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Systems pharmacology

Meng-Yi Xu, Albert H C Wong
Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing...
March 22, 2018: Acta Pharmacologica Sinica
Suzanne Oparil, Maria Czarina Acelajado, George L Bakris, Dan R Berlowitz, Renata Cífková, Anna F Dominiczak, Guido Grassi, Jens Jordan, Neil R Poulter, Anthony Rodgers, Paul K Whelton
Systemic arterial hypertension is the most important modifiable risk factor for all-cause morbidity and mortality worldwide and is associated with an increased risk of cardiovascular disease (CVD). Fewer than half of those with hypertension are aware of their condition, and many others are aware but not treated or inadequately treated, although successful treatment of hypertension reduces the global burden of disease and mortality. The aetiology of hypertension involves the complex interplay of environmental and pathophysiological factors that affect multiple systems, as well as genetic predisposition...
March 22, 2018: Nature Reviews. Disease Primers
Godela M Brosnahan, Kaleab Z Abebe, Charity G Moore, Kyongtae T Bae, William E Braun, Arlene B Chapman, Michael F Flessner, Peter C Harris, Marie C Hogan, Ronald D Perrone, Frederic F Rahbari-Oskoui, Theodore I Steinman, Vicente E Torres, The Halt Pkd Investigators
BACKGROUND: The HALT PKD trial in early autosomal dominant polycystic kidney disease (ADPKD) showed that intensive control of systolic blood pressure to 95-110 mmHg was associated with a 14% slower rate of kidney volume growth compared to standard control. It is unclear whether this result was due to greater blockade of the renin-angiotensin-aldosterone system (RAAS) by allowing the use of higher drug doses in the low blood pressure arm, or due to the lower blood pressure per se. METHODS: In this secondary analysis of HALT PKD Study A, we categorized participants into high and low dose groups based on the median daily equivalent dose of RAAS blocking drugs used after the initial dose titration period...
March 21, 2018: Current Hypertension Reviews
Jeffrey Lambe, Olwen C Murphy, Shiv Saidha
PURPOSE OF REVIEW: With the recognition that neurodegeneration represents the principal substrate of disability in multiple sclerosis (MS), there has been increased strives towards identifying biomarkers for accurately quantifying and tracking neurodegeneration during the disease course. The retina provides an opportune "window" into the central nervous system (CNS) in MS, with retinal changes in MS reflecting not only local, but also global aspects of neurodegeneration and inflammation operative in the disease...
March 21, 2018: Current Treatment Options in Neurology
Bruno Fautrel, Rieke Alten, Bruce Kirkham, Inmaculada de la Torre, Frederick Durand, Jane Barry, Thorsten Holzkaemper, Walid Fakhouri, Peter C Taylor
Current guidelines for the management of rheumatoid arthritis (RA) recommend early treatment and a treat-to-target goal of remission or low disease activity. Over the past decade, this approach has been extremely successful in reducing disease activity and joint damage in patients with RA. At the same time, however, overall patient perception of well-being appears to have decreased with respect to outcome measures considered important by patients themselves, such as pain, fatigue, physical function and quality of life...
March 21, 2018: Rheumatology International
Mitul A Mehta, Anne Schmechtig, Vasileia Kotoula, Juliet McColm, Kimberley Jackson, Claire Brittain, Sitra Tauscher-Wisniewski, Bruce J Kinon, Paul D Morrison, Thomas Pollak, Timothy Mant, Steven C R Williams, Adam J Schwarz
BACKGROUND: Aberrant glutamate neurotransmission, and in particular dysfunction of the N-methyl-D-aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system...
March 21, 2018: Psychopharmacology
Andrea Negro, Angela Koverech, Paolo Martelletti
Migraine is an important socioeconomic burden and is ranked the sixth cause of years of life lost because of disability in the general population and the third cause of years of life lost in people younger than 50 years. The cornerstone of pharmacological treatment is represented by the acute therapy. The serotonin (5-hydroxytryptamine [5-HT]) receptor subtype 1B /1D agonists, called triptans, are nowadays the first-line acute therapy for patients who experience moderate-to-severe migraine attacks. Unfortunately, a high percentage of patients are not satisfied with this acute treatment, either for lack of response or side effects...
