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Expert Opinion on Pharmacotherapy Jun 2017The major unmet needs in the medical treatment of Parkinson disease (PD) are reduction of motor side effects from dopaminergic drugs, management of non-motor symptoms... (Review)
Review
The major unmet needs in the medical treatment of Parkinson disease (PD) are reduction of motor side effects from dopaminergic drugs, management of non-motor symptoms and disease modification. Areas covered: Motor fluctuations and OFF periods are a significant determinant of quality of life in PD and reducing their duration and severity can significantly improve motor function. This aim may be partly facilitated by the development of effective adjunctive drugs for dopamine replacement. Safinamide (Xadago), which is a first generation anticonvulsant, has pharmacological properties which are of interest in the context of neurodegenerative diseases, leading to research into its potential as an adjunct to levodopa in PD. Expert opinion: Although its mechanism has not been fully defined, safinamide provides enhanced symptom control of motor function in advanced PD and improves quality of life.
Topics: Alanine; Antiparkinson Agents; Benzylamines; Dopamine; Dopamine Agents; Humans; Levodopa; Parkinson Disease; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 28504022
DOI: 10.1080/14656566.2017.1329819 -
Psychiatry and Clinical Neurosciences Aug 2015Psychotropic dose equivalence is an important concept when estimating the approximate psychotropic doses patients receive, and deciding on the approximate titration dose... (Review)
Review
Psychotropic dose equivalence is an important concept when estimating the approximate psychotropic doses patients receive, and deciding on the approximate titration dose when switching from one psychotropic agent to another. It is also useful from a research viewpoint when defining and extracting specific subgroups of subjects. Unification of various agents into a single standard agent facilitates easier analytical comparisons. On the basis of differences in psychopharmacological prescription features, those of available psychotropic agents and their approved doses, and racial differences between Japan and other countries, psychotropic dose equivalency tables designed specifically for Japanese patients have been widely used in Japan since 1998. Here we introduce dose equivalency tables for: (i) antipsychotics; (ii) antiparkinsonian agents; (iii) antidepressants; and (iv) anxiolytics, sedatives and hypnotics available in Japan. Equivalent doses for the therapeutic effects of individual psychotropic compounds were determined principally on the basis of randomized controlled trials conducted in Japan and consensus among dose equivalency tables reported previously by psychopharmacological experts. As these tables are intended to merely suggest approximate standard values, physicians should use them with discretion. Updated information of psychotropic dose equivalence in Japan is available at http://www.jsprs.org/en/equivalence.tables/. [Correction added on 8 July 2015, after first online publication: A link to the updated information has been added.].
Topics: Antidepressive Agents; Antiparkinson Agents; Antipsychotic Agents; Humans; Hypnotics and Sedatives; Japan; Psychotropic Drugs; Therapeutic Equivalency
PubMed: 25601291
DOI: 10.1111/pcn.12275 -
Current Neuropharmacology 2018Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines,... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Although the scientific community has performed great efforts in the study of PD, and from the most diverse points of view, the disease remains incurable. The exact mechanism underlying its progression is unclear, but oxidative stress, mitochondrial dysfunction and inflammation are thought to play major roles in the etiology.
OBJECTIVE
Current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate, and new therapeutic agents are much needed.
METHODS
In this review, recent advances in computer-aided drug design for the rational design of new compounds against Parkinson disease; using methods such as Quantitative Structure-Activity Relationships (QSAR), molecular docking, molecular dynamics and pharmacophore modeling are discussed.
RESULTS
In this review, four targets were selected: the enzyme monoamine oxidase, dopamine agonists, acetylcholine receptors, and adenosine receptors.
CONCLUSION
Computer aided-drug design enables the creation of theoretical models that can be used in a large database to virtually screen for and identify novel candidate molecules.
Topics: Animals; Antiparkinson Agents; Drug Design; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Parkinson Disease
PubMed: 29189169
DOI: 10.2174/1570159X15666171128145423 -
World Journal of Gastroenterology Aug 2014Drug absorption represents an important factor affecting the efficacy of oral drug treatment. Gastric secretion and motility seem to be critical for drug absorption. A... (Review)
Review
Drug absorption represents an important factor affecting the efficacy of oral drug treatment. Gastric secretion and motility seem to be critical for drug absorption. A causal relationship between impaired absorption of orally administered drugs and Helicobacter pylori (H. pylori) infection has been proposed. Associations have been reported between poor bioavailability of l-thyroxine and l-dopa and H. pylori infection. According to the Maastricht Florence Consensus Report on the management of H. pylori infection, H. pylori treatment improves the bioavailability of both these drugs, whereas the direct clinical benefits to patients still await to be established. Less strong seems the association between H. pylori infection and other drugs malabsorption, such as delavirdine and ketoconazole. The exact mechanisms forming the basis of the relationship between H. pylori infection and impaired drugs absorption and/or bioavailability are not fully elucidated. H. pylori infection may trigger a chronic inflammation of the gastric mucosa, and impaired gastric acid secretion often follows. The reduction of acid secretion closely relates with the wideness and the severity of the damage and may affect drug absorption. This minireview focuses on the evidence of H. pylori infection associated with impaired drug absorption.
