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Sample records for channel entry blockers

  1. Calcium channel blocker overdose

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/002580.htm Calcium-channel blocker overdose To use the sharing features on this page, please enable JavaScript. Calcium-channel blockers are a type of medicine used ...

  2. Calcium Channel Blockers

    Science.gov (United States)

    ... Certain calcium channel blockers interact with grapefruit products. Kaplan NM, et al. Treatment of hypertension: Drug therapy. In: Kaplan's Clinical Hypertension. 11th ed. Philadelphia, Pa.: Wolters Kluwer ...

  3. Calcium channel blocker poisoning

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    Miran Brvar

    2005-04-01

    Full Text Available Background: Calcium channel blockers act at L-type calcium channels in cardiac and vascular smooth muscles by preventing calcium influx into cells with resultant decrease in vascular tone and cardiac inotropy, chronotropy and dromotropy. Poisoning with calcium channel blockers results in reduced cardiac output, bradycardia, atrioventricular block, hypotension and shock. The findings of hypotension and bradycardia should suggest poisoning with calcium channel blockers.Conclusions: Treatment includes immediate gastric lavage and whole-bowel irrigation in case of ingestion of sustainedrelease products. All patients should receive an activated charcoal orally. Specific treatment includes calcium, glucagone and insulin, which proved especially useful in shocked patients. Supportive care including the use of catecholamines is not always effective. In the setting of failure of pharmacological therapy transvenous pacing, balloon pump and cardiopulmonary by-pass may be necessary.

  4. Calcium channel blockers and Alzheimer's disease★

    Science.gov (United States)

    Tan, Yi; Deng, Yulin; Qing, Hong

    2012-01-01

    Alzheimer's disease is characterized by two pathological hallmarks: amyloid plaques and neurofibrillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging. Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer's disease. Calcium channel blockers are effective therapeutics for treating Alzheimer's disease. This review provides an overview of the current research of calcium channel blockers involved in Alzheimer's disease therapy. PMID:25767489

  5. Discovery and Development of Calcium Channel Blockers

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    Théophile Godfraind

    2017-05-01

    Full Text Available In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovered by Sidney Ringer who reported this fact in 1883. Interest in the intracellular role of calcium arose 60 years later out of Kamada (Japan and Heibrunn (USA experiments in the early 1940s. Studies on pharmacology of calcium function were initiated in the mid 1960s and their therapeutic applications globally occurred in the the 1980s. The first part of this report deals with basic pharmacology in the cardiovascular system particularly in isolated arteries. In the section entitled from calcium antagonists to calcium channel blockers, it is recalled that drugs of a series of diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin were initially named calcium antagonists on the basis of their effect in depolarized arteries contracted by calcium. Studies on arteries contracted by catecholamines showed that the vasorelaxation resulted from blockade of calcium entry. Radiochemical and electrophysiological studies performed with dihydropyridines allowed their cellular targets to be identified with L-type voltage-operated calcium channels. The modulated receptor theory helped the understanding of their variation in affinity dependent on arterial cell membrane potential and promoted the terminology calcium channel blocker (CCB of which the various chemical families are introduced in the paper. In the section entitled tissue selectivity of CCBs, it is shown that characteristics of the drug, properties of the tissue, and of the stimuli are

  6. Use of calcium channel blockers in hypertension.

    Science.gov (United States)

    Conlin, P R; Williams, G H

    1998-01-01

    During the past 20 years the number of subclasses of calcium channel blockers has increased from one to four. Three classes have only a single clinically approved compound: verapamil, diltiazem, and mibefradil. The fourth class, dihydropyridines, contains numerous compounds. All agents are effective in lowering blood pressure in short-term studies, and side effects that trouble the patient are infrequent. Long-term studies in hypertensive patients are limited. Short-acting agents such as nifedipine have been associated with an increased cardiovascular risk in some, but not all studies. These agents also probably create a compliance problem for hypertensive patients because of the need for multiple daily doses and their unpleasant side effects, e.g., ankle edema, palpitations, and flushing. Therefore, they are not useful or indicated for the treatment of hypertensive patients. No data have suggested that long-acting dihydropyridines or nondihydropyridine calcium channel blockers share the same fate. Indeed, several lines of evidence suggest the opposite: they have a cardioprotective effect. However, definitive information will require the completion of several long-term trials, including ALLHAT, CONVINCE, HOT, INSIGHT and NORDIL. Finally, it is important to reflect on the lessons learned from the controversy associated with the potential risks of calcium channel blockers. First, disagreements are common when one uses case-controlled studies and are reflective of the poor precision of the methods used. What is statistically relevant in one study may not hold true for another and may have no clinical relevance, particularly if the relative risk is less than 2. Investigators need to temper their enthusiasm to reflect this reality. Second, at the cutting edge of science there is probably relatively little agreement about what is correct among equally competent scientists. All have bias in their positions and should both recognize and admit so to themselves and their

  7. A combined role of calcium channel blockers and angiotensin receptor blockers in stroke prevention

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    Ji-Guang Wang

    2009-07-01

    Full Text Available Ji-Guang WangCentre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaAbstract: Stroke is a leading cause of death and disability worldwide. The importance of lowering blood pressure for reducing the risk of stroke is well established. However, not all the benefits of antihypertensive treatments in stroke can be accounted for by reductions in BP and there may be differences between antihypertensive classes as to which provides optimal protection. Dihydropyridine calcium channel blockers, such as amlodipine, and angiotensin receptor blockers, such as valsartan, represent the two antihypertensive drug classes with the strongest supportive data for the prevention of stroke. Therefore, when combination therapy is required, a combination of these two antihypertensive classes represents a logical approach.Keywords: stroke, angiotensin, calcium channel, cerebrovascular, hypertension, blood pressure

  8. Metaflumizone is a novel sodium channel blocker insecticide.

    Science.gov (United States)

    Salgado, V L; Hayashi, J H

    2007-12-15

    Metaflumizone is a novel semicarbazone insecticide, derived chemically from the pyrazoline sodium channel blocker insecticides (SCBIs) discovered at Philips-Duphar in the early 1970s, but with greatly improved mammalian safety. This paper describes studies confirming that the insecticidal action of metaflumizone is due to the state-dependent blockage of sodium channels. Larvae of the moth Spodoptera eridania injected with metaflumizone became paralyzed, concomitant with blockage of all nerve activity. Furthermore, tonic firing of abdominal stretch receptor organs from Spodoptera frugiperda was blocked by metaflumizone applied in the bath, consistent with the block of voltage-dependent sodium channels. Studies on native sodium channels, in primary-cultured neurons isolated from the CNS of the larvae of the moth Manduca sexta and on Para/TipE sodium channels heterologously expressed in Xenopus (African clawed frog) oocytes, confirmed that metaflumizone blocks sodium channels by binding selectively to the slow-inactivated state, which is characteristic of the SCBIs. The results confirm that metaflumizone is a novel sodium channel blocker insecticide.

  9. Studies on endogenous circulating calcium entry blocker and stimulator

    International Nuclear Information System (INIS)

    Pang, P.K.T.; Yang, M.C.M.

    1986-01-01

    Several synthetic compounds have been studied extensively for their calcium entry blockade and stimulation in smooth muscles. It is hypothesized that there should be endogenous substances which control calcium entry into cells. We recently investigated the effect of some vasoactive hormones on calcium entry. Our studies on rat tail artery helical strip showed that the in vitro vasoconstriction produced by arginine vasopressin (AVP) decreased stepwise with decreasing concentration of both calcium. After exposure of the tail artery to calcium-free Ringer's solution for 1 minute or longer, the tissue lost its ability to respond to AVP. Subsequent addition of calcium to the medium produced immediate contraction. Measurements of low affinity lanthanum resistant pool of calcium with 45 Ca showed that AVP increased calcium uptake by tail artery in a dose-dependent manner. In another study rat tail artery helical strip indicated that the vasorelaxing action of parathyroid hormone (PTH) was related to an inhibition of calcium uptake. AVP or 60 mM potassium chloride increased the low affinity lanthanum resistant pool of calcium in rate tail artery and PTH inhibited the increase. In conclusion, AVP and PTH may behave like endogenous calcium entry stimulator and inhibitor respectively in vascular tissues

  10. Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons.

    Science.gov (United States)

    Song, M-K; Liu, H; Jiang, H-L; Yue, J-M; Hu, G-Y; Chen, H-Z

    2008-08-13

    Blocking specific K+ channels has been proposed as a promising strategy for the treatment of neurodegenerative diseases. Using a computational virtual screening approach and electrophysiological testing, we found four Aconitum alkaloids are potent blockers of the delayed rectifier K+ channel in rat hippocampal neurons. In the present study, we first tested the action of the four alkaloids on the voltage-gated K+, Na+ and Ca2+ currents in rat hippocampal neurons, and then identified that talatisamine is a specific blocker for the delayed rectifier K+ channel. External application of talatisamine reversibly inhibited the delayed rectifier K+ current (IK) with an IC50 value of 146.0+/-5.8 microM in a voltage-dependent manner, but exhibited very slight blocking effect on the voltage-gated Na+ and Ca2+ currents even at the high concentration of 1-3 mM. Moreover, talatisamine exerted a significant hyperpolarizing shift of the steady-state activation, but did not influence the steady state inactivation of IK and its recovery from inactivation, suggesting that talatisamine had no allosteric action on IK channel and was a pure blocker binding to the external pore entry of the channel. Our present study made the first discovery of potent and specific IK channel blocker from Aconitum alkaloids. It has been argued that suppressing K+ efflux by blocking IK channel may be favorable for Alzheimer's disease therapy. Talatisamine can therefore be considered as a leading compound worthy of further investigations.

  11. A novel hypothesis for the binding mode of HERG channel blockers

    International Nuclear Information System (INIS)

    Choe, Han; Nah, Kwang Hoon; Lee, Soo Nam; Lee, Han Sam; Lee, Hui Sun; Jo, Su Hyun; Leem, Chae Hun; Jang, Yeon Jin

    2006-01-01

    We present a new docking model for HERG channel blockade. Our new model suggests three key interactions such that (1) a protonated nitrogen of the channel blocker forms a hydrogen bond with the carbonyl oxygen of HERG residue T623; (2) an aromatic moiety of the channel blocker makes a π-π interaction with the aromatic ring of HERG residue Y652; and (3) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. The previous model assumes two interactions such that (1) a protonated nitrogen of the channel blocker forms a cation-π interaction with the aromatic ring of HERG residue Y652; and (2) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. To test these models, we classified 69 known HERG channel blockers into eight binding types based on their plausible binding modes, and further categorized them into two groups based on the number of interactions our model would predict with the HERG channel (two or three). We then compared the pIC 5 value distributions between these two groups. If the old hypothesis is correct, the distributions should not differ between the two groups (i.e., both groups show only two binding interactions). If our novel hypothesis is correct, the distributions should differ between Groups 1 and 2. Consistent with our hypothesis, the two groups differed with regard to pIC 5 , and the group having more predicted interactions with the HERG channel had a higher mean pIC 5 value. Although additional work will be required to further validate our hypothesis, this improved understanding of the HERG channel blocker binding mode may help promote the development of in silico predictions methods for identifying potential HERG channel blockers

  12. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

    Directory of Open Access Journals (Sweden)

    John D Bisognano

    2007-11-01

    Full Text Available John D Bisognano1, Trent McLaughlin2, Craig S Roberts3, Simon SK Tang31Internal Medicine Department, Cardiology Division, the University of Rochester Medical Center, Rochester, NY, USA; 2NDC Health, Phoenix, Arizona, USA; 3Pfizer Inc, New York, NY, USAAbstract: This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs, angiotensin-converting enzyme (ACE inhibitors, and angiotensin receptor blockers (ARBs added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were –17.5/–8.8, –15.7/–6.3, and –13.0/–8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs.Keywords: hypertension, amlodipine besylate, lisinopril, valsartan, Joint National Committee (JNC 6 and 7

  13. Calcium channel blockers inhibit endogenous pyrogen fever in rats and rabbits.

    Science.gov (United States)

    Stitt, J T; Shimada, S G

    1991-09-01

    We have previously shown that febrile responses in both rats and rabbits are elicited by the intravenous injection of a semipurified endogenous pyrogen (EP) prepared from human monocytes. We are now presenting evidence that these febrile responses are mediated via activation of Ca2+ channels by EP. The febrile responses of male New Zealand White rabbits and Sprague-Dawley rats to a standard dose of EP were determined at their respective thermoneutral ambient temperatures. The animals were then treated with Ca2+ channel blocker verapamil (7.5 mg/kg iv) 30-60 min before the EP challenge. In every case the febrile response to EP was markedly attenuated after verapamil pretreatment, while administration of verapamil by itself had no detectable effect on body temperature. Another Ca2+ channel blocker, nifedipine (5 mg/kg iv), was shown to possess antipyretic activity in rats also. To localize where in the fever pathway these Ca2+ channel blockers were acting, we investigated the effect of verapamil at the same dose on fevers that were produced by microinjection of prostaglandin E (PGE) directly into the brain. These PGE fevers were unaffected by verapamil pretreatment, indicating that the antipyretic action of Ca2+ channel blockers occurs before the formation of PGE in response to EP stimulation. The most likely locus of action is the activation of the enzyme phospholipase A2, which regulates the production of arachidonic acid from cellular phospholipids in the prostanoid cascade.

  14. Atrial fibrillation: Therapeutic potential of atrial K+ channel blockers.

    Science.gov (United States)

    Ravens, Ursula; Odening, Katja E

    2017-08-01

    Despite the epidemiological scale of atrial fibrillation, current treatment strategies are of limited efficacy and safety. Ideally, novel drugs should specifically correct the pathophysiological mechanisms responsible for atrial fibrillation with no other cardiac or extracardiac actions. Atrial-selective drugs are directed toward cellular targets with sufficiently different characteristics in atria and ventricles to modify only atrial function. Several potassium (K + ) channels with either predominant expression in atria or distinct electrophysiological properties in atria and ventricles can serve as atrial-selective drug targets. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting I Kur , the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting I K,ACh , the Ca 2+ -activated K + channels of small conductance (SK) conducting I SK , and the two pore domain K + (K2P) channels TWIK-1, TASK-1 and TASK-3 that are responsible for voltage-independent background currents I TWIK-1 , I TASK-1 , and I TASK-3 . Here, we briefly review the characteristics of these K + channels and their roles in atrial fibrillation. The antiarrhythmic potential of drugs targeting the described channels is discussed as well as their putative value in treatment of atrial fibrillation. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. THE ROLE OF S-AMLODIPINE IN ARTERIAL HYPERTENSION THERAPY WITH COMBINATION OF CALCIUM CHANNEL BLOCKERS AND BETA-BLOCKERS

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    M. A. Maksimova

    2013-01-01

    Full Text Available Aim. To study efficacy and safety of calcium channel blocker, S-amlodipine, in combination with β-blocker, atenolol, in patients with arterial hypertension (HT 1-2 degree com- pared to fixed combination of racemic amlodipine and atenolol.Material and methods. Patients (n=31, 7 men and 24 women with HT 1–2 degree were included into the study. The patients were randomized into two groups by the com- binations sequence. Treatment with each combination lasted 4 weeks. Office blood pressure (BP was assessed at baseline and at the end of the treatment periods, possible side effects were registered.Results. All patients completed the study. Both combination of S-amlodipine+atenolol and fixed combination of racemic amlodipine+atenolol reduced systolic (in average, -15.9 and -12.7 mm Hg, respectively and diastolic (in average, -7.3 and -5.3 mmHg, respectively BP significantly. Heart rate also decreased during therapy (in average, -3 and -4 bt/min, respectively. The differences between combinations BP and heart rate effects were not significant. 8 and 16 adverse events were registered during S-amlodipine+atenolol and racemic amlodipine+atenolol therapies, respectively Conclusion. Combination of S-amlodipine+atenolol, as well as combination of racemic amlodipine+atenolol are effective in the treatment of patients with HT 1-2 degree, however combination with S-amlodipine has less number of adverse events.

  16. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia

    DEFF Research Database (Denmark)

    Zakrzewska, Joanna M; Palmer, Joanne; Morisset, Valerie

    2017-01-01

    BACKGROUND: Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker...

  17. Mechanism of Proarrhythmic Effects of Potassium Channel Blockers

    DEFF Research Database (Denmark)

    Skibsbye, Lasse; Ravens, Ursula

    2016-01-01

    Any disturbance of electrical impulse formation in the heart and of impulse conduction or action potential (AP) repolarization can lead to rhythm disorders. Potassium (K(+)) channels play a prominent role in the AP repolarization process. In this review we describe the causes and mechanisms...

  18. Effects of a K+ channel blocker on glomerular filtration rate and electrolyte excretion in conscious rats.

    Science.gov (United States)

    Ludens, J H; Clark, M A; Lawson, J A

    1995-06-01

    Effects of a K+ channel blocker on glomerular filtration rate and electrolyte excretion in conscious rats were observed. Effects of K+ channel modulation on glomerular filtration rate and electrolyte excretion were studied using the adenosine-triphosphate- (ATP)-sensitive K+ channel blocker 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (U-37883A) in conscious rats previously equipped with catheters for clearance studies. In saline-loaded rats, i.v. doses of U-37883A of 1.7, 5.0 and 15 mg/kg increased absolute and fractional Na+ excretion dose-dependently without changing K+ excretion. The glomerular filtration rate remained constant during diuresis. In water-loaded (hypotonic dextrose) rats, free-water clearance studies revealed that the ATP-sensitive K+ channel blocker significantly decreased an index of solute reabsorption (free-water clearance adjusted for chloride clearance) in the diluting segment during peak natriuretic activity. In addition, U-37883A significantly decreased the osmolality of renal papillary interstitial fluid, indicative of an effect in the medullary portion of the diluting segment. Together, these findings suggest that ATP-sensitive K+ channels, possibly those located at the apical boarder, play a pivotal role in Na+ reabsorption in the thick ascending limb of the loop of Henle.

  19. Calcium channel blockers as the treatment of choice for hypertension in renal transplant recipients: fact or fiction.

    Science.gov (United States)

    Baroletti, Steven A; Gabardi, Steven; Magee, Colm C; Milford, Edgar L

    2003-06-01

    Posttransplantation hypertension has been identified as an independent risk factor for chronic allograft dysfunction and loss. Based on available morbidity and mortality data, posttransplantation hypertension must be identified and managed appropriately. During the past decade, calcium channel blockers have been recommended by some as the antihypertensive agents of choice in this population, because it was theorized that their vasodilatory effects would counteract the vasoconstrictive effects of the calcineurin inhibitors. With increasing data becoming available, reexamining the use of traditional antihypertensive agents, including diuretics and beta-blockers, or the newer agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, may be beneficial. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit, from both a renal and a cardiovascular perspective. Beta-blockers, diuretics, and ACE inhibitors have all demonstrated significant benefit on morbidity and mortality in patients with cardiovascular disease. Calcium channel blockers have been shown to possess the ability to counteract cyclosporine-induced nephrotoxicity. When compared with beta-blockers, diuretics, and ACE inhibitors, however, the relative risk of cardiovascular events is increased with calcium channel blockers. With the long-term benefits of calcium channel blockers on the kidney unknown and a negative cardiovascular profile, these agents are best reserved as adjunctive therapy to beta-blockers, diuretics, and ACE inhibitors.

  20. Calcium channel blockers, more than diuretics, enhance vascular protective effects of angiotensin receptor blockers in salt-loaded hypertensive rats.

    Directory of Open Access Journals (Sweden)

    Eiichiro Yamamoto

    Full Text Available The combination therapy of an angiotensin receptor blocker (ARB with a calcium channel blocker (CCB or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP were divided into 6 groups, and they were orally administered (1 vehicle, (2 olmesartan, an ARB, (3 azelnidipine, a CCB, (4 hydrochlorothiazide, a diuretic, (5 olmesartan combined with azelnidipine, or (6 olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

  1. Comparative effects of sodium channel blockers in short term rat whole embryo culture

    International Nuclear Information System (INIS)

    Nilsson, Mats F; Sköld, Anna-Carin; Ericson, Ann-Christin; Annas, Anita; Villar, Rodrigo Palma; Cebers, Gvido; Hellmold, Heike; Gustafson, Anne-Lee; Webster, William S

    2013-01-01

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development

  2. Comparative effects of sodium channel blockers in short term rat whole embryo culture

    Energy Technology Data Exchange (ETDEWEB)

    Nilsson, Mats F, E-mail: Mats.Nilsson@farmbio.uu.se [Department of Pharmaceutical Biosciences, Uppsala University (Sweden); Sköld, Anna-Carin; Ericson, Ann-Christin; Annas, Anita; Villar, Rodrigo Palma [AstraZeneca R and D Södertälje (Sweden); Cebers, Gvido [AstraZeneca R and D, iMed, 141 Portland Street, Cambridge, MA 02139 (United States); Hellmold, Heike; Gustafson, Anne-Lee [AstraZeneca R and D Södertälje (Sweden); Webster, William S [Department of Anatomy and Histology, University of Sydney (Australia)

    2013-10-15

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development.

  3. L-Carnitine for the treatment of a calcium channel blocker and metformin poisoning.

    Science.gov (United States)

    St-Onge, Maude; Ajmo, Ian; Poirier, Diane; Laliberté, Martin

    2013-09-01

    The object of the current communication is to discuss the theory and the evidence for the use of L-carnitine in calcium channel blocker and metformin poisonings. A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of L-carnitine was administered as a last resort. One hour after L-carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days. L-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning.

  4. The effect of long-term administered CRAC channels blocker on the functions of respiratory epithelium in guinea pig allergic asthma model.

    Science.gov (United States)

    Sutovska, Martina; Kocmalova, Michaela; Joskova, Marta; Adamkov, Marian; Franova, Sona

    2015-04-01

    Previously, therapeutic potency of CRAC channels blocker was evidenced as a significant decrease in airway smooth muscle hyperreactivity, antitussive and anti-inflammatory effects. The major role of the respiratory epithelium in asthma pathogenesis was highlighted only recently and CRAC channels were proposed as the most significant route of Ca2+ entry into epithelial cells. The aim of the study was to analyse the impact of long-term administered CRAC channels blocker on airway epithelium, e.g. cytokine production and ciliary beat frequency (CBF) using an animal model of allergic asthma. Ovalbumin-induced allergic airway inflammation of guinea pigs was followed by long-term (14 days lasted) therapy by CRAC blocker (3-fluoropyridine-4-carboxylic acid, FPCA). The influence of long-term therapy on cytokines (IL-4, IL-5 and IL-13) in BALF and in plasma, immunohistochemical staining of pulmonary tissue (c-Fos positivity) and CBF in vitro were used for analysis. Decrease in cytokine levels and in c-Fos positivity confirmed an anti-inflammatory effect of long-term administered FPCA. Cytokine levels in BALF and distribution of c-Fos positivity suggested that FPCA was a more potent inhibitor of respiratory epithelium secretory functions than budesonide. FPCA and budesonide reduced CBF only insignificantly. All findings supported CRAC channels as promising target in the new strategy of antiasthmatic treatment.

  5. Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ying [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Department of Pathology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang 050200, Hebei (China); Zhao, Xin [Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei (China); Chang, Yanzhong [Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei (China); Zhang, Yuanyuan [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Chu, Xi [Department of Pharmacy, The Forth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei (China); Zhang, Xuan [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Liu, Zhenyi; Guo, Hui [Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Wang, Na [Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Gao, Yonggang [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Zhang, Jianping, E-mail: zhangjianping14@126.com [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Chu, Li, E-mail: chuli0614@126.com [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei (China)

    2016-06-15

    Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n = 8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. - Highlights: • Calcium channel blockers (CCBs) reduced hepatic iron content. • CCBs decreased hepatic fibrotic areas and collagen expression levels. • CCBs resolve fibrosis by regulating iron transport and

  6. The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels.

    Science.gov (United States)

    Ozoe, Yoshihisa; Asahi, Miho; Ozoe, Fumiyo; Nakahira, Kunimitsu; Mita, Takeshi

    2010-01-01

    A structurally unique isoxazoline class compound, A1443, exhibits antiparasitic activity against cat fleas and dog ticks comparable to that of the commercial ectoparasiticide fipronil. This isoxazoline compound inhibits specific binding of the gamma-aminobutyric acid (GABA) receptor channel blocker [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) to housefly-head membranes, with an IC(50) value of 455pM. In contrast, the IC(50) value in rat-brain membranes is>10muM. To study the mode of action of this isoxazoline, we utilized MdGBCl and MdGluCl cDNAs, which encode the subunits of housefly GABA- and glutamate-gated chloride channels, respectively. Two-electrode voltage clamp electrophysiology was used to confirm that A1443 blocks GABA- and glutamate-induced chloride currents in Xenopus oocytes expressing MdGBCl or MdGluCl channels, with IC(50) values of 5.32 and 79.9 nM, respectively. Blockade by A1443 was observed in A2'S-MdGBCl and S2'A-MdGluCl mutant channels at levels similar to those of the respective wild-types, and houseflies expressing A2'S-MdGBCl channels were as susceptible to A1443 as standard houseflies. These findings indicate that A1443 is a novel and specific blocker of insect ligand-gated chloride channels. Copyright 2009 Elsevier Inc. All rights reserved.

  7. Calcium channel blockers inhibit retinal degeneration in the retinal-degeneration-B mutant of Drosophila.

    Science.gov (United States)

    Sahly, I; Bar Nachum, S; Suss-Toby, E; Rom, A; Peretz, A; Kleiman, J; Byk, T; Selinger, Z; Minke, B

    1992-01-01

    Light accelerates degeneration of photoreceptor cells of the retinal degeneration B (rdgB) mutant of Drosophila. During early stages of degeneration, light stimuli evoke spikes from photoreceptors of the mutant fly; no spikes can be recorded from photoreceptors of the wild-type fly. Production of spike potentials from mutant photoreceptors was blocked by diltiazem, verapamil hydrochloride, and cadmium. Little, if any, effect of the (-)-cis isomer or (+)-cis isomer of diltiazem on the light response was seen. Further, the (+)-cis isomer was approximately 50 times more effective than the (-)-cis isomer in blocking the Ca2+ spikes, indicating that diltiazem action on the rdgB eye is mediated by means of blocking voltage-sensitive Ca2+ channels, rather than by blocking the light-sensitive channels. Application of the Ca(2+)-channel blockers (+)-cis-diltiazem and verapamil hydrochloride to the eyes of rdgB flies over a 7-day period largely inhibited light-dependent degeneration of the photoreceptor cells. Pulse labeling with [32P]phosphate showed much greater incorporation into eye proteins of [32P]phosphate in rdgB flies than in wild-type flies. Retarding the light-induced photoreceptor degeneration in the mutant by Ca(2+)-channel blockers, thus, suggests that toxic increase in intracellular Ca2+ by means of voltage-gated Ca2+ channels, possibly secondary to excessive phosphorylation, leads to photoreceptor degeneration in the rdgB mutant. Images PMID:1309615

  8. Acrolein-mediated conduction loss is partially restored by K+ channel blockers

    Science.gov (United States)

    Yan, Rui; Page, Jessica C.

    2015-01-01

    Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure and activation of juxtaparanodal voltage-gated K+ channels due to myelin damage leads to conduction block, and K+ channel blockers have long been studied as a means for restoring axonal conduction in spinal cord injury (SCI) and multiple sclerosis (MS). In this study, we have found that 100 μM K+ channel blockers 4-aminopyridine-3-methanol (4-AP-3-MeOH), and to a lesser degree 4-aminopyridine (4-AP), can significantly restore compound action potential (CAP) conduction in spinal cord tissue following acrolein-mediated myelin damage using a well-established ex vivo SCI model. In addition, 4-AP-3-MeOH can effectively restore CAP conduction in acrolein-damaged axons with a range of concentrations from 0.1 to 100 μM. We have also shown that while both compounds at 100 μM showed no preference of small- and large-caliber axons when restoring CAP conduction, 4-AP-3-MeOH, unlike 4-AP, is able to augment CAP amplitude while causing little change in axonal responsiveness measured in refractory periods and response to repetitive stimuli. In a prior study, we show that 4-AP-3-MeOH was able to functionally rescue mechanically injured axons. In this investigation, we conclude that 4-AP-3-MeOH is an effective K+ channel blocker in restoring axonal conduction following both primary (physical) and secondary (chemical) insults. These findings also suggest that 4-AP-3-MeOH is a viable alternative of 4-AP for treating myelin damage and improving function following central nervous system trauma and neurodegenerative diseases. PMID:26581866

  9. Synthesis and biological evaluation of pyrrolidine derivatives as novel and potent sodium channel blockers for the treatment of ischemic stroke.

    Science.gov (United States)

    Seki, Maki; Tsuruta, Osamu; Tatsumi, Ryo; Soejima, Aki

    2013-07-15

    A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Inhibitory effect of calcium channel blockers on proliferation of human glioma cells in vitro

    International Nuclear Information System (INIS)

    Kunert-Radek, J.; Stepien, H.; Lyson, K.; Pawlikowski, M.; Radek, A.

