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Pharmacology Research & Perspectives

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https://read.qxmd.com/read/30873284/a-novel-soluble-guanylate-cyclase-activator-with-reduced-risk-of-hypotension-by-short-acting-vasodilation
#1
Toshihiro Sawabe, Toshiki Chiba, Akihiro Kobayashi, Kosuke Nagasaka, Kazuyuki Aihara, Akiyuki Takaya
Cinaciguat, a soluble guanylate cyclase (sGC) activator, was under clinical development for use in acute decompensated heart failure (ADHF), but was discontinued due to occurrence of hypotension. We hypothesized that short-term activation of sGC in ADHF patients would exert a vasodilative effect without hypotension irrespective of disease state, using a novel short-acting sGC activator, TY-55002. The objective of this study was to investigate the vasodilation and hemodynamic effects of TY-55002 in comparison with those of cinaciguat...
April 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30784208/phase-i-study-of-pf-04895162-a-kv7-channel-inhibitor-reveals-unexpected-hepatotoxicity-in-healthy-subjects-but-not-rats-or-monkeys-clinical-evidence-of-disrupted-bile-acid-homeostasis
#2
Michael D Aleo, Jiri Aubrecht, Paul D Bonin, Deborah A Burt, Jennifer Colangelo, Lina Luo, Shelli Schomaker, Rachel Swiss, Simon Kirby, Greg C Rigdon, Pinky Dua
During a randomized Phase 1 clinical trial the drug candidate, PF-04895162 (ICA-105665), caused transaminase elevations (≥grade 1) in six of eight healthy subjects treated at 300 mg twice daily for 2-weeks (NCT01691274). This was unexpected since studies in rats (<6 months) and cynomolgus monkeys (<9 months) treated up to 100 mg/kg/day did not identify the liver as a target organ. Mechanistic studies showed PF-04895162 had low cytotoxic potential in human hepatocytes, but inhibited liver mitochondrial function and bile salt export protein (BSEP) transport...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30784207/memantine-protects-thalamocortical-hyper-glutamatergic-transmission-induced-by-nmda-receptor-antagonism-via-activation-of-system-xc
#3
Motohiro Okada, Kouji Fukuyama, Yasuhiro Kawano, Takashi Shiroyama, Yuto Ueda
Deficiencies in N-methyl-d-aspartate (NMDA)/glutamate receptor (NMDAR) signaling have been considered central to the cognitive impairments of schizophrenia; however, an NMDAR antagonist memantine (MEM) improves cognitive impairments of Alzheimer's disease and schizophrenia. These mechanisms of paradoxical clinical effects of NMDAR antagonists remain unclear. To explore the mechanisms by which MK801 and MEM affect thalamocortical transmission, we determined interactions between local administrations of MK801, MEM, system xc- (Sxc), and metabotropic glutamate receptors (mGluRs) on extracellular glutamate and GABA levels in the mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) using dual-probe microdialysis with ultra-high-pressure liquid chromatography...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30784206/binding-characterization-of-n-2-chloro-5-thiomethylphenyl-n-3-3-h-3-methoxy-phenyl-n-methylguanidine-3-h-gmom-a-non-competitive-n-methyl-d-aspartate-nmda-receptor-antagonist
#4
Athanasios Metaxas, Bart N M van Berckel, Pieter J Klein, Joost Verbeek, Emily C Nash, Esther J M Kooijman, Véronique A Renjaän, Sandeep S V Golla, Ronald Boellaard, Johannes A M Christiaans, Albert D Windhorst, Josée E Leysen
Labeled with carbon-11, N-(2-chloro-5-thiomethylphenyl)-N'-(3-methoxyphenyl)-N'-methylguanidine ([11 C]GMOM) is currently the only positron emission tomography (PET) tracer that has shown selectivity for the ion-channel site of N-methyl-D-aspartate (NMDA) receptors in human imaging studies. The present study reports on the selectivity profile and in vitro binding properties of GMOM. The compound was screened on a panel of 80 targets, and labeled with tritium ([3 H]GMOM). The binding properties of [3 H]GMOM were compared to those of the reference ion-channel ligand [3 H](+)-dizocilpine maleate ([3 H]MK-801), in a set of concentration-response, homologous and heterologous inhibition, and association kinetics assays, performed with repeatedly washed rat forebrain preparations...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30774960/mutagenesis-of-gpr139-reveals-ways-to-create-gain-or-loss-of-function-receptors
#5
