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Genes Sep 2021Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on... (Review)
Review
Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on genetically defined subtypes of disease and targets for drug development have seen an unprecedented success. With more than 20 genes associated with Parkinson's disease (PD), most of which are highly penetrant and often cause early onset or atypical signs and symptoms, and an increasing understanding of the associated pathophysiology culminating in dopaminergic neurodegeneration, applying the technologies and designs into the field of neurodegeneration seems a logical step. This review describes some of the methods used in oncology clinical trials and some attempts in Parkinson's disease and the potential of further implementing genetics, biomarkers and smart clinical trial designs in this disease area.
Topics: Antiparkinson Agents; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Parkinson Disease; Precision Medicine
PubMed: 34680924
DOI: 10.3390/genes12101529 -
The Journal of Clinical Psychiatry Oct 2020 The pathophysiology of PD has been elusive, but the motor symptoms of the disease are believed to result from a dopamine deficiency in the substantia nigra.... (Review)
Review
The pathophysiology of PD has been elusive, but the motor symptoms of the disease are believed to result from a dopamine deficiency in the substantia nigra. As a patient's disease progresses, OFF episodes emerge due to a shorter duration of response to levodopa treatment. OFF episodes include both motor and nonmotor symptoms, are common, and can occur at any time. OFF episodes can be predictable or unpredictable, significantly impact patient quality of life and functionality, and place a burden on families. By facilitating communication with patients and care partners using assessment tools, clinicians can detect symptoms of OFF episodes earlier.
Topics: Antiparkinson Agents; Cost of Illness; Disease Progression; Humans; Levodopa; Parkinson Disease; Physician-Patient Relations; Quality of Life
PubMed: 33113598
DOI: 10.4088/JCP.SU19004BR1C -
CNS Drugs Feb 2021Infusion of levodopa-carbidopa intestinal gel (LCIG; also designated carbidopa-levodopa enteral suspension) for 16 hours is a standard treatment for patients with... (Review)
Review
Infusion of levodopa-carbidopa intestinal gel (LCIG; also designated carbidopa-levodopa enteral suspension) for 16 hours is a standard treatment for patients with advanced Parkinson's disease, and clinical observations suggest that 24-hour LCIG infusion may further reduce symptoms. This review provides practical advice on the management of patients transitioning to 24-hour LCIG infusion. We review available clinical data for 24-hour infusion and discuss adjustments to dosing, recommendations for monitoring, and management of patient concerns, based on our clinical experience. Data from multiple studies suggest that LCIG may improve non-motor symptoms. Although few studies have examined 24-hour LCIG infusion, available data indicate that certain patients may benefit from around-the-clock treatment. Studies of 24-hour LCIG infusion are limited by small sample sizes and open-label study designs, which may hamper translation to clinical practice. In our experience, we have found that patients may benefit from 24-hour infusion when reductions in nocturnal symptoms and improvements to quality of sleep are needed. Levodopa-unresponsive freezing of gait or poorly controlled troublesome dyskinesias may also indicate a patient may benefit from 24-hour infusion. Dose adjustments, especially of the nocturnal rate, are typically necessary and, as with 16-hour infusion, patients should be monitored for autonomic dysfunction; overnight wearing off symptoms; weight changes; fluctuations in plasma levels of vitamins B/B, folate, and homocysteine; changes in sleep patterns; or worsening of hallucinations, delusions, and/or nightmares. Available data and our clinical experience suggest that 24-hour LCIG may be warranted among selected patients who have poorly controlled nocturnal fluctuations or early morning "off" symptoms.
Topics: Antiparkinson Agents; Carbidopa; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Gels; Humans; Levodopa; Parkinson Disease; Time Factors
PubMed: 33582982
DOI: 10.1007/s40263-020-00782-w -
Journal of Parkinson's Disease 2020The majority of current pharmacological treatments for Parkinson's disease (PD) were approved for clinical use in the second half of the last century and they only... (Review)
Review
BACKGROUND
The majority of current pharmacological treatments for Parkinson's disease (PD) were approved for clinical use in the second half of the last century and they only provide symptomatic relief. Derivatives of these therapies continue to be explored in clinical trials, together with potentially disease modifying therapies that can slow, stop or reverse the condition.