Topics: Administration, Oral; Animals; Anti-Infective Agents; Antiparkinson Agents; Biological Availability; Gastric Absorption; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Host-Pathogen Interactions; Humans; Pharmaceutical Preparations; Risk Factors; Stomach; Thyroxine
PubMed: 25132749
DOI: 10.3748/wjg.v20.i30.10331 -
Journal of Neural Transmission (Vienna,... Aug 2018With the advent of rodent models of L-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression... (Review)
Review
With the advent of rodent models of L-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression of abnormal involuntary movements. Changes in information processing at the striatal level are assumed to impact on the activity of downstream basal ganglia nuclei, which in turn influence brain-wide networks, but very little is actually known about systems-level mechanisms of dyskinesia. As an aid to approach this topic, we here review the anatomical and physiological organisation of cortico-basal ganglia-thalamocortical circuits, and the changes affecting these circuits in animal models of parkinsonism and LID. We then review recent findings indicating that an abnormal cerebellar compensation plays a causal role in LID, and that structures outside of the classical motor circuits are implicated too. In summarizing the available data, we also propose hypotheses and identify important knowledge gaps worthy of further investigation. In addition to informing novel therapeutic approaches, the study of LID can provide new clues about the interplay between different brain circuits in the control of movement.
Topics: Animals; Antiparkinson Agents; Brain; Dyskinesia, Drug-Induced; Levodopa; Neural Pathways
PubMed: 29704061
DOI: 10.1007/s00702-018-1886-0 -
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 -
Annals of Medicine Dec 2024Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can... (Observational Study)
Observational Study
BACKGROUND
Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD.
PATIENTS AND METHODS
PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) patient chart review/interview.
RESULTS
Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%).
CONCLUSION
This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.
Topics: Humans; Male; Aged; Female; Parkinson Disease; Levodopa; Antiparkinson Agents; Retrospective Studies; Catechol O-Methyltransferase; Quality of Life; Prospective Studies; Catechol O-Methyltransferase Inhibitors
PubMed: 38381654
DOI: 10.1080/07853890.2024.2315226 -
Biomolecules Aug 2019Parkinson's disease (PD) is a neurodegenerative disorder that features progressive, disabling motor symptoms, such as bradykinesia, rigidity, and resting tremor.... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder that features progressive, disabling motor symptoms, such as bradykinesia, rigidity, and resting tremor. Nevertheless, some non-motor symptoms, including depression, REM sleep behavior disorder, and olfactive impairment, are even earlier features of PD. At later stages, apathy, impulse control disorder, neuropsychiatric disturbances, and cognitive impairment can present, and they often become a heavy burden for both patients and caregivers. Indeed, PD increasingly compromises activities of daily life, even though a high variability in clinical presentation can be observed among people affected. Nowadays, symptomatic drugs and non-pharmaceutical treatments represent the best therapeutic options to improve quality of life in PD patients. The aim of the present review is to provide a practical, stage-based guide to pharmacological management of both motor and non-motor symptoms of PD. Furthermore, warning about drug side effects, contraindications, as well as dosage and methods of administration, are highlighted here, to help the physician in yielding the best therapeutic strategies for each symptom and condition in patients with PD.
Topics: Antiparkinson Agents; Humans; Parkinson Disease
PubMed: 31434341
DOI: 10.3390/biom9080388 -
Journal of Parkinson's Disease 2022Levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD), occurs in ∼30% of patients after five years' treatment with levodopa. In... (Review)
Review
Levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD), occurs in ∼30% of patients after five years' treatment with levodopa. In atypical parkinsonism, LID occurs less frequently than in PD. Lower frequency of LID in atypical parkinsonism has traditionally been attributed to lower amounts of levodopa used by these patients; however, recent studies have shown lower frequency of LID in atypical parkinsonism compared with PD when adjusting for levodopa dose. The mechanism of LID is complex but requires pulsatile levodopa stimulation, progressive presynaptic dopaminergic degeneration, and a relatively intact postsynaptic dopaminergic system. The globus pallidus internus (GPi), the main inhibitory nucleus of the basal ganglia, may play a major role in the development and treatment of LID. Surgical lesioning of the posteroventral GPi is directly antidyskinetic; animal models showing GPi-associated striatal neurons are directly responsible for the development of LID. However, other cortical areas, particularly the primary sensory and motor cortices may also play a role in LID. In some cases of atypical parkinsonism, particularly progressive supranuclear palsy and corticobasal degeneration, severe degeneration of the GPi, a so-called "autopallidotomy," may explain the absence of LID in these patients. In other atypical parkinsonisms, such as PD dementia and dementia with Lewy bodies, the lower incidence of LID may partly be attributed to more striatal degeneration but likely also relates to the degeneration of the motor cortex and resultant network dysfunction. Overall, atypical parkinsonism serves as a natural model that may ultimately reveal more effective therapies for LID.
Topics: Animals; Antiparkinson Agents; Basal Ganglia; Dyskinesias; Globus Pallidus; Levodopa; Parkinson Disease; Parkinsonian Disorders
PubMed: 36120793
DOI: 10.3233/JPD-223491 -
Journal of Neural Transmission (Vienna,... Nov 2023Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many... (Review)
Review
Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others-levodopa and apomorphine-but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals 'unknown' aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as 'known unknowns' or ignored as 'unknown unknowns'. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.
Topics: Humans; Apomorphine; Levodopa; Parkinson Disease; Antiparkinson Agents; Dopamine
PubMed: 37210460
DOI: 10.1007/s00702-023-02655-0