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Parkinson drugs trials

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https://www.readbyqxmd.com/read/28733961/a-review-of-biomarkers-for-neurodegenerative-disease-will-they-swing-us-across-the-valley
#1
REVIEW
Thomas G Beach
Measures of the severity of cognitive impairment or parkinsonism are the usual endpoints in clinical trials for Alzheimer's disease (AD) and Parkinson's disease (PD), but are critically hampered by their lack of disease sensitivity and specificity. Due to the high failure rate of clinical trials, the rate of regulatory approval for efficacious new drugs has stagnated in the past few decades, with the gap between basic science discovery and clinical application metaphorically termed the "Valley of Death". While the causes for this are probably multiple and complex, the usage of biomarkers as surrogate endpoints, particularly when they are molecularly-specific for the disease, has achieved some success in cancer trials, and it is likely that neurodegenerative disease trials would benefit from the same approach...
July 2017: Neurology and Therapy
https://www.readbyqxmd.com/read/28695401/item-response-theory-as-an-efficient-tool-to-describe-a-heterogeneous-clinical-rating-scale-in-de-novo-idiopathic-parkinson-s-disease-patients
#2
Simon Buatois, Sylvie Retout, Nicolas Frey, Sebastian Ueckert
PURPOSE: This manuscript aims to precisely describe the natural disease progression of Parkinson's disease (PD) patients and evaluate approaches to increase the drug effect detection power. METHODS: An item response theory (IRT) longitudinal model was built to describe the natural disease progression of 423 de novo PD patients followed during 48 months while taking into account the heterogeneous nature of the MDS-UPDRS. Clinical trial simulations were then used to compare drug effect detection power from IRT and sum of item scores based analysis under different analysis endpoints and drug effects...
July 10, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28692855/recuperation-of-slow-walking-in-de-novo-parkinson-s-disease-is-more-closely-associated-with-increased-cadence-rather-than-with-expanded-stride-length
#3
Kyum-Yil Kwon, Hye Mi Lee, Sung Hoon Kang, Seon Jong Pyo, Han Jun Kim, Seong-Beom Koh
INTRODUCTION: Gait characteristics in the early stages of Parkinson's disease (PD) have been less investigated so far. Moreover, the levodopa effect on gait in early PD remains to be further elucidated. We prospectively designed the study to examine gait dynamics and effect of dopaminergic treatment in patients with de novo PD. METHODS: Spatiotemporal parameters were measured in healthy controls and drug naïve patients with PD, using computerized analysis with GAITRite system during usual gait...
July 1, 2017: Gait & Posture
https://www.readbyqxmd.com/read/28686320/the-emerging-science-of-precision-medicine-and-pharmacogenomics-for-parkinson-s-disease
#4
Haydeh Payami
Current therapies for Parkinson's disease are problematic because they are symptomatic and have adverse effects. New drugs have failed in clinical trials because of inadequate efficacy. At the core of the problem is trying to make one drug work for all Parkinson's disease patients, when we know this premise is wrong because (1) Parkinson's disease is not a single disease, and (2) no two individuals have the same biological makeup. Precision medicine is the goal to strive for, but we are only at the beginning stages of building the infrastructure for one of the most complex projects in the history of science, and it will be a long time before Parkinson's disease reaps the benefits...
July 7, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28676842/subthalamic-nucleus-deep-brain-stimulation-in-early-stage-parkinson-s-disease-is-not-associated-with-increased-body-mass-index
#5
Sarah H Millan, Mallory L Hacker, Maxim Turchan, Anna L Molinari, Amanda D Currie, David Charles
Previous studies suggest that deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson's disease (PD) leads to weight gain. This study analyzes changes in body mass index (BMI) in 29 subjects from a prospective, single-blind trial of DBS in early stage PD (age 50-75, Hoehn & Yahr stage II off medication, treated with antiparkinsonian medications for ≥6 months but <4 years, and without a history of motor fluctuations, dyskinesias, or dementia). Subjects were randomized to DBS plus optimal drug therapy (DBS+ODT; n = 15) or ODT (n = 14) and followed for 24 months...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/28675424/predicting-qrs-and-pr-interval-prolongations-in-humans-using-nonclinical-data
#6
L Bergenholm, J Parkinson, J Mettetal, N D Evans, M J Chappell, T Collins
BACKGROUND AND PURPOSE: Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. EXPERIMENTAL APPROACH: Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterised using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data...
