Thailand.

Levodopa: A new look at an old friend

Levodopa is the most effective antiparkinsonian agent, but chronic treatment is associated with the development of motor complications in the majority of patients with PD. Recent scientific and clinical advances are improving this situation. Long-term, double-blind studies demonstrate that dose is an important risk factor for the development of both motor fluctuations and dyskinesia, and suggest that it is best to use low doses of l-dopa when possible. Inhaled l-dopa and sublingual apomorphine are now being developed as rescue therapies that permit rapid and predictable reversal of off periods. Finally, substantial evidence suggests that motor complications are related to the nonphysiological restoration of brain dopamine with intermittent oral doses of standard l-dopa. Double-blind studies demonstrate significant clinical benefits with continuous intraintestinal infusion of l-dopa. New approaches that provide continuous plasma l-dopa levels without the need for a surgical procedure are currently being investigated. Finally, the development of an oral long-acting form of l-dopa that provides continuous plasma l-dopa levels is actively being pursued. Collectively, these approaches offer the potential to considerably reduce and even prevent the disability associated with l-dopa-induced motor complications. © 2017 International Parkinson and Movement Disorder Society.

Studies on 16,17-Pyrazoline Substituted Heterosteroids as Anti-Alzheimer and Anti-Parkinsonian Agents Using LPS Induced Neuroinflammation Models of Mice and Rats

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common forms of neurodegenerative disorders. Dehydroepiandrosterone (DHEA) has been reported as a neuroprotective steroid useful in the therapeutic management of neurodegenerative disorders such as AD and PD. Herein we report the synthesis and evaluation of a new series of 16,17-pyrazolinyl DHEA analogues 2-4a-d as neuroprotective agents using LPS-induced neuroinflammation animal models. Treatment with the pyrazoline substituted steroids considerably improved the LPS-induced learning, memory and movement deficits in animal models. Suppression of biochemical parameters of oxidative and nitrosative stress, acetylcholinesterase activity, and TNF-α levels was also observed. 16,17-Pyrazolinyl steroids 2c-4c substituted with a 4-pyridyl moiety at the 5-position of the heterocyclic ring were found to be the most potent agents and produced neuroprotective effects better than standard drugs celecoxib and dexamethasone. Of these pyrazoline substituted steroids, the N-acetyl analogue 3c displayed neuroprotective effects better than N-phenyl (4c), which in turn showed potency more than N-unsubstituted analogue 2c.

Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents

New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual-target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19.

Medicaments and oral healthcare 5. Adverse effects of -medications and over-the-counter drugs on teeth

Intrinsic tooth discoloration may occur as an adverse effect of fluoride and tetracyclines. Extrinsic tooth discoloration may occur as superficial staining or as discoloration of the superficial pellicle and/or biofilm due to chlorhexidine, liquid iron salts, essential oils, some antibiotics and stannous fluoride. Inhibition of orthodontic tooth movement has been reported due to the use of prostaglandin synthetase inhibitors. If medications or over-the-counter drugs induce hyposalivation or contain much sucrose, caries may develop. Erosion may occur if the acidity of medications or over-the-counter drugs is excessive. Attrition is a well-known adverse effect of serotonin reuptake inhibitors, antiparkinson agents, and antipsychotics. Congenital dysplasia is observed following childhood treatment with cytostatic drugs. External cervical root resorption is an adverse effect of internal teeth-whitening products. Prenatal exposure to antiepileptic drugs and childhood treatment with cytostatic drugs may cause dental agenesis. Antiseptic drugs applied for external teeth-whitening and toothpastes with additional ingredients to prevent extrinsic discoloration and creation of calculus, may cause tooth hypersensitivity.

Antiparkinsonian Efficacy of Guanosine in Rodent Models of Movement Disorder.

Guanosine (GUO) is a guanine-based purine nucleoside with important trophic functions and promising neuroprotective properties. Although the neuroprotective effects of GUO have been corroborated in cellular models of Parkinson’s disease (PD), its efficacy as an antiparkinsonian agent has not been fully explored in PD animal models. Accordingly, we evaluated the effectiveness of GUO in reversing motor impairments in several rodent movement disorder models, including catalepsy, tremor, and hemiparkinsonism. Our results showed that orally administered GUO antagonized reserpine-mediated catalepsy, reduced reserpine-induced tremulous jaw movements, and potentiated the number of contralateral rotations induced by L-3,4-dihydroxyphenylalanine in unilaterally 6-hydroxidopamine-lesioned rats. In addition, at 5 and 7.5 mg/kg, GUO inhibited L-DOPA-induced dyskinesia in rats chronically treated with a pro-dopaminergic agent. Overall, we describe the therapeutic potential of GUO, which may be effective not only for reversing parkinsonian motor impairments but also for reducing dyskinesia induced by treatment for PD.

