-
Journal of Parkinson's Disease 2023The pathophysiology of Parkinson's disease (PD) tremor remains incompletely understood and there is a lack of clinical trials specifically addressing its pharmacological... (Review)
Review
The pathophysiology of Parkinson's disease (PD) tremor remains incompletely understood and there is a lack of clinical trials specifically addressing its pharmacological treatment. Levodopa is the most efficacious drug for most patients and should be used as primary approach to control troublesome tremor. While the efficacy of oral dopamine agonists on PD tremor has been demonstrated in controlled trials, there is no evidence of greater antitremor efficacy compared to levodopa. The magnitude of the antitremor effect of anticholinergics is generally lower than that of levodopa. Due to their adverse effects, anticholinergics have a limited role in selected young and cognitively intact patients. Propranolol may improve resting and action tremor and may be considered as an adjunct in patients with insufficient tremor response to levodopa and this also applies to clozapine, despite its unfavorable adverse effect profile. Treating motor fluctuations with MAO-B and COMT inhibitors, dopamine agonists, amantadine, or on-demand treatments such as subcutaneous or sublingual apomorphine and inhaled levodopa as well as with continuous infusions of levodopa or apomorphine will improve off period tremor episodes. For patients with drug-refractory PD tremor despite levodopa optimization deep brain stimulation and focused ultrasound are first-line considerations. Surgery can also be highly effective for the treatment medication-refractory tremor in selected patients without motor fluctuations. The present review highlights the clinical essentials of parkinsonian tremor, critically examines available trial data on the effects of medication and surgical approaches and provides guidance for the choice of treatments to control PD tremor in clinical practice.
Topics: Humans; Parkinson Disease; Levodopa; Tremor; Dopamine Agonists; Antiparkinson Agents; Apomorphine; Cholinergic Antagonists
PubMed: 36847017
DOI: 10.3233/JPD-225060 -
Cell Feb 2021The D1- and D2-dopamine receptors (D1R and D2R), which signal through G and G, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the...
The D1- and D2-dopamine receptors (D1R and D2R), which signal through G and G, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-G and D2R-G signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amino Acid Sequence; Conserved Sequence; Cryoelectron Microscopy; Cyclic AMP; GTP-Binding Proteins; HEK293 Cells; Humans; Ligands; Models, Molecular; Mutant Proteins; Receptors, Adrenergic, beta-2; Receptors, Dopamine D1; Receptors, Dopamine D2; Signal Transduction; Structural Homology, Protein
PubMed: 33571431
DOI: 10.1016/j.cell.2021.01.027 -
Neurology and Therapy Apr 2023Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in... (Review)
Review
Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor - Opicapone-, two MAO-B inhibitors plus channel blocker - Zonisamide and Safinamide and one amantadine extended-release formulation - ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients' preference, caregiver's availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.
PubMed: 36633762
DOI: 10.1007/s40120-022-00435-8 -
Journal of Neural Transmission (Vienna,... Nov 2023Advanced Parkinson's disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite... (Review)
Review
Advanced Parkinson's disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally.
Topics: Humans; Parkinson Disease; Levodopa; Carbidopa; Antiparkinson Agents; Catechol O-Methyltransferase; Catechols; Dopamine Agonists; Drug Combinations
PubMed: 37672049
DOI: 10.1007/s00702-023-02693-8 -
Cell Death & Disease Apr 2020Parkinson's disease (PD) is a progressively debilitating neurodegenerative condition that leads to motor and cognitive dysfunction. At present, clinical treatment can...
Parkinson's disease (PD) is a progressively debilitating neurodegenerative condition that leads to motor and cognitive dysfunction. At present, clinical treatment can only improve symptoms, but cannot effectively protect dopaminergic neurons. Several reports have demonstrated that human umbilical cord mesenchymal stem cells (hucMSCs) afford neuroprotection, while their application is limited because of their uncontrollable differentiation and other reasons. Stem cells communicate with cells through secreted exosomes (Exos), the present study aimed to explore whether Exos secreted by hucMSCs could function instead of hucMSCs. hucMSCs were successfully isolated and characterized, and shown to contribute to 6-hydroxydopamine (6-OHDA)-stimulated SH-SY5Y cell proliferation; hucMSC-derived Exos were also involved in this process. The Exos were purified and identified, and then labeled with PKH 26, it was found that the Exos could be efficiently taken up by SH-SY5Y cells after 12 h of incubation. Pretreatment with Exos promoted 6-OHDA-stimulated SH-SY5Y cells to proliferate and inhibited apoptosis by inducing autophagy. Furthermore, Exos reached the substantia nigra through the blood-brain barrier (BBB) in vivo, relieved apomorphine-induced asymmetric rotation, reduced substantia nigra dopaminergic neuron loss and apoptosis, and upregulated the level of dopamine in the striatum. These results demonstrate that hucMSCs-Exos have a treatment capability for PD and can traverse the BBB, indicating their potential for the effective treatment of PD.
Topics: Animals; Autophagy; Blood-Brain Barrier; Cell Differentiation; Exosomes; Humans; Mesenchymal Stem Cells; Mice; Parkinson Disease
PubMed: 32341347
DOI: 10.1038/s41419-020-2473-5 -
Translational Neurodegeneration Oct 2022Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods).... (Review)
Review
Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of 'OFF' periods. However, data suggest that despite their efficacy in reducing the number and duration of 'OFF' periods, these strategies still do not prevent 'OFF' periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent 'OFF' periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent 'OFF' periods unresponsive to dopaminergic therapy delivered via CDD.
Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Dopamine; Humans; Levodopa; Parkinson Disease
PubMed: 36229860
DOI: 10.1186/s40035-022-00317-x -
Journal of Parkinson's Disease 2023Patients with Parkinson's disease often suffer from OFF symptoms disrupting their daily routines and adding to disabilities. Despite polypharmacy and adjustments to... (Review)
Review
Patients with Parkinson's disease often suffer from OFF symptoms disrupting their daily routines and adding to disabilities. Despite polypharmacy and adjustments to medication schedules, they often do not experience consistent relief from their motor symptoms. As the disease progresses, impaired gastric emptying may evolve, making it even more challenging for dopaminergic drugs to provide consistent results. This review focuses on a group of drugs that have the pharmacokinetic advantage of a much earlier onset of action by virtue of their non-oral routes of absorption. We compare the current marketed options: subcutaneous apomorphine, sublingual apomorphine, and inhaled levodopa. Subcutaneous apomorphine is the speediest to take effect, whereas sublingual apomorphine offers the longest clinical effect. Inhaled levodopa has the most favorable side effect profile among the three options. An inhaled form of apomorphine is currently under development, having passed safety and efficacy studies. Each of these drugs has unique characteristics for the user, including different side effect profiles and onset of action. The best choice for a patient will depend on individual needs and circumstances. In this review, we explore those nuances to allow clinicians to select the best option for their patients.
Topics: Humans; Parkinson Disease; Apomorphine; Levodopa; Antiparkinson Agents; Dopamine Agonists; Drug-Related Side Effects and Adverse Reactions
PubMed: 37182902
DOI: 10.3233/JPD-230055