Lien Wang, Grace Lee, Amy Shih, Chester Kuei, Diane Nepomuceno, Michelle Wennerholm, Frances Fan, Jiejun Wu, Pascal Bonaventure, Timothy W Lovenberg, Changlu Liu
GPR139 is a Gq-coupled receptor activated by the essential amino acids L-tryptophan (L-Trp) and L-phenylalanine (L-Phe). We carried out mutagenesis studies of the human GPR139 receptor to identify the critical structural motifs required for GPR139 activation. We applied site-directed and high throughput random mutagenesis approaches using a double addition normalization strategy to identify novel GPR139 sequences coding receptors that have altered sensitivity to endogenous ligands. This approach resulted in GPR139 clones with gain-of-function, reduction-of-function or loss-of-function mutations...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30766684/drug-related-teratogenic-and-pathologic-causes-of-birth-defects-in-a-tertiary-hospital-in-southwestern-nigeria
#6
Ifeanyichukwu Offor, Olufunsho Awodele, Kazeem A Oshikoya
Birth defects are important causes of neonatal morbidity and mortality. A good understanding of the etiology is a vital step toward developing improved treatment and preventive strategies. We conducted an audit of medical records of newborns with birth abnormalities in a tertiary hospital over a 10-year period, using a Pro forma designed to collect information on obstetric history, antenatal history, sociodemographics of parents, and the type of birth abnormality. Of the 180 medical records reviewed, female babies were 92 (51...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30705758/a-pharmacokinetic-study-of-radiprodil-oral-suspension-in-healthy-adults-comparing-conventional-venous-blood-sampling-with-two-microsampling-techniques
#7
David Sciberras, Christian Otoul, Françoise Lurquin, John Smeraglia, Aurélia Lappert, Steven De Bruyn, Jan Jaap van Lier
In this phase I, single-center, open-label study of ten heathy adults (18-45 years; NCT02647697), the PK, safety, and tolerability profile of radiprodil oral suspension in healthy adults were assessed, as well as two PK microsampling techniques. All participants received a single 30 mg radiprodil dose (12 mL oral suspension). Blood was collected at various time points using conventional venous sampling (intravenous catheter or venepuncture), and Mitra™ and Aqua-Cap™ Drummond microsampling (finger-prick and blood taken from venous blood sample tubes)...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30705757/ph-as-a-potential-therapeutic-target-to-improve-temozolomide-antitumor-efficacy-a-mechanistic-modeling-study
#8
Angélique Stéphanou, Annabelle Ballesta
Despite intensive treatments including temozolomide (TMZ) administration, glioblastoma patient prognosis remains dismal and innovative therapeutic strategies are urgently needed. A systems pharmacology approach was undertaken to investigate TMZ pharmacokinetics-pharmacodynamics (PK-PD) incorporating the effect of local pH, tumor spatial configuration and micro-environment. A hybrid mathematical framework was designed coupling ordinary differential equations describing the intracellular reactions, with a spatial cellular automaton to individualize the cells...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30693089/treatment-with-new-organic-nitrites-in-pulmonary-hypertension-of-acute-experimental-pulmonary-embolism
#9
Kristofer F Nilsson, Lars E Gustafsson
Acute pulmonary embolism may cause right heart failure due to increased pulmonary vascular resistance and arterial hypoxemia. Effective vasodilator therapy of the pulmonary hypertension is highly needed. Therefore, we investigated the effects of a newly developed effective pulmonary vasodilator, the organic mononitrites of 1,2-propanediol (PDNO), in a rabbit model of acute pulmonary embolism. In anesthetized and ventilated rabbits, systemic and pulmonary hemodynamics, exhaled nitric oxide (NO), plasma nitrite concentration, and blood gases were monitored...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30693088/frequency-and-predictors-of-the-potential-overprescribing-of-antidepressants-in-elderly-residents-of-a-geographically-defined-u-s-population
#10
William V Bobo, Brandon R Grossardt, Maria I Lapid, Jonathan G Leung, Cynthia Stoppel, Paul Y Takahashi, Robert W Hoel, Zheng Chang, Christian Lachner, Mohit Chauhan, Lee Flowers, Scott M Brue, Mark A Frye, Jennifer St Sauver, Walter A Rocca, Bruce Sutor
