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https://www.readbyqxmd.com/read/27793923/enhancing-the-therapeutic-efficacy-of-2-deoxyglucose-in-breast-cancer-cells-using-cell-cycle-synchronization
#1
Su Jin Lee, Bok-Nam Park, Jung Hyun Roh, Young-Sil An, Hoon Hur, Joon-Kee Yoon
AIM: We assessed the effect of cell-cycle synchronization using the T-type calcium channel inhibitor mibefradil on the anticancer effects of 2-deoxy-D-glucose (2-DG) and glucose metabolism in breast cancer cells. MATERIALS AND METHODS: MDA-MB-231 cells were treated with mibefradil, followed by 2-DG with/without paclitaxel, then cells were assessed for viability. Glucose metabolism was evaluated by (3)H-2-DG uptake, lactate concentration, and membrane glucose transporter 1 expression after mibefradil treatment...
November 2016: Anticancer Research
https://www.readbyqxmd.com/read/27765616/chronic-intrathecal-infusion-of-t-type-calcium-channel-blockers-attenuates-cav3-2-upregulation-in-nerve-ligated-rats
#2
Sheng-Jie Shiue, Chi-Hsu Wang, Tao-Yeuan Wang, Yi-Chun Chen, Jen-Kun Cheng
OBJECTIVE: T-type channel (TCC) CaV3.2 plays a pivotal role in pain transmission. In this study, we examined the effects of intrathecal TCC blockers on CaV3.2 expression in a L5/6 spinal nerve ligation (SNL) pain model. The neurotoxicity of TCC blockers were also evaluated. METHODS: Male Sprague-Dawley rats (200-250 g) were used for right L5/6 SNL to induce neuropathic pain. Intrathecal infusion of saline or TCC blockers [mibefradil (0.7 μg/h) or ethosuximide (60 μg/h)] was started after surgery for 7 days...
October 17, 2016: Acta Anaesthesiologica Taiwanica: Official Journal of the Taiwan Society of Anesthesiologists
https://www.readbyqxmd.com/read/27676055/mibefradil-dihydrochloride-with-hypofractionated-radiation-for-recurrent-glioblastoma-preliminary-results-of-a-phase-1-dose-expansion-trial
#3
N H Lester-Coll, J Kluytenaar, K F Pavlik, J B Yu, J N Contessa, J Moliterno, J Piepmeier, K P Becker, J Baehring, A J Huttner, A O Vortmeyer, R Ramani, R J Lampert, X Yao, R S Bindra
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/27517811/synthesis-and-t-type-calcium-channel-blocking-effects-of-aryl-1-5-disubstituted-pyrazol-3-yl-methyl-sulfonamides-for-neuropathic-pain-treatment
#4
Jung Hyun Kim, Gyochang Keum, Hesson Chung, Ghilsoo Nam
A novel series of aryl(1,5-disubstituted pyrazol-3-yl)methyl sulfonamide derivatives was designed, synthesized, and evaluated for T-type calcium channel (α1G and α1H) inhibitory activity. We identified several compounds, 9a, 9b, 9g, and 9h that displayed good T-type channel inhibitory potency with low hERG channel and CYP450 inhibition. Among them, 9a and 9b exhibited neuropathic pain alleviation effects in mechanical and cold allodynia induced in the SNL rat model. Compounds 9a and 9b displayed better efficacy than mibefradil and gabapentin against cold allodynia...
November 10, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27498589/comprehensive-evaluation-of-liver-microsomal-cytochrome-p450-3a-cyp3a-inhibition-comparison-of-cynomolgus-monkey-and-human
#5
Zuzana E Haarhoff, Melissa A Kramer, Tatyana A Zvyaga, Jun Zhang, Priyadeep Bhutani, Murali Subramanian, A David Rodrigues
1. Members of the cytochrome P450 3A (CYP3A) subfamily metabolize numerous compounds and serve as the loci of drug-drug interactions (DDIs). Because of high amino acid sequence identity with human CYP3A, the cynomolgus monkey has been proposed as a model species to support DDI risk assessment. 2. Therefore, the objective of this study was to evaluate 35 known inhibitors of human CYP3A using human (HLM) and cynomolgus monkey (CLM) liver microsomes. Midazolam was employed as substrate to generate IC50 values (concentration of inhibitor rendering 50% inhibition) in the absence and presence of a preincubation (30 mins) with NADPH...