2018: Journal of Pain Research
Eline T S van Maanen, Tamara S van Steeg, Maurice Ahsman, Maria S Michener, Mary J Savage, Matthew E Kennedy, Huub J Kleijn, Julie A Stone, Meindert Danhof
The abnormal accumulation of amyloid-β (Aβ) in the brain parenchyma has been posited as a central event in the pathophysiology of Alzheimer's disease. Recently, we have proposed a systems pharmacology model of the APP pathway, describing the Aβ precursor protein (APP) metabolite responses (Aβ40, Aβ42, sAPPα and sAPPβ) to β-secretase 1 (BACE1) inhibition (van Maanen et al., 2016). In this investigation this model was challenged to describe Aβ dynamics following γ-secretase (GS) inhibition. This led an extended systems pharmacology model, with separate descriptions to characterize the sequential cleavage steps of APP by BACE1 and GS, to describe the differences in Aβ response to their respective inhibition...
March 21, 2018: Journal of Pharmacology and Experimental Therapeutics
Yuki Domon, Naohisa Arakawa, Tatsuya Inoue, Fumihiko Matsuda, Makoto Takahashi, Naotoshi Yamamura, Kiyonori Kai, Yutaka Kitano
Mirogabalin ([(1 R ,5 S ,6 S )-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid), a novel ligand for the α2 δ subunit of voltage-gated calcium channels, is being developed to treat pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. In the present study, we investigated the in vitro binding characteristics and in vivo analgesic effects of mirogabalin, compared to those of pregabalin, a standard α2 δ ligand. Mirogabalin showed potent and selective binding affinities for the α2 δ subunits, while having no effects on 186 off-target proteins...
March 21, 2018: Journal of Pharmacology and Experimental Therapeutics
Jianjia Fan, Rui Qi Zhao, Cameron Parro, Wenchen Zhao, Hsien-Ya Chou, Jerome Robert, Tarek Z Deeb, Carina Raynoschek, Samantha Barichievy, Ola Engvist, Marcello Maresca, Ryan Hicks, Johan Meuller, Stephen J Moss, Nicholas J Brandon, Michael W Wood, Iva Kulic, Cheryl L Wellington
Apolipoprotein E (apoE) is the primary lipid carrier within the central nervous system (CNS) and the strongest genetic risk factor for late onset Alzheimer's disease (AD). ApoE is primarily lipidated via the ATP-binding cassette transporter 1 (ABCA1), and both are under transcriptional regulation by the liver X nuclear receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden...
March 21, 2018: Journal of Lipid Research
Julio A Chalela
BACKGROUND: Headaches among military personnel are very common and headgear wear is a frequently identified culprit. Helmet wear may cause migrainous headaches, external compression headache, other primary cranial neuralgias, and occipital neuralgia. The clinical features and the response to treatment allow distinction between the different types of headaches. Headaches among aviators are particularly concerning as they may act as distractors while flying and the treatment options are often incompatible with flying status...
April 1, 2018: Aerospace Medicine and Human Performance
Pradeep Phadnis, Purnima Dey Sarkar, Mithun Singh Rajput
BACKGROUND: Initial evidences have shown that diabetes mellitus occurs concomitantly with obsessive-compulsive disorder (OCD) symptomatology. Serotonergic psychiatric therapy posits that serotonin is a central character in the management of OCD. Hence, it is worth investigating novel chemical entities affecting the serotonergic system for targeting OCD. An isoflavonoid phytoestrogen, genistein, has been recognized as of great pharmacological value especially for protecting neurodegeneration, depression (serotonin regulation), and diabetes...
March 21, 2018: Journal of Basic and Clinical Physiology and Pharmacology
Andres Canales, Seongjun Park, Antje Kilias, Polina Anikeeva
Multifunctional devices for modulation and probing of neuronal activity during free behavior facilitate studies of functions and pathologies of the nervous system. Probes composed of stiff materials, such as metals and semiconductors, exhibit elastic and chemical mismatch with the neural tissue, which is hypothesized to contribute to sustained tissue damage and gliosis. Dense glial scars have been found to encapsulate implanted devices, corrode their surfaces, and often yield poor recording quality in long-term experiments...
