33 results on '"Valenzuela, Carmen"'
Search Results
2. CIGB-300: A peptide-based drug that impairs the Protein Kinase CK2-mediated phosphorylation
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Perea, Silvio E., Baladrón, Idania, Valenzuela, Carmen, and Perera, Yasser
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Protein kinase CK2, formerly referred to as casein kinase II, is a serine/threonine kinase often found overexpressed in solid tumors and hematologic malignancies that phosphorylates many substrates integral to the hallmarks of cancer. CK2 has emerged as a viable oncology target having been experimentally validated with different kinase inhibitors, including small molecule ATP-competitors, synthetic peptides, and antisense oligonucleotides. To date only two CK2 inhibitors, CIGB-300 and CX-4945, have entered the clinic in phase 1-2 trials. This review provides information on CIGB-300, a cell-permeable cyclic peptide that inhibits CK2-mediated phosphorylation by targeting the substrate phosphoacceptor domain. We review data that support the concept of CK2 as an anticancer target, address the mechanism of action, and summarize preclinical studies showing antiangiogenic and antimetastatic effects as well as synergism with anticancer drugs in preclinical models. We also summarize early clinical research (phase 1/2 trials) of CIGB-300 in cervical cancer, including data in combination with chemoradiotherapy. The clinical data demonstrate the safety, tolerability, and clinical effects of intratumoral injections of CIGB-300 and provide the foundation for future phase 3 clinical trials in locally advanced cervical cancer in combination with standard chemoradiotherapy.
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- 2018
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3. 'Opening the heart and emotions of women': the No Estas Sola video project
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Fiorill, Joe and Valenzuela, Carmen
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Colombia -- Domestic policy ,No Estas Sola (Motion picture) -- Religious aspects ,No Estas Sola (Motion picture) -- Criticism and interpretation ,Abortion -- Laws, regulations and rules ,Abortion -- Forecasts and trends ,Abortion -- Statistics ,Government regulation ,Market trend/market analysis ,Family and marriage ,Philosophy and religion ,Women's issues/gender studies - Abstract
In Latin America every year, some 4 million women and their families face the difficult decision of ending a pregnancy by seeking an abortion. When Colombia's Constitutional Court ruled in [...]
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- 2006
4. IQM-22110, a new selective inhibitor of KChIP3 and its electrophysiological effects on Kv4.3, Kv4.3/KChIP3 and Kv4.3/KChIP2 currents
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Socuéllamos, Paula G., de Benito-Bueno, Angela, Ropero, Maria, Diez, Sara, Elizalde, Pablo, Bonache, M. Angeles, Viedma, Carmen, Martín-Martínez, Mercedes, Gutiérrez-Rodríguez, Marta, and Valenzuela, Carmen
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- 2023
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5. Women need Amnesty International to support abortion rights
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Valenzuela, Carmen Angelica
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Human rights -- Laws, regulations and rules ,Abortion -- Laws, regulations and rules ,Abortion -- Forecasts and trends ,Government regulation ,Market trend/market analysis ,Company business management ,Family and marriage ,Philosophy and religion ,Women's issues/gender studies ,Amnesty International -- Management ,Amnesty International -- Laws, regulations and rules - Abstract
AMNESTY INTERNATIONAL IS IN THE MIDST OF considering whether to include access to abortion in the list of rights that it supports. Many other organizations and individuals have long made [...]
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- 2006
6. An Update of the Classical and Novel Methods Used for Measuring Fast Neurotransmitters During Normal and Brain Altered Function
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Castro, Victor Hugo Cifuentes, Valenzuela, Carmen Lucia Lopez, Sanchez, Juan Carlos Salazar, Pena, Kenia Pardo, Perez, Silvia J. Lopez, Ibarra, Jorge Ortega, and Villagran, Alberto Morales
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To understand better the cerebral functions, several methods have been developed to study the brain activity, they could be related with morphological, electrophysiological, molecular and neurochemical techniques. Monitoring neurotransmitter concentration is a key role to know better how the brain works during normal or pathological conditions, as well as for studying the changes in neurotransmitter concentration with the use of several drugs that could affect or reestablish the normal brain activity. Immediate response of the brain to environmental conditions is related with the release of the fast acting neurotransmission by glutamate (Glu), ?-aminobutyric acid (GABA) and acetylcholine (ACh) through the opening of ligand-operated ion channels. Neurotransmitter release is mainly determined by the classical microdialysis technique, this is generally coupled to high performance liquid chromatography (HPLC). Detection of neurotransmitters can be done by fluorescence, optical density, electrochemistry or other detection systems more sophisticated. Although the microdialysis method is the golden technique to monitor the brain neurotransmitters, it has a poor temporal resolution. Recently, with the use of biosensor the drawback of temporal resolution has been improved considerably, however other inconveniences have merged, such as stability, reproducibility and the lack of reliable biosensors mainly for GABA. The aim of this review is to show the important advances in the different ways to measure neurotransmitter concentrations; both with the use of classic techniques as well as with the novel methods and alternant approaches to improve the temporal resolution.