August 8, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27273014/p-q-type-and-t-type-voltage-gated-calcium-channels-are-involved-in-the-contraction-of-mammary-and-brain-blood-vessels-from-hypertensive-patients
#6
Anne D Thuesen, Kristina S Lyngsø, Lotte Rasmussen, Jane Stubbe, Ole Skøtt, Frantz R Poulsen, Christian Bonde Pedersen, Lars M Rasmussen, Pernille B L Hansen
AIM: Calcium channel blockers are widely used in cardiovascular diseases. Beside L-type channels, T- and P/Q-type calcium channels are involved in contraction of human renal blood vessels. It was hypothesized that T- and P/Q -type channels are involved in contraction of human brain and mammary blood vessels. METHODS: Internal mammary arteries from bypass surgery patients and cerebral arterioles from patients with brain tumors with and with-out hypertension were tested in a myograph and perfusion set-up...
June 7, 2016: Acta Physiologica
https://www.readbyqxmd.com/read/27258646/cacna1h-m1549v-mutant-calcium-channel-causes-autonomous-aldosterone-production-in-hac15-cells-and-is-inhibited-by-mibefradil
#7
Esther N Reimer, Gudrun Walenda, Eric Seidel, Ute I Scholl
We recently demonstrated that a recurrent gain-of-function mutation in a T-type calcium channel, CACNA1H(M1549V), causes a novel Mendelian disorder featuring early-onset primary aldosteronism and hypertension. This variant was found independently in five families. CACNA1H(M1549V) leads to impaired channel inactivation and activation at more hyperpolarized potentials, inferred to cause increased calcium entry. We here aimed to study the effect of this variant on aldosterone production. We heterologously expressed empty vector, CACNA1H(WT) and CACNA1H(M1549V) in the aldosterone-producing adrenocortical cancer cell line H295R and its subclone HAC15...
August 2016: Endocrinology
https://www.readbyqxmd.com/read/27255432/gating-modulation-of-the-tumor-related-kv10-1-channel-by-mibefradil
#8
Froylan Gomez-Lagunas, Elisa Carrillo, Luis A Pardo, Walter Stühmer
Several reports credit mibefradil with tumor suppressing properties arising from its known inhibition of Ca(2+) currents. Given that mibefradil (Mb) is also known to inhibit K(+) channels, we decided to study the interaction between this organic compound and the tumor-related Kv10.1 channel. Here we report that Mb modulates the gating of Kv10.1. Mb induces an apparent inactivation from both open and early closed states where the channels dwell at hyperpolarized potentials. Additionally Mb accelerates the kinetics of current activation, in a manner that depends on initial conditions...
June 3, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/26998034/protection-of-the-cochlear-hair-cells-in-adult-c57bl-6j-mice-by-t-type-calcium-channel-blockers
#9
Ya-Feng Yu, Wen-Ying Wu, Gen-Sheng Xiao, Hong-Yang Ling, Chen Pan
The aim of the present study was to investigate the protective effect of T-type calcium channel blockers against presbycusis, using a C57BL/6J mice model. The expression of three T-type calcium channel receptor subunits in the cochlea of 6-8-week-old C57BL/6J mice was evaluated using reverse transcription-quantitative polymerase chain reaction. The results confirmed that the three subunits were expressed in the cochlea. In addition, the capacity of T-type calcium channel blockers to protect the cochlear hair cells of 24-26-week-old C57BL/6J mice was investigated in mice treated with mibefradil, benidipine or saline for 4 weeks...
March 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/26941821/investigation-of-calcium-channel-blockers-as-antiprotozoal-agents-and-their-interference-in-the-metabolism-of-leishmania-l-infantum
#10
Juliana Quero Reimão, Juliana Tonini Mesquita, Daiane Dias Ferreira, Andre Gustavo Tempone
Leishmaniasis and Chagas disease are neglected parasitic diseases endemic in developing countries; efforts to find new therapies remain a priority. Calcium channel blockers (CCBs) are drugs in clinical use for hypertension and other heart pathologies. Based on previous reports about the antileishmanial activity of dihydropyridine-CCBs, this work aimed to investigate whether the in vitro anti-Leishmania infantum and anti-Trypanosoma cruzi activities of this therapeutic class would be shared by other non-dihydropyridine-CCBs...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/26875775/progesterone-suppressed-vasoconstriction-in-human-umbilical-vein-via-reducing-calcium-entry
#11
Yun He, Qinqin Gao, Bing Han, Xiaolin Zhu, Di Zhu, Jianying Tao, Jie Chen, Zhice Xu
The aim of this study was to evaluate the actions of progesterone on human umbilical vein (HUV) from normal pregnancies and the possible underlying mechanisms involved. HUV rings were suspended in organ baths and exposed to progesterone followed by phenylephrine (PE) or serotonin (5-HT). Progesterone suppressed PE- or 5-HT-induced vasoconstriction in HUV rings. The inhibitory effect induced by progesterone was not influenced by nitric oxide syntheses inhibitor, prostaglandins syntheses blocker, the integrity of endothelium, selective progesterone receptor or potassium channel antagonists...
