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Parkinsonism & Related Disorders Jul 2020Disorders of the gastrointestinal (GI) tract are common and distressing nonmotor symptoms of Parkinson's disease (PD) that can adversely affect levodopa absorption and... (Review)
Review
Disorders of the gastrointestinal (GI) tract are common and distressing nonmotor symptoms of Parkinson's disease (PD) that can adversely affect levodopa absorption and lead to OFF periods, also known as motor fluctuations. Gastroparesis, which is primarily defined as delayed gastric emptying (DGE), and Helicobacter pylori infection, which is present with increased frequency in PD, are among the most common and important GI disorders reported in PD that may impair oral levodopa absorption and increase OFF time. Symptoms of gastroparesis include nausea, vomiting, postprandial bloating, fullness, early satiety, abdominal pain, and weight loss. DGE has been reported in a substantial fraction of individuals with PD. Symptoms of H. pylori infection include gastritis and peptic ulcers. Studies have found that DGE and H. pylori infection are correlated with delayed peak levodopa plasma levels and increased incidence of motor fluctuations. Therapeutic strategies devised to minimize the potential that gastric complications will impair oral levodopa absorption and efficacy in PD patients include treatments that circumvent the GI tract, such as apomorphine injection, levodopa intestinal gel delivery, levodopa inhalation powder, and deep brain stimulation. Other strategies aim at improving gastric emptying in PD patients, primarily including prokinetic agents.
Topics: Antiparkinson Agents; Gastritis; Gastroparesis; Helicobacter Infections; Humans; Levodopa; Parkinson Disease; Peptic Ulcer
PubMed: 32461054
DOI: 10.1016/j.parkreldis.2020.05.001 -
Current Neuropharmacology 2018There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and... (Review)
Review
BACKGROUND
There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD.
METHODS
A review of literature was performed by searching PubMed and Google Scholar for relevant articles highlighting the pathogenic role of α-synuclein and the potential therapeutic implications of targeting various pathways related to this protein.
RESULTS
The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes. The mechanisms of monomeric α-synuclein aggregating to oligomers and fibrils have been investigated intensively, but it is still not certain which form of this natively unfolded protein is responsible for toxicity. Likewise the proteotoxic pathways induced by α- synuclein leading to neuronal death are not elucidated completely but mitochondrial dysfunction, endoplasmic reticulum (ER) stress and altered ER-golgi transport may play crucial roles in this process. At the molecular level, the ability of α-synuclein to form pores in biomembranes or to interact with specific proteins of the cell organelles and the cytosol could be determining factors in the toxicity of this protein.
CONCLUSION
Despite many limitations in our present knowledge of physiological and pathological functions of α-synuclein, it appears that this protein may be a target for the development of neuroprotective drugs against PD. This review has discussed many such potential drugs which prevent the expression, accumulation and aggregation of α-synuclein or its interactions with mitochondria or ER and thereby effectively abolish α-synuclein mediated toxicity in different experimental models.
Topics: Animals; Antiparkinson Agents; Humans; Neuroprotective Agents; Parkinson Disease; alpha-Synuclein
PubMed: 29189163
DOI: 10.2174/1570159X15666171129100944 -
International Journal of Molecular... May 2018Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders. Its main pathophysiological characteristic is the loss of dopaminergic neurons in... (Review)
Review
Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders. Its main pathophysiological characteristic is the loss of dopaminergic neurons in the substantia nigra pars compacta followed by a lack of striatal dopaminergic input and a consequent disinhibition of tonically active cholinergic interneurons. The resulting striatal hypercholinism causes major motor symptoms in PD. Anticholinergic pharmacotherapies have antiparkinsonian effects on motor symptoms, but, due to systemic actions, also numerous severe side effects occur on a regular basis. To circumvent these side effects, a local anticholinergic therapy acting exclusively in the striatum would be reasonable. Botulinum neurotoxin-A (BoNT-A) is synthesized by and blocks the release of acetylcholine from the presynaptic bouton. For several decades, BoNT-A has been used successfully for medical and cosmetic purposes to induce controlled paralyses of single muscles. Our group and others investigated the experimental treatment of striatal hypercholinism by the direct injection of BoNT-A into the striatum of rats and mice as well as of hemiparkinsonian animal models. This review gives an overview of the most important results of the experimental intrastriatal BoNT-A application, with a focus on hemiparkinsonian rats.
Topics: Acetylcholine Release Inhibitors; Animals; Antiparkinson Agents; Botulinum Toxins, Type A; Corpus Striatum; Drug Delivery Systems; Humans; Injections; Neuromuscular Agents; Parkinson Disease
PubMed: 29735936
DOI: 10.3390/ijms19051392 -
Movement Disorders : Official Journal... Mar 2021Nilotinib is US Food and Drug Administration-approved for leukemia, and this open-label study investigated the safety, tolerability, and potential clinical effects of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nilotinib is US Food and Drug Administration-approved for leukemia, and this open-label study investigated the safety, tolerability, and potential clinical effects of nilotinib in medically optimized patients with Parkinson's disease.