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- 2014
7. Comparison of four recombinant hepatitis B vaccines applied on an accelerated schedule in healthy adults
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Hernández-Bernal, Francisco, Aguilar-Betancourt, Arístides, Aljovin, Virginia, Arias, Gloria, Valenzuela, Carmen, Pérez de Alejo, Karen, Hernández, Karina, Oquendo, Orcilia, Figueredo, Niurka, Figueroa, Nelvis, Musacchio, Alexis, Véliz, Gloria, García, Elizeth, Mollineda, Alina D., Juvier, Ana Isabel, Trujillo, Janette, Delahanty, Aurora, Ortega, D., Cinza, Z., and González, Verena L. Muzio
- Abstract
A post-marketing, double blind, randomised, controlled clinical trial to assess the immunogenicity and safety profiles of four commercially available recombinant hepatitis B vaccines was performed. The vaccines included in this study were Heberbiovac-HB®(Heber Biotec S.A., Havana, Cuba), Euvax-B®(LG Chemical Ltd., Seoul, Korea), Hepavax-Gene® (Greencross Vaccine Corp., Seoul, Korea), and Engerix-B®(GlaxoSmithKline Biologicals, Rixensart, Belgium). Vaccines were administered intramuscularly to healthy adults in three 20mg doses at monthly intervals (0 - 1 - 2 months). Four hundred volunteers aged 18 to 45 years (average age, 35 years) non-reactive for serological markers of hepatitis B virus infection were vaccinated. Volunteers were randomly assigned (ratio 1:1:1:1) to one of the four treatment groups. The antibody response (anti-HBs) was assessed at days 60, 90 and 365 post-vaccination using a commercial kit. The four vaccines showed to be safe and highly immunogenic. Similar seroprotection rates (anti-HBs ≥10 IU/L) about one month after application of the second and third dose were obtained for Engerix-B®, Hepavax-Gene®, Euvax-B®, and Heberbiovac-HB®vaccines 96.7%, 96.6%, 100%, 100% and 98.8%, 89.5%, 100%, 100%, respectively.. Heberbiovac-HB®vaccine achieved significantly higher geometric mean antibody titers (GMT) and rate of good and hyper-responders at all time-points post-vaccination. The GMT on day 365 after full vaccination was significantly reduced in all groups compared to day 90, although Heberbiovac-HB®showed the highest anti-HBs GMT and good-responders rate. The four vaccines were well tolerated and poorly reactogenic. No serious adverse events were observed. This study confirms an overall good immune response and rapid priming for the four vaccines in the course of an accelerated schedule, with higher anti-HBs geometric mean concentrations and better responses for Heberbiovac-HB®. [WHO primary Registry Number: RPCEC00000075].
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- 2011
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8. Kv1.5-Kvβ Interactions: Molecular Determinants and Pharmacological Consequences
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Gonzalez, Teresa, David, Miren, Moreno, Cristina, Macias, Alvaro, and Valenzuela, Carmen
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Kv1.5 channels are homotetramers of α-pore subunits mainly present in human atrium and pulmonary vasculature. Thus, Kv1.5 is a pharmacological target for cardiovascular diseases. Kvβ1.3 assemblies with Kvα1.5 and modifies its gating and pharmacology. A further knowledge of α-β interactions and pharmacology will lead a better design of new drugs.
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- 2010
9. Effects of propafenone and 5‐hydroxy‐propafenone on hKv1.5 channels
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Franqueza, Laura, Valenzuela, Carmen, Delpón, Eva, Longobardo, Mónica, Caballero, Ricardo, and Tamargo, Juan
- Abstract
1The goal of this study was to analyse the effects of propafenone and its major metabolite, 5‐hydroxy‐propafenone, on a human cardiac K+channel (hKv1.5) stably expressed in Ltk−cells and using the whole‐cell configuration of the patch‐clamp technique.2Propafenone and 5‐hydroxy‐propafenone inhibited in a concentration‐dependent manner the hKv1.5 current with KDvalues of 4.4±0.3 μMand 9.2±1.6 μM, respectively.3Block induced by both drugs was voltage‐dependent consistent with a value of electrical distance (referenced to the cytoplasmic side) of 0.17±0.55 (n=10) and 0.16±0.81 (n=16).4The apparent association (k) and dissociation (l) rate constants for propafenone were (8.9±0.9)×106M−1s−1and 39.5±4.2 s−1, respectively. For 5‐hydroxy‐propafenone these values averaged (2.3±0.3)×106M−1s−1and 21.4±3.1 s−1, respectively.5Both drugs reduced the tail current amplitude recorded at −40 mV after 250 ms depolarizing pulses to +60 mV, and slowed the deactivation time course resulting in a ‘crossover’ phenomenon when the tail currents recorded under control conditions and in the presence of each drug were superimposed.6Both compounds induced a small but statistically significant use‐dependent block when trains of depolarizations at frequencies between 0.5 and 3 Hz were applied.7These results indicate that propafenone and its metabolite block hKv1.5 channels in a concentration‐, voltage‐, time‐ and use‐dependent manner and the concentrations needed to observe these effects are in the therapeutical range.
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- 1998
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10. Effects of rupatadine, a new dual antagonist of histamine and platelet‐activating factor receptors, on human cardiac Kv1.5 channels
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Caballero, Ricardo, Valenzuela, Carmen, Longobardo, Mónica, Tamargo, Juan, and Delpón, Eva
- Abstract
The effects of rupatadine, a new dual antagonist of both histamine H1and platelet‐activating factor receptors, were studied on human cloned hKv1.5 channels expressed in Ltk−cells using the whole‐cell patch‐clamp technique.Rupatadine produced a use‐ and concentration‐dependent block of hKv1.5 channels (KD=2.4±0.7 μM) and slowed the deactivation of the tail currents, thus inducing the ‘crossover’ phenomenon.Rupatadine‐induced block was voltage‐dependent increasing in the voltage range for channel opening suggesting an open channel interaction. At potentials positive to +10 mV the blockade decreased with a shallow voltage‐dependence. Moreover, rupatadine also modified the voltage‐dependence of hKv1.5 channel activation, which exhibited two components, the midpoint of the steeper component averaging −25.2±2.7 mV.When the intracellular K+concentration ([K+]i) was lowered to 25% the voltage‐dependent unblock observed at positive potentials was suppressed and the activation curve in the presence of rupatadine did not exhibit two components even when the midpoint of the activation curve was shifted to more negative potentials (−30.3±1.3 mV).On channels mutated on the residue R485 (R485Y) which is located on the external entryway of the pore the rupatadine‐induced block did not decrease at potentials positive to +10 mV. In contrast, on V512M channels rupatadine reproduced all the features of the blockade observed on wild type channels.All these results suggest that rupatadine blocks hKv1.5 channels binding to an external and to an internal binding site but only at concentrations much higher than therapeutic plasma levels in man. Efflux of K+promotes the unbinding from the external site. Furthermore, rupatadine binds to an internal site and dramatically modifies the voltage‐dependence of channel opening.