    1989-01-01

    The effects of 2 specific calcium channel blockers, verapamil and nimodipine, on the proliferation of human glioma tumour cells were investigated in vitro. Tumour tissues for primary cell cultures were obtained bioptically from 3 patients with the histopathological diagnosis of glioblastoma. The [ 3 H]-thymidine incorporation into glioma tumour cells DNA was used as a sensitive index of the cell proliferation. It was found that varapamil (10 4 -10 5 M) and nimodipine (10 4 -10 6 M) significantly inhibited the [ 3 H]-thymidine uptake in a dose-related manner. The inhibitory effect of both calcium channel antagonists was reversed by stimultancous addition of calcium chloride (5x10 3 M). These results indicate that verapamil and nimodipine may exert an antiproliferative effect on glioma cells growth acting through a blokade of specific voltage-dependent calcium channels. (author)

  11. POSITIONS OF CALCIUM CHANNEL BLOCKER LERCANIDIPINE ACCORDING TO EVIDENCE BASED CARDIOLOGY

    Directory of Open Access Journals (Sweden)

    Yu. V. Lukina

    2010-01-01

    Full Text Available Data of evidence based cardiology including results of international clinical trials on efficacy and safety of the modern calcium channel blocker (CCB, lercanidipine, are presented. Results of these trials show the firm position of lercanidipine in the modern cardiology and confirm that treatment with lercanidipine leads to significant reduction of systolic and diastolic blood pressure (BP with no effect on heart rate (HR. Peripheral edema (the common side effect of CCBs occurs rarer with lercanidipine treatment than this with any other CCB treatment. Lercanidipine can be recommended to patients with concomitant diseases due to its additional features.

  12. Effects of Calcium Channel Blockers on Antidepressant Action of Alprazolam and Imipramine

    Directory of Open Access Journals (Sweden)

    Gorash ZM

    2007-01-01

    Full Text Available Alprazolam is effective as an anxiolytic and in the adjunct treatment of depression. In this study, the effects of calcium channel antagonists on the antidepressant action of alprazolam and imipramine were investigated. A forced swimming maze was used to study behavioral despair in albino mice. Mice were divided into nine groups (n = 7 per group. One group received a single dose of 1% Tween 80; two groups each received a single dose of the antidepressant alone (alprazolam or imipramine; two groups each received a single dose of the calcium channel blocker (nifedipine or verapamil; four groups each received a single dose of the calcium channel blocker followed by a single dose of the antidepressant (with same doses used for either in the previous four groups. Drug administration was performed concurrently on the nine groups. Our data confirmed the antidepressant action of alprazolam and imipramine. Both nifedipine and verapamil produced a significant antidepressant effect (delay the onset of immobility when administered separately. Verapamil augmented the antidepressant effects of alprazolam and imipramine (additive antidepressant effect. This may be due to the possibility that verapamil might have antidepressant-like effect through different mechanism. Nifedipine and imipramine combined led to a delay in the onset of immobility greater than their single use but less than the sum of their independent administration. This may be due to the fact that nifedipine on its own might act as an antidepressant but blocks one imipramine mechanism that depends on L-type calcium channel activation. Combining nifedipine with alprazolam produced additional antidepressant effects, which indicates that they exert antidepressant effects through different mechanisms.

  13. The anti-proliferative effect of cation channel blockers in T lymphocytes depends on the strength of mitogenic stimulation.

    Science.gov (United States)

    Petho, Zoltan; Balajthy, Andras; Bartok, Adam; Bene, Krisztian; Somodi, Sandor; Szilagyi, Orsolya; Rajnavolgyi, Eva; Panyi, Gyorgy; Varga, Zoltan

    2016-03-01

    Ion channels are crucially important for the activation and proliferation of T lymphocytes, and thus, for the function of the immune system. Previous studies on the effects of channel blockers on T cell proliferation reported variable effectiveness due to differing experimental systems. Therefore our aim was to investigate how the strength of the mitogenic stimulation influences the efficiency of cation channel blockers in inhibiting activation, cytokine secretion and proliferation of T cells under standardized conditions. Human peripheral blood lymphocytes were activated via monoclonal antibodies targeting the TCR-CD3 complex and the co-stimulator CD28. We applied the blockers of Kv1.3 (Anuroctoxin), KCa3.1 (TRAM-34) and CRAC (2-Apb) channels of T cells either alone or in combination with rapamycin, the inhibitor of the mammalian target of rapamycin (mTOR). Five days after the stimulation ELISA and flow cytometric measurements were performed to determine IL-10 and IFN-γ secretion, cellular viability and proliferation. Our results showed that ion channel blockers and rapamycin inhibit IL-10 and IFN-γ secretion and cell division in a dose-dependent manner. Simultaneous application of the blockers for each channel along with rapamycin was the most effective, indicating synergy among the various activation pathways. Upon increasing the extent of mitogenic stimulation the anti-proliferative effect of the ion channel blockers diminished. This phenomenon may be important in understanding the fine-tuning of T cell activation. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  14. d-Tubocurarine and Berbamine: Alkaloids That Are Permeant Blockers of the Hair Cell's Mechano-Electrical Transducer Channel and Protect from Aminoglycoside Toxicity

    Directory of Open Access Journals (Sweden)

    Nerissa K. Kirkwood

    2017-09-01

    Full Text Available Aminoglycoside antibiotics are widely used for the treatment of life-threatening bacterial infections, but cause permanent hearing loss in a substantial proportion of treated patients. The sensory hair cells of the inner ear are damaged following entry of these antibiotics via the mechano-electrical transducer (MET channels located at the tips of the hair cell's stereocilia. d-Tubocurarine (dTC is a MET channel blocker that reduces the loading of gentamicin-Texas Red (GTTR into rat cochlear hair cells and protects them from gentamicin treatment. Berbamine is a structurally related alkaloid that reduces GTTR labeling of zebrafish lateral-line hair cells and protects them from aminoglycoside-induced cell death. Both compounds are thought to reduce aminoglycoside entry into hair cells through the MET channels. Here we show that dTC (≥6.25 μM or berbamine (≥1.55 μM protect zebrafish hair cells in vivo from neomycin (6.25 μM, 1 h. Protection of zebrafish hair cells against gentamicin (10 μM, 6 h was provided by ≥25 μM dTC or ≥12.5 μM berbamine. Hair cells in mouse cochlear cultures are protected from longer-term exposure to gentamicin (5 μM, 48 h by 20 μM berbamine or 25 μM dTC. Berbamine is, however, highly toxic to mouse cochlear hair cells at higher concentrations (≥30 μM whilst dTC is not. The absence of toxicity in the zebrafish assays prompts caution in extrapolating results from zebrafish neuromasts to mammalian cochlear hair cells. MET current recordings from mouse outer hair cells (OHCs show that both compounds are permeant open-channel blockers, rapidly and reversibly blocking the MET channel with half-blocking concentrations of 2.2 μM (dTC and 2.8 μM (berbamine in the presence of 1.3 mM Ca2+ at −104 mV. Berbamine, but not dTC, also blocks the hair cell's basolateral K+ current, IK,neo, and modeling studies indicate that berbamine permeates the MET channel more readily than dTC. These studies reveal key properties of

  15. Evaluation Effects of Verapamil as a Calcium Channel Blocker on Acquisition, Consolidation and Retrieval of Memory in Mice

    OpenAIRE

    Nooshin Masoudian; Nahid Masoudian; Ali Rashidy Pour; Abbas Ali Vafaiee; Sasan Andalib; Golnaz Vaseghi

    2015-01-01

    Many factors are involved in learning and memory processes including brain nuclei, neurotransmitter systems, and the activity of ion channels. Studies showed inconsistent effects of calcium channel blockers on learning process, especially memory consolidation; however, little is known about their effect on memory acquisition and retrieval. Accordingly, the present study aimed to determine the effects of verapamil calcium channel antagonist as a representative of the phenylalkylamine group on ...

  16. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

    Science.gov (United States)

    Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C

    2015-10-27

    Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.

  17. Effect of Topical Calcium Channel Blockers on Intraocular Pressure in Steroid-induced Glaucoma.

    Science.gov (United States)

    Ganekal, Sunil; Dorairaj, Syril; Jhanji, Vishal; Kudlu, Krishnaprasad

    2014-01-01

    To evaluate the effect of 0.125% verapamil and 0.5% diltiazem eye drops on intraocular pressure (IOP) in steroid-induced glaucoma in rabbit eyes. A total of 18 rabbits with steroid-induced glaucoma were divided into three groups (A, B and C; n = 6 each). Right eyes in groups A, B and C received 0.5% diltiazem, 0.125% verapamil and 0.5% timolol eye drops twice daily for 12 days, respectively; whereas, left eyes received distilled water. IOP was measured with Tono-pen XL at baseline, day 4, day 8, and day 12 of treatment. Both 0.5% diltiazem and 0.125% verapamil eye drops significantly reduced IOP compared to control eyes (p cite this article: Ganekal S, Dorairaj S, Jhanji V, Kudlu K. Effect of Topical Calcium Channel Blockers on Intraocular Pressure in Steroid-induced Glaucoma. J Current Glau Prac 2014;8(1):15-19.

  18. The relationship between functional inhibition and binding for K(Ca2 channel blockers.

    Directory of Open Access Journals (Sweden)

    David Charles Hammond Benton

    Full Text Available Small conductance calcium-activated potassium channels (KCa2.1,2.2,2.3 are blocked with high affinity by both peptide toxins (e.g. apamin and small molecule blockers (e.g. UCL 1848. In electrophysiological experiments, apamin shows subtype selectivity with IC50s of ∼100 pM and ∼1 nM for block KCa2.2 and KCa2.3 respectively. In binding studies, however, apamin appears not to discriminate between KCa2.2 and 2.3 and is reported to have a significantly higher (∼20-200-fold affinity (∼5 pM. This discrepancy between binding and block has been suggested to reflect an unusual mode of action of apamin. However, these binding and electrophysiological block experiments have not been conducted in the same ionic conditions, so it is also possible that the discrepancy arises simply because of differences in experimental conditions. We have now examined this latter possibility. Thus, we measured (125I-apamin binding to intact HEK 293 cells expressing KCa2 channels under the same ionic conditions (i.e. normal physiological conditions that we also used for current block measurements. We find that binding and block experiments agree well if the same ionic conditions are used. Further, the binding of apamin and other blockers showed subtype selectivity when measured in normal physiological solutions (e.g.(125I-apamin bound to KCa2.2 with K L 91±40 pM and to KCa2.3 with K L 711±126 pM, while inhibiting KCa2.2 current at IC50 103±2 pM. We also examined KCa2 channel block in Ca(2+ and Mg(2+ free solutions that mimic conditions reported in the literature for binding experiments. Under these (non-physiological conditions the IC50 for apamin block of KCa2.2 was reduced to 20±3 pM. Our results therefore suggest that the apparent discrepancy between blocking and binding reported in the literature can be largely accounted for by the use of non-physiological ionic conditions in binding experiments.

  19. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

    Directory of Open Access Journals (Sweden)

    Shuyuan Liu

    Full Text Available Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers, amlodipine (AML, nifedipine (NIF, benidipine (BEN and flunarizine (FNZ with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1 expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2. The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin and YVC1 (encoding calcium channel protein in vacuole membrane.

  20. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

    Science.gov (United States)

    Liu, Shuyuan; Yue, Longtao; Gu, Wenrui; Li, Xiuyun; Zhang, Liuping; Sun, Shujuan

    2016-01-01

    Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane).

  1. Ligand-based design and synthesis of novel sodium channel blockers from a combined phenytoin–lidocaine pharmacophore

    OpenAIRE

    Wang, Yuesheng; Jones, Paulianda J.; Batts, Timothy W.; Landry, Victoria; Patel, Manoj K.; Brown, Milton L.

    2008-01-01

    The voltage-gated sodium channel remains a rich area for the development of novel blockers. In this study we used comparative molecular field analysis (CoMFA), a ligand-based design strategy, to generate a 3D model based upon local anesthetics, hydantoins, and α-hydroxyphenylamides to elucidate a SAR for their binding site in the neuronal sodium channel. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as pIC50) and the CoMFA descripto...

  2. Polyaniline-graphene oxide nanocomposite sensor for quantification of calcium channel blocker levamlodipine.

    Science.gov (United States)

    Jain, Rajeev; Sinha, Ankita; Khan, Ab Lateef

    2016-08-01

    A novel polyaniline-graphene oxide nanocomposite (PANI/GO/GCE) sensor has been fabricated for quantification of a calcium channel blocker drug levamlodipine (LAMP). Fabricated sensor has been characterized by electrochemical impedance spectroscopy, square wave and cyclic voltammetry, Raman spectroscopy and Fourier transform infrared (FTIR) spectroscopy. The developed PANI/GO/GCE sensor has excellent analytical performance towards electrocatalytic oxidation as compared to PANI/GCE, GO/GCE and bare GCE. Under optimized experimental conditions, the fabricated sensor exhibits a linear response for LAMP for its oxidation over a concentration range from 1.25μgmL(-1) to 13.25μgmL(-1) with correlation coefficient of 0.9950 (r(2)), detection limit of 1.07ngmL(-1) and quantification limit of 3.57ngmL(-1). The sensor shows an excellent performance for detecting LAMP with reproducibility of 2.78% relative standard deviation (RSD). The proposed method has been successfully applied for LAMP determination in pharmaceutical formulation with a recovery from 99.88% to 101.75%. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy.

    Science.gov (United States)

    Dilena, Robertino; Striano, Pasquale; Gennaro, Elena; Bassi, Laura; Olivotto, Sara; Tadini, Laura; Mosca, Fabio; Barbieri, Sergio; Zara, Federico; Fumagalli, Monica

    2017-04-01

    Recent clinical evidence supports a targeted therapeutic approach for genetic epileptic encephalopathies based on the molecular dysfunction. A 2-day-old male infant presented with epileptic encephalopathy characterized by burst-suppression EEG background and tonic-clonic migrating partial seizures. The condition was refractory to phenobarbital, pyridoxine, pyridoxal phosphate and levetiracetam, but a dramatic response to an intravenous loading dose of phenytoin was documented by video-EEG monitoring. Over weeks phenytoin was successfully switched to carbamazepine to prevent seizure relapses associated with difficulty in maintaining proper blood levels of phenytoin. Genetic analysis identified a novel de novo heterozygous mutation (c.[4633A>G]p.[Met1545Val]) in SCN2A. At two years and three months of age the patient is still seizure-free on carbamazepine, although a developmental delay is evident. Sodium channel blockers represent the first-line treatment for confirmed or suspected SCN2A-related epileptic encephalopathies. In severe cases with compatible electro-clinical features we propose a treatment algorithm based on a test trial with high dose intravenous phenytoin followed in case of a positive response by carbamazepine, more suitable for long-term maintenance treatment. Because of their rarity, collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  4. Site of action of calcium channel blockers in inhibiting endogenous pyrogen fever in rats.

    Science.gov (United States)

    Stitt, J T; Shimada, S G

    1991-09-01

    We have demonstrated that the Ca2+ channel blocker verapamil, administered intravenously, exerts an antipyretic effect on the febrile responses of rats to intravenously injected endogenous pyrogen (EP). We have also shown that the same intravenous dose of verapamil is ineffective in blocking fevers induced by the microinjection of exogenous prostaglandin E (PGE) into the organum vasculosum laminae terminalis (OVLT) of rats. Experiments were conducted to determine whether the site of this verapamil antipyresis was in the OVLT itself. The febrile responses of six male Sprague-Dawley rats to EP were determined at thermoneutrality. Verapamil (10 micrograms/rat) was microinjected directly into the OVLT, and the febrile responses to the EP dose were redetermined 15-30 min later. In every case the EP fevers were attenuated after verapamil pretreatment. Intra-OVLT injections of verapamil alone were without effect on body temperature. When the same dose of verapamil was injected into the OVLT 15 min before the injection of PGE into the same site, it had no effect on the ensuing PGE-induced fever. In view of the fact that less than 1/250th of the effective systemic dose of verapamil, when injected into the OVLT, was equally effective in blocking the EP fevers, we conclude that verapamil acts within the OVLT to block fever rather than peripherally. Furthermore, because verapamil administered into the OVLT does not block PGE fevers, it is unlikely that PGE produces fever by acting as a Ca2+ ionophore on hypothalamic neurons.

  5. Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect GABA-Gated Chloride Channels.

    Directory of Open Access Journals (Sweden)

    Yan Xu

    Full Text Available Meroterpenoid chrodrimanins, produced from Talaromyces sp. YO-2, are known to paralyze silkworm (Bombyx mori larvae, but their target is unknown. We have investigated the actions of chrodrimanin B on ligand-gated ion channels of silkworm larval neurons using patch-clamp electrophysiology. Chrodrimanin B had no effect on membrane currents when tested alone at 1 μM. However, it completely blocked the γ-aminobutyric acid (GABA-induced current and showed less pronounced actions on acetylcholine- and L-glutamate-induced currents, when delivered at 1 μM for 1 min prior to co-application with transmitter GABA. Thus, chrodrimanins were also tested on a wild-type isoform of the B. mori GABA receptor (GABAR RDL using two-electrode voltage-clamp electrophysiology. Chrodrimanin B attenuated the peak current amplitude of the GABA response of RDL with an IC50 of 1.66 nM. The order of the GABAR-blocking potency of chrodrimanins B > D > A was in accordance with their reported insecticidal potency. Chrodrimanin B had no open channel blocking action when tested at 3 nM on the GABA response of RDL. Co-application with 3 nM chrodrimanin B shifted the GABA concentration response curve to a higher concentration and further increase of chrodrimanin B concentration to 10 nM; it reduced maximum current amplitude of the GABA response, pointing to a high-affinity competitive action and a lower affinity non-competitive action. The A282S;T286V double mutation of RDL, which impairs the actions of fipronil, hardly affected the blocking action of chrodrimanin B, indicating a binding site of chrodrimanin B distinct from that of fipronil. Chrodrimanin B showed approximately 1,000-fold lower blocking action on human α1β2γ2 GABAR compared to RDL and thus is a selective blocker of insect GABARs.

  6. Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels

    DEFF Research Database (Denmark)

    Dupuis, Delphine S; Klaerke, Dan A; Olesen, Søren-Peter

    2005-01-01

    Patients with congenital long QT syndrome may develop arrhythmias under conditions of increased sympathetic tone. We have addressed whether some of the beta-adrenoceptor blockers commonly used to prevent the development of these arrhythmias could per se block the cardiac HERG (Human Ether....... These data showed that HERG blockade by beta-adrenoceptor blockers occurred only at high micromolar concentrations, which are significantly above the recently established safe margin of 100 (Redfern et al., 2003).......-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) blocked the HERG channel with similar affinity, whereas the beta1-receptor antagonists metoprolol and atenolol showed weak effects. Further, the four compounds blocked HERG channels expressed in a mammalian HEK293 cell line...

  7. Effects of Potassium Channel Blockers on the Negative Inotropic Responses Induced by Cromakalim and Pinacidil in Guinea Pig Atrium

    Science.gov (United States)

    1992-01-01

    RD-A2•4 875 EFFECTS OF POTASSIUM CHANNEL BLOCKERS ON THE NEGATIVE 1/1 INOTROPIC RESPONSES INDUCED BY CRONAKALIM RND PINACIDIL IN GUINEA PIG ATRIUM(U...INOTROPICTRSPONSES INDUCED BY CROMAKAUM AND PINACIDILIN GUINEA PIG ATRIUM a AUTHOR WAI-MAN LAU 7 FORMING ORG NAMES/ADDRESSES DEFENCE SCIENCE AND a...and Technology Organisaio Aot Val. Negative Inotropic Responses Victoria. Australia Induced by Cromakalim and Pinacidil in Guinea Pig Atrium Key

  8. The effects of prior calcium channel blocker therapy on creatine kinase-MB levels after percutaneous coronary interventions

    OpenAIRE

    Gulmez, Oyku; Atar, Ilyas; Ozin, B?lent; Korkmaz, Mehmet Emin; Atar, Asli; Aydinalp, Alp; Yildirir, Aylin; Muderrisoglu, Haldun

    2008-01-01

    Background: Use of intracoronary calcium channel blockers (CCBs) during percutaneous coronary intervention (PCI) has been shown to have favorable effects on coronary blood flow. We aimed to investigate the effects of CCBs administrated perorally on creatine kinase-MB (CK-MB) levels in patients undergoing elective PCI. Methods: A total of 570 patients who underwent PCI were evaluated for CK-MB elevation. Patients who were on CCB therapy when admitted to the hospital constituted the CCB group. ...

  9. The effects of prior calcium channel blocker therapy on creatine kinase-MB levels after percutaneous coronary interventions

    OpenAIRE

    Gulmez, Oyku

    2008-01-01

    Oyku Gulmez, Ilyas Atar, Bülent Ozin, Mehmet Emin Korkmaz, Aslı Atar, Alp Aydinalp, Aylin Yildirir, Haldun MuderrisogluBaskent University Faculty of Medicine, Department of Cardiology, Ankara, TurkeyBackground: Use of intracoronary calcium channel blockers (CCBs) during percutaneous coronary intervention (PCI) has been shown to have favorable effects on coronary blood flow. We aimed to investigate the effects of CCBs administrated perorally on creatine kinase-MB (CK-MB) levels in pa...

  10. The effects of prior calcium channel blocker therapy on creatine kinase-MB levels after percutaneous coronary interventions

    OpenAIRE

    Oyku Gulmez; Ilyas Atar; Bülent Ozin; Mehmet Emin Korkmaz; Asli Atar; et al

    2008-01-01

    Oyku Gulmez, Ilyas Atar, Bülent Ozin, Mehmet Emin Korkmaz, Asli Atar, Alp Aydinalp, Aylin Yildirir, Haldun MuderrisogluBaskent University Faculty of Medicine, Department of Cardiology, Ankara, TurkeyBackground: Use of intracoronary calcium channel blockers (CCBs) during percutaneous coronary intervention (PCI) has been shown to have favorable effects on coronary blood flow. We aimed to investigate the effects of CCBs administrated perorally on creatine kinase-MB (CK-MB) levels in pat...

  11. Severe iatrogenic bradycardia related to the combined use of beta-blocking agents and sodium channel blockers

    Directory of Open Access Journals (Sweden)

    Kawabata M

    2015-02-01

    Full Text Available Mihoko Kawabata,1 Yasuhiro Yokoyama,1 Takeshi Sasaki,1 Susumu Tao,1 Kensuke Ihara,1 Yasuhiro Shirai,1 Tetsuo Sasano,2 Masahiko Goya,1 Tetsushi Furukawa,3 Mitsuaki Isobe,4 Kenzo Hirao1 1Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan; 2Department of Biofunctional Informatics, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 3Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; 4Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan Purpose: Drug-induced bradycardia is common during antiarrhythmic therapy; the major culprits are beta-blockers. However, whether other antiarrhythmic drugs are also a significant cause of this, alone or in combination with beta-blockers, is not well known. Methods: We retrospectively investigated the records of all patients hospitalized at our institution for drug-related bradycardia from the years 2004 to 2012. Patients with cardiac disease and electrolytic or hormonal abnormalities that could cause bradyarrhythmias were excluded. Results: Eight patients were identified (mean age, 79±5 years; range, 71–85 years; 6 women. Three patients were taking only beta-blockers (hereafter referred to as the BB group, while five patients were on both beta-blockers and Na channel blockers (hereafter referred to as the BB + Na group. Heart rates ranged from 20~49 beats/minute on arrival. The initial electrocardiogram showed sinus bradycardia (n=6 or sinus arrest with escape beats (n=2. QRS duration was 80–100 ms. The clinical presentation of the BB + Na group was considerably worse than that of the BB group, and included cardiogenic shock and heart failure. Four of the BB + Na patients had been on their medications for over 300 days. The BB group recovered solely with drug discontinuation, while 4 of the 5 patients in the BB + Na group needed additional

  12. Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Nishida Yayoi

    2012-05-01

    Full Text Available Abstract Background Both angiotensin II type I receptor blockers (ARBs and calcium channel blockers (CCBs are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus. Methods We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601 and propensity-score matched new CCB users (n = 601, with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG, total cholesterol (TC, non-fasting blood glucose, hemoglobin A1c (HbA1c, sodium, potassium, creatinine, alanine aminotransferase (ALT, aspartate aminotransferase (AST, gamma-glutamyltransferase (GGT, hemoglobin and hematocrit, and white blood cell (WBC, red blood cell (RBC and platelet (PLT counts up to 12 months after the start of ARB or CCB monotherapy. Results We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users. Conclusions Our study suggested that hematological adverse effects and

  13. Angiotensin Converting-Enzyme Inhibitors, Angiotensin Receptor Blockers, and Calcium Channel Blockers Are Associated with Prolonged Vascular Access Patency in Uremic Patients Undergoing Hemodialysis.

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    Fu-An Chen

    Full Text Available Vascular access failure is a huge burden for patients undergoing hemodialysis. Many efforts have been made to maintain vascular access patency, including pharmacotherapy. Angiotensin converting enzyme inhibitor (ACE-I, angiotensin receptor blocker (ARB, and calcium channel blocker (CCB are known for their antihypertensive and cardio-protective effects, however, their effects on long-term vascular access patency are still inconclusive.We retrospectively enrolled patients commencing maintenance hemodialysis between January 1, 2000, and December 31, 2006 by using National Health Insurance Research Database in Taiwan. Primary patency was defined as the date of first arteriovenous fistula (AVF or arteriovenous graft (AVG creation to the time of access thrombosis or any intervention aimed to maintain or re-establish vascular access patency. Cox proportional hazards models were used to adjust the influences of patient characteristics, co-morbidities and medications.Total 42244 patients were enrolled in this study, 37771 (89.4% used AVF, 4473 (10.6% used AVG as their first long term dialysis access. ACE-I, ARB, and CCB use were all associated with prolonged primary patency of AVF [hazard ratio (HR 0.586, 95% confidence interval (CI 0.557-0.616 for ACE-I use; HR 0.532, CI 0.508-0.556 for ARB use; HR 0.485, CI 0.470-0.501 for CCB use] and AVG (HR 0.557, CI 0.482-0.643 for ACE-I use, HR 0.536, CI 0.467-0.614 for ARB use, HR 0.482, CI 0.442-0.526 for CCB use.In our analysis, ACE-I, ARB, and CCB were strongly associated with prolonged primary patency of both AVF and AVG. Further prospective randomized studies are still warranted to prove the causality.

  14. Scientific research related to calcium channel blockers poisoning: Bibliometric analysis in Scopus, 1968-2012.

    Science.gov (United States)

    Zyoud, S H; Al-Jabi, S W; Sweileh, W M; Waring, W S

    2015-11-01

    Calcium channel blockers (CCBs) were the most common agents associated with a significant morbidity and mortality rate. The main objective of this study was to examine the publication pattern related to CCBs poisoning at the global level using bibliometric analysis of articles published in SciVerse Scopus online database. Data were searched for documents that contained specific words regarding CCB poisoning as keywords in the title. No time period limitations were specified in the search regarding the starting year. The ending date of the search was 31 December 2012. The criteria were met by 713 publications from 53 countries. The largest number of articles associated with CCBs was from the United States (30%), followed by the United Kingdom (7.4%), Japan (6%), and Germany (5.6%). No data related to CCBs were published from 159 (75%) of 212 countries registered in World Bank online database. There was no correlation between the number of published articles in the country and its population size (r = 0.03, p > 0.926). United Kingdom and Australia were the leading countries in terms of number of CCBs publications per million inhabitants (0.83 and 0.82 articles per million inhabitants, respectively), followed by the United States (0.68). Countries with a large population, such as India, tended to rank relatively low (0.01 articles per million inhabitants). The total number of citations at the time of data analysis (23 October 2014) was 6462, with an average of 9.1 citations per document. The highest median (interquartile range) number of citations was 8 (8-18) for the United States, followed by 6 (1-21) for Australia, 5 (1-15) for the United Kingdom, and 5 (1-24) for Canada. The h-index of the retrieved documents was 37. Scientific production on CCBs poisoning is increasing; nonetheless, the international collaboration is still rare. The amount of CCBs-based research activity was low or not available in most countries. More regional epidemiological studies are

  15. The effect of the NMDA channel blocker memantine on salicylate-induced tinnitus in rats.

    Science.gov (United States)

    Ralli, M; Troiani, D; Podda, M V; Paciello, F; Eramo, S L M; de Corso, E; Salvi, R; Paludetti, G; Fetoni, A R

    2014-06-01

    Short-term tinnitus develops shortly after the administration of a high dose of salicylate. Since salicylate selectively potentiates N-methyl- D-aspartate (NMDA) currents in spiral ganglion neurons, it may play a vital role in tinnitus by amplifying NMDA-mediated neurotransmission. The aim of this study was to determine whether systemic treatment with a NMDA channel blocker, memantine, could prevent salicylate-induced tinnitus in animals. Additional experiments were performed to evaluate the effect of memantine on the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to test for changes in hearing function. Thirty-six rats were divided into 3 groups and treated daily for four consecutive days. One group (n = 12) was injected with salicylate (300 mg/kg/d, IP), the second (n = 12) was treated with memantine (5 mg/kg/d, IP) and the third group (n = 12) was injected with salicylate and memantine. All rats were tested for tinnitus and hearing loss at 2, 24, 48 and 72 h after the first drug administration and 24 h post treatment; tinnituslike behaviour was assessed with gap prepulse inhibition of acoustic startle (GPIAS), and hearing function was measured with DPOAE, ABR and noise burst prepulse inhibition of acoustic startle (NBPIAS). Rats in the salicylate group showed impaired GPIAS indicative of transient tinnitus-like behaviour near 16 kHz that recovered 24 h after the last salicylate treatment. Memantine did not cause a significant change in GPIAS. Combined injection of salicylate and memantine significantly attenuated GPIAS tinnitus-like behaviour at 48 hours after the first injection. None of the treatments induced permanent threshold shifts in the ABR and DPOAE, which recovered completely within one day post treatment. Animals treated with salicylate plus memantine showed results comparable to animals treated with salicylate alone, confirming that there is no effect of memantine on DPOAE which reflects OHC function. The

  16. Fatty acids and related Kv2 channel blockers: electrophysiology and toxicity on mosquitoes

    Science.gov (United States)

    Ligand-gated ion channels form an important superfamily of proteins involved in many biological processes. Among them, the potassium channels constitute a very diverse group involved in neural signaling, neuronal activity and action potential. Among the different types of channel activation, voltage...

  17. Expression and isotopic labelling of the potassium channel blocker ShK toxin as a thioredoxin fusion protein in bacteria.