The purpose of this study was to estimate the extent of potential antidepressant overprescribing in a geographically defined U.S. population, and to determine the indications and factors that account for it. We conducted a cohort study of new antidepressant prescriptions for elderly residents of Olmsted County, Minnesota, 2005-2012, using the Rochester Epidemiology Project medical records-linkage system. Indications for antidepressants were abstracted from health records for all cohort members. Potential antidepressant overprescribing was defined based on regulatory approval, the level of evidence identified from a standardized drug information database, and multidisciplinary expert review...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30693087/combined-antitumoral-effects-of-pretubulysin-and-methotrexate
#11
Sarah Kern, Ines Truebenbach, Miriam Höhn, Jan Gorges, Uli Kazmaier, Stefan Zahler, Angelika M Vollmar, Ernst Wagner
Pretubulysin (PT), a potent tubulin-binding antitumoral drug, and the well-established antimetabolite methotrexate (MTX) were tested separately or in combination (PT+MTX) for antitumoral activity in L1210 leukemia cells or KB cervix carcinoma cells in vitro and in vivo in NMRI-nu/nu tumor mouse models. In cultured L1210 cells, treatment with PT or MTX displays strong antitumoral effects in vitro , and the combination PT+MTX exceeds the effect of single drugs. PT also potently kills the MTX resistant KB cell line, without significant MTX combination effect...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30675363/development-and-validation-of-part-pharmacotherapy-assessment-in-renal-transplant-patients-criteria-to-assess-drug-related-problems-in-an-outpatient-renal-transplant-population-a-cross-sectional-study
#12
Layal El Raichani, Qian Du, Alexandre Mathieu, Sabrina Almassy, Lyne Lalonde, Djamal Berbiche, Elisabeth Gélinas-Lemay, Nathalie Boudreau, Héloïse Cardinal
Kidney transplant recipients are at risk of pharmacological interactions and adverse drug reactions. Community pharmacists are uniquely poised to detect and intervene in cases of drug-related problems. The aims of this study were to develop and validate a list of explicit criteria to be used by community pharmacists to assess drug-related problems in kidney transplant patients, and to assess their frequency and their determinants. First, we used a modified RAND method where a panel of experts established the PART (Pharmacotherapy Assessment in Renal Transplant Patient) criteria...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30651989/medical-simulation-in-pharmacology-learning-and-retention-a-comparison-study-with-traditional-teaching-in-undergraduate-medical-students
#13
Vincenzo Arcoraci, Francesco Squadrito, Domenica Altavilla, Alessandra Bitto, Letteria Minutoli, Olivia Penna, Antonio Amato, Rosario Bruno, Vincenzo Francesco Tripodi, Angela Alibrandi, Pier Luigi Ingrassia, Paola Santalucia, Vincenzo Fodale
The purpose of the study was to determine whether low-high fidelity medical simulation improves learning and long-lasting retention of pharmacology knowledge, compared to lecture alone, in undergraduate medical students. Ninety students, before a 45-minute lecture, were randomized into three groups - sham (S), low (LF), and high fidelity (HF) simulation - to participate in an interactive simulation session. To evaluate immediate and long-lasting retention, a 20-item structured questionnaire on inotropic agents was administered to 90 students before and after a 45-minute lecture, after simulation, and 3 months later...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30631447/memantine-protects-thalamocortical-hyper-glutamatergic-transmission-induced-by-nmda-receptor-antagonism-via-activation-of-system-xc-sup
#14
Motohiro Okada, Kouji Fukuyama, Yasuhiro Kawano, Takashi Shiroyama, Yuto Ueda
Deficiencies in N-methyl-d-aspartate (NMDA)/glutamate receptor (NMDAR) signaling have been considered central to the cognitive impairments of schizophrenia; however, an NMDAR antagonist memantine (MEM) improves cognitive impairments of Alzheimer's disease and schizophrenia. These mechanisms of paradoxical clinical effects of NMDAR antagonists remain unclear. To explore the mechanisms by which MK801 and MEM affect thalamocortical transmission, we determined interactions between local administrations of MK801, MEM, system xc- (Sxc), and metabotropic glutamate receptors (mGluRs) on extracellular glutamate and GABA levels in the mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) using dual-probe microdialysis with ultra-high-pressure liquid chromatography...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30631446/preclinical-tissue-distribution-and-metabolic-correlations-of-vigabatrin-an-antiepileptic-drug-associated-with-potential-use-limiting-visual-field-defects
