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Dhaval R Kalaria, Mayank Singhal, Vandana Patravale, Virginia Merino, Yogeshvar N Kalia
Effective treatment of Parkinson's disease (PD) involves administration of therapeutic agents with complementary mechanisms of action in order to replenish, sustain or substitute endogenous dopamine. The objective of this study was to investigate anodal co-iontophoresis of pramipexole (PRAM; dopamine agonist) and rasagiline (RAS; MAO-B inhibitor) in vitro and in vivo. Passive permeation of PRAM and RAS (20 mM each) across porcine skin after 6 h was 15.7±1.9 and 16.0±2.9 µg/cm2 , respectively. Co-iontophoresis at 0...
February 22, 2018: European Journal of Pharmaceutics and Biopharmaceutics
Dale E Edmondson, Claudia Binda
Monoamine oxidases A and B (MAO A and B) are mammalian flavoenzymes bound to the outer mitochondrial membrane. They were discovered almost a century ago and they have been the subject of many biochemical, structural and pharmacological investigations due to their central role in neurotransmitter metabolism. Currently, the treatment of Parkinson's disease involves the use of selective MAO B inhibitors such as rasagiline and safinamide. MAO inhibition was shown to exert a general neuroprotective effect as a result of the reduction of oxidative stress produced by these enzymes, which seems to be relevant also in non-neuronal contexts...
2018: Sub-cellular Biochemistry
Peter A LeWitt, Leo Verhagen Metman, Robert Rubens, Sarita Khanna, Sherron Kell, Suneel Gupta
OBJECTIVES: Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in "off" time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine)...
February 9, 2018: Clinical Neuropharmacology
Éva Szökő, Tamás Tábi, Peter Riederer, László Vécsei, Kálmán Magyar
The era of MAO-B inhibitors dates back more than 50 years. It began with Kálmán Magyar's outstanding discovery of the selective inhibitor, selegiline. This compound is still regarded as the gold standard of MAO-B inhibition, although newer drugs have also been introduced to the field. It was revealed early on that selective, even irreversible inhibition of MAO-B is free from the severe side effect of the non-selective MAO inhibitors, the potentiation of tyramine, resulting in the so-called 'cheese effect'...
February 7, 2018: Journal of Neural Transmission
Ana B Garcia-Delgado, Lourdes Valdés-Sánchez, Sofia M Calado, Francisco J Diaz-Corrales, Shom S Bhattacharya
AIMS: Retinitis pigmentosa (RP) is an inherited disease characterized by a progressive degeneration of rod photoreceptors. An imbalance between pro- and antiapoptotic factors, such as Bax/Bcl-2, has been involved in retinal degeneration. To date, no cure or effective treatments are available for RP. Rasagiline is an antiparkinsonian drug that has shown neuroprotective effects in part attributed to a modulation of Bax/Bcl-2 expression. In this study, we have evaluated the use of rasagiline as a potential treatment for RP...
January 25, 2018: CNS Neuroscience & Therapeutics
Bao-Dong Li, Jing-Jun Cui, Jia Song, Ce Qi, Pei-Feng Ma, Ya-Rong Wang, Jing Bai
BACKGROUND/AIMS: A network meta-analysis is used to compare the efficacy of ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil and levodopa, with placebo as a control, for non-motor symptoms in Parkinson's disease (PD). METHODS: PubMed, Embase and the Cochrane Library were searched from their establishment dates up to January 2017 for randomized controlled trials (RCTs) investigating the efficacy of the above ten drugs on the non-motor symptoms of PD...
January 15, 2018: Cellular Physiology and Biochemistry
Xuan Xiao, Xing-Xing Zhang, Mei-Miao Zhan, Kai Cheng, Shiyu Li, Zhouling Xie, Chenzhong Liao
Parkinson's disease (PD) is associated with elevated levels of hMAO-B in the brain, and MAO-B has been recognized a successful target for developing anti-PD drugs. Herein we report rasagiline derivatives as novel potent and selective hMAO-B inhibitors. They were designed by employing fragment-based drug design strategy to link rasagiline and hydrophobic fragments, which may target a hydrophobic pocket in the entrance cavity of hMAO-B. Different linkers such as -OCH2-, -SCH2-, -OCH2CH2-, -OCH2CH2O-, -OCH2CH2CH2O- were tried...