OBJECTIVES
Safety and tolerability were the primary objectives, and clinical outcomes were exploratory.
METHODS
A total of 63 patients completed a 15-month phase 2, double-blind, placebo-controlled study and were rerandomized 1:1 into an open-label study of nilotinib 150 mg versus 300 mg for 12 months.
RESULTS
Nilotinib was safe and tolerated, and no adverse effects seemed to be related to the drug, and no differences in adverse events were observed between groups. Exploratory clinical outcomes showed that nilotinib 300 mg was remarkably stable from baseline to 27 months using partial and total Unified Parkinson's Disease Scale (UPDRS). Nilotinib 150 mg versus 300 mg, significantly declined using partial or the sum of UPDRS Parts I and II. There was no significant difference in nilotinib 150 mg versus 300 mg using UPDRS Part III (on levodopa) and total UPDRS Parts I to III. Subgroup analysis showed that late-start nilotinib 150 mg significantly worsened using the sum of UPDRS Parts II + III and total UPDRS Parts I to III compared with late-start nilotinib 300 mg. Quality of life using the Parkinson's Disease Questionnaire in nilotinib 150 mg significantly declined between 15 and 27 months compared with nilotinib 300 mg, and there was no change in cognition using the Montreal Cognitive Assessment between groups.
CONCLUSIONS
This study provides evidence that nilotinib is safe and tolerated in Parkinson's disease. The exploratory clinical data will inform an adequately powered larger study to evaluate the efficacy of nilotinib 300 mg in Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Antiparkinson Agents; Double-Blind Method; Humans; Levodopa; Parkinson Disease; Pyrimidines; Quality of Life
PubMed: 33215762
DOI: 10.1002/mds.28389 -
Acta Pharmacologica Sinica Apr 2020
Topics: Antiparkinson Agents; Drug Development; Humans; Parkinson Disease
PubMed: 32203079
DOI: 10.1038/s41401-020-0369-7 -
Drugs in R&D Jun 2018Apomorphine is now recognized as the oldest antiparkinsonian drug on the market. Though still underused, it is increasingly prescribed in Europe for patients with... (Review)
Review
Apomorphine is now recognized as the oldest antiparkinsonian drug on the market. Though still underused, it is increasingly prescribed in Europe for patients with advanced Parkinson's disease (PD) with motor fluctuations. However, its history is far from being limited to movement disorders. This paper traces the history of apomorphine, from its earliest empirical use, to its synthesis, pharmacological development, and numerous indications in human and veterinary medicine, in light of its most recent uses and newest challenges. From shamanic rituals in ancient Egypt and Mesoamerica, to the treatment of erectile dysfunction, from being discarded as a pharmacological tool to becoming an essential antiparkinsonian drug, the path of apomorphine in the therapeutic armamentarium has been tortuous and punctuated by setbacks and groundbreaking discoveries. Throughout history, three main clinical indications stood out: emetic (gastric emptying, respiratory disorders, aversive conditioning), sedative (mental disorders, clinical anesthesia, alcoholism), and antiparkinsonian (fluctuations). New indications may arise in the future, both in PD (palliative care, nonmotor symptoms, withdrawal of oral dopaminergic medication), and outside PD, with promising work in neuroprotection or addiction.
Topics: Animals; Antiparkinson Agents; Apomorphine; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; Humans
PubMed: 29546602
DOI: 10.1007/s40268-018-0230-3 -
Biomedicine & Pharmacotherapy =... Nov 2020Parkinson's disease (PD) is a progressive neurodegenerative disease which affects millions of population worldwide. It is characterized by motor symptoms such as... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disease which affects millions of population worldwide. It is characterized by motor symptoms such as excessive tremor, bradykinesia, rigidity, postural instability and non-motor symptoms include neuropsychiatric complications like anxiety, depression, insomnia and cognitive impairment, orthostatic hypotension, sexual dysfunction and gastrointestinal complications. Treatment of anxiety in PD poses extensive challenge to global healthcare which makes it urgent to develop innovative treatment for the better management of the disease. The gold standard treatment by Levodopa provides symptomatic relief and its effect on neuropsychiatric complications like anxiety is elusive. Presence of anxiety worsens the condition and challenges therapeutic management of the PD. The in-depth analysis and understanding the molecular mechanism and pathophysiological pathways associated with the onset of anxiety in PD is essential. The disturbances in serotonergic, adrenergic and GABAergic neurons and hypothalamic pituitary adrenal axis play a significant role in the pathophysiology of anxiety. The drugs like Selective Serotonin Reuptake Inhibitors, tricyclic antidepressants and benzodiazepines are useful in the management of anxiety but due to severe side effects and progression of the disease it results in the failure of treatment. The present review imparts an insight in the management of anxiety in PD by understanding molecular mechanism and application of alternative treatment options which can enlighten the perception of researchers towards better therapeutic management of the disease.