July 3, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28674995/biomarkers-in-neurodegenerative-diseases
#7
Andreas Jeromin, Robert Bowser
The past decade has seen tremendous efforts in biomarker discovery and validation for neurodegenerative diseases. The source and type of biomarkers has continued to grow for central nervous system diseases, from biofluid-based biomarkers (blood or cerebrospinal fluid (CSF)), to nucleic acids, tissue, and imaging. While DNA remains a predominant biomarker used to identify familial forms of neurodegenerative diseases, various types of RNA have more recently been linked to familial and sporadic forms of neurodegenerative diseases during the past few years...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28666800/a-novel-glp-1-gip-dual-agonist-is-more-effective-than-liraglutide-in-reducing-inflammation-and-enhancing-gdnf-release-in-the-mptp-mouse-model-of-parkinson-s-disease
#8
Ziyue Yuan, Dongfang Li, Peng Feng, Guofang Xue, Chenhui Ji, Guanglai Li, Christian Hölscher
Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD...
June 27, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28659169/the-novel-compound-pbt434-prevents-iron-mediated-neurodegeneration-and-alpha-synuclein-toxicity-in-multiple-models-of-parkinson-s-disease
#9
David I Finkelstein, Jessica L Billings, Paul A Adlard, Scott Ayton, Amelia Sedjahtera, Colin L Masters, Simon Wilkins, David M Shackleford, Susan A Charman, Wojciech Bal, Izabela A Zawisza, Ewa Kurowska, Andrew L Gundlach, Sheri Ma, Ashley I Bush, Dominic J Hare, Philip A Doble, Simon Crawford, Elisabeth Cl Gautier, Jack Parsons, Penny Huggins, Kevin J Barnham, Robert A Cherny
Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions...
June 28, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28649610/evaluation-of-the-safety-and-immunomodulatory-effects-of-sargramostim-in-a-randomized-double-blind-phase-1-clinical-parkinson-s-disease-trial
#10
Howard E Gendelman, Yuning Zhang, Pamela Santamaria, Katherine E Olson, Charles R Schutt, Danish Bhatti, Bhagya Laxmi Dyavar Shetty, Yaman Lu, Katherine A Estes, David G Standaert, Elizabeth Heinrichs-Graham, LuAnn Larson, Jane L Meza, Matthew Follett, Erica Forsberg, Gary Siuzdak, Tony W Wilson, Carolyn Peterson, R Lee Mosley
A potential therapeutic role for immune transformation in Parkinson's disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson's disease patients...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/28643372/fine-tuning-perk-signaling-for-neuroprotection
#11
REVIEW
Mark Halliday, Daniel Hughes, Giovanna Mallucci
Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress due to protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the taopathies...
June 23, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28622913/targeting-urate-to-reduce-oxidative-stress-in-parkinson-disease
#12
REVIEW
Grace F Crotty, Alberto Ascherio, Michael A Schwarzschild
Oxidative stress has been implicated as a core contributor to the initiation and progression of multiple neurological diseases. Genetic and environmental factors can produce oxidative stress through mitochondrial dysfunction leading to the degeneration of dopaminergic and other neurons underlying Parkinson disease (PD). Although clinical trials of antioxidants have thus far failed to demonstrate slowed progression of PD, oxidative stress remains a compelling target. Rather than prompting abandonment of antioxidant strategies, these failures have raised the bar for justifying drug and dosing selections and for improving study designs to test for disease modification by antioxidants...
June 13, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28622912/clinical-approaches-to-the-development-of-a-neuroprotective-therapy-for-pd
#13
REVIEW
C W Olanow, K Kieburtz, R Katz
The development of a neuroprotective or disease-modifying therapy is the major unmet need in the management of Parkinson's Disease (PD) and the goal of much clinical and scientific research. However, despite enormous efforts and expense, no disease-modifying therapy for PD has been approved to date. Historically attempts to define such a therapy have been limited by confounding symptomatic/pharmacologic effects of the study intervention and the lack of a clear and well-defined regulatory and clinical development pathway that leads to a disease-modifying indication...
