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Journal of Parkinson's Disease 2018Continuous dopaminergic stimulation in Parkinson's disease (PD) has several advantages over pulsatile, non-continuous, stimulation. These therapies currently consist of... (Review)
Review
Continuous dopaminergic stimulation in Parkinson's disease (PD) has several advantages over pulsatile, non-continuous, stimulation. These therapies currently consist of pump-based and transcutaneous therapies and are based on a more constant delivery of the dopaminergic drug resulting in continuous dopaminergic stimulation and a more stable treatment effect. Several clinical and experimental observations have shown that continuous stimulation of dopaminergic receptors induces fewer complications, such as dyskinesia, compared to pulsatile stimulation. Currently available non-oral pharmacological continuous therapies in PD include the transdermal Rotigotine (RTG) patch, infusion therapies with Apomorphine and Intrajejunal Levodopa (IJLI) and the Rivastigmine patch. Here we aim to provide a concise review of these current therapies and discuss ongoing and future developments of continuous non-oral pharmacological dopaminergic therapies in PD.
Topics: Antiparkinson Agents; Dopamine Agonists; Drug Delivery Systems; Humans; Parkinson Disease
PubMed: 30584160
DOI: 10.3233/JPD-181476 -
Angewandte Chemie (International Ed. in... Aug 2021Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target...
Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure-based strategy to identify dual-target ligands of G-protein-coupled receptors is presented. We use this approach to design compounds that both antagonize the A adenosine receptor and activate the D dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure-based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual-target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism.
Topics: Animals; Antiparkinson Agents; Drug Design; Drug Evaluation, Preclinical; Humans; Ligands; Molecular Structure; Rats; Receptor, Adenosine A2A; Receptors, Dopamine D2; Small Molecule Libraries
PubMed: 33904641
DOI: 10.1002/anie.202101478 -
Biological & Pharmaceutical Bulletin 2017DJ-1, encoded in a causative gene of familial Parkinson's disease (PARK7), has multiple functions: it works as an antioxidant, in transcriptional regulation, as a... (Review)
Review
DJ-1, encoded in a causative gene of familial Parkinson's disease (PARK7), has multiple functions: it works as an antioxidant, in transcriptional regulation, as a molecular chaperone and in protein degradation. Three types of pathogenic mutants of DJ-1 (M26I, D149A and L166P) have been reported to disrupt proper structures and lead to a loss of function. DJ-1 receives oxidation at the cysteine residue, and the degree of oxidation at the C106 residue determines DJ-1 activity. In this decade, DJ-1 has been reported to suppress the progression of various neurodegenerative disorders in animal models. The administration of recombinant wild-type DJ-1 protein suppresses the neuronal loss associated with both Parkinson's disease and ischemic stroke in rats. Furthermore, in studies focused on DJ-1 as the therapeutic target, compounds that have the capacity of binding to DJ-1 at the C106 residue have been reported to exert therapeutic effects on various neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and ischemic stroke. DJ-1 and DJ-1-targeting molecules/compounds will be useful therapeutic targets for various neurodegenerative disorders due to their various functions such as antioxidant capacity, chaperone function and as a proteolytic pathway.
Topics: Animals; Antiparkinson Agents; Humans; Neurodegenerative Diseases; Parkinson Disease; Protein Deglycase DJ-1
PubMed: 28458339
DOI: 10.1248/bpb.b16-01006 -
Current Neuropharmacology 2019The research progress of understanding the etiology and pathogenesis of Parkinson's disease (PD) has yet lead to the development of some clinical approaches intended to... (Review)
Review
The research progress of understanding the etiology and pathogenesis of Parkinson's disease (PD) has yet lead to the development of some clinical approaches intended to treat cognitive and behavioral symptoms, such as memory and perception disorders. Despite the major advances in different genetic causes and risk factors for PD, which share common pathways to cell dysfunction and death, there is not yet a complete model of PD that can be used to accurately predict the effect of drugs on disease progression. Clinical trials are also important to test any novel neuro-protective agent, and recently there have been great advances in the use of anti-inflammatory drugs and plant flavonoid antioxidants to protect against specific neuronal degeneration and its interference with lipid and cholesterol metabolism. The increasing knowledge of the molecular events underlying the degenerative process of PD has stimulated research to identify natural compounds capable of halting or slowing the progress of neural deterioration. Polyphenols and flavonoids, which play a neuroprotective role in a wide array of in vitro and in vivo models of neurological disorders, emerged from among the multi-target bio-agents found mainly in plants and microorganisms. This review presents a detailed overview of the multimodal activities of neuroprotective bio-agents tested so far, emphasizing their neurorescue/neuroregenerative activity. The brain-penetrating property of bioagents may make these compounds an important class of natural drugs for the treatment of neurodegenerative diseases. Although there are numerous studies demonstrating beneficial effects in the laboratory by identifying critical molecular targets, the clinical efficacy of these neuroprotective treatments remains to be proven accurately.
