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Pharmacology Research & Perspectives

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https://www.readbyqxmd.com/read/30546909/efficacy-of-smtp-7-a-small-molecule-anti-inflammatory-thrombolytic-in-embolic-stroke-in-monkeys
#1
Eriko Suzuki, Naoko Nishimura, Tetsuya Yoshikawa, Yudai Kunikiyo, Keiko Hasegawa, Keiji Hasumi
SMTP-7 ( Stachybotrys microspora triprenyl phenol-7) is a small molecule that promotes thrombolysis and suppresses inflammation possibly through plasminogen modulation and soluble epoxide hydrolase (sEH) inhibition, respectively. Here, we demonstrate an efficacy of SMTP-7 in a severe embolic stroke model in monkeys. The middle cerebral artery was embolized by an autologous blood clot. Saline, SMTP-7, or tissue-type plasminogen activator (t-PA) (n = 5 in each group) was given after 3 hours, and neurologic deficit scoring and infarct characterization were performed after 24 hours...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30534379/pharmacological-profile-of-the-neuropeptide-s-receptor-dynamic-mass-redistribution-studies
#2
Chiara Ruzza, Federica Ferrari, Remo Guerrini, Erika Marzola, Delia Preti, Rainer K Reinscheid, Girolamo Calo
Neuropeptide S (NPS) is the endogenous ligand of the neuropeptide S receptor (NPSR). NPS modulates several biological functions including anxiety, wakefulness, pain, and drug abuse. The aim of this study was the investigation of the pharmacological profile of NPSR using the dynamic mass redistribution (DMR) assay. DMR is a label-free assay that offers a holistic view of cellular responses after receptor activation. HEK293 cells stably transfected with the murine NPSR (HEK293mNPSR ) have been used. To investigate the nature of the NPS-evoked DMR signaling, FR900359 (Gq inhibitor), pertussis toxin (Gi inhibitor), and rolipram (phosphodiesterase inhibitor) were used...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30519476/risdiplam-distributes-and-increases-smn-protein-in-both-the-central-nervous-system-and-peripheral-organs
#3
Agnès Poirier, Marla Weetall, Katja Heinig, Franz Bucheli, Kerstin Schoenlein, Jochem Alsenz, Simon Bassett, Mohammed Ullah, Claudia Senn, Hasane Ratni, Nikolai Naryshkin, Sergey Paushkin, Lutz Mueller
Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 ( SMN1) gene. A second gene, SMN2 , produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1 . Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30519475/a-comparison-of-biological-activity-of-commercially-available-purified-native-botulinum-neurotoxin-serotypes-a1-to-f1-in-vitro-ex-vivo-and-in-vivo
#4
Sarah Donald, Mark Elliott, Bryony Gray, Fraser Hornby, Agnieszka Lewandowska, Sandra Marlin, Christine Favre-Guilmard, Cindy Périer, Sylvie Cornet, Mikhail Kalinichev, Johannes Krupp, Elena Fonfria
Botulinum neurotoxin (BoNT) is a major therapeutic agent. Of seven native BoNT serotypes (A to G), only A and B are currently used in the clinic. Here we compared the potency of commercially available purified native serotypes A1 to F1 across in vitro, ex vivo, and in vivo assays. BoNT potency in vitro was assessed in rat primary cells (target protein cleavage and neurotransmitter release assays) in supraspinal, spinal, and sensory systems. BoNT potency ex vivo was measured in the mouse phrenic nerve hemidiaphragm (PNHD) assay, measuring muscle contractility...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30519474/synergistic-interaction-between-the-agonism-of-cebranopadol-at-nociceptin-orphanin-fq-and-classical-opioid-receptors-in-the-rat-spinal-nerve-ligation-model
#5
Thomas Christoph, Robert Raffa, Jean De Vry, Wolfgang Schröder
Cebranopadol (trans-6'-fluoro-4',9'-dihydro- N,N -dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ opioid peptide (NOP) and classical opioid receptor (MOP, DOP, and KOP) agonist with highly efficacious and potent activity in a broad range of rodent models of nociceptive, inflammatory, and neuropathic pain as well as limited opioid-type side effects such as respiratory depression. This study was designed to explore contribution and interaction of NOP and classical opioid receptor agonist components to cebranopadol analgesia in the rat spinal nerve ligation (SNL) model...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30464842/nonclinical-safety-assessment-of-a-human-interleukin-22fc-ig-fusion-protein-demonstrates-in-vitro-to-in-vivo-and-cross-species-translatability