OBJECTIVE
To provide an overview of the pharmacological therapies- both symptomatic and disease modifying- currently being clinically evaluated for PD, with the goal of creating greater awareness and opportunities for 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 database and performed a breakdown analysis of studies that were active as of January 21, 2020.
RESULTS
We identified 145 registered and ongoing clinical trials for therapeutics targeting PD, of which 51 were Phase 1 (35% of the total number of trials), 66 were Phase 2 (46% ), and 28 were Phase 3 (19% ). There were 57 trials (39% ) focused on long-term disease modifying therapies, with the remaining 88 trials (61% ) focused on therapies for symptomatic relief. A total of 50 (34% ) trials were testing repurposed therapies.
CONCLUSION
There is a broad pipeline of both symptomatic and disease modifying therapies currently being tested in clinical trials for PD.
Topics: Antiparkinson Agents; Clinical Trials as Topic; Drug Development; Humans; Neuroprotective Agents; Parkinson Disease; Treatment Outcome
PubMed: 32741777
DOI: 10.3233/JPD-202128 -
Tremor and Other Hyperkinetic Movements... 2021Apomorphine is a potent dopamine agonist used in the treatment of advanced and fluctuating Parkinson's Disease. However the need for its subcutaneous infusion can lead...
BACKGROUND
Apomorphine is a potent dopamine agonist used in the treatment of advanced and fluctuating Parkinson's Disease. However the need for its subcutaneous infusion can lead to skin reactions.
PHENOMENOLOGY SHOWN
We illustrate necrotic ulcers at infusion sites as a rare event during continuous subcutaneous apomorphine infusion.
EDUCATIONAL VALUE
This case demonstrates the rare adverse event of necrotic ulcers in a patient with long term apomorphine infusion.
Topics: Antiparkinson Agents; Apomorphine; Dopamine Agonists; Humans; Injections, Subcutaneous; Ulcer
PubMed: 35070491
DOI: 10.5334/tohm.648 -
Journal of Neural Transmission (Vienna,... Nov 2023Subcutaneous apomorphine infusion is a device-aided therapy for Parkinson's disease that can be considered when motor fluctuations become persistent and are no longer... (Randomized Controlled Trial)
Randomized Controlled Trial
Subcutaneous apomorphine infusion is a device-aided therapy for Parkinson's disease that can be considered when motor fluctuations become persistent and are no longer adequately controlled by oral/transdermal medication. Apomorphine infusion is less invasive than enteral levodopa, deep brain stimulation or focused ultrasound, and is often indicated even when neurosurgical approaches are contraindicated. This article aims to provide practical guidance for doctors and nurses initiating and treating patients with apomorphine infusion, and is based on both trial data and clinical experience from movement disorders specialists. A post hoc analysis of data from the TOLEDO randomized clinical trial of apomorphine infusion was conducted along with an analysis of 'real world' experience from 13 movement disorders specialists using a questionnaire that focused on starting patients on apomorphine infusion. Practical guidelines for starting treatment with apomorphine infusion are provided taking into consideration the regional disparities in healthcare. Apomorphine infusion is straightforward to administer but to be successful it requires concordance from the patient and family, and clinical support from an experienced team of doctors and nurses, particularly in the early months of treatment.
Topics: Humans; Apomorphine; Parkinson Disease; Antiparkinson Agents; Levodopa; Infusions, Parenteral
PubMed: 37658155
DOI: 10.1007/s00702-023-02686-7 -
European Journal of Pharmacology Sep 2021Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone...
Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone (GD) effect in vitro to inhibit the A and B isoforms of human monoamine oxidase (hMAO) enzyme and their citotoxicity in human hepatoma cell line (HepG2). Also, binding studies to A, A A and A adenosine receptors were performed. A docking study of gamma-decanolactone has been carried out with the molecular targets of MAO-A and MAO-B isoforms. The physicochemical properties and ability to cross physiological barriers, as the blood brain barrier (BBB), was elucidated by computational studies. The in vivo assays, the rota-rod test, body temperature assessment and open field test were performed in reserpinized mice (1.5 mg/kg, i.p.; 18:00 before) to evaluate the effect of gamma-decanolactone (300 mg/kg), alone or associated with Levodopa plus Benserazide (LD + BZ, 100:25 mg/kg, i.p.). Gamma-decanolactone inhibited preferentially the MAO-B in a reversible manner, with an inhibitory concentration of 50% (IC) 55.95 ± 9.06 μM. It was shown to be a safe drug since only at the highest concentration decreased the viability of HepG2 cells. It also does not bind to adenosine receptors investigated in this study. The molecular docking study show that the gamma-decanolactone ligand adopts a relatively compact conformation in the active site of hMAO-B, while we note an extended conformation of gamma-decanolactone ligand in the hMAO-A isoform. The physicochemical properties obtained, and the theoretical models utilized for the evaluation of ability to cross the BBB, predict a good gamma-decanolactone bioavailability and access to the central nervous system (CNS). In the in vivo studies, gamma-decanolactone partially reversed the ataxia of the reserpinized mice at 01:00 h and 01:30 h post-administration. Concomitant treatment of gamma-decanolactone with LD + BZ, at 01:30 h showed a potentiation of the reversibility of ataxia and facilitated the reversal of hypothermia caused by reserpine for all measured times (P <0.01 vs vehicle), except at 24:00 h, but not reversed the hypokinesia in the open field test. In summary, the results herein obtained and in conjunction with previous studies, suggest that gamma-decanolactone could be a drug with potential utility as antiparkinsonian drug.
Topics: Animals; Antiparkinson Agents; Blood-Brain Barrier; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Assays; Hep G2 Cells; Humans; Lactones; Male; Mice; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Parkinson Disease, Secondary; Permeability; Receptors, Purinergic P1; Recombinant Proteins; Reserpine; Structure-Activity Relationship
PubMed: 34174267
DOI: 10.1016/j.ejphar.2021.174276 -
Current Neuropharmacology 2016Patients with Parkinson's disease (PD) receiving L-3,4-dihydroxyphenylalanine (L-DOPA, the gold-standard treatment for this disease) frequently develop abnormal... (Review)
Review
Patients with Parkinson's disease (PD) receiving L-3,4-dihydroxyphenylalanine (L-DOPA, the gold-standard treatment for this disease) frequently develop abnormal involuntary movements, termed L-DOPA-induced dyskinesias (LID). Glutamate overactivity is well documented in PD and LID. An approach to manage LID is to add to L-DOPA specific agents to reduce dyskinesias such as metabotropic glutamate receptor (mGlu receptor) drugs. This article reviews the contribution of mGlu type 5 (mGlu5) receptors in animal models of PD. Several mGlu5 negative allosteric modulators acutely attenuate LID in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) monkeys and 6-hydroxydopamine(6-OHDA)-lesioned rats. Chronic administration of mGlu5 negative allosteric modulators to MPTP monkeys and 6-OHDA rats also attenuates LID while maintaining the antiparkinsonian effect of L-DOPA. Radioligand autoradiography shows an elevation of striatal mGlu5 receptors of dyskinetic L-DOPA-treated MPTP monkeys but not in those without LID. The brain molecular correlates of the long-term effect of mGlu5 negative allosteric modulators treatments with L-DOPA attenuating development of LID was shown to extend beyond mGlu5 receptors with normalization of glutamate activity in the basal ganglia of L-DOPA-induced changes of NMDA, AMPA, mGlu2/3 receptors and VGlut2 transporter. In the basal ganglia, mGlu5 receptor negative allosteric modulators also normalize the L-DOPA-induced changes of dopamine D2receptors, their associated signaling proteins (ERK1/2 and Akt/GSK3β) and neuropeptides (preproenkephalin, preprodynorphin) as well as the adenosine A2A receptors expression. These results show in animal models of PD reduction of LID with mGlu5 negative allosteric modulation associated with normalization of glutamate, dopamine and adenosine receptors suggesting a functional link of these receptors in chronic treatment with L-DOPA.