Topics: Animals; Anti-Anxiety Agents; Antiparkinson Agents; Anxiety; Disease Progression; Humans; Levodopa; Parkinson Disease
PubMed: 33152935
DOI: 10.1016/j.biopha.2020.110776 -
Journal of Neural Transmission (Vienna,... Nov 2023Continuous drug delivery (CDD) has emerged as a feasible and pragmatic therapeutic option for dopamine replacement therapy in advanced Parkinson's disease (PD). CDD aims... (Review)
Review
Continuous drug delivery (CDD) has emerged as a feasible and pragmatic therapeutic option for dopamine replacement therapy in advanced Parkinson's disease (PD). CDD aims to mimic the physiological tonic dopamine release from striatal dopaminergic neurons and thus reduces the severity and duration of motor and non-motor fluctuations partly related to pulsatile levodopa stimulation. Non-motor symptoms and fluctuations are ubiquitous in PD and include sleep dysfunction, a problem that occurs in over 90% of PD patients across all stages, from prodromal to palliative. In this review, we discuss the currently available and in development non-oral dopaminergic CDD strategies with a focus on their efficacy in the treatment of the burdensome sleep dysfunction in PD.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Dopamine; Levodopa; Sleep Wake Disorders; Sleep
PubMed: 37126118
DOI: 10.1007/s00702-023-02640-7 -
Journal of Parkinson's Disease 2021Despite the COVID-19 pandemic, there has been considerable activity in the clinical development of novel and improved drug-based therapies for the neurodegenerative... (Review)
Review
BACKGROUND
Despite the COVID-19 pandemic, there has been considerable activity in the clinical development of novel and improved drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) during 2020. The agents that were investigated can be divided into "symptomatic" (alleviating the features of the condition) and "disease modifying" (attempting to address the underlying biology of PD) treatments, ST and DMT respectively, with further categorisation possible based on mechanism of action and class of therapy.
OBJECTIVE
Our goal in this report was to provide an overview of the pharmacological therapies -both ST and DMT - in clinical trials for PD during 2020-2021, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst commercial and academic researchers as well as between the research and patient communities.
METHODS
We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of February 18th 2021. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next.
RESULTS
We identified 142 trials on ClinicalTrials.gov and 14 studies on the WHO registries that met our analysis criteria. Of these 156 trials, 91 were ST and 65 were DMT, Of the 145 trials registered on ClinicalTrials.gov in our 2020 analysis, 45 fell off the list and 42 were added. Despite this change, the balance of ST to DMT; the distribution across phases; the profile of therapeutic categories; and the proportion of repurposed therapies (33.5%); all remained very similar. There are only two DMTs in phase 3, and we identified 33 in-between-phase projects.
CONCLUSIONS
Despite the effects of the coronavirus pandemic, investment and effort in clinical trials for PD appears to remain strong. There has been little change in the profile of the clinical trial landscape even though, over the past year, there has been considerable change to the content of the list.
Topics: Antiparkinson Agents; COVID-19; Clinical Trials as Topic; Drug Development; Humans; Parkinson Disease
PubMed: 34151864
DOI: 10.3233/JPD-219006 -
Current Neuropharmacology 2016Although a variety of therapeutic approaches are available for the treatment of Parkinson's disease, challenges limit effective therapy. Among these challenges are... (Review)
Review
BACKGROUND
Although a variety of therapeutic approaches are available for the treatment of Parkinson's disease, challenges limit effective therapy. Among these challenges are delivery of drugs through the blood brain barier to the target brain tissue and the side effects observed during long term administration of antiparkinsonian drugs. The use of drug delivery systems such as liposomes, niosomes, micelles, nanoparticles, nanocapsules, gold nanoparticles, microspheres, microcapsules, nanobubbles, microbubbles and dendrimers is being investigated for diagnosis and therapy.
METHODS
This review focuses on formulation, development and advantages of nanosized drug delivery systems which can penetrate the central nervous system for the therapy and/or diagnosis of PD, and highlights future nanotechnological approaches.
RESULTS
It is esential to deliver a sufficient amount of either therapeutic or radiocontrast agents to the brain in order to provide the best possible efficacy or imaging without undesired degradation of the agent. Current treatments focus on motor symptoms, but these treatments generally do not deal with modifying the course of Parkinson's disease. Beyond pharmacological therapy, the identification of abnormal proteins such as α -synuclein, parkin or leucine-rich repeat serine/threonine protein kinase 2 could represent promising alternative targets for molecular imaging and therapy of Parkinson's disease.
CONCLUSION
Nanotechnology and nanosized drug delivery systems are being investigated intensely and could have potential effect for Parkinson's disease. The improvement of drug delivery systems could dramatically enhance the effectiveness of Parkinson's Disease therapy and reduce its side effects.
Topics: Animals; Antiparkinson Agents; Blood-Brain Barrier; Brain; Dopamine Plasma Membrane Transport Proteins; Drug Delivery Systems; Humans; Nanocapsules; Nanoparticles; Parkinson Disease; Receptors, Dopamine
PubMed: 26714584
DOI: 10.2174/1570159x14666151230124904