#6
Donna W Lee, Shelly Zhong, Rama Pai, Julie Rae, Siddharth Sukumaran, Eric G Stefanich, Jeff Lutman, Estelle Doudement, Xiaoting Wang, Brandon Harder, Annemarie Lekkerkerker, Ann Herman, Wenjun Ouyang, Dimitry M Danilenko
Although Interleukin-22 (IL-22) is produced by various leukocytes, it preferentially targets cells with epithelial origins. IL-22 exerts essential roles in modulating various tissue epithelial functions, such as innate host defense against extracellular pathogens, barrier integrity, regeneration, and wound healing. Therefore, IL-22 is thought to have therapeutic potential in treating diseases associated with infection, tissue injury or chronic tissue damage. A number of in vitro and in vivo nonclinical studies were conducted to characterize the pharmacological activity and safety parameters of UTTR1147A, an IL-22 recombinant fusion protein that links the human cytokine IL-22 with the Fc portion of a human immunoglobulin...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30459952/utility-of-glycosylated-timp3-molecules-inhibition-of-mmps-and-tace-to-improve-cardiac-function-in-rat-myocardial-infarct-model
#7
Vishnu Chintalgattu, Joanne Greenberg, Shivani Singh, Venice Chiueh, Amy Gilbert, Jason W O'Neill, Stephen Smith, Simon Jackson, Aarif Y Khakoo, TaeWeon Lee
Tissue Inhibitor of Metalloproteinase 3 (TIMP3) is a secreted protein that has a great utility to inhibit elevated metalloproteinase (MMP) activity in injured tissues including infarcted cardiac tissue, inflamed vessels, and joint cartilages. An imbalance between TIMP3 and active MMP levels in the local tissue area may cause worsening of disease progression. To counter balance elevated MMP levels, exogenous administration of TIMP3 appeared to be beneficial in preclinical studies. However, the current form of WT-TIMP3 molecule has a limitation to be a therapeutic candidate due to low production yield, short plasma half-life, injection site retention, and difficulty in delivery, etc...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30459951/the-role-of-loops-b-and-c-in-determining-the-potentiation-of-gaba-a-receptors-by-midazolam
#8
Olivia A Moody, Andrew Jenkins
Many benzodiazepines are positive allosteric modulators (PAMs) of GABAA receptors that cause sedation, hypnosis, and anxiolysis. Benzodiazepines bind GABAA receptors at the extracellular interface of the α and γ subunits. Within the α subunit, the benzodiazepine binding site is defined by three highly conserved structural loops, loops A-C. Although previous mutagenesis studies have identified His102 in Loop A as important for benzodiazepine modulation of GABAA receptors, the functional roles of many of the other conserved residues in loops A-C remain incompletely understood...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30455960/cellular-density-dependent-increases-in-hif-1%C3%AE-compete-with-c-myc-to-down-regulate-human-ep4-receptor-promoter-activity-through-sp-1-binding-region
#9
Naofumi Seira, Kazuyuki Yamagata, Keijo Fukushima, Yumi Araki, Naoki Kurata, Naoki Yanagisawa, Masato Mashimo, Hiroyuki Nakamura, John W Regan, Toshihiko Murayama, Hiromichi Fujino
The up-regulated expression of E-type prostanoid (EP) 4 receptors has been implicated in carcinogenesis; however, the expression of EP4 receptors has also been reported to be weaker in tumor tissues than in normal tissues. Indeed, EP4 receptors have been suggested to play a role in the maintenance of colorectal homeostasis. This study aimed to examine the underlying mechanisms/reasons for why inconsistent findings have been reported regarding EP4 receptor expression levels in homeostasis and carcinogenesis by focusing on cellular densities...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30455959/oral-administration-of-the-selective-gpr120-ffa4-agonist-compound-a-is-not-effective-in-alleviating-tissue-inflammation-in-mouse-models-of-prototypical-autoimmune-diseases
#10