April 2016: Steroids
https://www.readbyqxmd.com/read/26851262/electrophysiological-characterization-of-voltage-dependent-calcium-currents-and-trpv4-currents-in-human-pulmonary-fibroblasts
#12
Mozibur Rahman, Subhendu Mukherjee, Wei Sheng, Bernd Nilius, Luke J Janssen
We have presented indirect evidence of a key role for voltage-dependent Ca(2+) currents in TGFβ-induced synthetic function in human pulmonary fibroblast (HPF), as well as in bleomycin-induced pulmonary fibrosis in mice. Others, however, have provided indirect evidence for transient receptor potential vanilloid 4 (TRPV4) channels in both of those effects. Unfortunately, definitive electrophysiological descriptions of both currents in HPFs have been entirely lacking. In this study, we provide the first direct electrophysiological and pharmacological evidence of the currents in HPFs at rest and during overnight stimulation with TGFβ...
April 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/26832797/t-type-ca2-channel-inhibition-sensitizes-ovarian-cancer-to-carboplatin
#13
Barbara Dziegielewska, Eli V Casarez, Wesley Z Yang, Lloyd S Gray, Jaroslaw Dziegielewski, Jill K Slack-Davis
Ovarian cancer is the deadliest gynecologic cancer, due in large part to the diagnosis of advanced stage disease, the development of platinum resistance, and inadequate treatment alternatives. Recent studies by our group and others have shown that T-type calcium (Ca(2+)) channels play a reinforcing role in cancer cell proliferation, cell-cycle progression, and apoptosis evasion. Therefore, we investigated whether T-type Ca(2+) channels affect ovarian tumor growth and response to platinum agents. Inhibition of T-type Ca(2+) channels with mibefradil or by silencing expression resulted in growth suppression in ovarian cancer cells with a simultaneous increase in apoptosis, which was accompanied by decreased expression of the antiapoptotic gene survivin (BIRC5)...
March 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26781877/characterization-of-rebound-depolarization-in-neurons-of-the-rat-medial-geniculate-body-in-vitro
#14
Xin-Xing Wang, Yan Jin, Hui Sun, Chunlei Ma, Jinsheng Zhang, Ming Wang, Lin Chen
Rebound depolarization (RD) is a response to the offset from hyperpolarization of the neuronal membrane potential and is an important mechanism for the synaptic processing of inhibitory signals. In the present study, we characterized RD in neurons of the rat medial geniculate body (MGB), a nucleus of the auditory thalamus, using whole-cell patch-clamp and brain slices. RD was proportional in strength to the duration and magnitude of the hyperpolarization; was effectively blocked by Ni(2+) or Mibefradil; and was depressed when the resting membrane potential was hyperpolarized by blocking hyperpolarization-activated cyclic nucleotide-gated (HCN) channels with ZD7288 or by activating G-protein-gated inwardly-rectifying K(+) (GIRK) channels with baclofen...
February 2016: Neuroscience Bulletin
https://www.readbyqxmd.com/read/26690767/repurposing-and-rescuing-of-mibefradil-an-antihypertensive-for-cancer-a-case-study
#15
Andrew J Krouse, Lloyd Gray, Timothy Macdonald, John McCray
The expanding "valley of death" in drug development is leaving potentially life-saving new chemical entities and molecular targets fallow. This situation is forcing early-stage companies to think creatively about moving their technologies forward, especially as institutional investors show more interest in later stages of development. Drug repurposing, a strategy to examine existing drugs for therapeutic value against different diseases, is an emerging method to bring an off-market drug back onto the market...