    Science.gov (United States)

    Chang, Shih Chieh; Galea, Charles A; Leung, Eleanor W W; Tajhya, Rajeev B; Beeton, Christine; Pennington, Michael W; Norton, Raymond S

    2012-10-01

    The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which play a crucial role in the activation of human effector memory T-cells (T(EM)). Selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T(EM) cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. We have established a recombinant peptide expression system in order to generate isotopically-labelled ShK and various ShK analogues for in-depth biophysical and pharmacological studies. ShK was expressed as a thioredoxin fusion protein in Escherichia coli BL21 (DE3) cells and purified initially by Ni²⁺ iminodiacetic acid affinity chromatography. The fusion protein was cleaved with enterokinase and purified to homogeneity by reverse-phase HPLC. NMR spectra of ¹⁵N-labelled ShK were similar to those reported previously for the unlabelled synthetic peptide, confirming that recombinant ShK was correctly folded. Recombinant ShK blocked Kv1.3 channels with a K(d) of 25 pM and inhibited the proliferation of human and rat T lymphocytes with a preference for T(EM) cells, with similar potency to synthetic ShK in all assays. This expression system also enables the efficient production of ¹⁵N-labelled ShK for NMR studies of peptide dynamics and of the interaction of ShK with Kv1.3 channels. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Effect of voltage-gated sodium channels blockers on motility and viability of human sperm in vitro

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    Hammad Ahmad Gakhar

    2018-01-01

    Full Text Available Objective: To test the effect of voltage-gated sodium channels (VGSCs blockers on the motility and viability of human sperm in-vitro and to evaluate the tested compounds as potential contact spermicidal.Methods: Sperm samples were obtained from healthy nonsmoking volunteers of age 25-30 years who had not taken any drug 3 months before and during the course of the study. The effect of VGSCs blockers evaluated from two pharmacological classes including antiarrhythmic (amiodarone, procainamide and disopyramide and antiepileptic (carbamazepine, oxcarbazepine, phenytoin, and lamotrigine drugs. They were tested on the in-vitro motility and viability of human sperm using Computer Assisted Semen Analyzer.Results: All tested drugs except oxcarbazepine showed dose dependent inhibition of total motility with significant reduction (P<0.05 at the maximum concentration of 200 μΜ when compared with the control. The concentrations of drugs that reduced total sperm motility to 50% of control (half maximal inhibitory concentration were 2.76, 14.16 and 20.29 μΜ for phenytoin, lamotrigine and carbamazepine, respectively; and 2.53, 5.32 and 0.37 μΜ for amiodarone, procainamide and disopyramide, respectively. The anti-motility effects were reversible to various degrees. There was statistically insignificant difference in the inhibition of sperm viability among amiodarone, procainamide and disopyramide. Phenytoin demonstrated the most potent spermicidal action.Conclusions: VGSCs blockers have significant adverse effects on in-vitro motility of human spermatozoa. So in-vivo studies are required to determine their potential toxicological effects on human semen quality, which is an important factor regarding fertility. Moreover, these drugs have the potential to be developed into contact spermicidal.

  19. Calcium-channel blockers do not alter the clinical efficacy of clopidogrel after myocardial infarction: a nationwide cohort study

    DEFF Research Database (Denmark)

    Olesen, Jonas B; Gislason, Gunnar H; Charlot, Mette G

    2011-01-01

    Objectives The purpose of this study was to determine the risk of adverse cardiovascular events associated with concomitant use of clopidogrel and calcium-channel blockers (CCBs) in patients with myocardial infarction (MI). Background CCBs inhibit a variety of cytochrome P-450 enzymes, some...... patients treated and not treated with clopidogrel, with a hazard ratio of 1.15 (95% confidence interval [CI]: 1.07 to 1.24) and 1.05 (95% CI: 1.01 to 1.11), respectively. The increased risk was independent of clopidogrel use; the hazard rate ratio was 1.08 (95% CI: 0.99 to 1.18). Analyses of all additional...... adverse end points and propensity score–matched models provided similar results. Conclusions The clinical efficacy of clopidogrel in patients with a recent MI is not modified by concomitant CCB treatment. This potential drug interaction is unlikely to have clinical significance....

  20. The effects of prior calcium channel blocker therapy on creatine kinase-MB levels after percutaneous coronary interventions

    Directory of Open Access Journals (Sweden)

    Oyku Gulmez

    2008-12-01

    Full Text Available Oyku Gulmez, Ilyas Atar, Bülent Ozin, Mehmet Emin Korkmaz, Aslı Atar, Alp Aydinalp, Aylin Yildirir, Haldun MuderrisogluBaskent University Faculty of Medicine, Department of Cardiology, Ankara, TurkeyBackground: Use of intracoronary calcium channel blockers (CCBs during percutaneous coronary intervention (PCI has been shown to have favorable effects on coronary blood flow. We aimed to investigate the effects of CCBs administrated perorally on creatine kinase-MB (CK-MB levels in patients undergoing elective PCI.Methods: A total of 570 patients who underwent PCI were evaluated for CK-MB elevation. Patients who were on CCB therapy when admitted to the hospital constituted the CCB group. No CCBs were given to the rest of the patients during the periprocedural period and these patients served as the control group. Blood samples for CK-MB were obtained before and at 6 h, 24 h, and 36 h after the procedure.Results: 217 patients were in the CCB group (mean age 60.2 ± 9.3 years, 162 males, and 353 were in the control group (mean age 60.0 ± 10.1 years, 262 males. CK-MB levels increased above the normal values in 41 patients (18.9% of the CCBs group and in 97 patients (27.5% of the control group (p = 0.02. Median CK-MB levels were significantly higher in the control group for all studied hours (for all p < 0.05.Conclusions: Prior oral CCB therapy may have favorable effects in preventing myocyte necrosis after elective PCI.Keywords: calcium channel blockers, myonecrosis, percutaneous coronary interventions

  1. Current concepts in combination therapy for the treatment of hypertension: combined calcium channel blockers and RAAS inhibitors

    Directory of Open Access Journals (Sweden)

    Alberto F Rubio-Guerra

    2009-11-01

    Full Text Available Alberto F Rubio-Guerra1, David Castro-Serna2, Cesar I Elizalde Barrera2, Luz M Ramos-Brizuela21Metabolic and Research Clinic, 2Internal Medicine Department, Hospital General de Ticomán SS DF, MéxicoAbstract: Recent guidelines for the management of hypertension recommend target blood pressures <140/90 mmHg in hypertensive patients, or <130/80 mmHg in subjects with diabetes, chronic kidney disease, or coronary artery disease. Despite the availability and efficacy of antihypertensive drugs, most hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension.Keywords: hypertension, calcium channel blockers, renin-angiotensin-aldosterone system inhibitors, fixed-dose combination, adherence

  2. The gastric H,K-ATPase blocker lansoprazole is an inhibitor of chloride channels

    Science.gov (United States)

    Schmarda, Andreas; Dinkhauser, Patrick; Gschwentner, Martin; Ritter, Markus; Fürst, Johannes; Scandella, Elke; Wöll, Ewald; Laich, Andreas; Rossmann, Heidi; Seidler, Ursula; Lang, Florian; Paulmichl, Markus

    2000-01-01

    It was postulated that swelling dependent chloride channels are involved in the proton secretion of parietal cells. Since omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are structurally related to phenol derivatives known to block swelling dependent chloride channels, we set out to test, whether these substances – which are known to block the H,K-ATPase – could also lead to an inhibition of swelling-dependent chloride channels. Swelling-dependent chloride channels – characterized in many different cell types – show highly conserved biophysical and pharmacological features, therefore we investigated the effect of omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 on swelling-dependent chloride channels elicited in fibroblasts, after the reduction of the extracellular osmolarity. Omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are able to block swelling-dependent chloride channels (IClswell). Lansoprazole and its protonated metabolite AG2000 act on at least two different sites of the IClswell protein: on an extracellular site which seems to be in a functional proximity to the nucleotide binding site, and on an intracellular site which allows the formation of disulfide-bridges. The inhibition of the proton pump and the simultaneous blocking of chloride channels by omeprazole, lansoprazole and its acid activated sulphenamide form AG2000, as described here could be an effective mode to restrict proton secretion in parietal cells. PMID:10711360

  3. Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?

    Science.gov (United States)

    Ravens, Ursula

    2017-11-01

    In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K + ) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting I Kur , the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting I K,ACh , the Ca 2+ -activated K + channels of small conductance (SK) conducting I SK , and the two-pore domain K + (K2P) channels (tandem of P domains, weak inward-rectifying K + channels (TWIK-1), TWIK-related acid-sensitive K + channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents I TWIK-1 , I TASK-1 , and I TASK-3 . Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.

  4. Lipid Rescue Therapy and High-Dose insulin Euglycemic Therapy are Effective for Severe Refractory Calcium Channel Blocker Overdose: Case Report and Review of Literature

    Directory of Open Access Journals (Sweden)

    Niko Bekjarovski

    2013-09-01

    How to cite this article: Bekjarovski NG. Lipid Rescue Therapy and High-Dose insulin Euglycemic Therapy are Effective for Severe Refractory Calcium Channel Blocker Overdose: Case Report and Review of Literature. Asia Pac J Med Toxicol 2013;2:114-6.

  5. Isolation of proflavine as a blocker of G protein-gated inward rectifier potassium channels by a cell growth-based screening system.

    Science.gov (United States)

    Kawada, Hitoshi; Inanobe, Atsushi; Kurachi, Yoshihisa

    2016-10-01

    The overexpression of Kir3.2, a subunit of the G protein-gated inwardly rectifying K(+) channel, is implicated in some of the neurological phenotypes of Down syndrome (DS). Chemical compounds that block Kir3.2 are expected to improve the symptoms of DS. The purpose of this study is to develop a cell-based screening system to identify Kir3.2 blockers and then investigate the mode of action of the blocker. Chemical screening was carried out using a K(+) transporter-deficient yeast strain that expressed a constitutively active Kir3.2 mutant. The mode of action of an effective blocker was electrophysiologically analyzed using Kir channels expressed in Xenopus oocytes. Proflavine was identified to inhibit the growth of Kir3.2-transformant cells and Kir3.2 activity in a concentration-dependent manner. The current inhibition was strong when membrane potentials (Vm) was above equilibrium potential of K(+) (EK). When Vm was below EK, the blockage apparently depended on the difference between Vm and [K(+)]. Furthermore, the inhibition became stronger by lowering extracellular [K(+)]. These results indicated that the yeast strain serves as a screening system to isolate Kir3.2 blockers and proflavine is a prototype of a pore blocker of Kir3.2. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Molecular modeling and structural analysis of two-pore domain potassium channels TASK1 interactions with the blocker A1899

    Directory of Open Access Journals (Sweden)

    David Mauricio Ramirez

    2015-03-01

    Full Text Available A1899 is a potent and highly selective blocker of the Two-pore domain potassium (K2P channel TASK-1, it acts as an antagonist blocking the K+ flux and binds to TASK-1 in the inner cavity and shows an activity in nanomolar order. This drug travels through the central cavity and finally binds in the bottom of the selectivity filter with some threonines and waters molecules forming a H-bond network and several hydrophobic interactions. Using alanine mutagenesis screens the binding site was identify involving residues in the P1 and P2 pore loops, the M2 and M4 transmembrane segments, and the halothane response element; mutations were introduced in the human TASK-1 (KCNK3, NM_002246 expressed in Oocytes from anesthetized Xenopus laevis frogs. Based in molecular modeling and structural analysis as such as molecular docking and binding free energy calculations a pose was suggested using a TASK-1 homology models. Recently, various K2P crystal structures have been obtained. We want redefined – from a structural point of view – the binding mode of A1899 in TASK-1 homology models using as a template the K2P crystal structures. By computational structural analysis we describe the molecular basis of the A1899 binding mode, how A1899 travel to its binding site and suggest an interacting pose (Figure 1. after 100 ns of molecular dynamics simulation (MDs we found an intra H-Bond (80% of the total MDs, a H-Bond whit Thr93 (42% of the total MDs, a pi-pi stacking interaction between a ring and Phe125 (88% of the total MDs and several water bridges. Our experimental and computational results allow the molecular understanding of the structural binding mechanism of the selective blocker A1899 to TASK-1 channels. We identified the structural common and divergent features of TASK-1 channel through our theoretical and experimental studies of A1899 drug action.

  7. Neuroprotective effect of gadolinium: a stretch-activated calcium channel blocker in mouse model of ischemia-reperfusion injury.

    Science.gov (United States)

    Gulati, Puja; Muthuraman, Arunachalam; Jaggi, Amteshwar S; Singh, Nirmal

    2013-03-01

    The present study was designed to investigate the potential of gadolinium, a stretch-activated calcium channel blocker in ischemic reperfusion (I/R)-induced brain injury in mice. Bilateral carotid artery occlusion of 12 min followed by reperfusion for 24 h was given to induce cerebral injury in male Swiss mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using Morris water maze test and motor incoordination was evaluated using rota-rod, lateral push, and inclined beam walking tests. In addition, total calcium, thiobarbituric acid reactive substance (TBARS), reduced glutathione (GSH), and acetylcholinesterase (AChE) activity were also estimated in brain tissue. I/R injury produced a significant increase in cerebral infarct size. A significant loss of memory along with impairment of motor performance was also noted. Furthermore, I/R injury also produced a significant increase in levels of TBARS, total calcium, AChE activity, and a decrease in GSH levels. Pretreatment of gadolinium significantly attenuated I/R-induced infarct size, behavioral and biochemical changes. On the basis of the present findings, we can suggest that opening of stretch-activated calcium channel may play a critical role in ischemic reperfusion-induced brain injury and that gadolinium has neuroprotective potential in I/R-induced injury.

  8. In Silico Predictions of hERG Channel Blockers in Drug Discovery

    DEFF Research Database (Denmark)

    Taboureau, Olivier; Sørensen, Flemming Steen

    2011-01-01

    The risk for cardiotoxic side effects represents a major problem in clinical studies of drug candidates and regulatory agencies have explicitly recommended that all new drug candidates should be tested for blockage of the human Ether-a-go-go Related-Gene (hERG) potassium channel. Indeed, several ...

  9. Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus.

    NARCIS (Netherlands)

    Kortenoeven, M.L.A.; Li, Y.; Shaw, S.M.; Gaeggeler, H.P.; Rossier, B.C.; Wetzels, J.F.M.; Deen, P.M.T.

    2009-01-01

    Lithium therapy frequently induces nephrogenic diabetes insipidus; amiloride appears to prevent its occurrence in some clinical cases. Amiloride blocks the epithelial sodium channel (ENaC) located in the apical membrane of principal cells; hence one possibility is that ENaC is the main entry site

  10. A new candidate of calcium channel blocker in silico from Tectona grandis for treatment of gestational hypertension

    Science.gov (United States)

    Azizah, A.; Suselo, Y. H.; Muthmainah, M.; Indarto, D.

    2018-05-01

    grandis. Obtusifolin 2-glucoside computationally becomes a potensial candidate of calcium channel blocker. In vitro assays should be performed to evaluate the antagonist effect of obtusifolin 2-glucoside on calcium channel Cav1.2.

  11. Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers.

    Science.gov (United States)

    Mehanna, Ahmed S; Kim, Jin Yung

    2005-07-01

    The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of a total of 10 S-(p-methoxybenzyl), N-substituted thiosalicylamides as a series of non-cyclic compounds derived from diltiazem's structure. The new compounds maintained all diltiazem pharmacophores except the thiazepine ring system. In vitro evaluation of the new series for calcium channel blocking effects revealed moderate activities with IC50 values in the range of 4.8-56.0 microM. The data suggest that the ring system is not essential for activity; however, its absence leads to a considerable drop of activity relative to that of diltiazem (IC50=0.3 microM). Compounds of the current series showed optimum activity when the aliphatic alkyl chain on the salicylamide nitrogen is part of a piperidine or piperazine ring system substituted at the terminal nitrogen with a benzyl group.

  12. Calcium Channel Blockers and Esophageal Sclerosis: Should We Expect Exacerbation of Interstitial Lung Disease

    Directory of Open Access Journals (Sweden)

    Charalampos Seretis

    2012-01-01

    Full Text Available Esophageal sclerosis is the most common visceral manifestation of systemic sclerosis, resulting in impaired esophageal clearance and retention of ingested food; in addition, co-existence of lung fibrosis with esophageal scleroderma is not uncommon. Both the progression of generalized connective tissue disorders and the damaging effect of chronic aspiration due to esophageal dysmotility appear to be involved in this procedure of interstitial fibrosis. Nifedipine is a widely prescribed calcium antagonist in a significant percentage of rheumatologic patients suffering from Raynaud syndrome, in order to inhibit peripheral vasospasm. Nevertheless, blocking calcium channels has proven to contribute to exacerbation of gastroesophageal reflux, which consequently can lead to chronic aspiration. We describe the case of severe exacerbation of interstitial lung disease in a 76-year-old female with esophageal sclerosis who was treated with oral nifedipine for Raynaud syndrome.

  13. Calcium channel blocker prevents stress-induced activation of renin and aldosterone in conscious pig

    International Nuclear Information System (INIS)

    Ceremuzynski, L.K.; Klos, J.; Barcikowski, B.; Herbaczynska-Cedro, K.

    1991-01-01

    A considerable amount of data suggest the involvement of calcium-mediated processes in the activation of the renin-angiotensin-aldosterone (RAA) cascade. To investigate the effect of calcium-channel inhibition on the RAA system, the authors studied 21 conscious pigs. Blood renin and aldosterone levels increased by subjecting animals to 24 hours of immobilization stress. Renin and aldosterone levels were repeatedly measured by radioimmunoassay in blood samples taken periodically over 24 hours from a chronically implanted arterial cannula. Pretreatment of the animals (N = 11) with nisoldipine, 2 x 20 mg p.o. daily for 2 days before and on the day of immobilization, transiently attenuated the stress-induced increase of plasma renin activity and completely prevented the rise of aldosterone, as compared to nontreated controls (N = 10). The finding that nisoldipine suppresses RAA activation induced by a nonpharmacologic stimulus in the conscious intact animal may have clinical implications

  14. Dose calcium channel blocker verapamil decrease urinary VMA levels in sympathoadrenal hyperactive patients with posttraumatic stress disorder?

    Institute of Scientific and Technical Information of China (English)

    Munawar Alam Ansari; Shahida PAhmed; Zahida Memon

    2008-01-01

    Objective:The majority of the patients with posttraumatic stress disorders (PTSD)embrace augmented urina-ry flow of Vanillylmandelic Acid (VMA)than normal subjects owing to superior sympathetic doings,which steer to cardiovascular catastrophe.Urinary flow of VMA was evaluated as sympathoadrenal bustle marker in patients with posttraumatic stress disorder.Calcium ion shows a noteworthy dependability in nervousness owing to its special effects on brain synaptosomes.So this study was conducted to explore the effects of Verapamil on sympathoadrenal motion in patients with PTSD.Methods:Placebo controlled clinical tryout was conducted. At first hundred (100)PTSD patients were chosen and enrolled in the study,from department of Psychological Medicine Dow University of Health Sciences,Karachi.Verapamil 120 mg/day was specified in divided doses to group-I (n =50)patients and group-II (n =50)patients received placebo therapy on a daily basis for nine weeks.Each and every patient was monitored weekly,all the way through extent of study.Results:Under-neath the posttraumatic stress disorder,urinary excretion of VMA was greater.Calcium channel blocker vera-pamil additionally abolished the embellished retort in urinary flow of VMA appreciably in patients with PTSD. Conclusion:Verapamil was experiential to be exceedingly effectual treatment.It reduces VMA levels in u-rine,and on the whole cardiovascular threat in PTSD patients.

  15. Transcranial Random Noise Stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive

    Directory of Open Access Journals (Sweden)

    Leila eChaieb

    2015-04-01

    Full Text Available Background: Application of transcranial random noise stimulation (tRNS between 0.1 and 640 Hz of the primary motor cortex (M1 for 10 minutes induces a persistent excitability increase lasting for at least 60 minutes. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1mA for 10mins stimulation duration and a pharmacological agent (or sham on 8 healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency towards inhibiting MEPs 5-60 mins poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS.Conclusions: In contrast to transcranial direct current stimulation (tDCS, aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.

  16. Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations.

    Science.gov (United States)

    DeMarco, Kevin R; Bekker, Slava; Clancy, Colleen E; Noskov, Sergei Y; Vorobyov, Igor

    2018-01-01

    Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel K v 11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology

  17. Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

    Directory of Open Access Journals (Sweden)

    Kevin R. DeMarco

    2018-02-01

    Full Text Available Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety

  18. Evaluation Effects of Verapamil as a Calcium Channel Blocker on Acquisition, Consolidation and Retrieval of Memory in Mice

    Directory of Open Access Journals (Sweden)

    Nooshin Masoudian

    2015-04-01

    Full Text Available Many factors are involved in learning and memory processes including brain nuclei, neurotransmitter systems, and the activity of ion channels. Studies showed inconsistent effects of calcium channel blockers on learning process, especially memory consolidation; however, little is known about their effect on memory acquisition and retrieval. Accordingly, the present study aimed to determine the effects of verapamil calcium channel antagonist as a representative of the phenylalkylamine group on different stages of memory and learning processes including acquisition, consolidation and retrieval in mice. In this experimental study, 150 male albino mice with a mean weight of 30 g were used. The mice were trained in a passive avoidance-learning task (1 mA shock for 2 seconds for evaluation of memory acquisition and consolidation and 3 seconds for evaluation of memory retrieval. The effect of verapamil (1, 2.5, 5, 10, and 20 mg/kg on memory consolidation and the most effective dose of consolidation phase on memory acquisition and retrieval was assessed. For the evaluation of memory consolidation, the animals received the drug intraperitoneally immediately after training, while for evaluation of memory acquisition and retrieval, the drug was injected one hour before training. Memory retrieval test was performed 48 hours after training (the length of time it took the animal to enter the dark part of the device. The results showed that verapamil injection exerted no effect on memory acquisition and consolidation; nevertheless, it was capable to disrupt memory retrieval in 10 and 20 mg doses. These results indicate that as a phenylalkylamine calcium channel antagonist, high doses of verapamil can impair memory. Normal 0 false false false EN-US X-NONE AR-SA /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso

  19. Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.

    Science.gov (United States)

    Bezençon, Olivier; Heidmann, Bibia; Siegrist, Romain; Stamm, Simon; Richard, Sylvia; Pozzi, Davide; Corminboeuf, Olivier; Roch, Catherine; Kessler, Melanie; Ertel, Eric A; Reymond, Isabelle; Pfeifer, Thomas; de Kanter, Ruben; Toeroek-Schafroth, Michael; Moccia, Luca G; Mawet, Jacques; Moon, Richard; Rey, Markus; Capeleto, Bruno; Fournier, Elvire

    2017-12-14

    We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

  20. Additive effects of cilnidipine, an L-/N-type calcium channel blocker, and an angiotensin II receptor blocker on reducing cardiorenal damage in Otsuka Long-Evans Tokushima Fatty rats with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Mori Y

    2014-06-01

    Full Text Available Yutaka Mori,1,2 Shizuka Aritomi,3 Kazumi Niinuma,3 Tarou Nakamura,3 Kenichi Matsuura,1 Junichi Yokoyama,1 Kazunori Utsunomiya1 1Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Japan; 2Department of Clinical Research, National Hospital Organization, Utsunomiya National Hospital, Utsunomiya, Japan; 3Research Center, Ajinomoto Pharmaceuticals Co, Ltd, Kanagawa, Japan Abstract: Cilnidipine (Cil, which is an L-/N-type calcium channel blocker (CCB, has been known to provide renal protection by decreasing the activity of the sympathetic nervous system (SNS and the renin–angiotensin system. In this study, we compared the effects of the combination of Cil and amlodipine (Aml, which is an L-type CCB, with an angiotensin (Ang II receptor blocker on diabetic cardiorenal damage in spontaneously type 2 diabetic rats. Seventeen-week-old Otsuka Long-Evans Tokushima Fatty rats were randomly assigned to receive Cil, Aml, valsartan (Val, Cil + Val, Aml + Val, or a vehicle (eight rats per group for 22 weeks. Antihypertensive potencies were nearly equal among the CCB monotherapy groups and the combination therapy groups. The lowering of blood pressure by either treatment did not significantly affect the glycemic variables. However, exacerbations of renal and heart failure were significantly suppressed in rats administered Cil or Val, and additional suppression was observed in those administered Cil + Val. Although Val increased the renin–Ang system, Aml + Val treatment resulted in additional increases in these parameters, while Cil + Val did not show such effects. Furthermore, Cil increased the ratio of Ang-(1–7 to Ang-I, despite the fact that Val and Aml + Val decreased the Ang-(1–7 levels. These actions of Cil + Val might be due to their synergistic inhibitory effect on the activity of the SNS, and on aldosterone secretion through N-type calcium channel antagonism and Ang II

  1. The effect of an L/N-type calcium channel blocker on intradialytic blood pressure in intradialytic hypertensive patients.

    Science.gov (United States)

    Ito, Takayasu; Fujimoto, Naoki; Ishikawa, Eiji; Dohi, Kaoru; Fujimoto, Mika; Murata, Tomohiro; Kiyohara, Michiyo; Takeuchi, Hideyuki; Koyabu, Sukenari; Nishimura, Hiroyuki; Takeuchi, Toshiaki; Ito, Masaaki

    2018-03-27

    Intradialytic hypertension (HTN), which is one of the poor prognostic markers in patients undergoing hemodialysis, may be associated with sympathetic overactivity. The L/N-type calcium channel blocker, cilnidipine, has been reported to suppress sympathetic nerves activity in vivo. Therefore, we hypothesized that cilnidipine could attenuate intradialytic systolic blood pressure (SBP) elevation. Fifty-one patients on chronic hemodialysis who had intradialytic-HTN (SBP elevation ≥10 mmHg during hemodialysis) and no fluid overload were prospectively randomized into two groups: control and cilnidipine groups. Cilnidipine group patients took cilnidipine (10 mg/day) for 12 weeks. The primary endpoint was the change in the intradialytic SBP elevation before and after the 12-week intervention. Before the intervention, no differences were observed in age, sex or pre-dialytic SBP (148.5 ± 12.9 vs. 148.3 ± 19.3 mmHg) between the two groups. Intradialytic SBP elevation was unchanged in the control group. Cilnidipine significantly lowered the post-dialytic SBP with an attenuation of the intradialytic SBP elevation from 12.0 ± 15.4 mmHg to 4.8 ± 10.1 mmHg. However, the observed difference in the intradialytic SBP elevation by cilnidipine did not reach statistical significance (group×time interaction effect p = 0.25). Cathecolamine levels were unaffected by the intervention in both groups. Cilnidipine lowers both the pre- and post-dialytic SBP and might attenuate intradialytic SBP elevation. Therefore, cilnidipine may be effective in lowering SBP during HD in patients with intradialytic-HTN.

  2. MANAGEMENT OF HYPERTENSION- INSIGHTS INTO REAL-WORLD CLINICAL PRACTICE FOR DIFFERENTIAL USAGE OF CALCIUM CHANNEL BLOCKERS (CCBS

    Directory of Open Access Journals (Sweden)

    Arup Dasbiswas

    2017-05-01

    Full Text Available BACKGROUND Calcium channel blockers (CCB like amlodipine, S (- amlodipine and cilnidipine, etc. have established place in the treatment of hypertension (HTN. As perceived by most of the physicians, they have comparative antihypertensive efficacy. However, available evidences suggest varied differences in incidence of pedal oedema. Aim- This survey was planned to understand real-world clinical practice pattern of Indian physicians for usage of various antihypertensive agents with emphasis on CCBs and whether differential incidence of oedema with CCBs is encountered in their clinical practice. MATERIALS AND METHODS Survey questionnaire consisting of 10 questions about preferred antihypertensive choice for different subsets of patients with HTN and efficacy and safety of S (- amlodipine was prepared and validated in small group of physicians. Overall, 494 general physicians and cardiologists practising in India were approached for seeking their opinion on usage of various CCBs. Statistical Analysis- Data were expressed in percentage. Design- Prospective, cross sectional, questionnaire-based survey. RESULTS Amongst various anti-hypertensive agents, majority of the physicians preferred CCB as their initial drug of choice for patients with HTN (53.8%, HTN with CKD (41.1%, elderly (55.3%, and young (30.8% patients. Though amlodipine was preferred by 75.7% physicians, pedal oedema was observed in >10% patients by 40.5% physicians. Most of the physicians rated S (- amlodipine to have better efficacy (79.4% and safety profile (88.3% with decreased incidence of pedal oedema than racemic Amlodipine. CONCLUSION Available evidences suggest comparative efficacy of S (- amlodipine and racemic amlodipine with varied differences in incidence of pedal oedema. However, our survey suggests better efficacy and safety of S (- amlodipine over racemic amlodipine as opined by most of the physicians of India. The survey findings need to be further evaluated in randomised

  3. Calcium channel blockers and breast cancer incidence: An updated systematic review and meta-analysis of the evidence.

    Science.gov (United States)

    Wright, Cameron M; Moorin, Rachael E; Chowdhury, Enayet K; Stricker, Bruno H; Reid, Christopher M; Saunders, Christobel M; Hughes, Jeffery D

    2017-10-01

    Controversy exists regarding the potential association between taking calcium channel blockers (CCBs) and the development of breast cancer. As a positive association would have important public health implications due to the widespread use of CCBs, this study aimed to incorporate new evidence to determine whether an association is likely to exist. We searched MEDLINE, EMBASE and the Cochrane Library to 28 June 2016 for relevant literature. References and citing articles were checked and authors contacted as necessary. Two authors independently selected articles and extracted data. Twenty-nine studies were reviewed; 26 were non-randomised studies (NRS). Meta-analysis of study data where adjustment for 'confounding by indication' was judged to be present suggests that an association, if any, is likely to be modest in magnitude (pooled odds/risk ratio 1.09 (95% confidence interval (CI) 1.03-1.15, I 2 =0%, 8 sub-studies; pooled hazard ratio 0.99 (95% CI 0.94-1.03, I 2 =35%, 9 sub-studies)). There are credible study data showing an increased relative risk with long-term use of CCBs, but the results of our meta-analysis and of meta-regression of log relative risk against minimum follow-up time are mixed. The current summative evidence does not support a clear association between taking CCBs and developing breast cancer. However, uncertainty remains, especially for long-term use and any association might not be uniform between different populations and/or breast cancer sub-types. We thus recommend further NRS in settings where CCB use is highly prevalent and population-based cancer, prescription and health-registries exist, to resolve this continuing uncertainty. PROSPERO, CRD42015026712. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Differential Modulation of Rhythmic Brain Activity in Healthy Adults by a T-Type Calcium Channel Blocker: An MEG Study.