Melanie Wannick, Siegfried Bezdek, Nathalie Guillen, Markus Thieme, Fibi Meshrkey, Sadegh Mousavi, Michaela Seeling, Falk Nimmerjahn, Attila Mócsai, Detlef Zillikens, Tanya Sezin, Christian D Sadik
ω3-polyunsaturated free fatty acids (ω3-PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3-[2-chloro-5-(trifluoromethoxy)phenyl]-3-azaspiro[5.5]undecane-9-acetic acid ("compound A"; cpd A) has been developed...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30455958/natural-language-processing-based-assessment-of-consistency-in-summaries-of-product-characteristics-of-generic-antimicrobials
#11
Rumiko Shimazawa, Yoshinobu Kano, Masayuki Ikeda
To investigate consistency in summaries of product characteristics (SmPCs) of generic antimicrobials, we used natural language processing (NLP) to analyze and compare large amounts of text quantifying consistency between original and generic SmPCs. We manually compared each section of generic and original SmPCs for antimicrobials listed in the electronic Medicines Compendium in the United Kingdom, focusing on omissions and additions of clinically significant information (CSI). Independently, we quantified differences between the original and generic SmPCs using Kachako, a fully automatic NLP platform...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30443347/onset-timing-of-statin-induced-musculoskeletal-adverse-events-and-concomitant-drug-associated-shift-in-onset-timing-of-maes
#12
Hayato Akimoto, Akio Negishi, Shinji Oshima, Mitsuyoshi Okita, Sachihiko Numajiri, Naoko Inoue, Shigeru Ohshima, Daisuke Kobayashi
To evaluate the onset timing of musculoskeletal adverse events (MAEs) that develop during statin monotherapy and to determine whether concomitant drugs used concurrently with statin therapy shifts the onset timing of MAEs. Cases in which statins (atorvastatin, rosuvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, and pravastatin) were prescribed were extracted from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) Data Files. The onset timing of MAEs during statin monotherapy was evaluated by determining the difference between statin start date and MAE onset date...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30410768/effects-of-cardiopulmonary-bypass-on-the-disposition-of-cefazolin-in-patients-undergoing-cardiothoracic-surgery
#13
Mizuho Asada, Masashi Nagata, Tomohiro Mizuno, Tokujiro Uchida, Naoki Kurashima, Hiromitsu Takahashi, Koshi Makita, Hirokuni Arai, Hirotoshi Echizen, Masato Yasuhara
The aim of the study was to evaluate the disposition of plasma unbound cefazolin in patients undergoing cardiothoracic surgery with cardiopulmonary bypass (CPB). Adult patients undergoing cardiothoracic surgery with CPB were enrolled in the study. Cefazolin sodium was given intravenously before skin incision (1 g) and at the beginning of CPB (2 g). Thereafter, an additional dose (1 g) was given every 4 hours. Seven to ten blood samples were collected before and during surgery. Plasma total and unbound (ultrafiltrated) cefazolin concentrations were analyzed using an HPLC-UV method...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30410767/dual-androgen-receptor-ar-and-stat3-inhibition-by-a-compound-targeting-the-ar-amino-terminal-domain
#14
Yaping Hua, Waqas Azeem, Yunheng Shen, Shoude Zhang, Jan R Olsen, Anne M Øyan, Xisong Ke, Weidong Zhang, Karl-Henning Kalland
Prostate cancer (PCa) often recurs as incurable castration-resistant prostate cancer (CRPC) after the failure of androgen deprivation therapy. CRPC development relies on androgen receptor (AR) signaling. The IL6/STAT3 pathway is also a key driver of CRPC. The crosstalk between IL6/STAT3 and the AR pathways provides opportunities to explore next-generation agents to treat PCa. Through screening of around 600 natural compounds in our newly established prostate tumorigenesis model, potential STAT3 signaling inhibitors were found and additionally examined for effects on AR signaling...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30386625/pharmacokinetics-and-safety-of-enasidenib-following-single-oral-doses-in-japanese-and-caucasian-subjects
#15
Yan Li, Liangang Liu, Diana Gomez, Jian Chen, Zeen Tong, Maria Palmisano, Simon Zhou