Topics: Animals; Antiparkinson Agents; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease
PubMed: 30479218
DOI: 10.2174/1570159X17666181127125704 -
Current Opinion in Neurology Aug 2014Later stage Parkinson's disease, sometimes referred to as advanced disease, has been characterized by motor complication, as well as by the potential emergence of... (Review)
Review
PURPOSE OF REVIEW
Later stage Parkinson's disease, sometimes referred to as advanced disease, has been characterized by motor complication, as well as by the potential emergence of nonlevodopa responsive motor and nonmotor symptoms. The management of advanced stage Parkinson's disease can be complex. This review summarizes the currently available treatment strategies for addressing advanced Parkinson's disease.
RECENT FINDINGS
We will discuss the latest pharmacological strategies (e.g., inhibitors of dopamine-metabolizing enzymes, dopamine agonists, and extended release dopamine formulations) for addressing motor dysfunction. We will summarize the risks and benefits of current invasive treatments. Finally, we will address the current evidence supporting the treatment of nonmotor symptoms in the advanced Parkinson's disease patient. We will conclude by detailing the potential nonpharmacological and multidisciplinary approaches for advanced stage Parkinson's disease.
SUMMARY
The optimization of levodopa is, in most cases, the most powerful therapeutic option available; however, medication optimization requires an advanced understanding of Parkinson's disease. Failure of conventional pharmacotherapy should precipitate a discussion of the potential risks and benefits of more invasive treatments. Currently, there are no comparative studies of invasive treatment. Among the invasive treatments, deep brain stimulation has the largest amount of existing evidence, but also has the highest individual per patient risk. Nonmotor symptoms will affect quality of life more than the motor Parkinson's disease symptoms, and these nonmotor symptoms should be aggressively treated. Many advanced Parkinson's disease patients will likely benefit from multi and interdisciplinary Parkinson's disease teams with multiple professionals collaborating to develop a collective and tailored strategy for an individual patient.
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 24978634
DOI: 10.1097/WCO.0000000000000118 -
Movement Disorders Clinical Practice Sep 2023Continuous subcutaneous apomorphine infusion (CSAI) is one of the advanced therapies for Parkinson's disease (PD). (Review)
Review
BACKGROUND
Continuous subcutaneous apomorphine infusion (CSAI) is one of the advanced therapies for Parkinson's disease (PD).
METHODS
A systematic review of all published articles in English on CSAI for PD till January 30, 2022 was conducted.
RESULTS
A total of 82 articles met the search criteria. Publications included retrospective or prospective open-label observational studies, with a limited number of randomized control trials (RCT). Publications were highly heterogeneous and focused on different aspects of CSAI and included clinical audits, effects on cognition/behavior, axial symptoms, nocturnal issues, adverse events/reasons for discontinuation and comparison with other continuous dopaminergic therapies. CSAI was used in patients who presented severe motor fluctuations not resolved by oral therapy, poor candidates for deep brain stimulation (DBS) due to cognitive/behavioral issues or in those with DBS weaning effect. Recent studies have also shown that CSAI was useful for nocturnal usage in advanced PD, in addition to daytime utilization. Adverse effects were common and include skin lesions, sedation and nausea. Pump management difficulties and patient decisions were common reasons for therapy dropout, predominantly during the initial stages of the CSAI.
CONCLUSION
There is consistent agreement on the benefits of CSAI in reducing OFF periods and improving ON periods without troublesome dyskinesia and specific motor and non-motor symptoms. Although there is a paucity of RCTs, current data from almost 30 years of use suggests CSAI to be beneficial in advanced cases of PD.
