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Circadian in PD

Siyue Li, Yali Wang, Fen Wang, Li-Fang Hu, Chun-Feng Liu
Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson's disease (PD) exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative consequences to the homeostasis and even exacerbate the disease progression...
December 19, 2016: Neuroscience Bulletin
Lama M Chahine, Amy W Amara, Aleksandar Videnovic
Sleep disorders are among the most common non-motor manifestations in Parkinson's disease (PD) and have a significant negative impact on quality of life. While sleep disorders in PD share most characteristics with those that occur in the general population, there are several considerations specific to this patient population regarding diagnosis, management, and implications. The available research on these disorders is expanding rapidly, but many questions remain unanswered. We thus conducted a systematic review of the literature published from 2005 to 2015 on the following disorders of sleep and wakefulness in PD: REM sleep behavior disorder, insomnia, nocturia, restless legs syndrome and periodic limb movements, sleep disordered breathing, excessive daytime sleepiness, and circadian rhythm disorders...
August 31, 2016: Sleep Medicine Reviews
Karim Fifel
Alterations of circadian rhythms are among the most debilitating non-motor symptoms in Parkinson's Disease (PD). Although a growing awareness towards these symptoms has occurred during the last decade, their underlying neuropathophysiology remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these problems. Recent studies have investigated multiple circadian rhythms at different stages of PD. The advances made have allowed an accurate evaluation of the affected underlying pathways and mechanisms...
November 15, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Sonja Rutten, Chris Vriend, Jan H Smit, Henk W Berendse, Adriaan W Hoogendoorn, Odile A van den Heuvel, Ysbrand D van der Werf
BACKGROUND: A disturbed circadian rhythm seems to be a causal factor in the occurrence of depressive disorders in patients with Parkinson's disease (PD). The circadian rhythm can be restored with light. Therefore, Bright Light Therapy (BLT) might be a new treatment option for depression in PD patients. METHODS/DESIGN: In this double-blind controlled trial, 84 subjects with idiopathic PD are randomized to either BLT or a control light condition. The BLT condition emits white light with an intensity of 10,000 Lux, while the control device emits dim white light of 200 Lux, which is presumed to be too low to influence the circadian rhythm...
October 21, 2016: BMC Psychiatry
Dong-Seok Yim
In the early phase of clinical development of antihypertensive drugs, quantitative modeling to predict their dose-concentration-response relationship is important to plan future clinical development and finding optimal dosage regimen at marketing approval. Two cases of concentration-response models of antihypertensive are presented here.Case 1: Carvedilol is a α1- and nonselective β- adrenergic receptor antagonist currently used for the management of mild-to-moderate essential hypertension and congestive heart failure...
September 2016: Journal of Hypertension
E Vichayanrat, D A Low, V Iodice, E Stuebner, E M Hagen, C J Mathias
BACKGROUND AND PURPOSE: Twenty-four-hour ambulatory blood pressure and heart rate monitoring (24-h ABPM) can provide vital information on circadian blood pressure (BP) profiles, which are commonly abnormal in Parkinson's disease with and without autonomic failure (PD + AF and PD) and multiple system atrophy (MSA). Twenty-four-hour ABPM has not been directly compared between these disorders regarding cardiovascular autonomic function. Our aim was to determine the usefulness of 24-h ABPM with diary compared to head-up tilting (HUT) in diagnosing orthostatic hypotension (OH) in these patients...
January 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Richard Gordon, Matthew L Neal, Jie Luo, Monica R Langley, Dilshan S Harischandra, Nikhil Panicker, Adhithiya Charli, Huajun Jin, Vellareddy Anantharam, Trent M Woodruff, Qun-Yong Zhou, Anumantha G Kanthasamy, Arthi Kanthasamy
Prokineticin-2 (PK2), a recently discovered secreted protein, regulates important physiological functions including olfactory biogenesis and circadian rhythms in the CNS. Interestingly, although PK2 expression is low in the nigral system, its receptors are constitutively expressed on nigrostriatal neurons. Herein, we demonstrate that PK2 expression is highly induced in nigral dopaminergic neurons during early stages of degeneration in multiple models of Parkinson's disease (PD), including PK2 reporter mice and MitoPark mice...