Topics: Animals; Antiparkinson Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Neostriatum; Parkinsonian Disorders; Receptor, Adenosine A2A; Receptor, Metabotropic Glutamate 5; Receptors, Dopamine D2
PubMed: 26639458
DOI: 10.2174/1570159x14666151201185652 -
Toxins Jan 2021For well over 30 years, the botulinum neurotoxin (BoNT) has been used for a large number of indications, some of which however have not been licensed. Admittedly,... (Review)
Review
For well over 30 years, the botulinum neurotoxin (BoNT) has been used for a large number of indications, some of which however have not been licensed. Admittedly, approval varies in many countries and this permits a large spectrum for evaluation. Thus, BoNT is used for patients with Parkinson's disease (PD) and other Parkinson's syndromes (PS) in varying degrees of frequency. We have to distinguish between (1) indications that are either approved or (2) those not approved, (3) indications that might be a result of PS and (4) finally those which appear independent of PS. The most important indication for BoNT in PS patients is probably sialorrhea, for which approval has been granted in the majority of countries. Cervical dystonia is a frequent symptom in PS, with anterocollis as a specific entity. A further indication is blepharospasm in the different forms, especially the inhibition of eyelid opening in atypical PS. The use of BoNT in cases of camptocormia, the Pisa syndrome and neck rigidity is still a matter of debate. In dystonia of the extremities BoNT can be recommended, especially in dystonia of the feet. One well-known indication, for which however sufficient data are still lacking, involves treating tremor with BoNT. As to autonomic symptoms: Focal hyperhidrosis and detrusor hyperactivity can be mentioned, in this last case BoNT has already been approved. A number of further but rare indications such as freezing-of-gait, dyskinesia, and dysphagia will be discussed and evaluated.
Topics: Acetylcholine Release Inhibitors; Animals; Antiparkinson Agents; Botulinum Toxins; Humans; Motor Activity; Parkinson Disease; Treatment Outcome
PubMed: 33503872
DOI: 10.3390/toxins13020087 -
Neurotherapeutics : the Journal of the... Oct 2020Parkinson disease (PD), as a slowly progressive neurodegenerative disorder, undergoes six neuropathological stages. The earliest clinical manifestation presents in the... (Review)
Review
Parkinson disease (PD), as a slowly progressive neurodegenerative disorder, undergoes six neuropathological stages. The earliest clinical manifestation presents in the middle stage of the disorder pathologically, when 50% or more of the dopaminergic neurons have degenerated in the substantia nigra. This discrepancy between the early stage clinically and that pathologically has, in part, spurred the debate as to when it is best to initiate symptomatic therapy. The most well-studied monotherapeutic agents for PD in its early course include levodopa (the cornerstone of PD therapy), dopamine agonists, and monoamine oxidase inhibitors (MAOIs). With several options for initiating pharmacologic therapy, along with the heterogenous presentation of the disorder, an individualized approach is warranted. Careful deliberation must be done to optimize risk reduction while providing effective symptom control, taking the chronological age, comorbidities, social and financial disposition, work status, and both immediate- and long-term goals into consideration. Generally, treatment can be delayed in patients with mild symptoms and minimal functional impairment at any age. If treatment must be initiated, dopamine agonists and monoamine oxidase type B inhibitors can be used, especially in younger patients with milder disease. However, for older patients, those with moderate to severe PD symptoms, regardless of age, or for patients with greater comorbidities, levodopa generally remains the better choice. Eventually, regardless of initial therapy, studies have shown that most will eventually require levodopa therapy when symptoms become more disabling.
Topics: Antiparkinson Agents; Dopamine Agonists; Early Diagnosis; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Treatment Outcome
PubMed: 32935299
DOI: 10.1007/s13311-020-00924-4