June 13, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28604926/ads-5102-amantadine-extended-release-capsules-for-levodopa-induced-dyskinesia-in-parkinson-disease-ease-lid-study-a-randomized-clinical-trial
#14
Rajesh Pahwa, Caroline M Tanner, Robert A Hauser, Stuart H Isaacson, Paul A Nausieda, Daniel D Truong, Pinky Agarwal, Keith L Hull, Kelly E Lyons, Reed Johnson, Mary Jean Stempien
Importance: Medical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need. Objective: To evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact...
June 12, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28571531/c-abl-inhibition-a-novel-therapeutic-target-for-parkinson-s-disease
#15
Abdelrahman Ibrahim Abushouk, Ahmed Negida, Rasha Abdelsalam Elshenawy, Hossam Zein, Ali M Hammad, Ahmed Menshawy, Wael M Y Mohamed
Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. To the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of PD. However, due to ignorance of the main pathological sequence of PD, many drug targets failed recently to provide neuroprotective effects in human trials...
June 1, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28552230/strategies-for-bringing-stem-cell-derived-dopamine-neurons-to-the-clinic-the-kyoto-trial
#16
Jun Takahashi
Concerted efforts are realizing cell-based therapy for Parkinson's disease (PD). In this chapter, I describe efforts at the Center for iPS Cell Research and Application (CiRA), Kyoto University. These efforts use induced pluripotent stem cells (iPSCs) as donor cells. The iPSCs were established as human leukocyte antigen homozygous at CiRA and are intended for allogeneic transplantation. Our manufacturing protocol includes a feeder-free cell culture with laminin fragment LM511-E8 and the sorting of CORIN(+) cells...
2017: Progress in Brain Research
https://www.readbyqxmd.com/read/28537214/pharmacokinetic-drug-evaluation-of-safinamide-mesylate-for-the-treatment-of-mid-to-late-stage-parkinson-s-disease
#17
REVIEW
Thomas Müller
Patients with Parkinson's disease suffer from a heterogeneous expression of neurotransmitter deficits. They cause an individual variable expression of motor and non-motor symptoms. Thus, drugs with various mechanisms of actions are suitable to counteract these disease related neurotransmitter alterations. Areas covered: This invited review suggests safinamide as an ideal compound for therapy of Parkinson's disease, as its pharmacological profile includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and abnormal glutamate release...
June 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28535734/investigational-drugs-in-phase-i-and-phase-ii-for-levodopa-induced-dyskinesias
#18
REVIEW
Silvia Cerri, Francesca Siani, Fabio Blandini
Prolonged treatment of Parkinson's disease (PD) with levodopa (L-DOPA) results in motor complications, including motor fluctuations and involuntary movements known as L-DOPA induced dyskinesias (LIDs). LIDs represent an additional cause of disability for PD patients and a major challenge for the clinical neurologist. Preclinical research has provided invaluable insights into the molecular and neural substrates of LIDs, identifying a number of potential targets for new anti-dyskinetic strategies. Areas covered: This review article is centered on drugs currently in Phase I and II clinical trials for LIDs and their relative pharmacological targets, which include glutamate, acetylcholine, serotonin, adrenergic receptors and additional targets of potential therapeutic interest...
July 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28521682/repurposing-of-copper-ii-chelating-drugs-for-the-treatment-of-neurodegenerative-diseases
#19
Valeria Lanza, Danilo Milardi, Giuseppe Di Natale, Giuseppe Pappalardo
BACKGROUND: There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews has exhaustively described either the molecular or clinical aspects of neurodegenerative diseases as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can be also effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) interacting molecules as potential drug candidates in neurodegeneration...
May 17, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28506500/autonomic-and-electrocardiographic-findings-in-parkinson-s-disease
#20
Christopher H Gibbons, David K Simon, Meilin Huang, Barbara Tilley, Michael J Aminoff, Jacquelyn L Bainbridge, Matthew Brodsky, Roy Freeman, John Goudreau, Robert W Hamill, Sheng T Luo, Carlos Singer, Aleksandar Videnovic, Ivan Bodis-Wollner, Pei S Wong
Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms and signs. Many reports suggest that diminished heart rate variability occurs early, even prior to the cardinal signs of PD. In a longitudinal study of PD, we evaluated whether heart rate variability (HRV) obtained using a 10-second ECG tracing, and the electrocardiographic QT-interval would be associated with PD severity and progression. Subjects were derived from a longitudinal study of 1741 individuals with early, stable PD...
April 14, 2017: Autonomic Neuroscience: Basic & Clinical
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