January 10, 2018: European Journal of Medicinal Chemistry
Wiebke Schrempf, Mareike Fauser, Miriam Wienecke, Sebastian Brown, Antonia Maaß, Christiana Ossig, Karolin Otto, Moritz D Brandt, Matthias Löhle, Uta Schwanebeck, Xina Graehlert, Heinz Reichmann, Alexander Storch
OBJECTIVE: To study the effects of rasagiline on sleep quality in Parkinson's disease (PD) patients with sleep disturbances. INTRODUCTION: Sleep disorders are common in PD. Rasagiline is widely used in PD patients, but double-blind polysomnographic trials on its effects on sleep disturbances are missing. METHODS: Single-center, double-blind, baseline-controlled investigator-initiated clinical trial of rasagiline 1 mg/day over 8 weeks in PD patients with sleep disturbances...
January 11, 2018: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Makoto Naoi, Wakako Maruyama, Masayo Shamoto-Nagai
Type A and B monoamine oxidases (MAO-A, -B) mediate and modulate intracellular signal pathways for survival or death of neuronal cells. MAO-A is associated with development of neuronal architecture, synaptic activity, and onset of psychiatric disorders, including depression, and antisocial aggressive impulsive behaviors. MAO-B produces hydrogen peroxide and plays a vital role in neuronal loss of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. This review presents a novel role of MAO-A and B, their substrates and inhibitors, and hydrogen peroxide in brain function and neuronal survival and death...
December 26, 2017: Journal of Neural Transmission
Ying Jiang, Xuemei Zhang, Hongjie Mu, Hongchen Hua, Dongyu Duan, Xiuju Yan, Yiyun Wang, Qingqing Meng, Xiaoyan Lu, Aiping Wang, Wanhui Liu, Youxin Li, Kaoxiang Sun
A microsphere-gel in situ forming implant (MS-Gel ISFI) dual-controlled drug delivery system was applied to a high water-soluble small-molecule compound Rasagiline mesylate (RM) for effective treatment of Parkinson's disease. This injectable complex depot system combined an in situ phase transition gel with high drug-loading and encapsulation efficiency RM-MS prepared by a modified emulsion-phase separation method and optimized by Box-Behnken design. It was evaluated for in vitro drug release, in vivo pharmacokinetics, and in vivo pharmacodynamics...
November 2018: Drug Delivery
József Attila Szász, Viorelia Constantin, Péter Alpár Fazakas, Eszter Blényesi, Levente Gábor Grieb, Antal Balla, Mónika Sárig, Kinga Szegedi, Eszter Noémi Bartha, Szabolcs Szatmári
INTRODUCTION: Selective monoamine oxidase B inhibitors have an accurate place in therapeutical strategy of Parkinsons's disease. In the early stages of the disease, especially in younger patients with milder symptoms, the introduction of levodopa substitution could be efficacious in delaying; in advanced stages they are mainly used to treat motor complications, as an adjunct to levodopa. AIM: The evaluation of therapeutical strategies used in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital in order to define the role of monoamine oxidase B inhibitors...
December 2017: Orvosi Hetilap
Wenjia Zhou, Chengzhe Lv, Quanying Zhang, Shunlin Zong, Meng Wang
BACKGROUND AND OBJECTIVES: Rasagiline tablet is an oral MAO-B inhibitor applied in early or advanced Parkinson's disease (PD). However, when patients with PD cannot take their usual oral medications, a rasagiline transdermal patch can be used as a way to offer continuous rasagiline while avoiding plasma concentration peaks and troughs. The objectives of this study were to investigate the pharmacokinetics, pharmacodynamics, and safety of the rasagiline transdermal patch in healthy Chinese subjects...
November 20, 2017: Clinical Drug Investigation
Michele Pistacchi, Manuela Gioulis, Flavio Sanson, Sandro Z Marsala
BACKGROUND: 'Wearing off' refers to the phenomenology of movement disorders in Parkinson's disease (PD) that appears early and is much commoner than generally believed. It may be present in the form of either motor symptoms or non-motor symptoms. AIM: To investigate the utility of wearing-off questionnaire (WOQ-19, Italian version) in the outpatient clinical practice to assess the suitability of different combinations of treatment, in various stages of PD. METHODS: 73 consecutive patients (58% male and 42% female) suffering from PD were recruited through the Santorso Hospital and San Martino Hospital from September 2012 to March 2014...