Topics: Apomorphine; Parkinson Disease; Humans; Infusions, Subcutaneous; Antiparkinson Agents; Dopamine Agonists; Deep Brain Stimulation
PubMed: 37772305
DOI: 10.1002/mdc3.13810 -
Cellular and Molecular Life Sciences :... Jun 2015Levodopa-induced dyskinesias (LIDs) occur in the majority of patients with Parkinson's disease (PD) following years of levodopa treatment. The pathophysiology underlying... (Review)
Review
Levodopa-induced dyskinesias (LIDs) occur in the majority of patients with Parkinson's disease (PD) following years of levodopa treatment. The pathophysiology underlying LIDs in PD is poorly understood, and current treatments generate only minor benefits for the patients. Studies with positron emission tomography (PET) molecular imaging have demonstrated that in advanced PD patients, levodopa administration induces sharp increases in striatal dopamine levels, which correlate with LIDs severity. Fluctuations in striatal dopamine levels could be the result of the attenuated buffering ability in the dopaminergically denervated striatum. Lines of evidence from PET studies indicate that serotonergic terminals could also be responsible for the development of LIDs in PD by aberrantly processing exogenous levodopa and by releasing dopamine in a dysregulated manner from the serotonergic terminals. Additionally, other downstream mechanisms involving glutamatergic, cannabinoid, opioid, cholinergic, adenosinergic, and noradrenergic systems may contribute in the development of LIDs. In this article, we review the findings from preclinical, clinical, and molecular imaging studies, which have contributed to our understanding the pathophysiology of LIDs in PD.
Topics: Antiparkinson Agents; Dopamine; Dopamine Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Molecular Imaging; Parkinson Disease; Receptors, Dopamine
PubMed: 25681866
DOI: 10.1007/s00018-015-1854-x -
Current Neuropharmacology 2023Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its... (Review)
Review
Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.
Topics: Humans; Antiparkinson Agents; Dopamine; Dyskinesias; Levodopa; Parkinson Disease; Serotonin; Zonisamide
PubMed: 35193486
DOI: 10.2174/1570159X20666220222150811 -
Ugeskrift For Laeger Feb 2017Parkinson's disease (PD) is a neurogenerative disease, which causes motoric disorders, and the risk of developing PD increases with age. There is an increasing number of... (Review)
Review
Parkinson's disease (PD) is a neurogenerative disease, which causes motoric disorders, and the risk of developing PD increases with age. There is an increasing number of persons above 60 years undergoing anaesthesia, and PD is becoming a common comorbidity. PD symptoms, delayed medicine administration or medical side effects can complicate anaesthesia. The importance of correct administration of PD medication administration must be emphasized to avoid complications. Optimized perioperative care can potentially prevent complicated and prolonged admission periods.
Topics: Aged; Anesthesia; Antiparkinson Agents; Humans; Intraoperative Complications; Middle Aged; Parkinson Disease; Perioperative Care; Postoperative Complications
PubMed: 28397662
DOI: No ID Found -
Frontiers in Bioscience (Landmark... Jan 2017The cortico-striatal network plays a major role in executive functions (EF), and is believed to play a role in the pathophysiology of Parkinson's disease (PD). However,... (Review)
Review
The cortico-striatal network plays a major role in executive functions (EF), and is believed to play a role in the pathophysiology of Parkinson's disease (PD). However, the tools to assess EF are limited. This review assesses the impact of all PD interventions, namely, pharmacotherapy, physical exercise and Deep Brain Stimulation (DBS) surgery on EF. The effect of PD pharmacotherapy varies with the drug class, neuropsychological test used and the affected dopamine receptor family. There appears to be a benefit of aerobic exercise on EF, including judgment and attention. The effect of Deep Brain Stimulation on EF might vary with site of brain stimulation, the neuropsychological test performed and the pre-operative cognitive state. The effect of EF on underlying manifestations and as a factor in the pathway to the motor benefit needs to be better assessed with more accurate tests that focus on motor component of EF.
Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Deep Brain Stimulation; Dopamine Agonists; Executive Function; Exercise Therapy; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease
PubMed: 27814622
DOI: 10.2741/4492