Prescription pattern and awareness of disease and treatment in patients of Parkinson's disease.

This cross-sectional study aimed to evaluate the prescription pattern, awareness of disease and treatment in patients with Parkinson's disease (PD). A total of 100 PD patients, attending a tertiary care hospital in Mumbai were included. Prescriptions were analyzed and awareness was evaluated using a questionnaire. The mean number of anti-Parkinson agents (APA) prescribed was 1.52±0.65. Number of APA strongly correlated with disease duration (ρ =0.818; p<0.001). Many APA were underutilized (prescribed daily dose/defined daily dose < 1). There was no awareness of all items on symptoms and alternative therapeutic options. Awareness of disease impairments (32%), long-term complications (28%), dosing regimen (46%) and follow-up (36%) was poor. More than one APA is commonly prescribed in PD patients. Awareness of disease and treatment of PD is poor among the patients.

Preliminary studies of berberine and its semi-synthetic derivatives as a promising class of multi-target anti-parkinson agents

Parkinson’s disease (PD) is a neurodegenerative disorder bearing motor and nonmotor symptoms. The treatment today is symptomatical rather than preventive or curative and this leaves the field open for the search of both novel molecular targets and drug candidates. Interference with α-synuclein fibrillation, monoamine oxidase (MAO) inhibition, modulation of adenosine receptors and the inhibition of specific phosphodiesterase (PDE) isoforms are some of the currently pursued strategies. We synthesised and studied some semi-synthetic berberine derivatives using a set of in silico tools. We evaluated their drug-likeness and tested the compounds against a set of target proteins involved in the onset or progression of PD, with a particular attention to MAO-B. Preliminary in vitro assay on MAO-B confirmed our in silico predictions.

In silico ADME, Bioactivity and Toxicity Prediction of Some Selected Anti-Parkinson Agents

Parkinsonism, one of the most frequent CNS disorders characterized by tremor and hypokinesia. Several people affected from this disorder due to concurrent use of medications results as side effect. In this computational research investigation, we performed In-silico pharmacokinetic, bioactivity and toxicity study of some selected anti-parkinsonism agents. To design a new molecule having good pharmacological profile, this study will provide the lead information.Key Words: QSAR, TPSA, In Silico, bioactivity, Log P

Adverse drug reaction to antiparkinson agents in Idiopathic Parkinson Disease: a prospective observational study in a Movement Disorder outpatient clinic

Background: Parkinson disease (PD) generally requires therapy for prolonged periods often with multiple drugs; drug-related adverse effects often add to the existing morbidity. Although, such ADRs are common, comprehensive information about their incidence, severity, and ultimate health effects are not available. The objective of the study was to analyze the pattern of occurrence of Adverse Drug Reactions (ADRs) in patients receiving anti-parkinson agents (APA) in a tertiary care hospital. We also aimed to assess the causality, severity and preventability of these ADRs.Methods: This prospective, observational study with 6 month follow up was conducted among consecutive PD patients receiving anti parkinson agents attending the Movement disorder clinic of Neurology department between April 1st 2011 and September 30th 2012. Tools used were ADR Reporting form of National Pharmacovigilance centre, WHO causality scale, Hartwig and Siegel scale to assess severity and Schumock and Thornton scale to assess preventability of ADRs. Descriptive statistics was used and the values were expressed in numbers and percentages.Results: ADRs were experienced in 87 patients (82.1%) out of 106 patients and most of these patients were on combination therapy (66%). No gender difference in distribution of ADRs was observed. The most common reactions were sedation, dizziness, dry mouth and fatigue. The drug usage was in the order of pramipexole (58.4%), levodopa+carbidopa (55.7%), trihexyphenidyl (28.3%), entacapone (5.7%) and amantadine (7.5%). Majority of the ADRs were mild level 1 (71.1%). ADR was maximum with entacapone. Majority of ADRs belonged to the causality possible ADR category. All the ADRs came under the definitely or probably preventable category.Conclusions: ADRs with antiparkinsonian drugs is common but mild and preventable.

Trends in antipsychotic prescriptions for Japanese outpatients during 2006-2012: a descriptive epidemiological study.