    Science.gov (United States)

    Walton, Kerry D; Maillet, Emeline L; Garcia, John; Cardozo, Timothy; Galatzer-Levy, Isaac; Llinás, Rodolfo R

    2017-01-01

    1-octanol is a therapeutic candidate for disorders involving the abnormal activation of the T-type calcium current since it blocks this current specifically. Such disorders include essential tremor and a group of neurological and psychiatric disorders resulting from thalamocortical dysrhythmia (TCD). For example, clinically, the observable phenotype in essential tremor is the tremor itself. The differential diagnostic of TCD is not based only on clinical signs and symptoms. Rather, TCD incorporates an electromagnetic biomarker, the presence of abnormal thalamocortical low frequency brain oscillations. The effect of 1-octanol on brain activity has not been tested. As a preliminary step to such a TCD study, we examined the short-term effects of a single dose of 1-octanol on resting brain activity in 32 healthy adults using magnetoencephalograpy. Visual inspection of baseline power spectra revealed that the subjects fell into those with strong low frequency activity (set 2, n = 11) and those without such activity, but dominated by an alpha peak (set 1, n = 22). Cross-validated linear discriminant analysis, using mean spectral density (MSD) in nine frequency bands as predictors, found overall that 82.5% of the subjects were classified as determined by visual inspection. The effect of 1-octanol on the MSD in narrow frequency bands differed between the two subject groups. In set 1 subjects the MSD increased in the 4.5-6.5Hz and 6.5-8.5 Hz bands. This was consistent with a widening of the alpha peak toward lower frequencies. In the set two subjects the MSD decrease in the 2.5-4.5 Hz and 4.5-6.5 Hz bands. This decreased power is consistent with the blocking effect of 1-octanol on T-type calcium channels. The subjects reported no adverse effects of the 1-octanol. Since stronger low frequency activity is characteristic of patients with TCD, 1-octanol and other T-type calcium channel blockers are good candidates for treatment of this group of disorders following a placebo

  5. Differential Modulation of Rhythmic Brain Activity in Healthy Adults by a T-Type Calcium Channel Blocker: An MEG Study

    Science.gov (United States)

    Walton, Kerry D.; Maillet, Emeline L.; Garcia, John; Cardozo, Timothy; Galatzer-Levy, Isaac; Llinás, Rodolfo R.

    2017-01-01

    1-octanol is a therapeutic candidate for disorders involving the abnormal activation of the T-type calcium current since it blocks this current specifically. Such disorders include essential tremor and a group of neurological and psychiatric disorders resulting from thalamocortical dysrhythmia (TCD). For example, clinically, the observable phenotype in essential tremor is the tremor itself. The differential diagnostic of TCD is not based only on clinical signs and symptoms. Rather, TCD incorporates an electromagnetic biomarker, the presence of abnormal thalamocortical low frequency brain oscillations. The effect of 1-octanol on brain activity has not been tested. As a preliminary step to such a TCD study, we examined the short-term effects of a single dose of 1-octanol on resting brain activity in 32 healthy adults using magnetoencephalograpy. Visual inspection of baseline power spectra revealed that the subjects fell into those with strong low frequency activity (set 2, n = 11) and those without such activity, but dominated by an alpha peak (set 1, n = 22). Cross-validated linear discriminant analysis, using mean spectral density (MSD) in nine frequency bands as predictors, found overall that 82.5% of the subjects were classified as determined by visual inspection. The effect of 1-octanol on the MSD in narrow frequency bands differed between the two subject groups. In set 1 subjects the MSD increased in the 4.5-6.5Hz and 6.5–8.5 Hz bands. This was consistent with a widening of the alpha peak toward lower frequencies. In the set two subjects the MSD decrease in the 2.5–4.5 Hz and 4.5–6.5 Hz bands. This decreased power is consistent with the blocking effect of 1-octanol on T-type calcium channels. The subjects reported no adverse effects of the 1-octanol. Since stronger low frequency activity is characteristic of patients with TCD, 1-octanol and other T-type calcium channel blockers are good candidates for treatment of this group of disorders following a

  6. Comparison of the efficacy of dihydropyridine calcium channel blockers in African American patients with hypertension. ISHIB Investigators Group. International Society on Hypertension in Blacks.

    Science.gov (United States)

    Hall, W D; Reed, J W; Flack, J M; Yunis, C; Preisser, J

    1998-10-12

    Hypertension is a prevalent disease among African Americans, and successful treatment rates are low. Since calcium channel blockers are well-tolerated and efficacious in African Americans, we undertook this study to compare the efficacy, safety, and tolerability of 3 commonly prescribed calcium channel blockers: amlodipine besylate (Norvasc), nifedipine coat core (CC) (Adalat CC), and nifedipine gastrointestinal therapeutic system (GITS) (Procardia XL). One hundred ninety-two hypertensive patients across 10 study centers were randomly assigned to double-blind monotherapy with amlodipine besylate (5 mg/d), nifedipine CC (30 mg/d), or nifedipine GITS (30 mg/d) for 8 weeks. Patients not achieving therapeutic response after 4 weeks had their dose doubled for the next 4 weeks. The primary end point was a comparison of the average reduction (week 8 minus baseline) in 24-hour ambulatory diastolic blood pressure (DBP). Secondary end points included a comparison of average 24-hour ambulatory systolic blood pressure (SBP), office SBP or DBP reduction, responder rates, safety, and tolerability. One hundred sixty-three patients were evaluable for efficacy after 8 weeks. There was no significant difference in the average 24-hour ambulatory DBP (-8.5, -9.0, and -6.1 mm Hg, respectively) or SBP (-14.3, -15.7, and -11.8 mm Hg, respectively) reduction. Average office SBP and DBP were reduced to a comparable degree (19-22 mm Hg [P =.50] and 12-14 mm Hg [P =.51], respectively). Responder rates (DBP or = 10 mm Hg) were similar (P = .38). Discontinuation rates and adverse event frequency were distributed similarly across the 3 treatment groups. The efficacy, safety, and tolerability of the 3 dihydropyridine calcium channel blockers are equivalent in African Americans with stages 1 and 2 hypertension.

  7. Investigation of the role of non-selective calcium channel blocker (flunarizine) on cerebral ischemic-reperfusion associated cognitive dysfunction in aged mice.

    Science.gov (United States)

    Gulati, Puja; Muthuraman, Arunachalam; Kaur, Parneet

    2015-04-01

    The present study was designed to investigate the role of flunarizine (a non-selective calcium channel blocker) on cerebral ischemic-reperfusion associated cognitive dysfunction in aged mice. Bilateral carotid artery occlusion of 12min followed by reperfusion for 24h was given to induce cerebral injury in male Swiss mice. The assessment of learning & memory was performed by Morris water maze test; motor in-coordination was evaluated by rota rod, lateral push and inclined beam walking tests; cerebral infarct size was quantified by triphenyltetrazolium chloride staining. In addition, reduced glutathione (GSH), total calcium and acetylcholinesterase (AChE) activity were also estimated in aged brain tissue. Donepezil treated group served as a positive control in this study. Ischemia reperfusion (I/R) injury produced significant increase in cerebral infarct size. A significant loss of memory along with impairment of motor performance was also noted. Further, I/R injury also produced significant increase in levels of total calcium, AChE activity and decrease in GSH levels. Pretreatment of flunarizine significantly attenuated I/R induced infarct size, behavioral and biochemical changes. Hence, it may be concluded that, a non-selective calcium channel blocker can be useful in I/R associated cognitive dysfunction due to its anti-oxidant, anti-infarct and modulatory actions of neurotransmitters & calcium channels. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Is Shock Index a Valid Predictor of Mortality in Emergency Department Patients With Hypertension, Diabetes, High Age, or Receipt of β- or Calcium Channel Blockers?

    DEFF Research Database (Denmark)

    Kristensen, Anders K B; Holler, Jon G; Hallas, Jesper

    2016-01-01

    STUDY OBJECTIVE: Shock index is a widely reported tool to identify patients at risk for circulatory collapse. We hypothesize that old age, diabetes, hypertension, and β- or calcium channel blockers weaken the association between shock index and mortality. METHODS: This was a cohort study of all...... first-time emergency department (ED) visits between 1995 and 2011 (n=111,019). We examined whether age 65 years or older, diabetes, hypertension, and use of β- or calcium channel blockers modified the association between shock index and 30-day mortality. RESULTS: The 30-day mortality was 3.0%. For all...... than or equal to 1 in patients aged 65 years or older was 8.2 (95% CI 7.2 to 9.4) compared with 18.9 (95% CI 15.6 to 23.0) in younger patients. β- Or calcium channel-blocked patients had an OR of 6.4 (95% CI 4.9 to 8.3) versus 12.3 (95% CI 11.0 to 13.8) in nonusers and hypertensive patients had...

  9. Alpha Blockers

    Science.gov (United States)

    ... quickly, but their effects last only a few hours. Long-acting medications take longer to work, but their effects last longer. Which alpha blocker is best for you depends on your health and the condition being treated. Alpha blockers are ...

  10. Recombinant expression of margatoxin and agitoxin-2 in Pichia pastoris: an efficient method for production of KV1.3 channel blockers.

    Directory of Open Access Journals (Sweden)

    Raveendra Anangi

    Full Text Available The K(v1.3 voltage-gated potassium channel regulates membrane potential and calcium signaling in human effector memory T cells that are key mediators of autoimmune diseases such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Thus, subtype-specific K(v1.3 blockers have potential for treatment of autoimmune diseases. Several K(v1.3 channel blockers have been characterized from scorpion venom, all of which have an α/β scaffold stabilized by 3-4 intramolecular disulfide bridges. Chemical synthesis is commonly used for producing these disulfide-rich peptides but this approach is time consuming and not cost effective for production of mutants, fusion proteins, fluorescently tagged toxins, or isotopically labelled peptides for NMR studies. Recombinant production of K(v1.3 blockers in the cytoplasm of E. coli generally necessitates oxidative refolding of the peptides in order to form their native disulfide architecture. An alternative approach that avoids the need for refolding is expression of peptides in the periplasm of E. coli but this often produces low yields. Thus, we developed an efficient Pichia pastoris expression system for production of K(v1.3 blockers using margatoxin (MgTx and agitoxin-2 (AgTx2 as prototypic examples. The Pichia system enabled these toxins to be obtained in high yield (12-18 mg/L. NMR experiments revealed that the recombinant toxins adopt their native fold without the need for refolding, and electrophysiological recordings demonstrated that they are almost equipotent with the native toxins in blocking K(V1.3 (IC(50 values of 201±39 pM and 97 ± 3 pM for recombinant AgTx2 and MgTx, respectively. Furthermore, both recombinant toxins inhibited T-lymphocyte proliferation. A MgTx mutant in which the key pharmacophore residue K28 was mutated to alanine was ineffective at blocking K(V1.3 and it failed to inhibit T-lymphocyte proliferation. Thus, the approach described here provides an efficient method of

  11. A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non-diabetic patients.

    Science.gov (United States)

    Yang, Yue; Wei, Ri-bao; Xing, Yue; Tang, Lu; Zheng, Xiao-yong; Wang, Zi-cheng; Gao, Yu-wei; Li, Min-xia; Chen, Xiang-mei

    2013-12-01

    This study compared the efficacy of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) in the effect of insulin resistance (IR) as assessed using the homeostasis model assessment of insulin resistance (HOMA-IR) in non-diabetic patients. The MEDLINE, EMBASE, and Cochrane Library databases were searched to identify studies published before December 2012 that investigated the use of ARBs and CCBs to determine the effect on the HOMA-IR index in non-diabetics. Parameters on IR and blood pressure were collected. Review Manager 5.2 and Stata 12.0 were used to perform the meta-analysis. Fixed and random effects models were applied to various aspects of the meta-analysis, which assessed the therapeutic effects of the two types of drug using the HOMA-IR index in non-diabetic patients. The meta-analysis included five clinical trials. Patient comparisons before and after treatment with ARBs and CCBs revealed that ARBs reduced the HOMA-IR index (weighted mean difference (WMD) -0.65, 95% confidence interval (CI) -0.93 to -0.38) and fasting plasma insulin (FPI) (WMD -2.01, 95% CI -3.27 to -0.74) significantly more than CCBs. No significant differences in the therapeutic effects of these two types of drug on blood pressure were observed. Given that there are no significant differences in the therapeutic effects of ARBs and CCBs on blood pressure, as ARBs are superior to CCBs in their effect on the HOMA-IR index in non-diabetics, they might be a better choice in hypertension patients without diabetes. © 2013.

  12. Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

    International Nuclear Information System (INIS)

    Zheng, Kai; Chen, Maoyun; Xiang, Yangfei; Ma, Kaiqi; Jin, Fujun; Wang, Xiao; Wang, Xiaoyan; Wang, Shaoxiang; Wang, Yifei

    2014-01-01

    Highlights: • We analyze the anti-HSV potential of chloride channel inhibitors. • Tamoxifen and NPPB show anti-HSV-1 and anti-ACV-resistant HSV-1 activities. • HSV-1 infection induces intracellular chloride concentration increasing. • Tamoxifen and NPPB inhibit HSV-1 early infection. • Tamoxifen and NPPB prevent the fusion process of HSV-1. - Abstract: Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoic acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections

  13. Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Kai [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of Life Science and Technology, Jinan University, Guangzhou (China); Chen, Maoyun [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of pharmacy, Jinan University, Guangzhou (China); Xiang, Yangfei; Ma, Kaiqi [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); Jin, Fujun [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of pharmacy, Jinan University, Guangzhou (China); Wang, Xiao [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China); Wang, Xiaoyan; Wang, Shaoxiang [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); Wang, Yifei, E-mail: twang-yf@163.com [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China)

    2014-04-18

    Highlights: • We analyze the anti-HSV potential of chloride channel inhibitors. • Tamoxifen and NPPB show anti-HSV-1 and anti-ACV-resistant HSV-1 activities. • HSV-1 infection induces intracellular chloride concentration increasing. • Tamoxifen and NPPB inhibit HSV-1 early infection. • Tamoxifen and NPPB prevent the fusion process of HSV-1. - Abstract: Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoic acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections.

  14. When lithium does not help: the use of anticonvulsants and calcium channel blockers in the treatment of bipolar disorder in the older person.

    Science.gov (United States)

    Masters, J C

    1996-01-01

    Although anticonvulsant agents and calcium channel blockers do not have any clear advantages over lithium, they do offer patients who cannot (or will not) take lithium another treatment option. It is not yet clear from the literature who will respond best to which drug or combination of drugs. The nurse should be supportive to the patients and family, in what may be a drawn out process, to find the best treatment. Optimism is justified because a lack of response to one drug is not indicative of nonresponse to other drugs. It is important to actively treat bipolar disorder because each episode of mania increases the risk of progression of the illness, with increasingly severe episodes occurring closer together. Bipolar disorder has high social costs (legal, financial, and relationship problems) that make improvements in treatment important for the patient and society. Anticonvulsant agents and calcium channel blockers may also be useful in treating depression. The number of people whose depressive symptoms respond is far less (25% to 30%) than the number who respond to the anti-manic effects, but this is an option when antidepressants and electroconvulsive therapy are not effective.

  15. Dielectrophoretic analysis of changes in cytoplasmic ion levels due to ion channel blocker action reveals underlying differences between drug-sensitive and multidrug-resistant leukaemic cells

    International Nuclear Information System (INIS)

    Duncan, L; Shelmerdine, H; Hughes, M P; Coley, H M; Huebner, Y; Labeed, F H

    2008-01-01

    Dielectrophoresis (DEP)-the motion of particles in non-uniform AC fields-has been used in the investigation of cell electrophysiology. The technique offers the advantages of rapid determination of the conductance and capacitance of membrane and cytoplasm. However, it is unable to directly determine the ionic strengths of individual cytoplasmic ions, which has potentially limited its application in assessing cell composition. In this paper, we demonstrate how dielectrophoresis can be used to investigate the cytoplasmic ion composition by using ion channel blocking agents. By blocking key ion transporters individually, it is possible to determine their overall contribution to the free ions in the cytoplasm. We use this technique to evaluate the relative contributions of chloride, potassium and calcium ions to the cytoplasmic conductivities of drug sensitive and resistant myelogenous leukaemic (K562) cells in order to determine the contributions of individual ion channel activity in mediating multi-drug resistance in cancer. Results indicate that whilst K + and Ca 2+ levels were extremely similar between sensitive and resistant lines, levels of Cl - were elevated by three times to that in the resistant line, implying increased chloride channel activity. This result is in line with current theories of MDR, and validates the use of ion channel blockers with DEP to investigate ion channel function. (note)

  16. Beta Blockers

    Science.gov (United States)

    ... may not work as effectively for people of African heritage and older people, especially when taken without ... conditions/high-blood-pressure/in-depth/beta-blockers/ART-20044522 . Mayo Clinic Footer Legal Conditions and Terms ...

  17. H2 blockers

    Science.gov (United States)

    Peptic ulcer disease - H2 blockers; PUD - H2 blockers; Gastroesophageal reflux - H2 blockers; GERD - H2 blockers ... H2 blockers are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  18. Clinical usefulness of a dual L/N-type Ca2+ channel blocker, cilnidipine, in patients with chronic heart failure. Assessment with 123I-MIBG myocardial scintigraphy

    International Nuclear Information System (INIS)

    Ito, Kazuki; Nishikawa, Susumu; Adachi, Yoshihiko; Kato, Shuuji; Azuma, Akihiro; Matsubara, Hiroaki

    2003-01-01

    Sympathetic nerve system is activated as a compensatory mechanism in heart failure. However excessive activation of sympathetic nerve system deteriorates disease state. Sympathetic nerve system can be suppressed with N-type Ca 2+ channel blocker. An antihypertensive drug, cilnidipine, is a dual L/N-type Ca 2+ channel blocker. We studies usefulness of cilnidipine in treating with chronic heart failure with 123 I-MIBG myocardial scintigraphy. We enrolled 24 patients with stable chronic heart failure. Twelve patients were treated with angiotensin converting enzyme (ACE)-inhibitors, diuretics and cardiotonics (control group), and the other 12 patients were treated with ACE-inhibitors, diuretics, cardiotonics and cilnidipine (cilnidipine group). We examined blood pressure, heart rate, norepinephrine level, brain natriuretic peptide (BNP) level, cardiothoracic ratio on chest X-ray, ejection fraction of left ventricle on two-dimensional echocardiography, count rate of heart to mediastinum (H/M) and washout rate (WOR) on 123 I-MIBG myocardial scintigraphy before and six months after medication. Symptom was improved in 8 patients in the control group and 10 patients in the cilnidipine group after medication. And another parameters were also improved in the both groups after medication. However the degree of change in blood pressure (mmHg) was 21.2±8.0 in the cilnidipine group and 10.8±9.1 in the control group, that in heart rate (/min) was 24.1±6.8 and 16.2±11.0, that in BNP level (pg/ml) was 65.2±12.0 and 42.8±11.1, that in H/M was 0.30±0.08 and 0.19±0.09, that in WOR was 19.4±5.6 and 12.2±7.0, respectively. And the degree of these changes were larger in the cilnidipine group (p 2+ channel blocker, might be useful in treating with chronic heart failure. (author)

  19. A study on the action of two calcium channel blockers (verapamil and flunarizine upon an experimental model of tardive dyskinesia in rats

    Directory of Open Access Journals (Sweden)

    João S. Pereira

    1992-09-01

    Full Text Available Tardive dyskinesia (TD, a serious complications of neuroleptic chronic use, has no effective therapy yet. We performed an experiment to study the action on TD, of the calcium channel blockers (CCB drugs, verapamil and flunarizine. We obtained the TD model in rats, administering haloperidol for a 21-day period. After this, the stereotyped movement induced by apomorphyne was rated. The CCB drugs were administered in acute (in the 28th. day and chronic (for 8 days, after the 25th day experiments. Acutely, verapamil increased the stereotyped behaviour, and promoted a reduction of it in the chronic experiment. The results suggest that CCB drugs should be tested in clinical trials of TD.

  20. Reduction in renal blood flow following administration of norepinephrine and phenylephrine in septic rats treated with Kir6.1 ATP-sensitive and KCa1.1 calcium-activated K+ channel blockers.

    Science.gov (United States)

    da Rosa Maggi Sant'Helena, Bruna; Guarido, Karla L; de Souza, Priscila; Crestani, Sandra; da Silva-Santos, J Eduardo

    2015-10-15

    We evaluated the effects of K+ channel blockers in the vascular reactivity of in vitro perfused kidneys, as well as on the influence of vasoactive agents in the renal blood flow of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Both norepinephrine and phenylephrine had the ability to increase the vascular perfusion pressure reduced in kidneys of rats subjected to CLP at 18 h and 36 h before the experiments. The non-selective K+ channel blocker tetraethylammonium, but not the Kir6.1 blocker glibenclamide, normalized the effects of phenylephrine in kidneys from the CLP 18 h group. Systemic administration of tetraethylammonium, glibenclamide, or the KCa1.1 blocker iberiotoxin, did not change the renal blood flow in control or septic rats. Norepinephrine or phenylephrine also had no influence on the renal blood flow of septic animals, but its injection in rats from the CLP 18 h group previously treated with either glibenclamide or iberiotoxin resulted in an exacerbated reduction in the renal blood flow. These results suggest an abnormal functionality of K+ channels in the renal vascular bed in sepsis, and that the blockage of different subtypes of K+ channels may be deleterious for blood perfusion in kidneys, mainly when associated with vasoactive drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Structural implications of hERG K+ channel block by a high-affinity minimally structured blocker

    Science.gov (United States)

    Helliwell, Matthew V.; Zhang, Yihong; El Harchi, Aziza; Du, Chunyun; Hancox, Jules C.; Dempsey, Christopher E.

    2018-01-01

    Cardiac potassium channels encoded by human ether-à-go-go–related gene (hERG) are major targets for structurally diverse drugs associated with acquired long QT syndrome. This study characterized hERG channel inhibition by a minimally structured high-affinity hERG inhibitor, Cavalli-2, composed of three phenyl groups linked by polymethylene spacers around a central amino group, chosen to probe the spatial arrangement of side chain groups in the high-affinity drug-binding site of the hERG pore. hERG current (IhERG) recorded at physiological temperature from HEK293 cells was inhibited with an IC50 of 35.6 nm with time and voltage dependence characteristic of blockade contingent upon channel gating. Potency of Cavalli-2 action was markedly reduced for attenuated inactivation mutants located near (S620T; 54-fold) and remote from (N588K; 15-fold) the channel pore. The S6 Y652A and F656A mutations decreased inhibitory potency 17- and 75-fold, respectively, whereas T623A and S624A at the base of the selectivity filter also decreased potency (16- and 7-fold, respectively). The S5 helix F557L mutation decreased potency 10-fold, and both F557L and Y652A mutations eliminated voltage dependence of inhibition. Computational docking using the recent cryo-EM structure of an open channel hERG construct could only partially recapitulate experimental data, and the high dependence of Cavalli-2 block on Phe-656 is not readily explainable in that structure. A small clockwise rotation of the inner (S6) helix of the hERG pore from its configuration in the cryo-EM structure may be required to optimize Phe-656 side chain orientations compatible with high-affinity block. PMID:29545312

  2. Oxidizing reagent copper-o-phenanthroline is an open channel blocker of the vanilloid receptor TRPV1

    Czech Academy of Sciences Publication Activity Database

    Toušová, Karolina; Sušánková, Klára; Teisinger, Jan; Vyklický st., Ladislav; Vlachová, Viktorie

    2004-01-01

    Roč. 47, č. 2 (2004), s. 273-285 ISSN 0028-3908 R&D Projects: GA ČR GA305/03/0802; GA ČR GA309/02/1479; GA MŠk LN00B122 Institutional research plan: CEZ:AV0Z5011922 Keywords : vanilloid receptor * TRP channels * capsaicin Subject RIV: ED - Physiology Impact factor: 3.734, year: 2004

  3. Cloning and characterization of BmK86, a novel K+-channel blocker from scorpion venom

    International Nuclear Information System (INIS)

    Mao, Xin; Cao, Zhijian; Yin, Shijin; Ma, Yibao; Wu, Yingliang; Li, Wenxin

    2007-01-01

    Scorpion venom represents a tremendous hitherto unexplored resource for understanding ion channels. BmK86 is a novel K + -channel toxin gene isolated from a cDNA library of Mesobuthus martensii Karsch, which encodes a signal peptide of 22 amino acid residues and a mature toxin of 35 residues with three disulfide bridges. The genomic sequence of BmK86 consists of two exons disrupted by an intron of 72 bp. Comparison with the other scorpion toxins BmK86 shows low sequence similarity. The GST-BmK86 fusion protein was successfully expressed in Escherichia coli. The fusion protein was cleaved by enterokinase and the recombinant BmK86 was purified by HPLC. Using whole-cell patch-clamp recording, the recombinant BmK86 was found to inhibit the potassium current of mKv1.3 channel expressed in COS7 cells. These results indicated that BmK86 belongs to a representative member of a novel subfamily of α-KTxs. The systematic number assigned to BmK86 is α-KTx26.1

  4. The concentration of adrenaline and noradrenaline in the serum of dogs under the influence of calcium channels blockers

    Directory of Open Access Journals (Sweden)

    Milanović Tamara

    2015-01-01

    Full Text Available The most important characteristic of calcium channels is selective regulation of slow incoming stream of calcium into the cell tissue providing the slow increasement of action potential. Such tissues include smooth muscles of blood vessels, cardiocytes and heart noduses (AV and SA node. Different calcium antagonists have different effects on previous tissues due to their different chemical formula. Verapamile, Nifedipin and Diltiazem are the most frequently used of all. Their commonest characteristic is blocking the calcium channels causing vasodilatation of blood vessels as well as negative inotropic and chronotropic influence. By blocking the incoming calcium through slow channels of myofibrils of smooth muscles, the antagonists of calcium decrease the quantity of available calcium for contraction which causes vasodilatation. The most famous and most frequently used calcium antagonist is Verapamile. In terms of electrophysiology, Verapamile inhibits action potentials of heart noduses, especially the AV node, where the slow incoming of calcium is the most important for depolarization. Prolongation of the efective refractory period of SA node causes the heart frequency decreasement while prolongation of the effective refractory period of AV node slows down the work of chambers in case of flater and fibrillation of atriums. The molecules of calcium-bonding protein called kalmodulin are located in synaptic endings. Each kalmodulin can bond four calcium ions providing transfer into active calcium-kalmodulin complex which activates the kinase protein. Activated kinase protein starts the exocytosis of neurotransmitters into synaptic gap. Apart from activating kinase protein, calcium-kalmodulin complex also starts the activity of calcium pump presynaptic membrane which pumps calcium out of presynaptic ending stopping the further exocytosis of neurotransmitters into synaptic gap. Taking into consideration the fact that opening the calcium channels on

  5. An Assessment of the Oral Bioavailability of Three Ca-Channel Blockers Using a Cassette-Microdose Study: A New Strategy for Streamlining Oral Drug Development.

    Science.gov (United States)

    Yamashita, Shinji; Kataoka, Makoto; Suzaki, Yuki; Imai, Hiromitsu; Morimoto, Takuya; Ohashi, Kyoichi; Inano, Akihiro; Togashi, Kazutaka; Mutaguchi, Kuninori; Sugiyama, Yuichi

    2015-09-01

    A cassette-microdose (MD) clinical study was performed to demonstrate its usefulness for identifying the most promising compound for oral use. Three Ca-channel blockers (nifedipine, nicardipine, and diltiazem) were chosen as model drugs. In the MD clinical study, a cassette-dose method was employed in which three model drugs were administered simultaneously. Both intravenous (i.v.) and oral (p.o.) administration studies were conducted to calculate the oral bioavailability (BA). For comparison, p.o. studies with therapeutic dose (ThD) levels were also performed. In all studies, blood concentrations of each drug were successfully determined using liquid chromatography-mass spectrometry with the lower limit of quantification of 0.2-2.0 pg/mL. Oral BA of nifedipine in the MD study was approximately 50% and in the same range with that obtained in the ThD study, whereas other two drugs showed significantly lower BA in the MD study, indicating a dose-dependent absorption. In addition, compared with the ThD study, absorption of nicardipine was delayed in the MD study. As a result, nifedipine was considered to be most promising for oral use. In conclusion, a cassette-MD clinical study is of advantage for oral drug development that enables to identify the candidate having desired properties for oral use. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  6. Radio protective effects of calcium channel blockers (Deltiazem) on survival of Saccharomyces cerevisiae cells irradiated with different doses of gamma rays

    Energy Technology Data Exchange (ETDEWEB)

    Alya, G; Shamma, M; Sharabi, N [Atomic Energy Commission, Damascus (Syrian Arab Republic), Dept. of Molecular Biology and Biotechnology

    2007-03-15

    Investigations of radioprotective effects of Deltiazem (as one of the commonly used calcium channel blockers, which is used in the treatment of acute and chronic angina and spasmo angina, in addition to the treatment of different types of essential hypertension) has been carried on Saccharomyces Cerevisiae cells. Cells cultures of the most famous yeast Saccharomyces Cerevisiae (bakers yeast) were irradiated with different doses of gamma rays. Results revealed that the necessary dose of gamma rays that leads to 10% of survived cellular population (D10 value) was about 256 Gy. This irradiation dose was used then in all irradiation experiments on culture of S. Cerevisiae cells in which different concentrations of Deltiazem (55, 110, 165 mg/Kg medium) were added before and after irradiation in order to study the radio protective effect of Deltiazem. Results showed that Deltiazem enhances survival percentage of irradiated S. Cerevisiae cultures in a concentration dependent manner. This study confirmed our previous works, which had demonstrated that Deltiazem protects lethally and supralethally irradiated rats, and enhances survival of pre-irradiated Deltiazem treated animals.(author)

  7. Radio protective effects of calcium channel blockers (Deltiazem) on survival of Saccharomyces cerevisiae cells irradiated with different doses of gamma rays

    International Nuclear Information System (INIS)

    Alya, G.; Shamma, M.; Sharabi, N.