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- 1999
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11. Electromechanical Effects of Zatebradine on Isolated Guinea Pig Cardiac Preparations
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PÉREZ, ONÉSIMA, GAY, PILAR, FRANQUEZA, LAURA, CARRÓN, ROSALÍA, VALENZUELA, CARMEN, DELPÓN, EVA, and TAMARGO, JUAN
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The effects of zatebradine on rate and contractile force and transmembrane action potentials were studied in isolated guinea pig atria and ventricular papillary muscles. In spontaneously beating right atria, zatebradine, 10−7-10−4M, produced a negative chronotropic effect (IC50= 6.5 ± 3.0 ± 10−6M) and prolonged the recovery of the sinus function. In addition, it produced a biphasic effect on the atrial contractility, so that at concentrations up to 10−5M, it exerted a positive inotropic effect, whereas at higher concentrations, a negative inotropic effect was observed (IC50= 9.0 ± 0.3 χ 10−5M). In electrically driven left atria, zatebradine produced a negative inotropic effect, though no changes were observed in the total contraction time or the time to peak tension. In papillary muscles, zatebradine 3≥5 χ 10−6Mcaused a significant decrease in the maximum upstroke velocity (Vmax) without altering the resting membrane potential and exerted biphasic effects on the action potential duration (APD). At concentrations up to 5 χ 10−5M, it prolonged the APD, whereas at higher concentrations, it shortened the APD. In addition, zatebradine, 10−4M, significantly reduced the amplitude and Vmaxof the slow action potentials elicited by isoproterenol in K+-depolarized papillary fibres. In the presence of zatebradine, trains of stimuli at rates between 0.5 and 3 Hz led to an exponential decline in Vmax(frequency-dependent Vmaxblock), which was augmented at higher rates of stimulation. The time constant for the recovery of Vmaxfrom the frequency-dependent block was 2.9 s. The curve-relating membrane potential and Vmaxwere shifted by zatebradine in a hyperpolarizing direction by 4 mV. These findings confirmed and extended previous experimental evidence indicating that zatebradine belongs to the so-called specific bradycardie agents. The results obtained in guinea pig papillary muscles also demonstrated that zatebradine produced a frequency- and voltage-dependent block of Na+channels. From the onset and offset kinetics of the frequency-dependent Vmaxblock, zatebradine can be considered as an intermediate kinetics Na+channel blocker. These results must be confirmed by further patch-clamp experiments.
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- 1995
12. Electrophysiologic Interactions Between Mexiletine and Propafenone in Guinea Pig Papillary Muscles
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Valenzuela, Carmen, Delpón, Eva, and Tamargo, Juan
- Abstract
The effects of propafenone alone, mexiletine alone, and their combination at the sodium channel level were studied in isolated guinea pig papillary muscles. The maximum upstroke velocity (Vmax) was used as an indirect index of the magnitude of the sodium inward current. In muscles driven at 0.02 Hz, neither mexiletine (10−5M) nor propafenone (5 × 10−6M) had any effect on action potential characteristics, but their combination decreased Vmax. In the presence of mexiletine and propafenone, trains of stimuli at 1 Hz led to a use-dependent block (onset rate 0.11 ± 0.008 and 0.19 ± 0.02 per action potential, respectively). The combination of mexiletine plus propafenone increased the onset rate of the use-dependent Vmaxblock (0.32 ± 0.04 per action potential), but did not modify the time-constant of recovery of Vmaxblock or the magnitude of the slow component of reactivation induced by propafenone. Moreover, the combination of both drugs was more effective in suppressing early test stimuli than either drug alone. We conclude that the combination of mexiletine and propafenone is a synergistic one that affects only the onset kinetics of use-dependent Vmaxblock without detracting from the characteristics of the propafenone.
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- 1989
13. Tonic and FrequencyDependent VmaxBlock Induced by Imipramine in Guinea Pig Ventricular Muscle Fibers
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Delpón, Eva, Valenzuela, Carmen, and Tamargo, Juan
- Abstract
The effects of imipramine (IMI) on transmembrane action potentials were studied in isolated guinea pig papillary muscles. In muscles driven at 0.02 and I Hz, IMI (10−7to 5 ± 10−5M) produced a concentration-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential, but it had no effect on the resting membrane potential. In the presence of 10−5MIMI, trains of stimuli at rates between 0.5 and 2 Hz led to an exponential decline in Vmaxto a new steady-state level (K= 0.230 ± 0.09 AP−1at 2 Hz). This frequency-dependent Vmaxblock was augmented at higher stimulation frequencies and at higher drug concentrations. The time constant of the recovery of Vmaxfrom the frequency-dependent block was 2.5 s, this value being independent of the drug concentration. These values of onset and offset kinetics of IMI lie between those of drugs with fast and intermediate kinetie properties. IMI also shifted the curve relating membrane potential and Vmaxin hyperpolarizing directions. These results suggested that IMI exhibited a frequency- and voltage-dependent inhibition of the fast sodium channels similar to that exhibited by other class lb antiarrhythmics. The possible role of this frequency- and voltage-dependent Vmaxinhibition in the pro-antiarrhythmic effects of IMI is discussed.
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- 1990
14. Electrophysiological Effects of 5Hydroxypropafenone on Guinea Pig Ventricular Muscle Fibres
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Valenzuela, Carmen, Delgado, Carmen, and Tamargo, Juan
- Abstract
The effects of 5-hydroxypropafenone (5-OH-P), the main metabolite of propafenone, were studied in guinea pig papillary muscles obtained from untreated animals and from animals pretreated with 5-OH-P, 3 mg/kg for 24 days. In untreated muscles perfused with 2.7 and 5.4 m MK, 5-OH-P depressed action potential amplitude and Vmax, reduced the resting membrane potential, and prolonged the effective refractory period (ERP), but had no effect on the duration of the action potential (APD), recovery time (RT), or ERP/RT ratio. 5-OH-P also shifted the membrane responsiveness curve downward and to the left (i.e., in hyperpolarizing direction), prolonged the ERP/APD ratio, depressed the amplitude and Vmax, and shortened the duration of the slow action potentials induced by isoproterenol in K-depolarized muscles. Pretreatment with 5-OH-P had no effect on phase 0 characteristics or resting membrane potential, but it shortened the APD, ERP, and RT and decreased the ERP/APD ratio. Further addition of 5-OH-P produced similar but more marked changes than in untreated muscles. In papillary muscles perfused with 10 m MK, the depressant effects of 5-OH-P on phase 0 characteristics and ERP/APD ratio were potentiated. A slight lengthening of the APD was also observed. Because all these effects are similar to those previously described with propafenone, it is concluded that 5-OH-P is an active metabolite which exhibits class 1 antiarrhythmic effects and which may be responsible for some of the cardiodepressant and antiarrythmic effects previously described for propafenone.