This study aimed to assess the trends in antipsychotic prescriptions for outpatients in Japan, where a community-based approach to mental healthcare is emphasized. This descriptive epidemiological study used claims data from 1038 community pharmacies across Japan. Outpatients who were ≥18years old and receiving their initial antipsychotic prescription during 2006-2012 were evaluated. The annual trends were reported for monotherapies, polypharmacy, antipsychotic doses, and the concurrent prescription of psychotropic medications. The 152592 outpatients included 101133 (66%) adults (18-64years old) and 51459 (34%) older adults (≥65years old). Among the adults, second-generation antipsychotic monotherapy prescriptions increased from 49% in 2006 to 71% in 2012, first-generation antipsychotic monotherapy prescriptions decreased from 29 to 14%, and antipsychotic polypharmacy decreased from 23 to 15%, respectively. Among the older adults, second-generation antipsychotic monotherapy prescriptions increased from 64 to 82%, first-generation antipsychotic monotherapy prescriptions decreased from 29 to 12%, and antipsychotic polypharmacy decreased from 7 to 6%, respectively. During the study period, >80% of the adults and >90% of the older adults received antipsychotics at risperidone-equivalent doses of <6mg/day. Anxiolytics/hypnotics, antidepressants, antiparkinson agents, mood stabilizers, and anti-dementia agents were concurrently prescribed with antipsychotics for 70, 33, 20, 20, and 0.3% of the adults and for 43, 16, 19, 8, and 16% of the older adults, respectively. The present study evaluated large-scale claims-based datasets and found that high-dose prescriptions and antipsychotic polypharmacy among Japanese outpatients were not as prevalent as has been previously thought. Copyright © 2017 John Wiley & Sons, Ltd.

Brain Mitochondrial Subproteome of Rpn10-Binding Proteins and Its Changes Induced by the Neurotoxin MPTP and the Neuroprotector Isatin.

Mitochondria play an important role in molecular mechanisms of neuroplasticity, adaptive changes of the brain that occur in the structure and function of its cells in response to altered physiological conditions or development of pathological disorders. Mitochondria are a crucial target for actions of neurotoxins, causing symptoms of Parkinson's disease in various experimental animal models, and also neuroprotectors. Good evidence exists in the literature that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria), and neuroprotective effects of certain antiparkinsonian agents (monoamine oxidase inhibitors) may be associated with their effects on UPS. The 19S proteasomal Rpn10 subunit is considered as a ubiquitin receptor responsible for delivery of ubiquitinated proteins to the proteasome proteolytic machinery. In this study, we investigated proteomic profiles of mouse brain mitochondrial Rpn10-binding proteins, brain monoamine oxidase B (MAO B) activity, and their changes induced by a single-dose administration of the neurotoxin MPTP and the neuroprotector isatin. Administration of isatin to mice prevented MPTP-induced inactivation of MAO B and influenced the profile of brain mitochondrial Rpn10-binding proteins, in which two pools of proteins were clearly recognized. The constitutive pool was insensitive to neurotoxic/neuroprotective treatments, while the variable pool was specifically influenced by MPTP and the neuroprotector isatin. Taking into consideration that the neuroprotective dose of isatin used in this study can result in brain isatin concentrations that are proapoptotic for cells in vitro, the altered repertoire of mitochondrial Rpn10-binding proteins may thus represent a part of a switch mechanism from targeted elimination of individual (damaged) proteins to more efficient ("global") elimination of damaged organelles and whole damaged cells.

Oxidation-Reduction Condensation of Diazaphosphites for Carbon-Heteroatom Bond Formation Based on Mitsunobu Mechanism.

An efficient oxidation-reduction condensation reaction of diazaphosphites with various nonacidic pronucleophiles in the presence of DIAD as a weak oxidant has been developed for carbon-heteroatom bond formation. This mild process affords structurally diverse tertiary amines, secondary amines, esters, ethers, and thioethers in moderate to excellent yields. The selective synthesis of secondary amines from primary amines has been achieved. Importantly, a practical application to the synthesis of antiparkinsonian agent piribedil has been demonstrated.

Natural Products Combating Neurodegeneration: Parkinson's Disease.