    2007-03-01

    Investigations of radioprotective effects of Deltiazem (as one of the commonly used calcium channel blockers, which is used in the treatment of acute and chronic angina and spasmo angina, in addition to the treatment of different types of essential hypertension) has been carried on Saccharomyces Cerevisiae cells. Cells cultures of the most famous yeast Saccharomyces Cerevisiae (bakers yeast) were irradiated with different doses of gamma rays. Results revealed that the necessary dose of gamma rays that leads to 10% of survived cellular population (D10 value) was about 256 Gy. This irradiation dose was used then in all irradiation experiments on culture of S. Cerevisiae cells in which different concentrations of Deltiazem (55, 110, 165 mg/Kg medium) were added before and after irradiation in order to study the radio protective effect of Deltiazem. Results showed that Deltiazem enhances survival percentage of irradiated S. Cerevisiae cultures in a concentration dependent manner. This study confirmed our previous works, which had demonstrated that Deltiazem protects lethally and supralethally irradiated rats, and enhances survival of pre-irradiated Deltiazem treated animals.(author)

  8. Potential impact of renin-angiotensin system inhibitors and calcium channel blockers on plasma high-molecular-weight adiponectin levels in hemodialysis patients

    International Nuclear Information System (INIS)

    Nakagawa, Naoki; Yao, Naoyuki; Hirayama, Tomoya

    2011-01-01

    Although metabolic syndrome confers an increased risk of cardiovascular disease in the general population, little is known about the alteration of abdominal adiposity and its association with adipocytokines in hemodialysis patients. We investigated the plasma high-molecular-weight (HMW) adiponectin level and its relationship to visceral fat area (VFA) and various markers of atherosclerosis in hemodialysis patients. In a cross-sectional study, conventional cardiovascular risk factors, plasma total and HMW adiponectin, the number of components of the metabolic syndrome and, using computed tomography, the distribution of abdominal adiposity were assessed in 144 hemodialysis patients (90 men and 54 women; mean age, 60.7 years) and 30 age- and sex-matched patients with chronic kidney disease (CKD). Plasma HMW adiponectin levels in hemodialysis patients were significantly higher than those in patients with CKD, negatively associated with VFA and serum triglycerides and positively associated with plasma total adiponectin, as well as the HMW-to-total adiponectin ratio in men and women (all P<0.05) in a simple regression analysis. In a multiple regression analysis, VFA was a significant determinant of HMW adiponectin in hemodialysis patients. Furthermore, after adjustment for classical risk factors, HMW adiponectin levels were significantly higher in patients undergoing treatment with renin-angiotensin system inhibitors or calcium channel blockers compared with patients not undergoing such treatment. This study shows that plasma HMW adiponectin levels were negatively associated with VFA and positively associated with treatment with blockade of the renin-angiotensin system and of the calcium channel. Therefore, these drugs might be effective for improving adipocytokine-related metabolic abnormalities in hemodialysis patients. (author)

  9. Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers

    Directory of Open Access Journals (Sweden)

    P. A. Virych

    2017-05-01

    Full Text Available The development of modern organic chemistry and molecular modeling technologies simplify the search for potential inhibitors of various receptor systems and biological processes. The one of the directions is the development of analgesics of broad spectrum and low toxicity. It is important to search for inhibitors of the kinin-kallikrein system that regulates many functions: inflammation, pain, carcinogenesis, vascular tone, smooth muscle contraction and other. Derivatives of 3-substituted 1,4-benzodiazepine-2-ones have a unique spatial conformation that allows one to simulate β-structures of bioactive peptides. The functional activity of compounds is determined by properties of their peripheral chemical radicals. We analyzed the effect of 3-substituted 1,4-benzodiazepin-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction and relaxation of the stomach in the presence of calcium channel blockers: verapamil (1 μM, gadolinium (300 μM and 2-aminoethyl diphenylborinate (0.1 μM. The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in incubation solution were 10–6 M. Data processing on dynamics of contraction was performed according to the method of Burdyha and Kosterin. Compounds MX-1775 and MX-1925 reduced maximal normalized rate (Vn of bradykinin-induced smooth muscle contraction in the presence of Gd3+ by 21.2% and 31.0% respectively. Compound MX-1925 increased Vn of relaxation by 11.6%. A similar effect is typical for MX-2011, where there is an increase by 34.6%. In the presence of verapamil this compound additionally decreased Vn contraction by 20.5%. Substances MX-1775, MX-2004 and MX-1925 restored maximal normalized rate of relaxation to original values of bradykinin-induced contraction. In the presence of 2-aminoethyldiphenylborinate MX-1775 additionally reduced Vn of contractions by 7.5%. 3-substituted 1,4-benzo­diazepine-2-ones did not change the maximal

  10. K-ATP channel expression and pharmacological in vivo and in vitro studies of the K-ATP channel blocker PNU-37883A in rat middle meningeal arteries

    DEFF Research Database (Denmark)

    Ploug, K.B.; Boni, L.J.; Baun, M.

    2008-01-01

    closed cranial window model and in myograph baths, respectively. Key results: Expression studies indicate that inwardly rectifying K+ (Kir)6.1/sulphonylurea receptor (SUR) 2B is the major K-ATP channel complex in rat MMA. PNU-37883A (0.5 mg kg(-1)) significantly inhibited the in vivo dilatory effect...... of levcromakalim (0.025 mg kg(-1)), pinacidil (0.38 mg kg(-1)) and P-1075 (0.016 mg kg(-1)) in rat MMA. In vitro PNU-37883A significantly inhibited the dilatory responses of the three K-ATP channel openers in rat MMA at 10(-7) and 3 x 10(-7) M. Conclusions and implications: We suggest that Kir6.1/SUR2B...

  11. Osteoarthritis-dependent changes in antinociceptive action of Nav1.7 and Nav1.8 sodium channel blockers: An in vivo electrophysiological study in the rat.

    Science.gov (United States)

    Rahman, W; Dickenson, A H

    2015-06-04

    Voltage-gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA)-induced OA we used in vivo electrophysiology to assess the effects of the Nav1.7- and Nav1.8-selective antagonists, ProTxII and A-803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field. These studies allow examination of the roles of these channels in suprathreshold stimuli, not amenable to behavioral threshold measures. Spinal administration of ProTxII significantly reduced neuronal responses evoked by mechanical punctate (von Frey (vF) 8-60g) and noxious thermal (45 and 48°C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8-60g and 48°C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26-60g and 40-48°C stimuli after systemic administration; significantly inhibited the electrically evoked Aδ-, C-fiber, post-discharge, Input and wind-up responses and the brush, vFs 8-60g and 45-48°C evoked neuronal responses after intra plantar injection in the MIA group. In comparison A-803467 effects in the sham group were minimal and included a reduction of the neuronal response evoked by vF 60g and 45°C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45°C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA-treated group suggests an increased role of Nav1.7 and 1.8 within nociceptive pathways in the arthritic condition, located at peripheral and central sites. These findings demonstrate the importance of, and add to, the mechanistic understanding of these channels in

  12. Alterations in expression of Cat-315 epitope of perineuronal nets during normal ageing, and its modulation by an open-channel NMDA receptor blocker, memantine.

    Science.gov (United States)

    Yamada, Jun; Ohgomori, Tomohiro; Jinno, Shozo

    2017-06-15

    The perineuronal net (PNN), a specialized aggregate of the extracellular matrix, is involved in neuroprotection against oxidative stress, which is now recognized as a major contributor to age-related decline in brain functions. In this study, we investigated the age-related molecular changes of PNNs using monoclonal antibody Cat-315, which recognizes human natural killer-1 (HNK-1) glycan on aggrecan-based PNNs. Western blot analysis showed that the expression levels of Cat-315 epitope in the hippocampus were higher in middle-aged (MA, 12-month-old) mice than in young adult (YA, 2-month-old) mice. Although there were no differences in the expression levels of Cat-315 epitope between old age (OA, 20-month-old) and MA mice, Cat-315 immunoreactivity was also detected in astrocytes of OA mice. To focus on Cat-315 epitope in PNNs, we used YA and MA mice in the following experiments. Optical disector analysis showed that there were no differences in the numbers of Cat-315-positive (Cat-315 + ) PNNs between YA and MA mice. Fluorescence intensity analysis indicated that Cat-315 immunoreactivity in PNNs increased with age in the dorsal hippocampus, which is mainly involved in cognitive functions. Administration of an open-channel blocker of NMDA receptor, memantine, reduced the expression levels of Cat-315 epitope in the hippocampus. Furthermore, the numbers of glutamatergic and GABAergic terminals colocalized with Cat-315 epitope around parvalbumin-positive neurons were decreased by memantine. These findings provide novel insight into the involvement of PNNs in normal brain ageing, and suggest that memantine may counteract the age-related alterations in expression levels of Cat-315 epitope via regulation of its subcellular localization. © 2017 Wiley Periodicals, Inc.

  13. Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment.

    Science.gov (United States)

    Sakurai, Yasuteru; Kolokoltsov, Andrey A; Chen, Cheng-Chang; Tidwell, Michael W; Bauta, William E; Klugbauer, Norbert; Grimm, Christian; Wahl-Schott, Christian; Biel, Martin; Davey, Robert A

    2015-02-27

    Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy. Copyright © 2015, American Association for the Advancement of Science.

  14. Copper-induced activation of TRP channels promotes extracellular calcium entry and activation of CaMs and CDPKs leading to copper entry and membrane depolarization in Ulva compressa

    Directory of Open Access Journals (Sweden)

    Melissa eGómez

    2015-03-01

    Full Text Available In order to identify channels involved in membrane depolarization, Ulva compressa was incubated with agonists of TRP channels C5, A1 and V1 and the level of intracellular calcium was detected. Agonists of TRPC5, A1 and V1 induced increases in intracellular calcium at 4, 9 and 12 min of exposure, respectively, and antagonists of TRPC5, A1 and V1 corresponding to SKF-96365 (SKF, HC-030031 (HC and capsazepin (CPZ, respectively, inhibited calcium increases indicating that functional TRPs exist in U. compressa. In addition, copper excess induced increases in intracellular calcium at 4, 9 and 12 min which were inhibited by SKF, HC and CPZ, respectively, indicating that copper activate TRPC5, A1 and V1 channels. Moreover, copper-induced calcium increases were inhibited by EGTA, a non-permeable calcium chelating agent, but not by thapsigargin, an inhibitor of endoplasmic reticulum (ER calcium ATPase, indicating that activation of TRPs leads to extracellular calcium entry. Furthermore, copper-induced calcium increases were not inhibited by W-7, an inhibitor of CaMs, and staurosporine, an inhibitor of CDPKs, indicating that extracellular calcium entry did not require CaMs and CDPKs activation. In addition, copper induced membrane depolarization events at 4, 8 and 11 min and these events were inhibited by SKF, HC, CPZ and bathocuproine, a specific copper chelating agent, indicating copper entry through TRP channels leading to membrane depolarization. Moreover, membrane depolarization events were inhibited by W-7 and staurosporine, indicating that CaMs and CDPKs are required in order to activate TRPs to allow copper entry. Thus, light-dependent copper-induced activation TRPC5, A1 and V1 promotes extracellular calcium entry leading to activation of CaMs and CDPKs which, in turn, promotes copper entry through these TRP channels leading to membrane depolarization.

  15. Calcium Channel Blockers in Secondary Cardiovascular Prevention and Risk of Acute Events: Real-World Evidence from Nested Case-Control Studies on Italian Hypertensive Elderly.

    Science.gov (United States)

    Bettiol, Alessandra; Lucenteforte, Ersilia; Vannacci, Alfredo; Lombardi, Niccolò; Onder, Graziano; Agabiti, Nera; Vitale, Cristiana; Trifirò, Gianluca; Corrao, Giovanni; Roberto, Giuseppe; Mugelli, Alessandro; Chinellato, Alessandro

    2017-12-01

    Antihypertensive treatment with calcium channel blockers (CCBs) is consolidated in clinical practice; however, different studies observed increased risks of acute events for short-acting CCBs. This study aimed to provide real-world evidence on risks of acute cardiovascular (CV) events, hospitalizations and mortality among users of different CCB classes in secondary CV prevention. Three case-control studies were nested in a cohort of Italian elderly hypertensive CV-compromised CCBs users. Cases were subjects with CV events (n = 25,204), all-cause hospitalizations (n = 19,237), or all-cause mortality (n = 17,996) during the follow-up. Up to four controls were matched for each case. Current or past exposition to CCBs at index date was defined based on molecule, formulation and daily doses of the last CCB delivery. The odds ratio (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Compared to past users, current CCB users had significant reductions in risks of CV events [OR 0.88 (95% CI: 0.84-0.91)], hospitalization [0.90 (0.88-0.93)] and mortality [0.48 (0.47-0.49)]. Current users of long-acting dihydropyridines (DHPs) had the lowest risk [OR 0.87 (0.84-0.90), 0.86 (0.83-0.90), 0.55 (0.54-0.56) for acute CV events, hospitalizations and mortality], whereas current users of short-acting CCBs had an increased risk of acute CV events [OR 1.77 (1.13-2.78) for short-acting DHPs; 1.19 (1.07-1.31) for short-acting non-DHPs] and hospitalizations [OR 1.84 (0.96-3.51) and 1.23 (1.08-1.42)]. The already-existing warning on short-acting CCBs should be potentiated, addressing clinicians towards the choice of long-acting formulations.

  16. Reduced myocardial 18F-FDG uptake after calcium channel blocker administration. Initial observation for a potential new method to improve plaque detection

    International Nuclear Information System (INIS)

    Gaeta, Chiara; Flotats, Albert; Artigas, Carles; Deportos, Jordi; Geraldo, Llanos; Carrio, Ignasi; Fernandez, Yolanda; Pavia, Javier

    2011-01-01

    Physiological glucose uptake by the myocardium may hamper visualization of coronary atherosclerotic plaques in 18 F-FDG PET studies. Intracellular myocardial calcium relates to glucose influx. We assessed whether administration of a calcium channel blocker such as verapamil could decrease myocardial 18 F-FDG uptake in mice. Experiments were conducted on ten male C57BL/6JOlaHsd mice. The mice were studied by 18 F-FDG PET/CT under basal conditions and after a single administration of verapamil injected 1 h prior to 18 F-FDG administration at doses of 1 mg/kg (group A, n = 5) and 20 mg/kg (group B, n = 5). PET scanning was started 60 min after injection of 18 F-FDG employing a dedicated small-animal PET/CT system (ARGUS-CT). In each mouse, post-verapamil PET images were coregistered with the basal PET images. Volumetric regions of interest (VOI) were drawn on the basal study containing the myocardium of the whole left ventricle and quantitatively compared with the same VOI applied to the post-verapamil scan. The SUV mean was used to express the mean myocardial 18 F-FDG uptake. The relative coefficient of variation (RV) between the basal and post-verapamil conditions was calculated. Verapamil administration decreased myocardial 18 F-FDG uptake in all animals. The median (range) SUV mean values in group A were 2.6 (1.6-4.1) under basal conditions and 1.7 (1.1-2.9) after verapamil administration (p = 0.043), and in group B were 1.6 (1.3-2.0) under basal conditions and 1.0 (0.9-1.4) after verapamil administration (p = 0.043). The median (range) RV values were -31% (-5%, -50%) in group A, and -37% (-10%, -51%) in group B (p = 0.6). In this animal model there was a significant reduction in 18 F-FDG uptake in the myocardium following verapamil administration. This type of intervention could facilitate the definition of coronary atherosclerotic plaque inflammation on 18 F-FDG PET scans. (orig.)

  17. Calcium paradox and calcium entry blockers

    NARCIS (Netherlands)

    Ruigrok, T.J.C.; Slade, A.M.; Nayler, W.G.; Meijler, F.L.

    1984-01-01

    Reperfusion of isolated hearts with calcium-containing solution after a short period of calcium-free perfusion results in irreversible cell damage (calcium paradox). This phenomenon is characterized by an excessive influx of calcium into the cells, the rapid onset of myocardial contracture,

  18. T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers.

    Directory of Open Access Journals (Sweden)

    Wai-Ping Fung-Leung

    Full Text Available Kv1.3 is a voltage-gated potassium channel expressed on T cells that plays an important role in T cell activation. Previous studies have shown that blocking Kv1.3 channels in human T cells during activation results in reduced calcium entry, cytokine production, and proliferation. The aim of the present study was to further explore the effects of Kv1.3 blockers on the response of different human T cell subsets under various stimulation conditions. Our studies show that, unlike the immune suppressor cyclosporine A, the inhibitory effect of Kv1.3 blockers was partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulations. T cell responses to allergens including house dust mites and ragweed were partially reduced by Kv1.3 blockers. The effect of Kv1.3 inhibition was dependent on T cell subsets, with stronger effects on CCR7- effector memory compared to CCR7+ central memory CD4 T cells. Calcium entry studies also revealed a population of CD4 T cells resistant to Kv1.3 blockade. Activation of CD4 T cells was accompanied with an increase in Kv1.3 currents but Kv1.3 transcripts were found to be reduced, suggesting a posttranscriptional mechanism in the regulation of Kv1.3 activities. In summary, Kv1.3 blockers inhibit T cell activation in a manner that is highly dependent on the T cell identity and stimulation strength, These findings suggest that Kv1.3 blockers inhibit T cells in a unique, conditional manner, further refining our understanding of the therapeutic potential of Kv1.3 blockers.

  19. Efficacy and safety of a therapeutic interchange from high-dose calcium channel blockers to a fixed-dose combination of amlodipine/benazepril in patients with moderate-to-severe hypertension.

    Science.gov (United States)

    Hilleman, D E; Reyes, A P; Wurdeman, R L; Faulkner, M

    2001-08-01

    Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination

  20. NERVE EXCITABILITY CHANGES AFTER NA(V)1.8 CHANNEL BLOCKER TREATMENT IN MICE DEFICIENT OF MYELIN PROTEIN P-0

    DEFF Research Database (Denmark)

    Moldovan, M.; Rosberg, M. R.; Alvarez Herrero, Susana

    2016-01-01

    Mice deficient of myelin protein zero (P0) are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Recent work form our laboratory indicated that in severely affected P0−/− as well as in P0+/− (modeling CMT1B), the neuropathy is aggravated by associated changes in voltage...... function up to 2 hours after the blockers. Overall, the baseline excitability measures were much more abnormal in P0−/− at 4 months as compared to P0+/− at 20 months. Nevertheless, in both models, the NaV1.8 blockers produced similar deviations in excitability at a dose of 100 mg/Kg. Most notably...

  1. Intrathecal infusion of a Ca(2+)-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS.

    Science.gov (United States)

    Yin, Hong Z; Tang, Darryl T; Weiss, John H

    2007-10-01

    Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca(2+)-permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca(2+) overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild-type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90-100 days) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham-treated G93A animals, 30-day NAS infusions (starting at 67+/-2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes.

  2. Misperceptions About β-Blockers and Diuretics

    Science.gov (United States)

    Ubel, Peter A; Jepson, Christopher; Asch, David A

    2003-01-01

    BACKGROUND Based on a series of clinical trials showing no difference in the effectiveness or tolerability of most major classes of antihypertensive medications, the Joint National Commission on High Blood Pressure Treatment recommends that physicians prescribe β-blockers or diuretics as initial hypertensive therapy unless there are compelling indications for another type of medication. Nevertheless, many physicians continue to favor more expensive medications like angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as first line agents. The persistent use of these agents raises questions as to whether physicians perceive ACE inhibitors and calcium channel blockers to be better than β-blockers and diuretics. METHODS We surveyed 1,200 primary care physicians in 1997, and another 500 primary care physicians in 2000, and asked them to estimate the relative effectiveness and side effects of 4 classes of medication in treating a hypothetical patient with uncomplicated hypertension: ACE inhibitors, β-blockers, calcium channel blockers, and diuretics. In addition, we asked them to indicate whether they ever provided free samples of hypertension medications to their patients. RESULTS Perceptions of the relative effectiveness and side effects of the 4 classes of hypertension medications did not significantly change over the 3 years, nor did prescription recommendations. Physicians perceive that diuretics are less effective at lowering blood pressure than the other 3 classes (P diuretics were less effective and β-blockers were less tolerated than other medications. Moreover, their prescription practices were associated with their provision of free samples provided by pharmaceutical representatives, even after adjusting for other demographic characteristics. Efforts to increase physicians' prescribing of β-blockers and diuretics may need to be directed at overcoming misunderstandings about the effectiveness and tolerability of these medicines

  3. A New Baroreceptor Sensitivity-Restoring Ca-Channel Blocker Diminishes Age-Related Morning Blood Pressure Increase in Hypertensive Patients: Open-Label Monitoring of Azelnidipine Treatment for Hypertension in the Early Morning (At-HOME Study

    Directory of Open Access Journals (Sweden)

    Mitsunori Sugiyama

    2010-01-01

    Full Text Available Background: Morning blood pressure (BP surge, which exhibits an age-related increase, is a risk factor for stroke in elderly hypertensive patients, independently of the 24-h BP level. We studied the effect of the new baroreceptor sensitivity (BRS-restoring Ca-channel blocker (CCB azelnidipine (AZ on this age-related morning BP increase. Methods: We conducted a 16-week prospective study to clarify the effect of morning dosing of AZ on home BPs measured in the morning and in the evening in 2,546 hypertensive patients (mean age, 65.1 years; female, 53.6%. Results: At baseline, ME-Dif (morning systolic BP [SBP]–evening SBP increased with age, independently of ME-Ave (average of the morning and evening SBPs. This age-related increase of ME-Dif was exaggerated by regular alcohol drinking and beta-blocker use. After AZ treatment (14.3 ± 3.6 mg/day, ME-AV and ME-Dif were significantly reduced independently of each other, with reductions of –18.1 ± 15.6 and –2.5 ± 13.2 mmHg, respectively (both p < 0.001. AZ treatment decreased age-related increase in ME-Dif particularly in patients who were regular consumers of alcohol and in beta-blocker users. Conclusions: The new BRS-restoring CCB AZ significantly reduced age-related increase in morning BP and had some potential benefit on cardiovascular protection in hypertension, particularly in elderly patients and/or consumers of alcohol.

  4. Beta-blockers

    DEFF Research Database (Denmark)

    Arboe, Bente; Ulrik, Charlotte Suppli

    2013-01-01

    Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.......Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma....

  5. An open-label, randomized, controlled, 4-week comparative clinical trial of barnidipine hydrochloride, a calcium-channel blocker, and benazepril, an angiotensin-converting enzyme inhibitor, in Chinese patients with renal parenchymal hypertension.

    Science.gov (United States)

    Chen, X; Zheng, F; Chen, P; Tang, L; Wei, R; Yu, Y; Su, Y; Kikkawa, T; Yamamoto, M

    2006-01-01

    This study compared barnidipine, a calcium-channel blocker, and benazepril, an angiotensin-converting enzyme inhibitor, in 85 Chinese patients with renal parenchymal hypertension (diastolic blood pressure range 95 - 110 mmHg). Patients were randomly assigned to receive either 10 mg barnidipine or 10 mg benazepril orally daily for 4 weeks. In patients with diastolic blood pressure > 90 mmHg after 2 weeks of treatment, the dose of barnidipine or benazepril was increased by 5 or 10 mg, respectively. Both the barnidipine-treated group (n = 43) and the benazepril-treated group (n = 42) showed significant mean reductions from baseline in sitting systolic and diastolic blood pressures. The decrease in diastolic blood pressure with benazepril was significantly greater than with barnidipine treatment. Sitting heart rate was not changed by either drug. There was no significant difference in adverse events between the two groups. Barnidipine is similar to benazepril for the treatment of renal parenchymal hypertension.

  6. Pharmacovigilance database search discloses ClC-K channels as a novel target of the AT1 receptor blockers valsartan and olmesartan.

    Science.gov (United States)

    Imbrici, Paola; Tricarico, Domenico; Mangiatordi, Giuseppe Felice; Nicolotti, Orazio; Lograno, Marcello Diego; Conte, Diana; Liantonio, Antonella

    2017-07-01

    Human ClC-K chloride channels are highly attractive targets for drug discovery as they have a variety of important physiological functions and are associated with genetic disorders. These channels are crucial in the kidney as they control chloride reabsorption and water diuresis. In addition, loss-of-function mutations of CLCNKB and BSND genes cause Bartter's syndrome (BS), whereas CLCNKA and CLCNKB gain-of-function polymorphisms predispose to a rare form of salt sensitive hypertension. Both disorders lack a personalized therapy that is in most cases only symptomatic. The aim of this study was to identify novel ClC-K ligands from drugs already on the market, by exploiting the pharmacological side activity of drug molecules available from the FDA Adverse Effects Reporting System database. We searched for drugs having a Bartter-like syndrome as a reported side effect, with the assumption that BS could be causatively related to the block of ClC-K channels. The ability of the selected BS-causing drugs to bind and block ClC-K channels was then validated through an integrated experimental and computational approach based on patch clamp electrophysiology in HEK293 cells and molecular docking simulations. Valsartan and olmesartan were able to block ClC-Ka channels and the molecular requirements for effective inhibition of these channels have been identified. These results suggest additional mechanisms of action for these sartans further to their primary AT 1 receptor antagonism and propose these compounds as leads for designing new potent ClC-K ligands. © 2017 The British Pharmacological Society.

  7. Dental enamel cells express functional SOCE channels.

    Science.gov (United States)

    Nurbaeva, Meerim K; Eckstein, Miriam; Concepcion, Axel R; Smith, Charles E; Srikanth, Sonal; Paine, Michael L; Gwack, Yousang; Hubbard, Michael J; Feske, Stefan; Lacruz, Rodrigo S

    2015-10-30

    Dental enamel formation requires large quantities of Ca(2+) yet the mechanisms mediating Ca(2+) dynamics in enamel cells are unclear. Store-operated Ca(2+) entry (SOCE) channels are important Ca(2+) influx mechanisms in many cells. SOCE involves release of Ca(2+) from intracellular pools followed by Ca(2+) entry. The best-characterized SOCE channels are the Ca(2+) release-activated Ca(2+) (CRAC) channels. As patients with mutations in the CRAC channel genes STIM1 and ORAI1 show abnormal enamel mineralization, we hypothesized that CRAC channels might be an important Ca(2+) uptake mechanism in enamel cells. Investigating primary murine enamel cells, we found that key components of CRAC channels (ORAI1, ORAI2, ORAI3, STIM1, STIM2) were expressed and most abundant during the maturation stage of enamel development. Furthermore, inositol 1,4,5-trisphosphate receptor (IP3R) but not ryanodine receptor (RyR) expression was high in enamel cells suggesting that IP3Rs are the main ER Ca(2+) release mechanism. Passive depletion of ER Ca(2+) stores with thapsigargin resulted in a significant raise in [Ca(2+)]i consistent with SOCE. In cells pre-treated with the CRAC channel blocker Synta-66 Ca(2+) entry was significantly inhibited. These data demonstrate that enamel cells have SOCE mediated by CRAC channels and implicate them as a mechanism for Ca(2+) uptake in enamel formation.

  8. Use of drug therapy in the management of symptomatic ureteric stones in hospitalized adults (SUSPEND), a multicentre, placebo-controlled, randomized trial of a calcium-channel blocker (nifedipine) and an α-blocker (tamsulosin): study protocol for a randomized controlled trial

    Science.gov (United States)

    2014-01-01

    Background Urinary stone disease is common, with an estimated prevalence among the general population of 2% to 3%. Ureteric stones can cause severe pain and have a significant impact on quality of life, accounting for over 15,000 hospital admissions in England annually. Uncomplicated cases of smaller stones in the lower ureter are traditionally treated expectantly. Those who fail standard care or develop complications undergo active treatment, such as extracorporeal shock wave lithotripsy or ureteroscopy with stone retrieval. Such interventions are expensive, require urological expertise and carry a risk of complications. Growing understanding of ureteric function and pathophysiology has led to the hypothesis that drugs causing relaxation of ureteric smooth muscle, such as the selective α-blocker tamsulosin and the calcium-channel blocker nifedipine, can enhance the spontaneous passage of ureteric stones. The use of drugs in augmenting stone passage, reducing the morbidity and costs associated with ureteric stone disease, is promising. However, the majority of clinical trials conducted to date have been small, poor to moderate quality and lacking in comprehensive economic evaluation. This trial aims to determine the clinical and cost-effectiveness of tamsulosin and nifedipine in the management of symptomatic urinary stones. Methods/design The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial is a multicentre, double-blind, randomized controlled trial evaluating two medical expulsive therapy strategies (nifedipine or tamsulosin) versus placebo. Patients aged 18 to 65 with a ureteric stone confirmed by non-contrast computed tomography of the kidney, ureter and bladder will be randomized to receive nifedipine, tamsulosin or placebo (400 participants per arm) for a maximum of 28 days. The primary clinical outcome is spontaneous passage of ureteric stones at 4 weeks (defined as no further intervention required to facilitate stone passage). The

  9. Use of drug therapy in the management of symptomatic ureteric stones in hospitalized adults (SUSPEND), a multicentre, placebo-controlled, randomized trial of a calcium-channel blocker (nifedipine) and an α-blocker (tamsulosin): study protocol for a randomized controlled trial.