December 2015: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/26658945/no-apparent-role-for-t-type-ca%C3%A2-%C3%A2-%C2%BA-channels-in-renal-autoregulation
#16
Rasmus Hassing Frandsen, Max Salomonsson, Pernille B L Hansen, Lars J Jensen, Thomas Hartig Braunstein, Niels-Henrik Holstein-Rathlou, Charlotte Mehlin Sorensen
Renal autoregulation protects glomerular capillaries against increases in renal perfusion pressure (RPP). In the mesentery, both L- and T-type calcium channels are involved in autoregulation. L-type calcium channels participate in renal autoregulation, but the role of T-type channels is not fully elucidated due to lack of selective pharmacological inhibitors. The role of T- and L-type calcium channels in the response to acute increases in RPP in T-type channel knockout mice (CaV3.1) and normo- and hypertensive rats was examined...
April 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/26621126/cannabinoid-receptor-agonists-modulate-calcium-channels-in-rat-retinal-m%C3%A3-ller-cells
#17
W Yang, Q Li, S-Y Wang, F Gao, W-J Qian, F Li, M Ji, X-H Sun, Y Miao, Z Wang
While activation of cannabinoid CB1 receptor (CB1R) regulates a variety of retinal neuronal functions by modulating ion channels in these cells, effect of activated cannabinoid receptors on Ca(2+) channels in retinal Müller cells is still largely unknown. In the present work we show that three subunits of T-type Ca(2+) channels, CaV3.1, CaV3.2 and CaV3.3, as well as one subunit of L-type Ca(2+) channels, CaV1.2, were expressed in rat Müller cells by immunofluorescent staining. Consistently, nimodipine- and mibefradil-sensitive Na(+) currents through L- and T-type Ca(2+) channels could be recorded electrophysiologically...
January 28, 2016: Neuroscience
https://www.readbyqxmd.com/read/26602811/hydrogen-sulfide-induced-itch-requires-activation-of-cav3-2-t-type-calcium-channel-in-mice
#18
Xue-Long Wang, Bin Tian, Ya Huang, Xiao-Yan Peng, Li-Hua Chen, Jun-Cheng Li, Tong Liu
The contributions of gasotransmitters to itch sensation are largely unknown. In this study, we aimed to investigate the roles of hydrogen sulfide (H2S), a ubiquitous gasotransmitter, in itch signaling. We found that intradermal injection of H2S donors NaHS or Na2S, but not GYY4137 (a slow-releasing H2S donor), dose-dependently induced scratching behavior in a μ-opioid receptor-dependent and histamine-independent manner in mice. Interestingly, NaHS induced itch via unique mechanisms that involved capsaicin-insensitive A-fibers, but not TRPV1-expressing C-fibers that are traditionally considered for mediating itch, revealed by depletion of TRPV1-expressing C-fibers by systemic resiniferatoxin treatment...
2015: Scientific Reports
https://www.readbyqxmd.com/read/26303493/t-type-ca2-channel-regulation-by-co-a-mechanism-for-control-of-cell-proliferation
#19
Hayley Duckles, Moza M Al-Owais, Jacobo Elies, Emily Johnson, Hannah E Boycott, Mark L Dallas, Karen E Porter, John P Boyle, Jason L Scragg, Chris Peers
T-type Ca(2+) channels regulate proliferation in a number of tissue types, including vascular smooth muscle and various cancers. In such tissues, up-regulation of the inducible enzyme heme oxygenase-1 (HO-1) is often observed, and hypoxia is a key factor in its induction. HO-1 degrades heme to generate carbon monoxide (CO) along with Fe(2+) and biliverdin. Since CO is increasingly recognized as a regulator of ion channels (Peers et al. 2015), we have explored the possibility that it may regulate proliferation via modulation of T-type Ca(2+) channels...
2015: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/26231163/discovery-of-novel-bridged-tetrahydronaphthalene-derivatives-as-potent-t-l-type-calcium-channel-blockers
#20
Dorte Renneberg, Francis Hubler, Markus Rey, Patrick Hess, Stephane Delahaye, John Gatfield, Marc Iglarz, Kurt Hilpert
Chemical evolution of mibefradil resulted in the identification of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. A SAR study, in vitro and in vivo DMPK properties as well as the in vivo antihypertensive effect in rats are presented.
September 15, 2015: Bioorganic & Medicinal Chemistry Letters
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