October 5, 2016: Nature Communications
Dong-Seok Yim
In the early phase of clinical development of antihypertensive drugs, quantitative modeling to predict their dose-concentration-response relationship is important to plan future clinical development and finding optimal dosage regimen at marketing approval. Two cases of concentration-response models of antihypertensive are presented here.Case 1: Carvedilol is a α1- and nonselective β- adrenergic receptor antagonist currently used for the management of mild-to-moderate essential hypertension and congestive heart failure...
September 2016: Journal of Hypertension
Shuangshuang Zhang, Hongxiang Yan, Panpan Yu, Yulong Xia, Wenli Zhang, Jianping Liu
The present study was aimed to develope a proliposomal formulation to decrease the hepatic first-pass metabolism of protocatechualdehyde (PD), followed by pellet coating to modify the drug release for angina chronotherapy. PD proliposomes were prepared by depositing PD-phospholipid complex on mannitol powders to improve the drug encapsulation. Afterwards, the PD proliposomes were prepared into pellet cores via extrusion-spheronization using 10% κ-carrageenan as pelletization aid prior to the development of PD sustained-release pellets (PD-SRPs)...
October 10, 2016: European Journal of Pharmaceutical Sciences
Michal Dudek, Nan Yang, Jayalath Pd Ruckshanthi, Jack Williams, Elzbieta Borysiewicz, Ping Wang, Antony Adamson, Jian Li, John F Bateman, Michael R White, Raymond P Boot-Handford, Judith A Hoyland, Qing-Jun Meng
OBJECTIVES: The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration. METHODS: Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2::luc reporters) were monitored in real time by bioluminescence photon counting and imaging...
August 3, 2016: Annals of the Rheumatic Diseases
Christiana Ossig, Daniel Sippel, Mareike Fauser, Florin Gandor, Wolfgang H Jost, Georg Ebersbach, Alexander Storch
BACKGROUND: Since previous studies aimed to study nonmotor symptom (NMS) fluctuations in direct conjunction with motor oscillations, there are no data available on the temporal context of NMS fluctuations and motor oscillations in advanced Parkinson's disease (PD). OBJECTIVE: To evaluate circadian patterns and temporal connections of NMS and motor fluctuations in PD. METHODS: 15 controls, 17 non-fluctuating and 15 fluctuating PD patients completed two diaries by rating 4 key psychiatric (anxiety, depressive mood, inner restlessness, concentration/attention deficits), fatigue and 4 autonomic NMS (excessive sweating, sialorrhea, bladder urgency, dizziness) absent or present and motor function (Off, On with/without dyskinesia, and asleep) for every hour for 5 consecutive days...
May 31, 2016: Journal of Parkinson's Disease
Leijun Hu, Yan Jin, Ying Grace Li, Anthony Borel
BACKGROUND: LY500307 is a highly selective estrogen receptor β (ERβ) agonist, which loses its selectivity at high dose and leads to undesirable suppression of total testosterone (TT) concentration. The objective of the present analysis was to define the LY500307 dose with minimal effect on TT METHODS: LY500307 and TT concentrations were obtained from a single ascending-dose study in a total of 30 healthy male subjects. LY500307 (in the range of 0.5 to 500 mg) or placebo was administered orally as a single dose on 2 occasions with a 3-week washout period...
July 2015: Clinical Pharmacology in Drug Development
E Lauretti, A Di Meco, S Merali, D Praticò
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. Although rare genetically linked cases of PD have been reported, most incidences are sporadic in nature. Late-onset, sporadic PD is thought to result from the combined effects of genetic and environmental risk factors exposure. Sleep and circadian rhythm disorders are recurrent among PD patients and appear early in the disease. Although some evidence supports a relationship between circadian disruption (CD) and PD, whether this is secondary to the motor symptoms or, indeed, is a factor that contributes to the pathogenesis of the disease remains to be investigated...