#15
Dana C Walters, Erwin E W Jansen, Garrett R Ainslie, Gajja S Salomons, Madalyn N Brown, Michelle A Schmidt, Jean-Baptiste Roullet, K M Gibson
Vigabatrin (VGB; (S)-(+)/(R)-(-) 4-aminohex-5-enoic acid), an antiepileptic irreversibly inactivating GABA transaminase (GABA-T), manifests use-limiting ocular toxicity. Hypothesizing that the active S enantiomer of VGB would preferentially accumulate in eye and visual cortex (VC) as one potential mechanism for ocular toxicity, we infused racemic VGB into mice via subcutaneous minipump at 35, 70, and 140 mg/kg/d (n = 6-8 animals/dose) for 12 days. VGB enantiomers, total GABA and β-alanine (BALA), 4-guanidinobutyrate (4-GBA), and creatine were quantified by mass spectrometry in eye, brain, liver, prefrontal cortex (PFC), and VC...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30619611/diazepam-is-not-a-direct-allosteric-modulator-of-%C3%AE-1-adrenoceptors-but-modulates-receptor-signaling-by-inhibiting-phosphodiesterase-4
#16
Lisa M Williams, Xiaoji He, Tasneem M Vaid, Alaa Abdul-Ridha, Alice R Whitehead, Paul R Gooley, Ross A D Bathgate, Spencer J Williams, Daniel J Scott
α1A - and α1B -adrenoceptors (ARs) are G protein-coupled receptors (GPCRs) that are activated by adrenaline and noradrenaline to modulate smooth muscle contraction in the periphery, and neuronal outputs in the central nervous system (CNS). α1A - and α1B -AR are clinically targeted with antagonists for hypertension and benign prostatic hyperplasia and are emerging CNS targets for treating neurodegenerative diseases. The benzodiazepines midazolam, diazepam, and lorazepam are proposed to be positive allosteric modulators (PAMs) of α1 -ARs...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30598826/post-mi-treatment-with-g-csf-and-epo-liposome-with-slx-repairs-infarcted-myocardium-through-epcs-mobilization-and-activation-of-prosurvival-signals-in-rabbits
#17
Yoshihisa Yamada, Shingo Minatoguchi, Noriko Endo, Hiromitsu Kanamori, Masanori Kawasaki, Kazuhiko Nishigaki, Atsushi Mikami, Shinya Minatoguchi
We investigated whether combination therapy of G-CSF and erythropoietin (EPO)-liposome with Siaryl Lewis X (SLX) is more cardioprotective than G-CSF or EPO-liposome with SLX alone. For the purpose of generating myocardial infarction (MI), rabbits underwent 30 minutes of coronary occlusion and 14 days of reperfusion. We administered saline (control group, i.v.,), G-CSF (G group, 10 μg/kg/day × 5 days, i.c., starting at 24 hours after reperfusion), EPO-liposome with SLX (LE group, i.v., 2500 IU/kg EPO containing liposome with SLX, immediately after reperfusion), and G-CSF + EPO-liposome with SLX (LE + G group) to the rabbits...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30564368/mdm2-inhibitor-ameliorates-cisplatin-induced-nephropathy-via-nf%C3%AE%C2%BA%C3%AE-signal-inhibition
#18
Tomoyuki Fujikura, Hideo Yasuda, Takamasa Iwakura, Takayuki Tsuji, Hans-J Anders
Cisplatin is a platinum-containing chemotherapeutic drug, which is widely used and highly effective. While effective against tumors, its use is limited by severe side effects such as nephrotoxicity and bone marrow suppression. Murine double minute 2 (MDM2) is the E3 ubiquitin ligase of the tumor suppressor gene, p53, and inhibition of MDM2 can suppress tumor cell growth. However, independent of p53, MDM2 acts as a co-transcription factor for nuclear factor-κB (NFκB), whose signaling can be involved in cisplatin-induced tubular injury...
February 2019: Pharmacology Research & Perspectives
https://read.qxmd.com/read/30546909/efficacy-of-smtp-7-a-small-molecule-anti-inflammatory-thrombolytic-in-embolic-stroke-in-monkeys
#19
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://read.qxmd.com/read/30534379/pharmacological-profile-of-the-neuropeptide-s-receptor-dynamic-mass-redistribution-studies
#20
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
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