    Science.gov (United States)

    McClinton, Sam; Starr, Kathryn; Thomas, Ruth; McLennan, Graeme; McPherson, Gladys; McDonald, Alison; Lam, Thomas; N'Dow, James; Kilonzo, Mary; Pickard, Robert; Anson, Ken; Burr, Jennifer

    2014-06-20

    Urinary stone disease is common, with an estimated prevalence among the general population of 2% to 3%. Ureteric stones can cause severe pain and have a significant impact on quality of life, accounting for over 15,000 hospital admissions in England annually. Uncomplicated cases of smaller stones in the lower ureter are traditionally treated expectantly. Those who fail standard care or develop complications undergo active treatment, such as extracorporeal shock wave lithotripsy or ureteroscopy with stone retrieval. Such interventions are expensive, require urological expertise and carry a risk of complications.Growing understanding of ureteric function and pathophysiology has led to the hypothesis that drugs causing relaxation of ureteric smooth muscle, such as the selective α-blocker tamsulosin and the calcium-channel blocker nifedipine, can enhance the spontaneous passage of ureteric stones. The use of drugs in augmenting stone passage, reducing the morbidity and costs associated with ureteric stone disease, is promising. However, the majority of clinical trials conducted to date have been small, poor to moderate quality and lacking in comprehensive economic evaluation.This trial aims to determine the clinical and cost-effectiveness of tamsulosin and nifedipine in the management of symptomatic urinary stones. The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial is a multicentre, double-blind, randomized controlled trial evaluating two medical expulsive therapy strategies (nifedipine or tamsulosin) versus placebo.Patients aged 18 to 65 with a ureteric stone confirmed by non-contrast computed tomography of the kidney, ureter and bladder will be randomized to receive nifedipine, tamsulosin or placebo (400 participants per arm) for a maximum of 28 days. The primary clinical outcome is spontaneous passage of ureteric stones at 4 weeks (defined as no further intervention required to facilitate stone passage). The primary economic outcome is a

  10. The Nitric Oxide Donor SNAP-Induced Amino Acid Neurotransmitter Release in Cortical Neurons. Effects of Blockers of Voltage-Dependent Sodium and Calcium Channels

    Science.gov (United States)

    Merino, José Joaquín; Arce, Carmen; Naddaf, Ahmad; Bellver-Landete, Victor; Oset-Gasque, Maria Jesús; González, María Pilar

    2014-01-01

    Background The discovery that nitric oxide (NO) functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated. Findings The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA) in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated. Conclusions Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons. PMID:24598811

  11. The nitric oxide donor SNAP-induced amino acid neurotransmitter release in cortical neurons. Effects of blockers of voltage-dependent sodium and calcium channels.

    Science.gov (United States)

    Merino, José Joaquín; Arce, Carmen; Naddaf, Ahmad; Bellver-Landete, Victor; Oset-Gasque, Maria Jesús; González, María Pilar

    2014-01-01

    The discovery that nitric oxide (NO) functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated. The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA) in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated. Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons.

  12. The nitric oxide donor SNAP-induced amino acid neurotransmitter release in cortical neurons. Effects of blockers of voltage-dependent sodium and calcium channels.

    Directory of Open Access Journals (Sweden)

    José Joaquín Merino

    Full Text Available The discovery that nitric oxide (NO functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated.The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated.Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons.

  13. Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

    International Nuclear Information System (INIS)

    Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

    2009-01-01

    The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPAR-γ). Although nifedipine did not affect expression levels of PPAR-γ, it increased the PPAR-γ transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-γ activation.

  14. The structurally novel Ca2+ channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts

    International Nuclear Information System (INIS)

    Clozel, J.P.; Veniant, M.; Osterrieder, W.

    1990-01-01

    Ro 40-5967 is a structurally novel Ca 2+ channel blocker that binds to the verapamil-type receptor of cardiac membranes but that has been shown in isolated guinea-pig hearts to be about ten times less potent a negative inotropic agent than verapamil. The goals of the present study were to confirm these findings in vitro in isolated perfused rat hearts as well as in vivo in conscious rats and to compare Ro 40-5967 to verapamil. The effects of Ro 40-5967 and verapamil were tested not only in normal rats, but also in rats with heart failure induced by chronic myocardial infarction. In isolated Langendorff hearts (without heart failure), no decrease of contractility was observed with Ro 40-5967 up to complete AV block. In contrast, verapamil decreased contractility with an IC50 of 100 nM. In isolated, electrically stimulated rat papillary muscles, the IC50 values for the decrease of contractile force were 15,000 and 440 nM for Ro 40-5967 and verapamil, respectively. In vivo, Ro 40-5967 did not decrease left ventricular contractility (as assessed by changes of dP/dt max +) in rats without and with heart failure. In contrast, verapamil was markedly negative inotropic in both conditions

  15. An Improved Targeted cAMP Sensor to Study the Regulation of Adenylyl Cyclase 8 by Ca2+ Entry through Voltage-Gated Channels

    Science.gov (United States)

    Everett, Katy L.; Cooper, Dermot M. F.

    2013-01-01

    Here we describe an improved sensor with reduced pH sensitivity tethered to adenylyl cyclase (AC) 8. The sensor was used to study cAMP dynamics in the AC8 microdomain of MIN6 cells, a pancreatic β-cell line. In these cells, AC8 was activated by Ca2+ entry through L-type voltage-gated channels following depolarisation. This activation could be reconstituted in HEK293 cells co-expressing AC8 and either the α1C or α1D subunit of L-type voltage-gated Ca2+ channels. The development of this improved sensor opens the door to the study of cAMP microdomains in excitable cells that have previously been challenging due to the sensitivity of fluorescent proteins to pH changes. PMID:24086669

  16. An improved targeted cAMP sensor to study the regulation of adenylyl cyclase 8 by Ca2+ entry through voltage-gated channels.

    Directory of Open Access Journals (Sweden)

    Katy L Everett

    Full Text Available Here we describe an improved sensor with reduced pH sensitivity tethered to adenylyl cyclase (AC 8. The sensor was used to study cAMP dynamics in the AC8 microdomain of MIN6 cells, a pancreatic β-cell line. In these cells, AC8 was activated by Ca(2+ entry through L-type voltage-gated channels following depolarisation. This activation could be reconstituted in HEK293 cells co-expressing AC8 and either the α1C or α1D subunit of L-type voltage-gated Ca(2+ channels. The development of this improved sensor opens the door to the study of cAMP microdomains in excitable cells that have previously been challenging due to the sensitivity of fluorescent proteins to pH changes.

  17. Creating a marketing channels strategy for European market entry: a case study for eloSpaces Oy

    OpenAIRE

    Babanina, Daria

    2016-01-01

    This thesis is produced as a case study for eloSpaces, Finnish-Chinese startup company based in Espoo, Finland. eloSpaces develops a unique capsule for people to do the focus work and enjoy privacy. The home market for eloSpaces is China and their current aim is to enter also European market in the nearest future. Therefore, the main objective for thesis was to identify the shortest and most efficient market entry strategy for the full product launch in Europe with highest impact on profits. ...

  18. Effect of calcium channels blockers and inhibitors of the renin-angiotensin system on renal outcomes and mortality in patients suffering from chronic kidney disease: systematic review and meta-analysis.

    Science.gov (United States)

    Zhao, Hong-Jin; Li, Yan; Liu, Shan-Mei; Sun, Xiang-Guo; Li, Min; Hao, Yan; Cui, Lian-Qun; Wang, Ai-Hong

    2016-07-01

    The renoprotective effect of inhibitors of renin-angiotensin system (RAS) has been identified through placebo-controlled trials. However, the effect of calcium-channel blockers (CCBs) on renal system is still controversial. Our current meta-analysis includes available evidences to compare the effect of dihydropyridine CCBs and ACEIs or ARBs on renal outcomes and mortality. We also further investigate whether CCBs can be used in combination with inhibitors of RAS to improve the prognosis of patients with chronic kidney disease (CKD). Electronic databases were searched up to July 2012, for clinical randomized controlled trials, assessing the effect of dihydropyridine CCBs on the incidence of end-stage renal disease (ESRD) and all-cause mortality in contrast to ACEIs or ARBs. Eight clinical trials were included containing 25,647 participants. ESRD showed significantly higher frequency with CCBs therapy compared with ACEIs or ARBs therapy, though blood pressure was decreased similarly in both groups in every trial (OR, 1.25; 95% CI, 1.05-1.48; p = 0.01). In contrast, there was no significant difference in the incidence of all-cause mortality between these two groups, though ACEIs or ARBs exhibited better renoprotective effect compared to CCBs (OR, 0.96; 95% CI, 0.89-1.03; p = 0.24). CCBs did not increase all-cause mortality incidence in patients with CKD though they displayed weaker renoprotective, compared to ACEIs or ARBs therapy. Our results suggest the combination of a CCB and an ACEI or ARB should be a preferable antihypertensive therapy in patients with CKD, considering their higher effect in decreasing blood pressure and fewer adverse metabolic problems caused.

  19. The Effects of Arterial Blood Pressure Reduction on Endocan and Soluble Endothelial Cell Adhesion Molecules (CAMs and CAMs Ligands Expression in Hypertensive Patients on Ca-Channel Blocker Therapy

    Directory of Open Access Journals (Sweden)

    Refmir Tadzic

    2013-04-01

    Full Text Available Background/Aims: To determine the effect of arterial blood pressure (BP reduction on endocan and soluble cell adhesion molecules' (sCAM plasma concentration and expression of their ligands on circulatory leukocyte subpopulations. Methods: 24 hypertensive subjects of both sexes (age: 53±8 yrs were treated with Ca-channel blocker, amlodipin (5-10 mg/day for 8 weeks; to reach BP≤139/89mmHg. The serum sCAMs and endocan concentrations were determined by ELISA kits. Level of ICAM/VCAM ligands on leukocytes was assessed by flow cytometry. Paired t-test, or t-test were used as appropriate, with Pearson's correlation calculated; pResults: sICAM-1 and sVCAM-1 were decreased (p≤0.001 and p=0.002, respectively, while E-selectin concentration was increased after amlodipin treatment (P=0.014. CD11a/LFA-1 (ICAM-1 and endocan ligand was significantly increased in all three cell types with BP decrease. CD15 and CD49d/VLA-4 (VCAM-1 ligand did not change after the treatment. There was significant positive correlation of systolic and diastolic BP with ICAM-1 and VCAM-1, and significant negative correlation of systolic BP with CD11a/LFA-1. Endocan significantly positively correlated with ICAM-1. Conclusions: The increased expression of ICAM/VACM ligands, together with decrease of sCAMs and endocan suggests the de-activation of endothelium with reduction in BP, decreasing the adherence of circulatory leukocytes to endothelium; subsequently decreasing the risk for development of atherosclerosis.

  20. Azelnidipine, a long-acting calcium channel blocker, could control hypertension without decreasing cerebral blood flow in post-ischemic stroke patients. A 123I-IMP SPECT follow-up study

    International Nuclear Information System (INIS)

    Watanabe, Masaki; Hirano, Teruyuki; Okamoto, Sadahisa; Shiraishi, Shinya; Uchino, Makoto; Tomiguchi, Seiji

    2010-01-01

    Azelnidipine, a long-acting calcium channel blocker, is highly lipid soluble and selective for the vascular wall, and is expected to have an increasing effect on cerebral blood flow (CBF). The aim of this study is to investigate its safety and efficacy in stroke patients in the chronic stage as far as CBF is concerned using N-isopropyl-p- 123 I-iodo amphetamine ( 123 I-IMP) single-photon emission computed tomography (SPECT). The patients were orally administered 8 or 16 mg of azelnidipine. Regional CBF was evaluated by 123 I-IMP SPECT using three-dimensional stereotactic region-of-interest (ROI) template (3D-SRT), a technique using anatomical standardization and ROI template consisting of 636 ROIs for the whole brain. Mean hemispheric CBF was defined as the mean value of the corpus callosum, and the precentral, central, parietal, angular and temporal gyri. Mean hemispheric and regional CBF after 1, 3 and 6 months were analyzed using a one-way repeated-measures analysis of variance. Ten post-ischemic stroke patients with hypertension were enrolled between October 2005 and October 2007, and all of them were well controlled with normal blood pressure (before: 172.3±16.6/88.4±14.0 mm Hg; 6 months: 128.7±15.9/70.9±10.1 mm Hg). No vascular events were observed during the study period. The mean hemispheric CBF was maintained during the study period (before: 46.0±9.7 ml per 100 g per min; 6 months: 49.3±11.1 ml per 100 g per min). The regional CBF was also maintained. In the chronic stage of ischemic stroke, azelnidipine could safely decrease systemic blood pressure without decreasing CBF. (author)

  1. Pharmacogenetics of β-Blockers

    Science.gov (United States)

    Shin, Jaekyu; Johnson, Julie A.

    2009-01-01

    β-Blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a β-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to β-blockers. This review summarizes the pharmacogenetic data for β-blockers in patients with various diseases and discusses the potential implications of β-blocker pharmacogenetics in clinical practice. PMID:17542770

  2. Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats.

    Science.gov (United States)

    Ghazizadeh, Vahid; Nazıroğlu, Mustafa

    2014-09-01

    Incidence rates of epilepsy and use of Wi-Fi worldwide have been increasing. TRPV1 is a Ca(2+) permeable and non-selective channel, gated by noxious heat, oxidative stress and capsaicin (CAP). The hyperthermia and oxidant effects of Wi-Fi may induce apoptosis and Ca(2+) entry through activation of TRPV1 channel in epilepsy. Therefore, we tested the effects of Wi-Fi (2.45 GHz) exposure on Ca(2+) influx, oxidative stress and apoptosis through TRPV1 channel in the murine dorsal root ganglion (DRG) and hippocampus of pentylentetrazol (PTZ)-induced epileptic rats. Rats in the present study were divided into two groups as controls and PTZ. The PTZ groups were divided into two subgroups namely PTZ + Wi-Fi and PTZ + Wi-Fi + capsazepine (CPZ). The hippocampal and DRG neurons were freshly isolated from the rats. The DRG and hippocampus in PTZ + Wi-Fi and PTZ + Wi-Fi + CPZ groups were exposed to Wi-Fi for 1 hour before CAP stimulation. The cytosolic free Ca(2+), reactive oxygen species production, apoptosis, mitochondrial membrane depolarization, caspase-3 and -9 values in hippocampus were higher in the PTZ group than in the control although cell viability values decreased. The Wi-Fi exposure induced additional effects on the cytosolic Ca(2+) increase. However, pretreatment of the neurons with CPZ, results in a protection against epilepsy-induced Ca(2+) influx, apoptosis and oxidative damages. In results of whole cell patch-clamp experiments, treatment of DRG with Ca(2+) channel antagonists [thapsigargin, verapamil + diltiazem, 2-APB, MK-801] indicated that Wi-Fi exposure induced Ca(2+) influx via the TRPV1 channels. In conclusion, epilepsy and Wi-Fi in our experimental model is involved in Ca(2+) influx and oxidative stress-induced hippocampal and DRG death through activation of TRPV1 channels, and negative modulation of this channel activity by CPZ pretreatment may account for the neuroprotective activity against oxidative stress.

  3. Effects of beta-blockers and nicardipine on oxotremorine-induced tremor in common marmosets.

    Science.gov (United States)

    Mitsuda, M; Nomoto, M; Iwata, S

    1999-10-01

    Effects of beta-blockers (propranolol, arotinolol and nipradilol) and a Ca2+ channel blocker (nicardipine) on oxotremorine-induced tremor were studied in common marmosets. Generalized tremor was elicited by an intraperitoneal administration of 0.25 mg/kg oxotremorine. Intensity of the tremor was classified into 7 degrees, and it was evaluated every 10 min. The total intensity of oxotremorine-induced tremor for each drug was expressed as "points", which were the sum of tremor intensity scores evaluated every 10 min up to 190 min following the administration of oxotremorine. Beta-blockers significantly suppressed the tremor. On the other hand, the Ca2+ channel blocker exacerbated the tremor.

  4. Cellular Entry of the Diphtheria Toxin Does Not Require the Formation of the Open-Channel State by Its Translocation Domain

    Directory of Open Access Journals (Sweden)

    Alexey S. Ladokhin

    2017-09-01

    Full Text Available Cellular entry of diphtheria toxin is a multistage process involving receptor targeting, endocytosis, and translocation of the catalytic domain across the endosomal membrane into the cytosol. The latter is ensured by the translocation (T domain of the toxin, capable of undergoing conformational refolding and membrane insertion in response to the acidification of the endosomal environment. While numerous now classical studies have demonstrated the formation of an ion-conducting conformation—the Open-Channel State (OCS—as the final step of the refolding pathway, it remains unclear whether this channel constitutes an in vivo translocation pathway or is a byproduct of the translocation. To address this question, we measure functional activity of known OCS-blocking mutants with H-to-Q replacements of C-terminal histidines of the T-domain. We also test the ability of these mutants to translocate their own N-terminus across lipid bilayers of model vesicles. The results of both experiments indicate that translocation activity does not correlate with previously published OCS activity. Finally, we determined the topology of TH5 helix in membrane-inserted T-domain using W281 fluorescence and its depth-dependent quenching by brominated lipids. Our results indicate that while TH5 becomes a transbilayer helix in a wild-type protein, it fails to insert in the case of the OCS-blocking mutant H322Q. We conclude that the formation of the OCS is not necessary for the functional translocation by the T-domain, at least in the histidine-replacement mutants, suggesting that the OCS is unlikely to constitute a translocation pathway for the cellular entry of diphtheria toxin in vivo.

  5. Pre-injury beta blocker use does not affect the hyperdynamic response in older trauma patients

    Directory of Open Access Journals (Sweden)

    David C Evans

    2014-01-01

    Full Text Available Purpose: Trauma dogma dictates that the physiologic response to injury is blunted by beta-blockers and other cardiac medications. We sought to determine how the pre-injury cardiac medication profile influences admission physiology and post-injury outcomes. Materials and Methods: Trauma patients older than 45 evaluated at our center were retrospectively studied. Pre-injury medication profiles were evaluated for angiotensin-converting enzyme inhibitors / angiotensin receptor blockers (ACE-I/ARB, beta-blockers, calcium channel blockers, amiodarone, or a combination of the above mentioned agents. Multivariable logistic regression or linear regression analyses were used to identify relationships between pre-injury medications, vital signs on presentation, post-injury complications, length of hospital stay, and mortality. Results: Records of 645 patients were reviewed (mean age 62.9 years, Injury Severity Score >10, 23%. Our analysis demonstrated no effect on systolic and diastolic blood pressures from beta-blocker, ACE-I/ARB, calcium channel blocker, and amiodarone use. The triple therapy (combined beta-blocker, calcium channel blocker, and ACE-I/ARB patient group had significantly lower heart rate than the no cardiac medication group. No other groups were statistically different for heart rate, systolic, and diastolic blood pressure. Conclusions: Pre-injury use of cardiac medication lowered heart rate in the triple-agent group (beta-blocker, calcium channel blocker, and ACEi/ARB when compared the no cardiac medication group. While most combinations of cardiac medications do not blunt the hyperdynamic response in trauma cases, patients on combined beta-blocker, calcium channel blocker, and ACE-I/ARB therapy had higher mortality and more in-hospital complications despite only mild attenuation of the hyperdynamic response.

  6. Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block

    Science.gov (United States)

    Brenneis, C; Kistner, K; Puopolo, M; Jo, S; Roberson, DP; Sisignano, M; Segal, D; Cobos, EJ; Wainger, BJ; Labocha, S; Ferreirós, N; Hehn, C; Tran, J; Geisslinger, G; Reeh, PW; Bean, BP; Woolf, C J

    2014-01-01

    Background and Purpose: Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314. Experimental Approach: We investigated TRP channel activation in dorsal root ganglion (DRG) neurons by calcium imaging and patch-clamp recordings, and cellular QX-314 uptake by MS. To characterize nerve block, compound action potential (CAP) recordings from isolated nerves and behavioural responses were analysed. Key Results: Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red-sensitive calcium entry in DRG neurons and activated heterologously expressed TRPA1 channels. QX-314 permeated through TRPA1 channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX-314 markedly prolonged bupivacaine's nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine's blockade of C-, but not A-fibre, CAPs in sciatic nerves was extended by co-application of QX-314. Surprisingly, however, this action was the same in wild-type, TRPA1-knockout and TRPV1/TRPA1-double knockout mice, suggesting a TRP-channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non-selective, cellular uptake of QX-314. Conclusions and Implications: Bupivacaine, combined with QX-314, produced a long-lasting sensory nerve block. This did not require QX-314 permeation through TRPA1, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX-314 and bupivacaine may be clinically useful. PMID:24117225

  7. Beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease

    DEFF Research Database (Denmark)

    Andersson, Charlotte; Shilane, David; Go, Alan S

    2014-01-01

    BACKGROUND: The effectiveness of beta-blockers for preventing cardiac events has been questioned for patients who have coronary heart disease (CHD) without a prior myocardial infarction (MI). OBJECTIVES: The purpose of this study was to assess the association of beta-blockers with outcomes among...... patients with new-onset CHD. METHODS: We studied consecutive patients discharged after the first CHD event (acute coronary syndrome or coronary revascularization) between 2000 and 2008 in an integrated healthcare delivery system who did not use beta-blockers in the year before entry. We used time......-varying Cox regression models to determine the hazard ratio (HR) associated with beta-blocker treatment and used treatment-by-covariate interaction tests (pint) to determine whether the association differed for patients with or without a recent MI. RESULTS: A total of 26,793 patients were included, 19...

  8. β-Blocker pharmacogenetics in heart failure

    Science.gov (United States)

    Shin, Jaekyu

    2009-01-01

    β-Blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a β-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a β-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for β-blockers in patients with HF and discusses the potential implications of β-blocker pharmacogenetics for HF patients. PMID:18437562

  9. Essential role of the unordered VP2 n-terminal domain of the parvovirus MVM capsid in nuclear assembly and endosomal enlargement of the virion fivefold channel for cell entry

    Energy Technology Data Exchange (ETDEWEB)

    Sanchez-Martinez, Cristina; Grueso, Esther [Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, 28049 Cantoblanco, Madrid (Spain); Carroll, Miles [Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury SP4 OJG, Wilts (United Kingdom); Rommelaere, Jean [Deutsches Krebsforschungszentrum Division F010, Im Neuenheimer Feld 242, D-69120 Heidelberg (Germany); Almendral, Jose M., E-mail: jmalmendral@cbm.uam.es [Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, 28049 Cantoblanco, Madrid (Spain)

    2012-10-10

    The unordered N-termini of parvovirus capsid proteins (Nt) are translocated through a channel at the icosahedral five-fold axis to serve for virus traffick. Heterologous peptides were genetically inserted at the Nt of MVM to study their functional tolerance to manipulations. Insertion of a 5T4-single-chain antibody at VP2-Nt (2Nt) yielded chimeric capsid subunits failing to enter the nucleus. The VEGFR2-binding peptide (V1) inserted at both 2Nt and VP1-Nt efficiently assembled in virions, but V1 disrupted VP1 and VP2 entry functions. The VP2 defect correlated with restricted externalization of V1-2Nt out of the coat. The specific infectivity of MVM and wtVP-pseudotyped mosaic MVM-V1 virions, upon heating and/or partial 2Nt cleavage, demonstrated that some 2Nt domains become intracellularly translocated out of the virus shell and cleaved to initiate entry. The V1 insertion defines a VP2-driven endosomal enlargement of the channel as an essential structural rearrangement performed by the MVM virion to infect.

  10. Essential role of the unordered VP2 n-terminal domain of the parvovirus MVM capsid in nuclear assembly and endosomal enlargement of the virion fivefold channel for cell entry

    International Nuclear Information System (INIS)

    Sánchez-Martínez, Cristina; Grueso, Esther; Carroll, Miles; Rommelaere, Jean; Almendral, José M.

    2012-01-01

    The unordered N-termini of parvovirus capsid proteins (Nt) are translocated through a channel at the icosahedral five-fold axis to serve for virus traffick. Heterologous peptides were genetically inserted at the Nt of MVM to study their functional tolerance to manipulations. Insertion of a 5T4-single-chain antibody at VP2-Nt (2Nt) yielded chimeric capsid subunits failing to enter the nucleus. The VEGFR2-binding peptide (V1) inserted at both 2Nt and VP1-Nt efficiently assembled in virions, but V1 disrupted VP1 and VP2 entry functions. The VP2 defect correlated with restricted externalization of V1-2Nt out of the coat. The specific infectivity of MVM and wtVP-pseudotyped mosaic MVM-V1 virions, upon heating and/or partial 2Nt cleavage, demonstrated that some 2Nt domains become intracellularly translocated out of the virus shell and cleaved to initiate entry. The V1 insertion defines a VP2-driven endosomal enlargement of the channel as an essential structural rearrangement performed by the MVM virion to infect.

  11. Sodium channels as targets for volatile anesthetics

    Directory of Open Access Journals (Sweden)

    Karl F. Herold

    2012-03-01

    Full Text Available The molecular mechanisms of modern inhaled anesthetics although widely used in clinical settings are still poorly understood. Considerable evidence supports effects on membrane proteins such as ligand- and voltage-gated ion channels of excitable cells. Na+ channels are crucial to action potential initiation and propagation, and represent potential targets for volatile anesthetics. Inhibition of presynaptic Na+ channels leads to reduced neurotransmitter release at the synapse and could therefore contribute to the mechanisms by which volatile anesthetics produce their characteristic effects: amnesia, unconsciousness, and immobility. Early studies on crayfish and squid giant axon showed inhibition of Na+ currents by volatile anesthetics. Subsequent studies using native neuronal preparations and heterologous expression systems with various mammalian Na+ channel isoforms implicated inhibition of presynaptic Na+ channels in anesthetic actions. Volatile anesthetics reduce peak Na+ current and shift the voltage of half-maximal steady-state inactivation towards more negative potentials, thus stabilizing the fast-inactivated state. Furthermore recovery from fast-inactivation is slowed together with an enhanced use-dependent block during pulse train protocols. These effects can reduce neurotransmitter release by depressing presynaptic excitability, depolarization and Ca entry, and ultimately transmitter release. This reduction in transmitter release is more portent for glutamatergic vs. GABAergic terminals. Involvement of Na+ channel inhibition in mediating the immobility caused by volatile anesthetics has been demonstrated in animal studies, in which intrathecal infusion of the Na+ channel blocker tetrodotoxin increases volatile anesthetic potency, whereas infusion of the Na+ channels agonist veratridine reduces anesthetic potency. These studies indicate that inhibition of presynaptic Na+ channels by volatile anesthetics is involved in mediating some of

  12. Is there a role for T-type Ca2+ channels in regulation of vasomotor tone in mesenteric arterioles?

    DEFF Research Database (Denmark)

    Jensen, Lars Jørn; Holstein-Rathlou, Niels-Henrik

    2009-01-01

    The largest peripheral blood pressure drop occurs in terminal arterioles (microm lumen diameter). L-type voltage-dependent Ca2+ channels (VDCCs) are considered the primary pathway for Ca2+ influx during physiologic activation of vascular smooth muscle cells (VSMC). Recent evidence suggests...... was predominantly expressed in endothelial cells. Voltage-dependent Ca2+ entry was inhibited by the new specific T-type blockers R(-)-efonidipine and NNC 55-0396. The effect of NNC 55-0396 persisted in depolarized arterioles, suggesting an unusually high activation threshold of mesenteric T-type channels. T...... that T-type VDCCs are expressed in renal afferent and efferent arterioles, mesenteric arterioles, and skeletal muscle arterioles. T-type channels are small-conductance, low voltage-activated, fast-inactivating channels. Thus, their role in supplying Ca2+ for contraction of VSMC has been disputed. However...

  13. Current role of beta-blockers in the treatment of hypertension.

    Science.gov (United States)

    Aronow, Wilbert S

    2010-11-01

    It is important to know which patients with hypertension will benefit from beta-blocker therapy and which beta-blockers should be used in the treatment of hypertension to reduce cardiovascular events and mortality. Studies between 1981 and 2009 using a Medline search are reported. Beta-blockers should be used to treat hypertension in patients with previous myocardial infarction, acute coronary syndromes, angina pectoris, congestive heart failure, ventricular arrhythmias, supraventricular tachyarrhythmias, diabetes mellitus, after coronary artery bypass graft surgery, and in patients who are pregnant, have thyrotoxicosis, glaucoma, migraine, essential tremor, perioperative hypertension, or an excessive blood pressure response after exercise. The use of beta-blockers as first-line therapy in patients with primary hypertension has been controversial. However, the 2009 guidelines of the European Society of Hypertension state that large-scale meta-analyses of available data confirm that diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium channel blockers do not significantly differ in their ability to lower blood pressure and to exert cardiovascular protection both in elderly and in younger patients. The key message of this paper is that atenolol should not be used as an antihypertensive drug and that the degree of reduction of mortality, myocardial infarction, stroke and congestive heart failure by antihypertensive therapy is dependent on the degree of lowering of aortic blood pressure. Newer vasodilator beta-blockers such as carvedilol and nebivolol may be more effective in reducing cardiovascular events than traditional beta-blockers, but this needs to be investigated by controlled clinical trials.