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- 1987
15. The Endophthalmitis Vitrectomy Study
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Johnson, Mark W., Doft, Bernard H., Kelsey, Sheryl F., Barza, Michael, Wilson, Louis A., Barr, Charles C., Wisniewski, Stephen R., Vine, Andrew K., Blodi, Barbara A., Elner, Susan G., Johnson, Mark W., Jessup, Laurie M., Khanderia, Sharad, Pierson, Carl L., Jessup, Laurie M., Willis, Julie, McIver, Frances, Stanley, Sally, Sneed, Scott R., Capone, Antonio, Aaberg, Thomas M., Lim, Jennifer I., Sternberg, Paul, Coffman, Diana S., Moore, Cameile N., Gardner, Susanne K., Nolte, Frederick S., Fremstad, Ann, Gibbs, Deborah, Gilman, James, Swords, Ray, Aguilar, H.Edith, Meredith, Travis A., Lakhanpal, Vinod, Christian, Faith D., Hood, A., Schwalbe, Richard S., Christian, Faith D., Billings, Emery E., Buie, William, Mallonee, James J., Millar, Mary Ann, Verbeek, Sharon, Campochiaro, Peter A., Palardy, Carol B., Reynolds, Lois, Dick, James D., Palardy, Carol B., Cain, Dennis, D'Amico, Donald J., Frederick, Albert R., Morley, Michael G., Pesavento, Richard D., Puliafito, Carmen A., Topping, Trexler M., Finn, Susan M., Raymond, Laura A., Baker, Ann Sullivan, Paton, Barbara, Evans, Claudia, Napoli, Jeffrey, Kierman, Christine, Makris, Kathryn, McInnes, Tom, Reidy, Wini T., White, Ruth, Garfinkel, Richard A., Pilkerton, A.Raymond, Frantz, Robert A., Abernathy, Gill B., Barbaccia, Jay G., Ensey, H.Russell, Ormes, Carol A., Park, Choong H., Caplan, Joel, Russell, Kathryn, Toma, Robert, Packo, Kirk H., de Bustros, Serge, Flood, Timothy P., Glazer, Louis, DeAlba, Maggie, Evanich, Evangeline, Montwill, Michael A., Rothman, Jeri J., Ruderman, Gail, Beard, Melodie, Landau, William, Shen, Min H., Gordon, Martha, Graff, Sharon, Kwiatkowski, Kathy, Pappas, Loreen, Bryant, Douglas, Doherty, Don, Morini, Frank, Arredondo, Linda, Garretson, Bruce R., Gerena, Carlos, Hunt, Maureen, Kinnaird, Sharon M., Neri, Toni, Rice, Thomas A., Novak, Michael A., Rowe, Pamela S., Jamieson, Scott, Newberry, Deborah, Rech, Glenn R., Dul, Michael J., Kinser, Livia, Strozewski, Krystyna, Clark-Rath, Susan, DeLisio, Marty, Dempsey, David L., Kukula, Donna, Pinter-Smith, Anne, Rowe, Pamela S., Smith-Brewer, Sheila, Ludwig, Tracey, Chambers, Robert B., Davidorf, Frederick H., Taylor, Cindy S., Hale, Karen N., Buesching, William J., Chaudhuri, Chhanda, Cover, Nanci J., Shortlidge, Gail R., Cover, Nanci J., Keating, Michael J., Savage, Scott J., Andrzejewska, Paula, Cometet, Susan, Milliron, Jill D., Richmond, Rob, Schneider, Lori, Weisenberger, Debra, Cantrill, Herbert L., Ramsay, Robert C., Brallier, Amy B., Johnson, Timothy P., Rossing, Edith E., Knauth, Kathleen A., Monahan, Martha M., Oestreich, Neal W., Oestreich, Neal W., Clark, Kenneth F., Glennen, Anita M., Yarian, David L., Green, Stuart N., Leff, Steven R., Masciulli, Leo, Lucido, Margaret M., Ludwig, Edward J., Marano, Charlotte L., Peters, Linda, Joho, Kim, Volkert, Doris C., Andersen, Finn, Coffey, Donna, Schlosser, Alex, Honeywell, Ann, Mames, Robert N., Driebe, William T., Stern, George A., Francis, Amye, Zam, Z.Suzanne, Cooper, Rhonda, Gaskins, Darla, Shamis, Diana J., Willingham, Melinda, Barker, Kay, Rosa, Harry, Friedman, Scott M., Gardner, Thomas W., Blankenship, George W., Coyle, Carole J., Bero, Christopher J., Halas, Cindy, Schick, Suzanne, Walker, Jean, Cunningham, Denise, Lambert, H.Michael, Clogston, Pamela S., Frady, Pamela M., Gardner, S.Neal, Osato, Michael S., Frady, Pamela M., Carr, Louise, Shigley, James, Frady, Pamela M., Lopez, Pedro F., Chong, Lawrence P., Frambach, Donald A., CisnerosMargaret^Padilla, Lupe, Yee, Edmond Ming, Nakamura, Tamako, Walonker, A.Frances, Morales, Ronald, Nichols, Tracy, Huete, Maria E., Liggett, Peter E., Ober, Richard R., Quillen-Thomas, Beth, Williams, Mark, Barr, Charles C., Bloom, Steven M., Greene, Pamela J., Whittington, Greg K., Martin, Mark E., Watson, Glen, Jenkins-Curry, Betty, Gilkey, Leigh A., Huelsman, Steven, Han, Dennis P., Burton, Thomas C., Mieler, William F., Pulido, Jose S., Reeser, Frederick H., Newman, Janet L., Werner, Kathy A., Pisarzewicz, Paul J., Reinerio, Nina A., Walloch, Mary Lee K., Wilmer, Zuzana, Laabs, Jan, Picchiottino, Ruth, Phillips, Jim, Picchiottino, Ruth, Wipplinger, Walter, Abrams, Gary