The aim of this study was to assess and compare the pharmacokinetics (PK) and safety of Enasidenib in healthy adult male Japanese subjects to healthy adult male Caucasian subjects. This was a phase 1, single dose study to evaluate the PK and safety of Enasidenib in healthy adult male Japanese subjects relative to healthy adult male Caucasian subjects. A total of 62 subjects (31 Japanese and 31 Caucasian) were enrolled into three dose cohorts (single doses of 50 mg, 100 mg, or 300 mg Enasidenib). Blood samples for PK assessment were collected up to 672 hours postdose...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30386624/polypharmacy-and-medication-deprescribing-a-survey-among-multimorbid-older-adults-in-denmark
#16
Michaela L Schiøtz, Anne Frølich, Anette K Jensen, Lene Reuther, Hans Perrild, Tonny S Petersen, Jonatan Kornholt, Mikkel B Christensen
Polypharmacy is common among multimorbid adults and associated with increased morbidity and mortality. Excessive polypharmacy (ie, ≥10 medicine) is strongly associated with inappropriate medication use, but little is known about attitudes toward deprescribing in patients with excessive polypharmacy. We surveyed 100 Danish individuals aged 65 years and above with ≥10 prescribed medications, using the validated Patients' Attitudes Towards Deprescribing (PATD) instrument. Most participants (81, 81%) thought they took a large number of medications, and 79 (79%) believed that their medications were necessary...
December 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30324768/patterns-of-adverse-drug-reaction-signals-in-nafdac-pharmacovigilance-activities-from-january-to-june-2015-safety-of-drug-use-in-nigeria
#17
Olufunsho Awodele, Rebecca Aliu, Ibrahim Ali, Yetunde Oni, Christianah Mojisola Adeyeye
Adverse drug reactions (ADRs) are expected to be associated with an economic drain on the healthcare systems. The study was carried out to determine the occurrence of ADRs reported to NAFDAC Pharmacovigilance from January to June 2015, to illustrate the pattern of organ system affected by ADRs, to assess the completeness of ADR report, to determine the relationship between the occurrence of ADRs with suspect drugs and the use of concomitant drugs as well as to generate possible signals from the reported ADRs...
October 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30263124/real-time-examination-of-camp-activity-at-relaxin-family-peptide-receptors-using-a-bret-based-biosensor
#18
Adam L Valkovic, Miranda B Leckey, Alice R Whitehead, Mohammed A Hossain, Asuka Inoue, Martina Kocan, Ross A D Bathgate
Relaxin family peptide (RXFPs) 1-4 receptors modulate the activity of cyclic adenosine monophosphate (cAMP) to produce a range of physiological functions. RXFP1 and RXFP2 increase cAMP via Gαs , whereas RXFP3 and RXFP4 inhibit cAMP via Gαi/o . RXFP1 also shows a delayed increase in cAMP downstream of Gαi3 . In this study we have assessed whether the bioluminescence resonance energy transfer (BRET)-based biosensor CAMYEL (cAMP sensor using YFP-Epac-Rluc), which allows real-time measurement of cAMP activity in live cells, will aid in understanding ligand- and cell-specific RXFP signaling...
October 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30258633/methods-for-the-assessment-of-selection-bias-in-drug-safety-during-pregnancy-studies-using-electronic-medical-data
#19
Mireille E Schnitzer, Lucie Blais
Electronic health data are routinely used for population drug studies. Due to the ethical dilemma in carrying out experimental drug studies on pregnant women, the effects of medication usage during pregnancy on fetal and maternal outcomes are largely evaluated using this data collection medium. One major limitation in this type of study is the delayed inclusion of pregnancies in the cohort. For example, in the province of Quebec, Canada, a major pregnancy cohort only captured pregnancies after 20 weeks gestation...
October 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/30239534/corrigendum
#20
(no author information available yet)
[This corrects the article DOI: 10.1002/prp2.2.70.].
October 2018: Pharmacology Research & Perspectives
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