November 2017: Neurology India
Matt R Adams, Chieh-Hung Tien, Robert McDonald, Alexander W H Speed
The first use of diazaphospholenes as chiral catalysts has been demonstrated with enantioselective imine hydroboration. A chiral diazaphospholene prepared in a simple three-step synthesis from commercial materials has been shown to achieve the highest enantioselectivity for the hydroboration of alkyl imines with pinacolborane reported to date. Enantiomer ratios of up to 88:12 were obtained with low (2 mol %) catalyst loadings. Twenty examples of asymmetric reduction employing this main-group catalysis protocol, including the synthesis of the pharmaceuticals ent-rasagiline and fendiline, are shown...
December 22, 2017: Angewandte Chemie
Aileen Cronin, Maura Grealy
Parkinson's disease is a common, debilitating, neurodegenerative disorder for which the current gold standard treatment, levodopa (L-DOPA) is symptomatic. There is an urgent, unmet need for neuroprotective or, ideally, neuro-restorative drugs. We describe a 6-hydroxydopamine (6-OHDA) zebrafish model to screen drugs for neuroprotective and neuro-restorative capacity. Zebrafish larvae at two days post fertilization were exposed to 6-OHDA for three days, with co-administration of test drugs for neuroprotection experiments, or for 32 h, with subsequent treatment with test drugs for neuro-restoration experiments...
December 26, 2017: Neuroscience
A V Rudakova, O S Levin
AIM: To assess the cost-efficiency of the fixed levodopa/carbidopa/entacapone combination and the free combination of levodopa/carbidopa with rasagiline. MATERIAL AND METHODS: An analysis was performed using the Markov model including three clinical states: duration of off-time ≤25%, duration of off-time >25% and fatal outcome. Costs of the drugs were calculated based on the results of auctions for 2016 by IMS Health data. RESULTS: In basic variant (drugs containing levodopa, 5-times a day), costs of treatment with the fixed levodopa/carbidopa/entacapone combination were 2...
2017: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
M Diana Neely, Carrie Ann Davison, Michael Aschner, Aaron B Bowman
Parkinson's disease (PD) is the result of complex interactions between genetic and environmental factors. Two chemically distinct environmental stressors relevant to PD are the metal manganese and the pesticide rotenone. Both are thought to exert neurotoxicity at least in part via oxidative stress resulting from impaired mitochondrial activity. Identifying shared mechanism of action may reveal clues towards an understanding of the mechanisms underlying PD pathogenesis. Here we compare the effects of manganese and rotenone in human-induced pluripotent stem cells-derived postmitotic mesencephalic dopamine neurons by assessing several different oxidative stress endpoints...
October 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Domiziana Rinaldi, Francesca Assogna, Michela Sforza, Stefania Tagliente, Francesco E Pontieri
Wearing-off refers to the predictable worsening of motor and sometimes non-motor symptoms of Parkinson's disease occurring at the end of levodopa dose that improves with the next drug dose. Here, we investigated the efficacy of rasagiline on executive functions at the end of levodopa dose in patients displaying symptoms of wearing-off. Rasagiline was well-tolerated and produced a significant improvement at the Frontal Assessment Battery, together with improvement of motor symptoms at the end of levodopa dose...
September 27, 2017: Neurological Sciences
Godwin A Aleku, Scott P France, Henry Man, Juan Mangas-Sanchez, Sarah L Montgomery, Mahima Sharma, Friedemann Leipold, Shahed Hussain, Gideon Grogan, Nicholas J Turner
Reductive amination is one of the most important methods for the synthesis of chiral amines. Here we report the discovery of an NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm, Uniprot code Q2TW47) that can catalyse the reductive coupling of a broad set of carbonyl compounds with a variety of primary and secondary amines with up to >98% conversion and with up to >98% enantiomeric excess. In cases where both carbonyl and amine show high reactivity, it is possible to employ a 1:1 ratio of the substrates, forming amine products with up to 94% conversion...
October 2017: Nature Chemistry
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Matthew J Benskey, Xuebing Cao, Jun Xu, Yi E Sun, Keqiang Ye
BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson's disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
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