W., Jurkiewicz, Dale T., Leet, Margaret L., Mandel, Paul, Metzger, Kim, Suchla, Lori, Zarling, Denise, Balles, Mark W., Ryan, Edwin H., Knobloch, William H., Cook, Sally M., Luke, Darlette G., Ferrieri, Patricia, Schiminsky, Norynne M., Genia, Anne, Philiph, David A., Stinson, Elizabeth K., Wright, Linda M., McMichael, William C., Mielke, Sandy J., Wright, Linda M., Ponwith, Lisa J., Pavan, Peter Reed, Pautler, Scott E., Coats, Marion L., Kirk, Nancy M., Millard, Sharon M., Castellano, Frank C., Edwards, Charlotte R., Marquardt, Angela, McCormack, Amy J., McCormick, Michael T., Renshaw, Bernard, Restuccia, Angela, Campbell, Monica, Christopher, Nell, Garrett, L.Scott, Halkias, Demetrios G., Hothersall, Kim, Mickler, Karen, Minnick, Thomas S., Burr, Cheryl, Millard, Sharon M., Burr, Cheryl, Saxon, Wyatt, Arcacha, Miguel A., Carlton, Steve, Edison, Sonya K., Mallis, Marc J., Sayers, Tamre L., Sudds, Thomas W., Tiberia, Robert J., Wolabaugh, Sherry, Bradford, Reagan H., Parke, David W., Wolf, Thomas C., Shofner, Janie M., Tobey, Lee E., Jensen, Harold G., Sanchez, Dinah, Shofner, Janie, Burris, Russell, Drake, Kellie K., Grissom, Kay R., Rowsey, J.James, Wilkinson, Charles P., Brown, Gary C., Benson, William E., Federman, Jay L., Lucier, Alfred C., Maguire, Joseph I., Sarin, Lov K., Shakin, Eric P., Sivalingam, Arunan, Tasman, William, Vander, James F., Ward, Nancy, Weisbecker, Clement A., Agnew, Caroline L., Lambert, Richard, Torner, Terrance, Carlson, Kathy, Franchine, Gerrie, Serfass, Michelle S., Doft, Bernard H., Bergren, Robert L., Lobes, Louis A., Olsen, Karl R., Rinkoff, Jeffrey S., Metz, Donna J., Leonard, Margaret N., Karenchak, Lisa M., Kowalski, Regis P., Wellman, Lynn A., Wilcox, Linda A., Campbell, Alan F., Steinberg, David R., Vagstad, Gary L., Flook, Kimberly A., Good, Mary M., Keenen, Beverly J., Mellinger, Kim A., Margherio, Raymond R., Abrams, Gary W., Cox, Morton S., Murphy, Patrick L., Trese, Michael T., Werner, Jane C., Williams, George A., Manatrey, Patricia E., Prote, Janet L., Lucarotti, Richard, Martin, Susan, Band, Jeff, Bostic, Grace, Gumming, Kristi, Manatrey, Patricia E., Mitchell, Beth, Regan, Virginia S., Bridges, Craig, Cox, Sam, Houston, Gary, Johnson, John, Streasik, Pat, Wood, Betty, Blumenkranz, Mark S., Cayo, Lisa, Kaye, Virginia, Valenzuela, Carmen Luz, Orgel, Ira K., Poliner, Lon S., Tornambe, Paul E., Cannon, Sarah V., Nielsen, Janet L., Carlson, Anne, Chan, Pauline, Drake, Lynne, Grim, Martha, Peterson, Corky, Borg, Lynn A., Gillyatt, Joann, Beyer, Conny, Hammer, Mark E., Grizzard, W.Sanderson, Shannon, Theresa L., Traynom, Janet R., Collado, Melinda J., McManus, Dennis W., Sweeney, Daniel E., Adams, Donald H., Watson, Thomas T., Traynom, Janet R., Shannon, Theresa L., Traynom, Janet R., Antworth, Michael V., Araos, Johanna Glacy, Greenwald, Mark A., Habib, Mohsen, Myers, Sandra K., Ockers, Karen M., Thibodeau, Judy-Ann, Watkins, Brett, Nelsen, Philip T., Rosenthal, J.Gregory, Mintz, Fay V., Biedenbach, Michael, Leonardy, Nicholas J., Orgel, Ira K., Lawniczak, Sue M., Bork, Chuck, Hageage, George, Hunter, Evelyn B., Marshall, MarLynn J., Roman, Patricia, Hill, Rick, Hofbauer, Thomas, Lemanowicz, Jack, Cupples, Howard P., Guzman, Gladys I., Brodeur, Richard J., Yee, Donald, Delaha, Edward C., Geyer, Stanley L., Slovis, Stacey, Shields, William J., Lauber, Susan, Michelitsch, Karl, Barza, Michael, Kassoff, Aaron, Leonard, Margaret N., Watling, Sharon, Wilson, Louis A., Buehler, JoAnne C., McVay, Jeffrey, Kelsey, Sheryl F., Wisniewski, Stephen R., Podobinski, Gale K., Sillett, Robert L., Groer, Shirley, Avery, Brian, Belle, Steven H., Boles, James, Henry, Linda, Shema, Sarah J., Titus-Emstoff, Linda, Davis, Matthew, Magli, Yvonne L., Hubbard, Larry, Thomas, Suzanne, Everett, Donald F., Mowery, Richard, Davis, Matthew, Doft, Bernard H., Everett, Donald, Kelsey, Sheryl F., Nelsen, Philip T., Packo, Kirk H., Rice, Thomas A., Davis, Kathryn, Azen, Stanley, Covey, Preston, McCuen, Brooks, Packer, Andrew, Robin, Jeffrey, Doft, Bernard H., Everett, Donald, Kelsey, Sheryl F., and Davis, Matthew
- Abstract
Purpose:The authors determine if specific features of the clinical presentation of acute postoperative endophthalmitis correlate with the microbiologic culture results.