  14. Topical beta-blockers and mortality

    NARCIS (Netherlands)

    Müskens, Rogier P. H. M.; Wolfs, Roger C. W.; Witteman, Jacqueline C. M.; Hofman, Albert; de Jong, Paulus T. V. M.; Stricker, Bruno H. C.; Jansonius, Nomdo M.

    2008-01-01

    To study the associations between long-term and short-term use of topical beta-blockers and mortality. Prospective population-based cohort study. To examine long-term effects, 3842 participants aged 55 years and older were recruited. To examine short-term effects, 484 incident beta-blocker users and

  15. How Do Beta Blocker Drugs Affect Exercise?

    Science.gov (United States)

    ... in lieu of exercise. Exercise has many other benefits and is important to maintain your health. Read how physical activity improves the quality of life . Concerns About Exercising While on Beta Blockers “It’s important to remember ...

  16. Evaluation of nitrendipine channel blocker a new calcium

    African Journals Online (AJOL)

    used with success in the treatment of systemic hypertension.7. ,8. For example, nifedipine ... the sitting position after 15 minutes' rest. A total of 38 patients .... pressure response in these 5 patients was no different from that in patients who did ...

  17. US Ports of Entry

    Data.gov (United States)

    Department of Homeland Security — HSIP Non-Crossing Ports-of-Entry A Port of Entry is any designated place at which a CBP officer is authorized to accept entries of merchandise to collect duties, and...

  18. Expression of voltage-activated calcium channels in the early zebrafish embryo.

    Science.gov (United States)

    Sanhueza, Dayán; Montoya, Andro; Sierralta, Jimena; Kukuljan, Manuel

    2009-05-01

    Increases in cytosolic calcium concentrations regulate many cellular processes, including aspects of early development. Calcium release from intracellular stores and calcium entry through non-voltage-gated channels account for signalling in non-excitable cells, whereas voltage-gated calcium channels (CaV) are important in excitable cells. We report the expression of multiple transcripts of CaV, identified by its homology to other species, in the early embryo of the zebrafish, Danio rerio, at stages prior to the differentiation of excitable cells. CaV mRNAs and proteins were detected as early as the 2-cell stages, which indicate that they arise from both maternal and zygotic transcription. Exposure of embryos to pharmacological blockers of CaV does not perturb early development significantly, although late effects are appreciable. These results suggest that CaV may have a role in calcium homeostasis and control of cellular process during early embryonic development.

  19. Detection of TRPV4 channel current-like activity in Fawn Hooded hypertensive (FHH rat cerebral arterial muscle cells.

    Directory of Open Access Journals (Sweden)

    Debebe Gebremedhin

    Full Text Available The transient receptor potential vallinoid type 4 (TRPV4 is a calcium entry channel known to modulate vascular function by mediating endothelium-dependent vasodilation. The present study investigated if isolated cerebral arterial myocytes of the Fawn Hooded hypertensive (FHH rat, known to display exaggerated KCa channel current activity and impaired myogenic tone, express TRPV4 channels at the transcript and protein level and exhibit TRPV4-like single-channel cationic current activity. Reverse transcription polymerase chain reaction (RT-PCR, Western blot, and immunostaining analysis detected the expression of mRNA transcript and translated protein of TRPV4 channel in FHH rat cerebral arterial myocytes. Patch clamp recording of single-channel current activity identified the presence of a single-channel cationic current with unitary conductance of ~85 pS and ~96 pS at hyperpolarizing and depolarizing potentials, respectively, that was inhibited by the TRPV4 channel antagonist RN 1734 or HC 067074 and activated by the potent TRPV4 channel agonist GSK1016790A. Application of negative pressure via the interior of the patch pipette increased the NPo of the TRPV4-like single-channel cationic current recorded in cell-attached patches at a patch potential of 60 mV that was inhibited by prior application of the TRPV4 channel antagonist RN 1734 or HC 067047. Treatment with the TRPV4 channel agonist GSK1016790A caused concentration-dependent increase in the NPo of KCa single-channel current recorded in cell-attached patches of cerebral arterial myocytes at a patch potential of 40 mV, which was not influenced by pretreatment with the voltage-gated L-type Ca2+ channel blocker nifedipine or the T-type Ca2+ channel blocker Ni2+. These findings demonstrate that FHH rat cerebral arterial myocytes express mRNA transcript and translated protein for TRPV4 channel and display TRPV4-like single-channel cationic current activity that was stretch-sensitive and

  20. β1-Adrenoceptor blocker aggravated ventricular arrhythmia.

    Science.gov (United States)

    Wang, Yan; Patel, Dimpi; Wang, Dao Wu; Yan, Jiang Tao; Hsia, Henry H; Liu, Hao; Zhao, Chun Xia; Zuo, Hou Juan; Wang, Dao Wen

    2013-11-01

    To assess the impact of β1 -adrenoceptor blockers (β1 -blocker) and isoprenaline on the incidence of idiopathic repetitive ventricular arrhythmia that apparently decreases with preprocedural anxiety. From January 2010 to July 2012, six patients were identified who had idiopathic ventricular arrhythmias that apparently decreased (by greater than 90%) with preprocedural anxiety. The number of ectopic ventricular beats per hour (VPH) was calculated from Holter or telemetry monitoring to assess the ectopic burden. The mean VPH of 24 hours from Holter before admission (VPH-m) was used as baseline (100%) for normalization. β1 -Blockers, isoprenaline, and/or aminophylline were administrated successively on the ward and catheter lab to evaluate their effects on the ventricular arrhythmias. Among 97 consecutive patients with idiopathic ventricular arrhythmias, six had reduction in normalized VPHs in the hour before the scheduled procedure time from (104.6 ± 4.6%) to (2.8 ± 1.6%) possibly due to preprocedural anxiety (P < 0.05), then increased to (97.9 ± 9.7%) during β1 -blocker administration (P < 0.05), then quickly reduced to (1.6 ± 1.0%) during subsequent isoprenaline infusion. Repeated β1 -blocker quickly counteracted the inhibitory effect of isoprenaline, and VPHs increased to (120.9 ± 2.4%) from (1.6 ± 1.0%; P < 0.05). Isoprenaline and β1 -blocker showed similar effects on the arrhythmias in catheter lab. In some patients with structurally normal heart and ventricular arrhythmias there is a marked reduction of arrhythmias associated with preprocedural anxiety. These patients exhibit a reproducible sequence of β1 -blocker aggravation and catecholamine inhibition of ventricular arrhythmias, including both repetitive ventricular premature beats and monomorphic ventricular tachycardia. ©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.

  1. Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study.

    Science.gov (United States)

    Shen, Lan; Shah, Bimal R; Reyes, Eric M; Thomas, Laine; Wojdyla, Daniel; Diem, Peter; Leiter, Lawrence A; Charbonnel, Bernard; Mareev, Viacheslav; Horton, Edward S; Haffner, Steven M; Soska, Vladimir; Holman, Rury; Bethel, M Angelyn; Schaper, Frank; Sun, Jie-Lena; McMurray, John J V; Califf, Robert M; Krum, Henry

    2013-12-09

    To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes. Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. NAVIGATOR trial. Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control. Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment. During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively). Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant. ClinicalTrials.gov NCT00097786.

  2. Clofilium inhibits Slick and Slack potassium channels.

    Science.gov (United States)

    de Los Angeles Tejada, Maria; Stolpe, Kathleen; Meinild, Anne-Kristine; Klaerke, Dan A

    2012-01-01

    Slick and Slack high-conductance potassium channels have been recently discovered, and are found in the central nervous system and in the heart. Both channels are activated by Na(+) and Cl(-), and Slick channels are also inhibited by adenosine triphospate (ATP). An important role of setting the resting membrane potential and controlling the basal excitability of neurons has been suggested for these channels. In addition, no specific blockers for these channels are known up to the present. With the purpose of studying the pharmacological characteristics of Slick and Slack channels, the effects of exposure to the antiarrhythmic compound clofilium were evaluated. Clofilium was able to modulate the activity of Slick and Slack channels effectively, with a stronger effect on Slack than Slick channels. In order to evaluate the pharmacological behavior of Slick and Slack channels further, 38 commonly used potassium channel blockers were tested. Screening of these compounds did not reveal any modulators of Slick and Slack channels, except for clofilium. The present study provides a first approach towards elucidating the pharmacological characteristics of Slick and Slack channels and could be the basis for future studies aimed at developing potent and specific blockers and activators for these channels.

  3. Topical beta-Blockers and Mortality

    NARCIS (Netherlands)

    Muskens, Rogier P. H. M.; Wolfs, Roger C. W.; Wittenian, Jacqueline C. M.; Hofman, Albert; de Jong, Paulus T. V. M.; Stricker, Bruno H. C.; Jansonius, Nomdo M.

    Purpose: To study the associations between long-term and short-term use of topical beta-blockers and mortality. Design: Prospective population-based cohort study. Participants: To examine long-term effects, 3842 participants aged 55 years and older were recruited. To examine short-term effects, 484

  4. Can Beta Blockers Cause Weight Gain?

    Science.gov (United States)

    ... cause weight gain? Can beta blockers cause weight gain? Answers from Sheldon G. Sheps, M.D. Yes. Weight gain can occur as a side effect of some ... and metoprolol (Lopressor, Toprol-XL). The average weight gain is about 2.6 pounds (about 1.2 ...

  5. SELECTIVE AND NONSELECTIVE β-BLOCKERS IN PRIMARY OPEN ANGLE GLAUCOMA THERAPY – RESULTS OF COLOR DOPPLER SONOGRAPHY

    Directory of Open Access Journals (Sweden)

    Vukoslava Maričić-Došen

    2002-12-01

    Full Text Available Background. Primary open angle glaucoma (POAG is a syndrome of progressive optic neuropathy characterized by optic nerve head excavation and visual field defects. Poor correlation between IOP and progression of glaucoma disease sets vascular mechanism in the centre of attention. By Color Doppler sonography, quantification of blood flow changes in vessels, which supply optic nerve head, is possible. We wanted to find out whether there are changes in the circulation of central retinal artery and posterior ciliary arteries in patients with primary open angle glaucoma treated with selective or nonselective β -blockers.Methods. 44 patients (88 eyes were divided into two groups: group 1: 22 patients (44 eyes treated with selective β -blockers (Betaxolol 0.5% and group 2: 22 patients (44 eyes treated with nonselective β -blockers (Timolol 0.5%. Vascular indices (RI, PI were measured in the central retinal artery and posterior ciliary arteries.Results. We found decreased blood flow and increased vascular indices in both groups of patients, statistically significant difference between group 1 and group 2: blood flow velocity was higher and vascular indices were lower in group 1 (Betaxolol 0.5% compared to group 2 (Timolol 0..5%.Conclusions. Selective β -blockers (calcium channel blockers act more vasoactively and neuroprotectively comparing to nonselective β -blockers.

  6. Exporting Complex Digital Products: Motives and Entry Modes

    DEFF Research Database (Denmark)

    Rask, Morten

    2005-01-01

    When the product is digital, it will most often be distributed directly to the customer through the Internet, and therefore the entry modes, considered in this paper, are different flavors of the entry mode called direct export: Virtual export channel are generally understood as the entry mode fo...... for digital product providers. However other types of entry modes like what wee call direct digital export with F2F-sales, direct digital export with F2F-support and virtual sales subsidiary are entry modes that respond to a higher degree of pre- and after-sales complexity....

  7. Jesus' Entry into Jerusalem

    Directory of Open Access Journals (Sweden)

    Juho Sankamo

    2014-12-01

    Full Text Available This article intends to contribute to the understanding of Jesus’ entry into Jerusalem. The author studies the entry, which is found in all the Gospels, in its Jewish context. The author argues that Jesus’ entry into Jerusalem on an ass is to be understood as a prophetic sign which was primarily meant to convey a message to the Jews.

  8. Pharmacological targeting of native CatSper channels reveals a required role in maintenance of sperm hyperactivation.

    Directory of Open Access Journals (Sweden)

    Anne E Carlson

    2009-08-01

    Full Text Available The four sperm-specific CatSper ion channel proteins are required for hyperactivated motility and male fertility, and for Ca(2+ entry evoked by alkaline depolarization. In the absence of external Ca(2+, Na(+ carries current through CatSper channels in voltage-clamped sperm. Here we show that CatSper channel activity can be monitored optically with the [Na(+](i-reporting probe SBFI in populations of intact sperm. Removal of external Ca(2+ increases SBFI signals in wild-type but not CatSper2-null sperm. The rate of the indicated rise of [Na(+](i is greater for sperm alkalinized with NH(4Cl than for sperm acidified with propionic acid, reflecting the alkaline-promoted signature property of CatSper currents. In contrast, the [Na(+](i rise is slowed by candidate CatSper blocker HC-056456 (IC(50 approximately 3 microM. HC-056456 similarly slows the rise of [Ca(2+](i that is evoked by alkaline depolarization and reported by fura-2. HC-056456 also selectively and reversibly decreased CatSper currents recorded from patch-clamped sperm. HC-056456 does not prevent activation of motility by HCO(3 (- but does prevent the development of hyperactivated motility by capacitating incubations, thus producing a phenocopy of the CatSper-null sperm. When applied to hyperactivated sperm, HC-056456 causes a rapid, reversible loss of flagellar waveform asymmetry, similar to the loss that occurs when Ca(2+ entry through the CatSper channel is terminated by removal of external Ca(2+. Thus, open CatSper channels and entry of external Ca(2+ through them sustains hyperactivated motility. These results indicate that pharmacological targeting of the CatSper channel may impose a selective late-stage block to fertility, and that high-throughput screening with an optical reporter of CatSper channel activity may identify additional selective blockers with potential for male-directed contraception.

  9. Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel.

    Directory of Open Access Journals (Sweden)

    Zoltán Oláh

    2007-06-01

    Full Text Available Ca(2+-loaded calmodulin normally inhibits multiple Ca(2+-channels upon dangerous elevation of intracellular Ca(2+ and protects cells from Ca(2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca(2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca(2+-uptake via the vanilloid inducible Ca(2+-channel/inflamatory pain receptor 1 (TRPV1, which suggests that calmodulin inhibitors may block pore formation and Ca(2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced (45Ca(2+-uptake at microM concentrations: calmidazolium (broad range > or = trifluoperazine (narrow range chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially. Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca(2+ or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca(2+-uptake in intact TRPV1(+ cells, and suggests an extracellular site of inhibition. TRPV1(+, inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca(2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca(2+-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca(2+-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca(2

  10. Absent Lung Deflation Because of Blockade Using an Endobronchial Blocker.

    Science.gov (United States)

    Garg, Rakesh; Pandit, Anuja

    2017-06-01

    One-lung ventilation is required for various thoracic procedures. In addition, various strategies such as the use of double-lumen tube, uninvent tubes, and endobronchial blocker have been used for performing one-lung ventilation. Each of these techniques has its advantages and limitations. Certain factors for failure of endobronchial blocker to provide lung deflation has been described in literature. We report a different aetiology of failure of lung deflation, although the endobronchial blocker was appropriately placed.

  11. Systematic review of use of β-blockers in sepsis

    Directory of Open Access Journals (Sweden)

    Cyril Jacob Chacko

    2015-01-01

    Conclusion: There is insufficient evidence to justify the routine use of β-blockers in sepsis. A large adequately powered multi-centered randomized controlled clinical trial is required to address the question on the efficacy of β-blocker usage in sepsis. This trial should also consider a number of important questions including the choice of β-blocker used, optimal dosing, timing of intervention, duration of intervention and discontinuation of the drug. Until such time based on the available evidence, there is no place for the use of β-blockers in sepsis in current clinical practice.

  12. Detecting Anti Ad-blockers in the Wild

    Directory of Open Access Journals (Sweden)

    Mughees Muhammad Haris

    2017-07-01

    Full Text Available The rise of ad-blockers is viewed as an economic threat by online publishers who primarily rely on online advertising to monetize their services. To address this threat, publishers have started to retaliate by employing anti ad-blockers, which scout for ad-block users and react to them by pushing users to whitelist the website or disable ad-blockers altogether. The clash between ad-blockers and anti ad-blockers has resulted in a new arms race on the Web. In this paper, we present an automated machine learning based approach to identify anti ad-blockers that detect and react to ad-block users. The approach is promising with precision of 94.8% and recall of 93.1%. Our automated approach allows us to conduct a large-scale measurement study of anti ad-blockers on Alexa top-100K websites. We identify 686 websites that make visible changes to their page content in response to ad-block detection. We characterize the spectrum of different strategies used by anti ad-blockers. We find that a majority of publishers use fairly simple first-party anti ad-block scripts. However, we also note the use of third-party anti ad-block services that use more sophisticated tactics to detect and respond to ad-blockers.

  13. Double entry bookkeeping vs single entry bookkeeping

    Directory of Open Access Journals (Sweden)

    Ileana Andreica

    2016-11-01

    Full Text Available Abstract: A financial management eficiently begin, primarily, with an accounting record kept in the best possible conditions, this being conditioned on the adoption of a uniform forms, rational, clear and simple accounting. Throughout history, there have been known two forms of accounting: the simple and double entry. Romanian society after 1990 underwent a substantial change in social structure, the sector on which put a great emphasis being private, that of small manufacturers, peddler, freelance, who work independently and authorized or as associative form (family enterprises, various associations (owners, tenants, etc., liberal professions, etc.. They are obliged to keep a simple bookkeeping, because they have no juridical personality. Companies with legal personality are required to keep double entry bookkeeping; therefore, knowledge and border demarcation between the two forms of organisation of accounting is an essential. The material used for this work is mainly represented by the financial and accounting documents, by the analysis of the economic, by legislative updated sources, and as the method was used the comparison method, using hypothetical data, in case of an authorized individual and a legal entity. Based on the chosen material, an authorized individual (who perform single entry accounting system and a juridical entity (who perform double entry accounting system were selected comparative case studies, using hypothetical data, were analysed advantages and disadvantages in term of fiscal, if using two accounting systems, then were highlighted some conclusion that result.

  14. Effects of calcium, calcium entry blockers and calmodulin inhibitors on atrioventricular conduction disturbances induced by hypoxia.

    OpenAIRE

    Anno, T.; Kodama, I.; Shibata, S.; Toyama, J.; Yamada, K.

    1986-01-01

    Effects of hypoxia on atrioventricular conduction were investigated in the Langendorff-perfused isolated heart of the rabbit with various extracellular calcium concentrations ([Ca2+]) as well as in the presence of verapamil, nifedipine, N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W-7) and chlorpromazine. The prolongation of the atrio-His (AH) interval by hypoxia for 7 min was greater with increasing [Ca2+]o ranging from 1.2 to 5.2 mM. At [Ca2+]o of over 3.2 mM under hypoxic condition...

  15. Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.

    Science.gov (United States)

    Yamada, Yuko; Kinoshita, Hideyuki; Kuwahara, Koichiro; Nakagawa, Yasuaki; Kuwabara, Yoshihiro; Minami, Takeya; Yamada, Chinatsu; Shibata, Junko; Nakao, Kazuhiro; Cho, Kosai; Arai, Yuji; Yasuno, Shinji; Nishikimi, Toshio; Ueshima, Kenji; Kamakura, Shiro; Nishida, Motohiro; Kiyonaka, Shigeki; Mori, Yasuo; Kimura, Takeshi; Kangawa, Kenji; Nakao, Kazuwa

    2014-10-01

    Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B(+/-) mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B(+/+) mice. Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  16. Beta blockers and their combinations in the management of ...

    African Journals Online (AJOL)

    Review Article: Beta blockers and their combinations in the management of hypertension. 409. Vol 54 No 5. S Afr Fam Pract 2012. Introduction. Beta blockers have been prescribed for the treatment of primary hypertension for a very long time. Currently, it is doubtful whether this is still a good idea. In fact, many are of the ...

  17. Perioperative beta blockers in patients having non-cardiac surgery

    DEFF Research Database (Denmark)

    Bangalore, Sripal; Wetterslev, Jørn; Pranesh, Shruthi

    2008-01-01

    American College of Cardiology and American Heart Association (ACC/AHA) guidelines on perioperative assessment recommend perioperative beta blockers for non-cardiac surgery, although results of some clinical trials seem not to support this recommendation. We aimed to critically review the evidence...... to assess the use of perioperative beta blockers in patients having non-cardiac surgery....

  18. Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well.

    Science.gov (United States)

    Frishman, William H

    Beta-adrenergic receptor blockers (β-blockers) are an appropriate treatment for patients having systemic hypertension (HTN) who have concomitant ischemic heart disease (IHD), heart failure, obstructive cardiomyopathy, aortic dissection or certain cardiac arrhythmias. β-Blockers can be used in combination with other antiHTN drugs to achieve maximal blood pressure control. Labetalol can be used in HTN emergencies and urgencies. β-Blockers may be useful in HTN patients having a hyperkinetic circulation (palpitations, tachycardia, HTN, and anxiety), migraine headache, and essential tremor. β-Blockers are highly heterogeneous with respect to various pharmacologic properties: degree of intrinsic sympathomimetic activity, membrane stabilizing activity, β 1 selectivity, α 1 -adrenergic blocking effects, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific properties may be important in the selection of a drug for clinical use. β-Blocker usage to reduce perioperative myocardial ischemia and cardiovascular (CV) complications may not benefit as many patients as was once hoped, and may actually cause harm in some individuals. Currently the best evidence supports perioperative β-blocker use in two patient groups: patients undergoing vascular surgery with known IHD or multiple risk factors for it, and for those patients already receiving β-blockers for known CV conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Beta-blocker use and fall risk in older individuals

    NARCIS (Netherlands)

    Ham, Annelies C.; Dijk, van S.C.; Swart, Karin M.A.; Enneman, Anke W.; Zwaluw, van der Nikita L.; Brouwer-Brolsma, Elske M.; Schoor, van Natasja M.; Zillikens, M.C.; Lips, Paul; Groot, de Lisette C.P.G.M.; Hofman, Albert; Witkamp, Renger F.; Uitterlinden, André G.; Stricker, Bruno H.; Velde, van der Nathalie

    2017-01-01

    Aims: To investigate the association between use of β-blockers and β-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Methods: Data from two prospective studies were used, including community-dwelling

  20. Double entry bookkeeping vs single entry bookkeeping

    OpenAIRE

    Ileana Andreica

    2016-01-01

    Abstract: A financial management eficiently begin, primarily, with an accounting record kept in the best possible conditions, this being conditioned on the adoption of a uniform forms, rational, clear and simple accounting. Throughout history, there have been known two forms of accounting: the simple and double entry. Romanian society after 1990 underwent a substantial change in social structure, the sector on which put a great emphasis being private, that of small manufacturers, ped...

  1. On the mechanism of TBA block of the TRPV1 channel.

    Science.gov (United States)

    Oseguera, Andrés Jara; Islas, León D; García-Villegas, Refugio; Rosenbaum, Tamara

    2007-06-01

    The transient receptor potential vanilloid 1 (TRPV1) channel is a nonselective cation channel activated by capsaicin and responsible for thermosensation. To date, little is known about the gating characteristics of these channels. Here we used tetrabutylammonium (TBA) to determine whether this molecule behaves as an ion conduction blocker in TRPV1 channels and to gain insight into the nature of the activation gate of this protein. TBA belongs to a family of classic potassium channel blockers that have been widely used as tools for determining the localization of the activation gate and the properties of the pore of several ion channels. We found TBA to be a voltage-dependent pore blocker and that the properties of block are consistent with an open-state blocker, with the TBA molecule binding to multiple open states, each with different blocker affinities. Kinetics of channel closure and burst-length analysis in the presence of blocker are consistent with a state-dependent blocking mechanism, with TBA interfering with closing of an activation gate. This activation gate may be located cytoplasmically with respect to the binding site of TBA ions, similar to what has been observed in potassium channels. We propose an allosteric model for TRPV1 activation and block by TBA, which explains our experimental data.

  2. Low voltage-activated calcium channels gate transmitter release at the dorsal root ganglion sandwich synapse.

    Science.gov (United States)

    Rozanski, Gabriela M; Nath, Arup R; Adams, Michael E; Stanley, Elise F

    2013-11-15

    A subpopulation of dorsal root ganglion (DRG) neurons are intimately attached in pairs and separated solely by thin satellite glial cell membrane septa. Stimulation of one neuron leads to transglial activation of its pair by a bi-, purinergic/glutamatergic synaptic pathway, a transmission mechanism that we term sandwich synapse (SS) transmission. Release of ATP from the stimulated neuron can be attributed to a classical mechanism involving Ca(2+) entry via voltage-gated calcium channels (CaV) but via an unknown channel type. Specific blockers and toxins ruled out CaV1, 2.1 and 2.2. Transmission was, however, blocked by a moderate depolarization (-50 mV) or low-concentration Ni(2+) (0.1 mM). Transmission persisted using a voltage pulse to -40 mV from a holding potential of -80 mV, confirming the involvement of a low voltage-activated channel type and limiting the candidate channel type to either CaV3.2 or a subpopulation of inactivation- and Ni(2+)-sensitive CaV2.3 channels. Resistance of the neuron calcium current and SS transmission to SNX482 argue against the latter. Hence, we conclude that inter-somatic transmission at the DRG SS is gated by CaV3.2 type calcium channels. The use of CaV3 family channels to gate transmission has important implications for the biological function of the DRG SS as information transfer would be predicted to occur not only in response to action potentials but also to sub-threshold membrane voltage oscillations. Thus, the SS synapse may serve as a homeostatic signalling mechanism between select neurons in the DRG and could play a role in abnormal sensation such as neuropathic pain.

  3. Border Crossing Entry Data

    Data.gov (United States)

    Department of Transportation — The Bureau of Transportation Statistics (BTS) Border Crossing/Entry Data provides summary statistics for inbound crossings at the U.S.-Canadian and the U.S.-Mexican...

  4. Long-term use of angiotensin receptor blockers and the risk of cancer.

    Directory of Open Access Journals (Sweden)

    Laurent Azoulay

    Full Text Available The association between angiotensin receptor blockers (ARBs and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs and 95% confidence intervals (CIs of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years. When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96-1.03 or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06-1.20 and RR: 1.19; 95% CI: 1.12-1.27, respectively. This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.

  5. Entry and Exit.

    Science.gov (United States)

    1987-03-01

    1. Introduction R Analyses of industrial competition have attained a new vigor with the application of game -theoretic methods. The process of... competition is represented in models that reflect genuine struggles for entry, market power, and continuing survival. Dynamics and informational effects are...presents a few of the models developed recently to study competitive processes that affect a firm’s entry into a market , and the decision to exit. The

  6. Adverse CNS-effects of beta-adrenoceptor blockers.

    Science.gov (United States)

    Gleiter, C H; Deckert, J

    1996-11-01

    In 1962 propranolol, the first beta adrenoceptor antagonist (beta blocker), was brought on to the market. There is now a host of different beta blockers available, and these compounds are among the most commonly prescribed groups of drugs. The efficacy of beta blockers has been proven predominantly for the treatment of cardiovascular diseases. Beta blockers are also used for certain types of CNS disorders, such as anxiety disorders, essential tremor and migraine. While low toxicity means that they have a favorable risk-benefit ratio, given the high intensity of use, it is essential to have a comprehensive knowledge of adverse events. Adverse events of beta blockers that can be related to the CNS are quite often neglected, even in textbooks of clinical pharmacology or review articles, and thus often misdiagnosed. The following article, therefore, after summarizing the use of beta blockers for CNS indications, critically reviews the literature on centrally mediated adverse events. General pharmacological features of beta blockers and their molecular basis of action will briefly be addressed to the extent that they are or may become relevant for central nervous pharmacotherapy and side-effects.

  7. Entry: direct control or regulation?

    NARCIS (Netherlands)

    Perotti, E.; Vorage, M.

    2009-01-01

    We model a setting in which citizens form coalitions to seek preferential entry to a given market. The lower entry the higher firm profits and political contributions, but the lower social welfare. Politicians choose to either control entry directly and be illegally bribed, or regulate entry using a

  8. Turbo Charge CPU Utilization in Fork/Join Using the ManagedBlocker

    CERN Multimedia

    CERN. Geneva

    2017-01-01

    Fork/Join is a framework for parallelizing calculations using recursive decomposition, also called divide and conquer. These algorithms occasionally end up duplicating work, especially at the beginning of the run. We can reduce wasted CPU cycles by implementing a reserved caching scheme. Before a task starts its calculation, it tries to reserve an entry in the shared map. If it is successful, it immediately begins. If not, it blocks until the other thread has finished its calculation. Unfortunately this might result in a significant number of blocked threads, decreasing CPU utilization. In this talk we will demonstrate this issue and offer a solution in the form of the ManagedBlocker. Combined with the Fork/Join, it can keep parallelism at the desired level.

  9. Exclusive Dealing and Entry

    OpenAIRE

    João Leão

    2008-01-01

    This paper examines the use of exclusive dealing agreements to prevent the entry of rival firms. An exclusive dealing agreement is a contract between a buyer and a seller where the buyer commits to buy a good exclusively from the seller. One main concern of the literature is to explain how an incumbent seller is able to persuade the buyers to sign an exclusive dealing agreement that deters the entry of a more efficient rival seller. We propose a new explanation when the buyers are downstream ...

  10. Fracture risk in perimenopausal women treated with beta-blockers

    DEFF Research Database (Denmark)

    Rejnmark, Lars; Vestergaard, Peter; Kassem, M.

    2004-01-01

    beta2-Adrenergic receptors have been identified on human osteoblastic and osteoclastic cells, raising the question of a sympathetic regulation of bone metabolism. We investigated effects of treatment with beta-adrenergic receptor antagonists (beta-blockers) on bone turnover, bone mineral density...... (BMD), and fracture risk. Within the Danish Osteoporosis Prevention Study (DOPS) a population based, comprehensive cohort study of 2016 perimenopausal women, associations between treatment with beta-blockers and bone turnover and BMD were assessed in a cross-sectional design at the start of study....... Moreover, in a nested case-control design, fracture risk during the subsequent 5 years was assessed in relation to treatment with beta-blockers at baseline. Multiple regression- and logistic regression-analyses were performed. Treatment with beta-blockers was associated with a threefold increased fracture...