March 21, 2018: Accounts of Chemical Research
Li Liu, Mingxing Miao, Yang Chen, Zhongjian Wang, Binbin Sun, Xiaodong Liu
This study investigated alterations in the function and expression of P-glycoprotein (P-GP), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) at the blood-brain barrier (BBB) of acute liver failure (ALF) mice and its clinical significance. ALF mice were developed using intraperitoneal injection of thioacetamide. P-GP, BCRP, and MRP2 functions were determined by measuring the ratios of brain-to-plasma concentration of rhodamine 123, prazosin, and dinitrophenyl- S -glutathione, respectively...
2018: Frontiers in Pharmacology
Eva Ceskova, Petr Silhan
In spite of tremendous development in central nervous system research, current treatment is suboptimal, especially in severe mental disorders. In medicine, there are two main methods of improving the health care provided: seeking new treatment procedures and perfecting (optimizing) the existing ones. Optimization of treatment includes not only practical tools such as therapeutic drug monitoring but also implementation of general trends in the clinical practice. New pharmacological options include new more sophisticated forms of monoaminergic drugs, old drugs rediscovered on the base of a better understanding of pathophysiology of mental illnesses, and drugs aimed at new treatment targets...
2018: Neuropsychiatric Disease and Treatment
Yue Zhang, Liying Zhang, Qi Zhang, Xitong Zhang, Tong Zhang, Bing Wang
Background: Brucea javanica oil (BJO), a traditional Chinese herbal medicine, has a variety of pharmacological activities and several BJO-related patent drugs have been widely used in China. Purpose: The objective of this study was to evaluate the gastric therapeutic effects of self-made BJO and its pharmaceutical potential to formulate novel BJO gastroretentive floating bead by comparing with commercial products. Methods: BJO was extracted from the seeds of B...
2018: Drug Design, Development and Therapy
Sana Hibino, Shunsuke Chikuma, Taisuke Kondo, Minako Ito, Hiroko Nakatsukasa, Setsuko Omata-Mise, Akihiko Yoshimura
Enhanced infiltration of regulatory T (Treg) cells into tumor tissue is detrimental to cancer patients and closely associated with poor prognosis as they create an immunosuppressive state that suppresses anti-tumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg cell genetic programs, contribute to Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment...
March 20, 2018: Cancer Research
Jolien Fleur Leijenaar, Geert Jan Groeneveld, Wiesje Maria van der Flier, Philip Scheltens, Erica Surya Klaassen, Henry Chanoch Weinstein, Geert Jan Biessels, Frederik Barkhof, Niels Daniël Prins
BACKGROUND: People with vascular cognitive impairment (VCI) constitute a clinically heterogeneous group, but previous symptomatic drug trials in VCI did not take this clinical heterogeneity into account. Executive dysfunction and memory impairment are the cognitive domains that are most frequently impaired in VCI, and these impairments are likely to reflect vascular damage to specific neurotransmitter systems, which opens the possibility for targeted symptomatic treatment directed at specific neurotransmitters...
March 20, 2018: JMIR Research Protocols
Hailong Li, Zhongyuan Tang, Peng Chu, Yanlin Song, Ying Yang, Bin Sun, Mengyue Niu, Eskandar Qaed, Abdullah Shopit, Guozhu Han, Xiaodong Ma, Jinyong Peng, Min Hu, Zeyao Tang
Methylglyoxal (MGO), an active metabolite of glucose, is observed in high levels in the tissues and blood of diabetic patients. Phosphocreatine (PCr), a high-energy phosphate compound, exhibits a range of pharmacological actions but little is well known of its neuroprotective action. The aim of the present study was to investigate the neuroprotective effects and the possible mechanisms of PCr. Diabetes is closely associated with neurodegenerative diseases, leading not only to the peripheral nervous system (PNS) and but also to central nervous system (CNS) damage...
March 17, 2018: Free Radical Biology & Medicine
Jordana Galizia, Mariano Prado Acosta, Estefanía Urdániz, Marcelo A Martí, Mariana Piuri
Nitroxyl (HNO) is a highly elusive and reactive molecule. Nitroxyl biological effects and pharmacological potential are becoming increasingly relevant. Mycobacterium tuberculosis infection needs new and more efficient drugs. Reactive Nitrogen and Oxygen Species (RNOS) are key compounds used by the immune system to fight intracellular infections, particularly Mycobacterium tuberculosis. In this context, we analyzed HNO potential to kill mycobacteria. We evaluated the viability and biological response of mycobacteria towards HNO releasing compounds...
March 2018: Tuberculosis
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