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- 1997
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16. Electrophysiologic Interactions Between Mexiletine-Quinidine and Mexiletine-Ropitoin in Guinea Pig Papillary Muscle
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Valenzuela, Carmen and Sanchez-Chapula, Jose
- Abstract
The effects of quinidine alone, ropitoin alone, and in combination with mexiletine at the sodium channel level were studied in isolated guinea pig papillary muscles using a sucrose gap technique. The maximum upstroke velocity (max) was used as an indirect index of the magnitude of the sodium current. With quinidine (24 μM) and ropitoin (1 μM) added, trains of stimuli led to an exponential decline of maxto a new steady-state level (use-dependent block). The combination of mexiletine and quinidine decreased use-dependent maxblock and magnitude of the slow component of reactivation induced by quinidine without modifying its time-constant of recovery. When we studied the interaction between mexiletine and ropitoin, we obtained similar results. Therefore, we conclude that mexiletine, quinidine, and ropitoin may bind to the same receptor site in the sodium channel. In addition, these antagonistic effects appeared only at frequencies >0.5 Hz, whereas at very slow frequencies of stimulation we observed a synergistic effect in both interactions studied.
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- 1989
17. Tonic and Phasic VmaxBlock Induced by 5Hydroxypropafenone in Guinea Pig Ventricular Muscles
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Valenzuela, Carmen, Delpón, Eva, and Tamargo, Juan
- Abstract
The effects of 5-hydroxypropafenone (5-OH-P) on transmembrane action potentials were studied in isolated guinea pig papillary muscles. 5-Hydroxypropafenone, 10−7Mto 5 × 10−5M, produced a dose-dependent decrease in the Vmaxand amplitude of the action potential and a depolarization of the resting membrane potential, whereas the action potential duration was not affected by the drug. In the presence of 5-OH-P, trains of stimuli at rates between 0.2 and 2 Hz led to an exponential decline in Vmax(onset rate at 1 Hz 0.07 ± 0.01 per action potential) to a new steady-state level. This phasic, use-dependent Vraaxblock was augmented at higher stimulation frequencies. The time constant for the recovery of Vmaxfrom the phasic block (offset) was 200.0 ± 9.3 s. In papillary muscles depolarized with 10 mMK. the inhibitory effect of 5-OH-P on Vmaxof the first action potential after a long quiescent period (tonic block) was markedly increased, but the rates of onset and offset of the phasic block were similar to those found in normally polarized fibers under 5.4 mMK. 5-OH-P also shifted the curves relating membrane potential and Vmaxin the hyperpolarizing direction. These findings suggest that 5-OH-P exhibited similar phasic inhibitory action of the fast sodium channels than other class Ic antiarrhythmic drugs. This phasic Vmaxblock, and its greater inhibition of Vmaxin depolarized muscles through the increase of tonic block, would play a major role for the antiarrhythmic effect of the drug.
- Published
- 1988
18. Voltage- and UseDependent Modulation of Calcium Channel Current in Guinea Pig Ventricular Cells by Amiodarone and DesOxo-Amiodarone
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Valenzuela, Carmen and Bennett, Paul B.
- Abstract
Amiodarone is an effective antiarrhythmic drug handicapped by serious side effects. The mechanism of its antiarrhythmic activity is not known but is presumed to involve inhibition of current flowing through ion channels. Des-oxo-amiodarone, a close structural analogue of amiodarone, was synthesized based on the hypothesis that the toxic and therapeutic properties reside in different parts of the molecule and that chemical modification could result in a less toxic agent that yet preserved amiodarone's antiarrhythmic efficacy. We compared the effects of amiodarone and des-oxo-amiodarone on Ca current in enzymatically dispersed guinea pig ventricular myocytes using the whole-cell patch-clamp method. Amiodarone caused both a tonic and a phasic fuse-dependent) reduction of the Ca current. The relationship between membrane potential and the availability for channel opening upon depolarization (inactivation curve) was shifted toward more negative membrane potentials by amiodarone (Δ - 10.6 $$ 2.2 mV, n = 7). The use-dependent reduction of the Ca current was also dependent on the frequency of the voltage clamp steps (0.5 Hz, 40.2 $$ 7.9; 1.0 Hz, 50.0 $$ 6.7). Dexoxo-amiodarone had a dual effect on the Ca current: After maintaining the membrane potential for several seconds at negative membrane potentials (-45 mV), the Ca current was increased by des-oxo-amiodarone. Des-oxo-amiodarone also shifted the Ca channel inactivation curve to more negative membrane potentials up to 16 mV. Consequently, Ca current could be increased or decreased depending on the experimental conditions. Enhancement of Ca current by des-oxo-amiodarone was transient and was supplanted entirely by the antagonistic effects of the drug after −5 min. The antagonistic effects of des-oxo-amiodarone on Ca current were also use- and frequency-dependent.
- Published
- 1991
19. Electrophysiological Effects of the Combination of Imipramine and Desipramine in Guinea Pig Papillary Muscles
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Delpón, Eva, Valenzuela, Carmen, Pérez, Onésima, and Tamargo, Juan
- Abstract
The electrophysiological effects of imipramine and its active metabolite desipramine, alone or in combination, were studied in isolated guinea pig papillary muscles. The maximum upstroke velocity (Vmax) of the action potential was used as an indirect index of the magnitude of the sodium inward current. In muscles driven at 0.02 Hz, imipramine alone (5 × 10-6M), desipramine alone (5 × 10 -6M), or their combination had no effect on action potential characteristics. However, in the presence of imipramine or desipramine, trains of stimuli at rates between 0.5 and 3 Hz led to a frequency-dependent Vmaxblock that was augmented at higher stimulation rates. At each driving rate, the Vmaxblock produced by desipramine was significantly greater than that produced by imipramine. The combination of imipramine and desipramine increased the onset rate of the frequency-dependent Vmaxblock, but the total amount of Vmaxblock was similar to that produced by desipramine alone. In the presence of imipramine alone, the recovery of Vmaxwas a monoexponential process, the time constant (τre) being 2.3 ± 0.4 s, whereas in the presence of desipramine, it was better defined by a biexponential function (τre= 1.5 ± 0.4 and 15.8 ± 2.8 s). In the presence of the combination, the recovery process was also defined by a biexponential function and the τrevalues were similar to those found in the presence of desipramine alone. Thus, according to their onset and offset kinetics of the frequency-dependent Vmaxblock, imipramine and desipramine can be classified as sodium channel blockers with intermediate and slow kinetics, respectively. Therefore, the active metabolite desipramine can be responsible for some of the cardiodepressant effects previously attributed to its parent compound, imipramine.