April 5, 2016: Molecular Psychiatry
Maria Salsone, Basilio Vescio, Alessandra Fratto, Miriam Sturniolo, Gennarina Arabia, Antonio Gambardella, Aldo Quattrone
OBJECTIVE: To compare circadian autonomic fluctuations in patients with Parkinson's Disease (PD) with or without REM sleep behavior disorder (RBD) by using heart rate variability (HRV) analysis. METHODS: This is a case-control study including 20 PD patients with RBD (PD-RBD) and 20 PD patients without RBD (PD). In all patients, we measured the components of HRV in the frequency domain during 24-h with daytime and night time recordings. Selected variables considered were low-frequency (LF) influenced by the sympathetic system and high-frequency (HF) influenced by the parasympathetic system...
May 2016: Parkinsonism & related Disorders
David P Breen, Cristina Nombela, Romina Vuono, P Simon Jones, Kate Fisher, David J Burn, David J Brooks, Akhilesh B Reddy, James B Rowe, Roger A Barker
BACKGROUND: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group...
July 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Dongyang Liu, Hong Yang, Ji Jiang, Péter Nagy, Kai Shen, Jiaming Qian, Pei Hu
Esomeprazole is one of the most commonly used drugs to treat gastroesophageal reflux disease and peptic ulcers, but the quantitative relationships among the pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenomics (PG) of the drug are not fully understood in special patient populations. A clinical PK/PD/PG study of intravenous (IV) esomeprazole in 5 dosing regimens was conducted in 20 healthy Chinese volunteers, who were categorized into Helicobacter pylori (HP)-negative and HP-positive subgroups...
July 2016: Journal of Clinical Pharmacology
Dario Arnaldi, Alice Latimier, Smaranda Leu-Semenescu, Marie Vidailhet, Isabelle Arnulf
OBJECTIVES: Melatonin is a chronobiotic treatment which also alleviates rapid eye movement (REM) sleep behavior disorder (RBD). Because the mechanisms of this benefit are unclear, we evaluated the clock-dependent REM sleep characteristics in patients with RBD, whether idiopathic (iRBD) or associated with Parkinson's Disease (PD), and we compared findings with PD patients without RBD and with healthy subjects. METHODS: An overnight videopolysomnography was performed in ten iRBD patients, ten PD patients with RBD (PD + RBD+), ten PD patients without RBD (PD + RBD-), and ten controls...
January 2016: Sleep Medicine
Hongmei Xu, Jianguo Li, Lorraine Webber, Rahul Kakkar, Yingxue Chen, Nidal Al-Huniti
Significant and reversible reductions in testosterone levels were observed with AZD4901 in both preclinical and clinical testing. A comprehensive population pharmacokinetic/pharmacodynamic (PK/PD) modeling of AZD4901 concentration and testosterone relationship from 3 phase 1 studies was performed using NONMEM to support dose selection for phase 2a development. A 2-compartment model with first-order absorption and first-order elimination best described AZD4901 PK. Circadian rhythm of baseline testosterone concentrations was well described by a cosine function...
August 2016: Journal of Clinical Pharmacology
Zhuqin Gu, BinBin Wang, Yong-Biao Zhang, Hui Ding, Yanli Zhang, Jun Yu, Mingliang Gu, Piu Chan, Yanning Cai
Circadian disruptions may result in sleep problems, oxidative stress and an altered inflammatory response. These symptoms may contribute to PD pathogenesis, despite a lack of direct experimental evidence supporting this relationship. Clock genes are essential to drive and maintain circadian rhythm. To elucidate the possible role of circadian disruptions in PD, we investigated 132 tag variants in eight clock genes. We genotyped these tags within 1,394 Chinese cases and 1,342 controls using Illumina GoldenGate chips...
2015: Scientific Reports
Gorica Micic, Nicole Lovato, Michael Gradisar, Helen J Burgess, Sally A Ferguson, David J Kennaway, Leon Lack
A significant delay in the timing of endogenous circadian rhythms has been associated with delayed sleep phase disorder (DSPD). More recently, other mechanisms have also been proposed to account for this disorder. To further explore the etiology of DSPD, the present study compared nocturnal melatonin profiles of 26 DSPD patients (18 males, 8 females; age, 21.73 ± 4.98 years) and 17 normally timed good sleepers (10 males, 7 females; age, 23.82 ± 5.23 years) in a time-free, dim-light (<10 lux) laboratory environment...
October 2015: Journal of Biological Rhythms
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