Parkinson's disease (PD) is characterized by neurodegeneration and a progressive functional impairment of the midbrain nigral dopaminergic neurons. The cause remains unknown; however, several pathological processes and central factors, such as protein aggregation, mitochondrial dysfunction, iron accumulation, neuroinflammation and oxidative stress, have been reported. The current treatment method primarily targets symptoms by using anti-Parkinson drugs such as levodopa, carbidopa, dopamine (DA) agonists, monoamine oxidase type B inhibitors and anticholinergics to replace DA. When drug therapy is not satisfactory, surgical treatments are recommended. Unfortunately, the existing conventional strategies that target PD are associated with numerous side effects and possess an economic burden. Therefore, novel therapeutic approaches that regulate the pathways leading to neuronal death and dysfunction are necessary. For many years, nature has provided the primary resource for the discovery of potential therapeutic agents. Remarkably, many natural products from medicinal plants, fruits and vegetables have been demonstrated to be efficacious anti-Parkinson agents. These products possess neuroprotective properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding iron accumulation, protein misfolding and the maintenance of proteasomal degradation, as well as mitochondrial homeostasis. The aim of this review is to report the available anti-Parkinson agents based on natural products and delineate their therapeutic actions, which act on various pathways. Overall, this review emphasizes the types of natural products that are potential future resources in the treatment of PD as novel regimens or supplementary agents.

Practical management of adverse events related to apomorphine therapy

The potential for adverse events is often cited as a barrier to the use of subcutaneous apomorphine therapy (intermittent injections and continuous infusion) in the management of Parkinson's disease. However, with proactive management most adverse effects are manageable if reported and tackled early enough. As such, proper clinician and patient awareness of the potential adverse effects is important to minimize their impact on the overall clinical utility of this efficacious antiparkinsonian agent. In this paper, we review the key local and systemic adverse effects reported during apomorphine titration, initiation and long-term treatment, and discuss practical management strategies.

Prescription Drug Use and Polypharmacy Among Medicaid-Enrolled Adults with Autism: A Retrospective Cross-Sectional Analysis.

BackgroundA lack of gold standard treatment for autism spectrum disorders (ASD), no clear ASD management guidelines, and lack of evidence-based pharmacological interventions other than aripiprazole and risperidone elevate the risk of off-label prescribing and adverse effects among individuals with ASD, more so among adults.ObjectiveThe aim of this study was to identify and compare the types of prescription drug use, rates of polypharmacy, and characteristics associated with polypharmacy among adults with and without ASD in a retrospective cross-sectional analysis of a three-state Medicaid Analytic eXtract database (2000–2008).MethodsAdults aged 22–64 years with ASD (ICD9-CM code: 299.xx) were propensity score-matched to ‘no ASD’ controls by age, sex, and race. General polypharmacy (≥6 unique classes of prescription drugs in a year) and psychotropic polypharmacy (≥3 unique prescription drug classes of psychotropic medications within a 90-day period) were the main study outcomes. Chi-square tests for rates, t tests for mean number of claims, and multivariate logistic regressions for likelihood of prescription drug use and polypharmacy were run.ResultsAnnually, almost 75% of adults with ASD had >20 prescription drug claims compared with 33% of adults without ASD. Around 85% of adults with ASD used at least one psychotropic drug class compared with 42% of adults without ASD. Highly common psychotropics were antipsychotics (66%ASD vs 20%noASD), anticonvulsants (59%ASD vs 20%noASD), and anxiolytics/hypnotics/sedatives (21%ASD vs 11%noASD). Other than psychotropics, many adults with ASD used medical prescription drugs such as antimicrobials (47%), dermatologic agents (48%), respiratory agents (38%), gastrointestinal agents (31%), alternative medications (25%), antiparkinsonian agents (22.6%), antihyperlipidemics/statins (7.3%), and immunologics (2.0%). Rates of general (48%ASD vs 32%noASD) and psychotropic polypharmacy (19%ASD vs 6%noASD) were significantly higher in the ASD group.ConclusionPrescription drug use and polypharmacy rates among adults with ASD are substantially higher than those in an age-, sex-, and race-matched cohort of adults without ASD. Adults with ASD frequently use therapeutic treatments other than psychotropics. Healthcare providers, who usually report low confidence in treating patients with ASD, should play an active role in constant monitoring of prescription drug use patterns and patient response to interventions. Prescribers and caregivers are encouraged to make decisions after weighing the benefits and risks associated with a pharmacological treatment. Further investigations into the common use of any alternative treatments that can affect a patient’s response to core treatments should also be conducted.Electronic supplementary materialThe online version of this article (doi:10.1007/s40801-016-0096-z) contains supplementary material, which is available to authorized users.