- Published
- 1993
20. Electrophysiological effects of CI‐980, a tubulin binding agent, on guinea‐pig papillary muscles
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Pérez, Onésima, Valenzuela, Carmen, Delpón, Eva, and Tamargo, Juan
- Abstract
The electrophysiological effects of CI‐980, a new tubulin‐binding agent that inhibits assembly of cytoplasmic microtubules, on transmembrane action potential characteristics were studied in right ventricular papillary muscles from guinea‐pig hearts.In papillary muscles driven at 1 Hz, CI‐980 at concentrations 10−5mproduced a concentration‐dependent increase in the maximum upstroke velocity (Vmax) and a lengthening of the action potential duration at 50% (APD50) and 90% (APD90) of repolarization without affecting the resting membrane potential. Prolongation of the APD90was accompanied by a parallel lengthening of the effective refractory period (ERP) so that the ERP/APD90ratio remained unaltered at all drug concentrations tested.CI‐980 exhibits a reverse use‐dependent effect on APD90values, that is, drug‐induced APD90prolongation become exagerated at slow rates and attenuated at fast rates.CI‐980 at concentrations 10−6mlengthened the APD of the slow action potentials elicited by isoprenaline in papillary muscles depolarized by high K+(27 mm) solution.At 10−5m, CI‐980 produced a small tonic Vmaxblock. However, in muscles driven at rates between 0.5 and 3 Hz it produced an exponential decline in Vmax(use‐dependent Vmaxblock) which was augmented at higher rates of stimulation. At 3 Hz the onset kinetics of the use‐dependent Vmaxblock was fitted by a monoexponential function with a Kvalue 0.07±0.01 per AP. The recovery time constant (τre) from the use‐dependent Vmaxblock was prolonged from 21.6±2.6 ms to 3.5±0.2 s.The curve relating membrane potential and Vmaxwas shifted by CI‐980 (10−5m) in the hyperpolarizing direction by 2.3±1.1 mV.It is concluded that in guinea‐pig papillary muscles, CI‐980 produces a use‐dependent inhibition of Vmaxand a reverse use‐dependent prolongation of the ventricular action potential, thus exhibiting class I and class III antiarrhythmic actions, respectively. From the onset and offset kinetics of use‐dependent Vmaxblock, CI‐980 can be considered to be an intermediate kinetics (IA) Na+channel blocker.
- Published
- 1997
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21. Tonic and frequency-dependent <img src="/fulltext-image.asp?format=htmlnonpaginated&src=H8P743K85Q8580W5_html\210_2004_Article_BF00184296_TeX2GIFIE1.gif" border="0" alt=" $$\mathop {\text{V}}\limits^{\text{.}} _{{\text{max}}} $$ " /> block induced b
- Author
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Delpó, Eva, Valenzuela, Carmen, Carrón, Rosalia, Pérez-Vizcaino, Francisco, and Tamargo, Juan
- Abstract
Summary The effects of (S)-nafenodone, a new antidepressant, on transmembrane action potentials were studied in guinea-pig papillary muscles. In muscles driven at 0.02 and 1 Hz, (S)-nafenodone, 10
−6 mol/l and 10−5 mol/l, produced a concentration-dependent decrease in the maximum upstroke velocity of the action potential, but it had no effect of the resting membrane potential. In the presence of 10−5 mol/l (S)-nafenodone, trains of stimuli at rates between 0.5 and 2 Hz led to an exponential decline in maximum upstroke velocity to a new steady-state level [K = 0.152±0.03 (action potential)−1 at 2 Hz]. This frequency-dependent maximum upstroke velocity block increased at higher stimulation frequencies and at higher drug concentrations. (S)-Nafenodone also prolonged the time constant of recovery of maximum upstroke velocity from the frequency-dependent block to 2.3 ± 0.6 s, this value being independent of the drug concentration. These values of onset and offset kinetics of (S)-nafenodone lie between those of drugs with fast and intermediate kinetic properties. (S)-nafenodone also shifted the curve relating membrane potential and maximum upstroke velocity in hyperpolarizing direction. All these results indicated that (S)-nafenodone produced a frequency- and voltage-dependent inhibition of the fast sodium channels similar to that exhibited with imipramine.- Published
- 1991
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22. Effect of descarboethoxyloratadine, the major metabolite of loratadine, on the human cardiac potassium channel Kv1.5
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Caballero, Ricardo, Delpón, Eva, Valenzuela, Carmen, Longobardo, Mónica, Franqueza, Laura, and Tamargo, Juan
- Abstract
The effects of descarboethoxyloratadine (DCL), the major metabolite of loratadine, were studied on a human cardiac K+channel (hKv1.5) cloned from human ventricle and stably expressed in a mouse cell line by means of the patch‐clamp technique. DCL (1–100 μM) inhibited hKv1.5 current in a concentration‐dependent manner with an apparent affinity constant of 12.5±1.2 μM. The blockade increased steeply over the voltage range of channel opening, which indicated that DCL binds preferentially to the open state of the channel. At more depolarized potentials a weaker voltage‐dependence was observed consistent with a binding reaction sensing ∼amp;20% of the transmembrane electrical field. DCL, 20 μM, increased the time constant of deactivation of tail currents, thus inducing a ‘crossover’ phenomenon. The present results demonstrated that DCL blocked hKv1.5 channels in a concentration‐, voltage‐, and time‐dependent manner.
- Published
- 1997
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23. A New KCNQ1 Mutation at the S5 Segment that Impairs its Association with KCNE1 is Responsible for Short QT Syndrome
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de la Cruz, Alicia, Moreno, Cristina, Oliveras, Anna, Bartolucci, Chiara, Gimeno, Juan R., Severi, Stefano, Felipe, Antonio, Gonzalez, Teresa, Lambiase, Pier, and Valenzuela, Carmen
- Published
- 2016
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24. Trabectedin Re-Educates Resting Peritoneal Macrophages into M1 Subtype
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Peraza, Diego A., Mojena, Marina, de la Cruz, Alicia, Gonzalez, Teresa, Bosca, Lisardo, Galmarini, Carlos M., and Valenzuela, Carmen
- Published
- 2017
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25. Irvalec Inserts Into the Plasma Membrane Causing Rapid Loss of Integrity and Necrotic Cell Death in Tumor Cells
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Macias, Alvaro, Molina-Guijarro, Jose M., David, Miren, Moreno, Cristina, Alicia, de la Cruz, Prieto, Angela, Gonzalez, Teresa, Galmarini, Carlos M., and Valenzuela, Carmen
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- 2012
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26. Differential Regulation Of Navß Subunits During Myogenesis
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David, Miren, Martinez-Marmol, Ramon, Gonzalez, Teresa, Felipe, Antonio, and Valenzuela, Carmen
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- 2009
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27. Effects of E-LXA4 on Kv and Kir Recorded from Bone Marrow Mouse Macrophages
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de la Cruz, Alicia, Moreno, Cristina, Macias, Alvaro, Prieto, Angela, Gonzalez, Teresa, and Valenzuela, Carmen
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- 2014
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28. Effects of Cl888 on Kv4.3, Kv4.3/Kchip2C and Kv4.3/KChiP3 Channels
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Prieto, Angela, Cercos, Pilar, de la Cruz, Alicia, Gonzalez, Teresa, Gutierrez-Rodriguez, Marta, Naranjo, Jose-Ramon, and Valenzuela, Carmen
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- 2014
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29. Modulation of Kvand KirCurrents by 15-Epi-Lipoxin-A4 in activated Macrophages. Implications for the Regulation of the Innate Immune Response
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Moreno, Cristina, Macias, Alvaro, Prieto, Patricia, Pimentel-Santillana, Maria, de la Cruz, Alicia, Prieto, Angela, Bosca, Lisardo, and Valenzuela, Carmen
- Published
- 2013
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30. Celecoxib Blocks Cardiac Kv1.5, Kv4.3 and Kv7.1 (KCNQ1) Channels. Effects on Cardiac Action Potentials
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Macias, Alvaro, Moreno, Cristina, Moral-Sanz, Javier, Cogolludo, Angel, David, Miren, Alemanni, Matteo, Perez-Vizcaino, Francisco, Zaza, Antonio, Valenzuela, Carmen, and Gonzalez, Teresa
- Published
- 2011
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31. Immunomodulation of Voltage-Dependent K+Channels in Macrophages: Molecular and Biophysical Consequences
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David, Miren, Villalonga, Nuria, Bielanska, Joanna, Vicente, Ruben, Comes, Nuria, Felipe, Antonio, and Valenzuela, Carmen
- Published
- 2010
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32. Benzocaine enhances and inhibits the K+ current through a human cardiac cloned channel (Kv1.5)
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Delpón, Eva, Caballero, Ricardo, Valenzuela, Carmen, Longobardo, Mónica, Snyders, Dirk, and Tamargo, Juan
- Abstract
Objective: The aim of this study was to analyze the effects of a neutral local anaesthetic, benzocaine, on a cardiac K+ channel cloned from human ventricle. Methods: Experiments were performed on hKv1.5 channels stably expressed on mouse cells using the whole-cell configuration of the patch clamp technique. Results: At 10 nM, benzocaine increased the current amplitude (“agonist effect”) by shifting the activation curve 8.4±2.7 mV in the negative direction, and slowed the time course of tail current decline. In contrast, benzocaine (100–700 μM) inhibited hKv1.5 currents (K
D =901±81 μM), modified the voltage-dependence of channel activation, which became biphasic, and accelerated the channel deactivation. Extracellular K+ concentration ([K+]o ) also affected the channel gating. At 140 mM [K+]o , the time course of tail currents deactivation was significantly accelerated, whereas at 0 mM [K+]o , it was slowed. At both [K+]o the activation curve became biphasic. Benzocaine accelerated the tail current decay at 0 mM but not at 140 mM [K+]o . The reduction in the permeation of K+ through the pore did not modify the blocking effects of micromolar concentrations of benzocaine, but suppressed the agonist effect observed at nanomolar concentrations. Conclusions: All these results suggest that benzocaine blocks and modifies the voltage- and time-dependent properties of hKv1.5 channels, binding to an extracellular and to an intracellular site at the channel level. Moreover, both sites are related to each other and can also interact with K+.- Published
- 1999
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33. Block of human cardiac Kv1.5 channels by loratadine: voltage-, time- and use-dependent block at concentrations above therapeutic levels
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Delpón, Eva, Valenzuela, Carmen, Gay, Pilar, Franqueza, Laura, Snyders, Dirk J, and Tamargo, Juan
- Abstract
Objective: The aim of this study was to analyze the effects of loratadine on a human cardiac K+ channel (hKv1.5) cloned from human ventricle and stably expressed in a mouse cell line. Methods: Currents were studied using the whole-cell configuration of the patch–clamp technique in Ltk– cells transfected with the gene encoding hKv1.5 channels. Results: Loratadine inhibited in a concentration-dependent manner the hKv1.5 current, the apparent affinity being 1.2±0.2 µM. The blockade increased steeply between –30 and 0 mV which corresponded with the voltage range for channel opening, thus suggesting that the drug binds preferentially to the open state of the channel. The apparent association and dissociation rate constants were (3.6±0.5)106·M–1·s–1 and 3.7±1.6·s–1, respectively. Loratadine, 1 µM, increased the time constant of deactivation of tail currents elicited on return to –40 mV after 500 ms depolarizing pulses to +60 mV from 36.2±3.4 to 64.9±3.6 ms (n = 6, P<0.01), thus inducing a crossover phenomenon. Application of trains of pulses at 1 Hz lead to a progressive increase in the blockade reaching a final value of 48.6±4.3%. Recovery from loratadine-induced block at –80 mV exhibited a time constant of 743.0±78.0 ms. Finally, the results of a mathematical simulation of the effects of loratadine, based on an open-channel block model, reproduced fairly well the main effects of the drug. Conclusions: The present results demonstrated that loratadine blocked hKv1.5 channels in a concentration-, voltage-, time- and use-dependent manner but only at concentrations much higher than therapeutic plasma levels in man.
- Published
- 1997
- Full Text
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