  11. Beta-blockers in cirrhosis and refractory ascites

    DEFF Research Database (Denmark)

    Kimer, Nina; Feineis, Martin; Møller, Søren

    2015-01-01

    OBJECTIVE: It is currently discussed if beta-blockers exert harmful effects and increase mortality in patients with cirrhosis and refractory ascites. In this study, we provide an overview of the available literature in this field in combination with a retrospective analysis of 61 patients...... trials (9 trials on propranolol, 1 case-control study and 4 retrospective analyses) were identified. One trial suggested an increased mortality in patients treated with beta-blockers and refractory ascites. The results of the remaining trials were inconclusive. No increase in mortality among beta-blocker......-treated patients was found in the present retrospective analysis. CONCLUSIONS: Treatment with beta-blockers may increase mortality in patients with cirrhosis and refractory ascites. However, the current evidence is sparse and high-quality studies are warranted to clarify the matter....

  12. Are lipophilic beta-blockers preferable for peri-operative ...

    African Journals Online (AJOL)

    Adele

    management of hypertension and post myocardial infarction.4-6. Are lipophilic ... studies in hypertensive medical patients showed no difference in cardiovascular ... atenolol and bendroflumethiazide arm.7 In meta-analyses of beta-blocker ...

  13. β-Blocker treatment during pregnancy and adverse pregnancy outcomes

    DEFF Research Database (Denmark)

    Petersen, Kasper Meidahl; Jimenez-Solem, Espen; Andersen, Jon Traerup

    2012-01-01

    To investigate the association between exposure to β-blockers during pregnancy and the risk of being born small for gestational age (SGA), preterm birth and perinatal mortality in a nationwide cohort.......To investigate the association between exposure to β-blockers during pregnancy and the risk of being born small for gestational age (SGA), preterm birth and perinatal mortality in a nationwide cohort....

  14. Systematic review of use of β-blockers in sepsis.

    Science.gov (United States)

    Chacko, Cyril Jacob; Gopal, Shameer

    2015-01-01

    We proposed a review of present literature and systematic analysis of present literature to summarize the evidence on the use of β-blockers on the outcome of a patient with severe sepsis and septic shock. Medline, EMBASE, Cochrane Library were searched from 1946 to December 2013. The bibliography of all relevant articles was hand searched. Full-text search of the grey literature was done through the medical institution database. The database search identified a total of 1241 possible studies. The citation list was hand searched by both the authors. A total of 9 studies were identified. Most studies found a benefit from β-blocker administration in sepsis. This included improved heart rate (HR) control, decreased mortality and improvement in acid-base parameters. Chronic β-blocker usage in sepsis was also associated with improved mortality. The administration of β-blockers during sepsis was associated with better control of HR. The methodological quality of all the included studies, however, was poor. There is insufficient evidence to justify the routine use of β-blockers in sepsis. A large adequately powered multi-centered randomized controlled clinical trial is required to address the question on the efficacy of β-blocker usage in sepsis. This trial should also consider a number of important questions including the choice of β-blocker used, optimal dosing, timing of intervention, duration of intervention and discontinuation of the drug. Until such time based on the available evidence, there is no place for the use of β-blockers in sepsis in current clinical practice.

  15. [Focus on beta-blockers for vascular specialists in 2012].

    Science.gov (United States)

    Mairesse, S; Blacher, J; Safar, M-E

    2011-12-01

    Since they were launched on the market in 1964, cardiovascular indications for beta-blockers have been validated and accepted worldwide. Numerous studies and meta-analysis have confirmed their benefits. They reduce mortality in post infarction and acute coronary syndrome populations and also in people with stable coronary heart disease. Moreover, heart failure with systolic left ventricular dysfunction is a major indication for this therapeutic class, providing a 30% decrease in mortality. In patients with permanent atrial fibrillation, beta-blockers are recommended for rate control. In hypertension patients, first-line drug treatment with beta-blockers is currently discussed. Indeed, several studies have shown that patients randomized in the beta-blocker arms experienced more coronary heart and cerebrovascular diseases than comparators. Their lesser effect on central blood pressure decrease could partially explain those results. Nevertheless, beta-blockers are still considered as first-line drugs for hypertension in the French and European guidelines. Long-term comparative studies focusing on central blood pressure are needed. Concerning the other indications for beta-blockers in vascular diseases, their use perioperatively to reduce surgical cardiovascular risk raised much hope, but the most recent results are disappointed and even suggest possible higher mortality. Finally, except for patients with critical ischemia of the lower limbs, presence of peripheral artery disease should probably be considered as a condition favoring their prescription. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  16. Non-selective beta-blockers decrease thrombotic events in patients with heart failure

    NARCIS (Netherlands)

    De Peuter, Olav R.; Souverein, Patrick C.; Klungel, Olaf H.; Lip, Gregory Y.; Buller, Harry R.; De Boer, Anthonius; Kamphuisen, Pieter W.

    2010-01-01

    Background: Beta-blockers are often prescribed to patients with heart failure (HF) without distinctions between types of beta-blockers. The 2002 COMET study showed superiority of carvedilol (a non-selective beta-blocker) over metoprolol (selective beta-blocker) on mortality and cardiovascular events

  17. Lobbying on entry

    NARCIS (Netherlands)

    Perotti, E.C.; Volpin, P.

    2004-01-01

    We develop a model of endogenous lobby formation in which wealth inequality and political accountability undermine entry and financial development. Incumbents seek a low level of effective investor protection to prevent potential entrants from raising capital. They succeed because they can promise

  18. Beta-blockers: friend or foe in asthma?

    Directory of Open Access Journals (Sweden)

    Arboe B

    2013-07-01

    Full Text Available Bente Arboe, Charlotte Suppli UlrikDepartment of Pulmonary Medicine, Hvidovre Hospital and University of Copenhagen, Hvidovre, DenmarkBackground and aim: Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.Method: Systematic literature review.Results: No significant increase in the number of patients requiring rescue oral corticosteroid for an exacerbation of asthma has been observed after initiation of β-blocker treatment. Patients with mild to moderate reactive airway disease, probably both asthma and chronic obstructive pulmonary disease, may have a limited fall in forced expiratory volume in 1 second (FEV1 following single-dose administration of β-blocker, whereas no change in FEV1 has been reported following long-term administration. In a murine model of asthma, long-term administration of β-blockers resulted in a decrease in airway hyperresponsiveness, suggesting an anti-inflammatory effect. In keeping with this, long-term administration of a nonselective β-blocker to steroid-naïve asthma patients has shown a dose-dependent improvement in airway hyperresponsiveness, and either an asymptomatic fall in FEV1 or no significant change in FEV1. Furthermore, available studies show that bronchoconstriction induced by inhaled methacholine is reversed by salbutamol in patients on regular therapy with a β-blocker. On the other hand, a recent placebo-controlled trial of propranolol and tiotropium bromide added to inhaled corticosteroids revealed no effect on airway hyperresponsiveness and a small, not statistically significant, fall in FEV1 in patients classified as having mild to moderate asthma.Conclusion: The available, although limited, evidence suggests that a dose-escalating model of β-blocker therapy to patients with asthma is well tolerated, does not

  19. Expression and contributions of the Kir2.1 inward-rectifier K+ channel to proliferation, migration and chemotaxis of microglia in unstimulated and anti-inflammatory states

    Directory of Open Access Journals (Sweden)

    Doris eLam

    2015-05-01

    Full Text Available When microglia respond to CNS damage, they can range from pro-inflammatory (classical, M1 to anti-inflammatory, alternative (M2 and acquired deactivation states. It is important to determine how microglial functions are affected by these activation states, and to identify molecules that regulate their behavior. Microglial proliferation and migration are crucial during development and following damage in the adult, and both functions are Ca2+-dependent. In many cell types, the membrane potential and driving force for Ca2+ influx are regulated by inward-rectifier K+ channels, including Kir2.1, which is prevalent in microglia. However, it is not known whether Kir2.1 expression and contributions are altered in anti-inflammatory states. We tested the hypothesis that Kir2.1 contributes to Ca2+ entry, proliferation and migration of rat microglia. Kir2.1 (KCNJ2 transcript expression, current amplitude, and proliferation were comparable in unstimulated microglia and following alternative activation (IL-4 stimulated and acquired deactivation (IL-10 stimulated. To examine functional roles of Kir2.1 in microglia, we first determined that ML133 was more effective than the commonly used blocker, Ba2+; i.e., ML133 was potent (IC50=3.5 M and voltage independent. Both blockers slightly increased proliferation in unstimulated or IL-4 (but not IL-10-stimulated microglia. Stimulation with IL-4 or IL-10 increased migration and ATP-induced chemotaxis, and blocking Kir2.1 greatly reduced both but ML133 was more effective. In all three activation states, blocking Kir2.1 with ML133 dramatically reduced Ca2+ influx through Ca2+-release-activated Ca2+ (CRAC channels. Thus, Kir2.1 channel activity is necessary for microglial Ca2+ signaling and migration under resting and anti-inflammatory states but the channel weakly inhibits proliferation.

  20. Photochemical fate of beta-blockers in NOM enriched waters

    International Nuclear Information System (INIS)

    Wang, Ling; Xu, Haomin; Cooper, William J.; Song, Weihua

    2012-01-01

    Beta-blockers, prescribed for the treatment of high blood pressure and for long-term use after a heart attack, have been detected in surface and ground waters. This study examines the photochemical fate of three beta-blockers, atenolol, metoprolol, and nadolol. Hydrolysis accounted for minor losses of these beta-blockers in the pH range 4–10. The rate of direct photolysis at pH 7 in a solar simulator varied from 6.1 to 8.9 h −1 at pH 7. However, the addition of a natural organic matter (NOM) isolate enhanced the photochemical loss of all three compounds. Indirect photochemical fate, generally described by reactions with hydroxyl radical (·OH) and singlet oxygen ( 1 ΔO 2 ), and, the direct reaction with the triplet excited state, 3 NOM ⁎ , also varied but collectively appeared to be the major loss factor. Bimolecular reaction rate constants of the three beta-blockers with 1 ΔO 2 and ·OH were measured and accounted for 0.02–0.04% and 7.2–38.9% of their loss, respectively. These data suggest that the 3 NOM ⁎ contributed 50.6–85.4%. Experiments with various 3 NOM ⁎ quenchers supported the hypothesis that it was singly the most important reaction. Atenolol was chosen for more detailed investigation, with the photoproducts identified by LC–MS analysis. The results suggested that electron-transfer could be an important mechanism in photochemical fate of beta-blockers in the presence of NOM. - Highlights: ► Photochemical degradation of beta-blockers in the simulated natural waters. ► Reactive Oxygen Species play a minor role in the indirect photodegradation. ► The loss of beta-blockers results from direct reaction with 3 DOM ⁎ .

  1. Atmospheric Entry Studies for Uranus

    Science.gov (United States)

    Agrawal, P.; Allen, G. A.; Hwang, H. H.; Marley, M. S.; McGuire, M. K.; Garcia, J. A.; Sklyanskiy, E.; Huynh, L. C.; Moses, R. W.

    2014-07-01

    To better understand the technology requirements for Uranus atmospheric entry probe, Entry Vehicle Technology project funded an internal study with a multidisciplinary team from NASA Ames, Langley and JPL. The results of this study are communicated.

  2. Border Crossing/Entry Data

    Data.gov (United States)

    Department of Transportation — The dataset is known as “Border Crossing/Entry Data.” The Bureau of Transportation Statistics (BTS) Border Crossing/Entry Data provides summary statistics to the...

  3. Formulary considerations in selection of beta-blockers.

    Science.gov (United States)

    Yedinak, K C

    1993-08-01

    Selection of beta-adrenergic blockers for formulary addition can be a difficult task, especially with the increasing availability of new beta-blockers, as well as the numerous differences in pharmacodynamic and pharmacokinetic properties of currently available agents. Nevertheless, appropriate evaluation of the important characteristics of beta-blockers should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in efficacy, product formulation and cost should be carefully considered when making formulary decisions. Notably, evidence from clinical trials indicates differences in efficacy among beta-blockers for post-myocardial infarction prophylaxis, situational anxiety, essential tremor, thyrotoxicosis, migraine prophylaxis and prevention of bleeding associated with oesophageal varices. For many clinical situations, it is also important to select an effective agent that is available in both an oral and intravenous formulation, especially for cardioprotection after acute myocardial infarction and for use in supraventricular arrhythmias. In addition, availability of sustained release products and generic formulations should be considered for their potential to increase compliance and decrease cost, respectively. Comparative drug costs, as well as costs associated with decreased compliance, should also be carefully evaluated. Differences in beta-receptor selectivity, duration of action and presence of intrinsic sympathomimetic activity (ISA) are also important considerations in the selection of beta-blockers for formulary consideration. Although degree of selectivity is relative, beta 1-selective agents may be less likely to induce bronchospasm in patients with chronic obstructive pulmonary disease (COPD) and may be less likely to affect glucose homeostasis in patients with diabetes mellitus. Duration of action of a beta-blocker is an important consideration for evaluation of efficacy throughout the recommended

  4. Point correlation dimension can reveal functional changes caused by gap junction blockers in the 4-aminopyridine in vivo rat epilepsy model

    Energy Technology Data Exchange (ETDEWEB)

    Jardanhazy, Anett [Department of Neurology, University of Szeged, Semmelweis u. 6, Szeged H-6725 (Hungary); Molnar, Mark [Department of Psychophysiology, Institute for Psychology of the Hungarian Academy of Sciences, P.O. Box 398, Budapest H-1394 (Hungary)], E-mail: molnar@cogpsyphy.hu; Jardanhazy, Tamas [Department of Neurology, University of Szeged, Semmelweis u. 6, Szeged H-6725 (Hungary)], E-mail: jt@nepsy.szote.u-szeged.hu

    2009-04-15

    The contribution of gap junction (GJ) blockers to seizure initiation was reexamined by means of an analysis on nonlinear dynamics with point correlation dimension (PD2i) at as well as around the primary focus, and mirror focus in an already active 4-aminopyridine-induced in vivo epilepsy model. From the data base of the ECoGs of anesthetized adult rats treated with quinine, a selective blocker of Cx36, and in combination with an additional broad-spectrum GJ blocker, carbenoxolone, 14 cases of each condition were reexamined with a stationarity insensitive nonlinear PD2i method. The blockade of the Cx36 channels decreased the usual drop of the point correlation dimension at the beginning of the seizures, and this was enhanced by the additional use of the global blocker carbenoxolone. The so-called characteristic DC shift just prior to seizure onset denotes a low dimensional seizure event and the recognizable seizures display very variable, rapidly changing dynamics, as revealed by the PD2i analysis. This nonlinear PD2i analysis demonstrated that the different GJ blockers in the already active epileptic model helped seizure initiation, but exerted inhibitory effects on the seizure onset itself, acting differently on the local components of the network organization generating seizure discharges, possibly changing the coupling strengths and time delays in the GJ-s.

  5. Point correlation dimension can reveal functional changes caused by gap junction blockers in the 4-aminopyridine in vivo rat epilepsy model

    International Nuclear Information System (INIS)

    Jardanhazy, Anett; Molnar, Mark; Jardanhazy, Tamas

    2009-01-01

    The contribution of gap junction (GJ) blockers to seizure initiation was reexamined by means of an analysis on nonlinear dynamics with point correlation dimension (PD2i) at as well as around the primary focus, and mirror focus in an already active 4-aminopyridine-induced in vivo epilepsy model. From the data base of the ECoGs of anesthetized adult rats treated with quinine, a selective blocker of Cx36, and in combination with an additional broad-spectrum GJ blocker, carbenoxolone, 14 cases of each condition were reexamined with a stationarity insensitive nonlinear PD2i method. The blockade of the Cx36 channels decreased the usual drop of the point correlation dimension at the beginning of the seizures, and this was enhanced by the additional use of the global blocker carbenoxolone. The so-called characteristic DC shift just prior to seizure onset denotes a low dimensional seizure event and the recognizable seizures display very variable, rapidly changing dynamics, as revealed by the PD2i analysis. This nonlinear PD2i analysis demonstrated that the different GJ blockers in the already active epileptic model helped seizure initiation, but exerted inhibitory effects on the seizure onset itself, acting differently on the local components of the network organization generating seizure discharges, possibly changing the coupling strengths and time delays in the GJ-s.

  6. Use of beta-blockers and risk of serious upper gastrointestinal bleeding

    DEFF Research Database (Denmark)

    Reilev, Mette; Damkier, Per; Rasmussen, Lotte

    2017-01-01

    Background: Some studies indicate a reduced risk of serious upper gastrointestinal bleeding (UGIB) for users of beta-blockers, but the association remains to be confirmed in larger studies and characterized with respect to differences among beta-blockers. We aimed to assess whether beta-blocker use...... and adjusted odds ratios (ORs) of the association between current beta-blocker use and the risk of UGIB by using conditional logistic regression and further stratified by selective and non-selective beta-blockers, respectively. Results: We identified 3571 UGIB cases and 35,582 controls. Use of beta-blockers...... was not found to be associated with a decreased risk of UGIB (adjusted OR 1.10; 95% CI: 1.00-1.21). The association remained neutral after stratification by selective and non-selective beta-blockers, and by single beta-blocker substances. Similarly, we found no association between current beta-blocker use...

  7. TNFα blockers and infectious risk in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    S. Todesco

    2011-06-01

    Full Text Available Patients suffering from rheumatoid arthritis have increased risk of infections when compared with general population. The risk depends directly from disease activity and severity. Furthermore, risk increases with aging, immunosuppressive agents and comorbidities such as diabetes, pulmonary and cardiac diseases. In particular corticosteroids, even at low doses, are a major risk factor. Due to disease related risk it is difficult to separate the risk deriving from the use of TNF alpha blockers. Data from clinical trials, meta-analysis and national registers are somewhat contradictory. In patients with rheumatoid arthritis on routine follow-up, treatment with TNF alpha blockers seems to carry an increased risk of infections compared to traditional DMARDs but not associated with increased risk of overall serious infection. Physicians should carefully monitor for signs of infection when using TNF alpha blockers, particularly shortly after treatment initiation.

  8. Beta-blocker therapy for tremor in Parkinson's disease.

    Science.gov (United States)

    Crosby, N J; Deane, K H O; Clarke, C E

    2003-01-01

    The tremor of Parkinson's disease can cause considerable disability for the individual concerned. Traditional antiparkinsonian therapies such as levodopa have only a minor effect on tremor. Beta-blockers are used to attenuate other forms of tremor such as Essential Tremor or the tremor associated with anxiety. It is thought that beta-blockers may be of use in controlling the tremor of Parkinson's disease. To compare the efficacy and safety of adjuvant beta-blocker therapy against placebo for the treatment of tremor in patients with Parkinson's disease. Electronic searches of MEDLINE, EMBASE, SCISEARCH, BIOSIS, GEROLIT, OLDMEDLINE, LILACS, MedCarib, PASCAL, JICST-EPLUS, RUSSMED, DISSERTATION ABSTRACTS, SIGLE, ISI-ISTP, Aslib Index to Theses, The Cochrane Controlled Trials Register, Clinicaltrials.gov, metaRegister of Controlled Trials, NIDRR, NRR and CENTRAL were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of beta-blockers were contacted. Randomised controlled trials of adjuvant beta-blocker therapy versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease. Data was abstracted independently by two of the authors onto standardised forms and disagreements were resolved by discussion. Four randomised controlled trials were found comparing beta-blocker therapy with placebo in patients with idiopathic Parkinson's disease. These were double-blind cross-over studies involving a total of 72 patients. Three studies did not present data from the first arm, instead presenting results as combined data from both treatment arms and both placebo arms. The risk of a carry-over effect into the second arm meant that these results were not analysed. The fourth study presented data from each arm. This was in the form of a mean total score for tremor for each group. Details of the baseline scores, the numbers of patients in each group and standard deviations were not

  9. G-protein-coupled inward rectifier potassium channels involved in corticostriatal presynaptic modulation.

    Science.gov (United States)

    Meneses, David; Mateos, Verónica; Islas, Gustavo; Barral, Jaime

    2015-09-01

    Presynaptic modulation has been associated mainly with calcium channels but recent data suggests that inward rectifier potassium channels (K(IR)) also play a role. In this work we set to characterize the role of presynaptic K(IR) channels in corticostriatal synaptic transmission. We elicited synaptic potentials in striatum by stimulating cortical areas and then determined the synaptic responses of corticostriatal synapsis by using paired pulse ratio (PPR) in the presence and absence of several potassium channel blockers. Unspecific potassium channels blockers Ba(2+) and Cs(+) reduced the PPR, suggesting that these channels are presynaptically located. Further pharmacological characterization showed that application of tertiapin-Q, a specific K(IR)3 channel family blocker, also induced a reduction of PPR, suggesting that K(IR)3 channels are present at corticostriatal terminals. In contrast, exposure to Lq2, a specific K(IR)1.1 inward rectifier potassium channel, did not induce any change in PPR suggesting the absence of these channels in the presynaptic corticostriatal terminals. Our results indicate that K(IR)3 channels are functionally expressed at the corticostriatal synapses, since blockage of these channels result in PPR decrease. Our results also help to explain how synaptic activity may become sensitive to extracellular signals mediated by G-protein coupled receptors. A vast repertoire of receptors may influence neurotransmitter release in an indirect manner through regulation of K(IR)3 channels. © 2015 Wiley Periodicals, Inc.

  10. Safe browsing - is an ad-blocker enough?

    CERN Multimedia

    CERN. Geneva

    2015-01-01

    An ad-blocker plugin in your browser stops advertisements and maybe some malware. But is it enough? Are you feeling secure while surfing the Web? If your answer is yes, think twice! What else can you do to protect yourself?

  11. Beta-Blockers and Nitrates: Pharmacotherapy and Indications.

    Science.gov (United States)

    Facchini, Emanuela; Degiovanni, Anna; Cavallino, Chiara; Lupi, Alessandro; Rognoni, Andrea; Bongo, Angelo S

    2015-01-01

    Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b-receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina.

  12. Norepinephrine transporter blocker atomoxetine increases salivary alpha amylase

    NARCIS (Netherlands)

    Warren, C.M.; van den Brink, R.L.; Nieuwenhuis, S.; Bosch, J.A.

    It has been suggested that central norepinephrine (NE) activity may be inferred from increases in salivary alpha-amylase (SAA), but data in favor of this proposition are limited. We administered 40mg of atomoxetine, a selective NE transporter blocker that increases central NE levels, to 24 healthy

  13. Photochemical fate of beta-blockers in NOM enriched waters

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ling; Xu, Haomin; Cooper, William J. [Urban Water Research Center, Department of Civil and Environmental Engineering, University of California, Irvine, Irvine, CA 92697-2175 (United States); Song, Weihua, E-mail: wsong@fudan.edu.cn [Department of Environmental Science and Engineering, Fudan University, Shanghai 200433 (China)

    2012-06-01

    Beta-blockers, prescribed for the treatment of high blood pressure and for long-term use after a heart attack, have been detected in surface and ground waters. This study examines the photochemical fate of three beta-blockers, atenolol, metoprolol, and nadolol. Hydrolysis accounted for minor losses of these beta-blockers in the pH range 4-10. The rate of direct photolysis at pH 7 in a solar simulator varied from 6.1 to 8.9 h{sup -1} at pH 7. However, the addition of a natural organic matter (NOM) isolate enhanced the photochemical loss of all three compounds. Indirect photochemical fate, generally described by reactions with hydroxyl radical ({center_dot}OH) and singlet oxygen ({sup 1}{Delta}O{sub 2}), and, the direct reaction with the triplet excited state, {sup 3}NOM{sup Low-Asterisk }, also varied but collectively appeared to be the major loss factor. Bimolecular reaction rate constants of the three beta-blockers with {sup 1}{Delta}O{sub 2} and {center_dot}OH were measured and accounted for 0.02-0.04% and 7.2-38.9% of their loss, respectively. These data suggest that the {sup 3}NOM{sup Low-Asterisk} contributed 50.6-85.4%. Experiments with various {sup 3}NOM{sup Low-Asterisk} quenchers supported the hypothesis that it was singly the most important reaction. Atenolol was chosen for more detailed investigation, with the photoproducts identified by LC-MS analysis. The results suggested that electron-transfer could be an important mechanism in photochemical fate of beta-blockers in the presence of NOM. - Highlights: Black-Right-Pointing-Pointer Photochemical degradation of beta-blockers in the simulated natural waters. Black-Right-Pointing-Pointer Reactive Oxygen Species play a minor role in the indirect photodegradation. Black-Right-Pointing-Pointer The loss of beta-blockers results from direct reaction with {sup 3}DOM{sup Low-Asterisk }.

  14. Advertising and generic market entry.

    Science.gov (United States)

    Königbauer, Ingrid

    2007-03-01

    The effect of purely persuasive advertising on generic market entry and social welfare is analysed. An incumbent has the possibility to invest in advertising which affects the prescribing physician's perceived relative qualities of the brand-name and the generic version of the drug. Advertising creates product differentiation and can induce generic market entry which is deterred without differentiation due to strong Bertrand competition. However, over-investment in advertising can deter generic market entry under certain conditions and reduces welfare as compared to accommodated market entry.

  15. Entry-Control Systems Handbook

    International Nuclear Information System (INIS)

    1978-09-01

    The function of an entry-control system in a total Physical Protection System is to allow the movement of authorized personnel and material through normal access routes, yet detect and delay unauthorized movement of personnel and material from uncontrolled areas. The ten chapters of this handbook cover: introduction, credentials, personnel identity verification systems, special nuclear materials monitors, metal detectors, explosives sensors, package search systems, criteria for selection of entry-control equipment, machine-aided manual entry-control systems, and automated entry-control systems. A system example and its cost are included as an appendix

  16. Modulation of ERG channels by XE991

    DEFF Research Database (Denmark)

    Elmedyb, Pernille; Calloe, Kirstine; Schmitt, Nicole

    2007-01-01

    In neuronal tissue, KCNQ2-5 channels conduct the physiologically important M-current. In some neurones, the M-current may in addition be conducted partly by ERG potassium channels, which have widely overlapping expression with the KCNQ channel subunits. XE991 and linopiridine are known to be stan......In neuronal tissue, KCNQ2-5 channels conduct the physiologically important M-current. In some neurones, the M-current may in addition be conducted partly by ERG potassium channels, which have widely overlapping expression with the KCNQ channel subunits. XE991 and linopiridine are known...... to be standard KCNQ potassium channel blockers. These compounds have been used in many different tissues as specific pharmacological tools to discern native currents conducted by KCNQ channels from other potassium currents. In this article, we demonstrate that ERG1-2 channels are also reversibly inhibited by XE......991 in the micromolar range (EC(50) 107 microM for ERG1). The effect has been characterized in Xenopus laevis oocytes expressing ERG1-2 and in the mammalian HEK293 cell line stably expressing ERG1 channels. The IC(50) values for block of KCNQ channels by XE991 range 1-65 microM. In conclusion, great...

  17. Pre-stroke use of beta-blockers does not affect ischaemic stroke severity and outcome

    NARCIS (Netherlands)

    De Raedt, S.; Haentjens, P.; De Smedt, A.; Brouns, R.; Uyttenboogaart, Maarten; Luijckx, G. J.; De Keyser, J.

    Background and purpose: It is unclear whether pre-stroke beta-blockers use may influence stroke outcome. This study evaluates the independent effect of pre-stroke use of beta-blockers on ischaemic stroke severity and 3 months functional outcome. Methods: Pre-stroke use of beta-blockers was

  18. Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention

    DEFF Research Database (Denmark)

    Battes, Linda C; Pedersen, Susanne S.; Oemrawsingh, Rohit M

    2012-01-01

    Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose-response relationship between...... beta blocker dose and depressive symptoms....

  19. The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels

    DEFF Research Database (Denmark)

    Bentzen, Bo Hjorth; Schmitt, Nicole; Calloe, Kirstine

    2006-01-01

    The family of Kv7 (KCNQ) potassium channels consists of five members. Kv7.2 and 3 are the primary molecular correlates of the M-current, but also Kv7.4 and Kv7.5 display M-current characteristics. M-channel modulators include blockers (e.g., linopirdine) for cognition enhancement and openers (e.g...

  20. Lycopene depresses glutamate release through inhibition of voltage-dependent Ca2+ entry and protein kinase C in rat cerebrocortical nerve terminals.

    Science.gov (United States)

    Lu, Cheng-Wei; Hung, Chi-Feng; Jean, Wei-Horng; Lin, Tzu-Yu; Huang, Shu-Kuei; Wang, Su-Jane

    2018-05-01

    Lycopene is a natural dietary carotenoid that was reported to exhibit a neuroprotective profile. Considering that excitotoxicity and cell death induced by glutamate are involved in many brain disorders, the effect of lycopene on glutamate release in rat cerebrocortical nerve terminals and the possible mechanism involved in such effect was investigated. We observed here that lycopene inhibited 4-aminopyridine (4-AP)-evoked glutamate release and intrasynaptosomal Ca 2+ concentration elevation. The inhibitory effect of lycopene on 4-AP-evoked glutamate release was markedly reduced in the presence of the Ca v 2.2 (N-type) and Ca v 2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was insensitive to the intracellular Ca 2+ -release inhibitors dantrolene and CGP37157. Furthermore, in the presence of the protein kinase C inhibitors GF109203X and Go6976, the action of lycopene on evoked glutamate release was prevented. These results are the first to suggest that lycopene inhibits glutamate release from rat cortical synaptosomes by suppressing presynaptic Ca 2+ entry and protein kinase C activity.

  1. Functional and pharmacological consequences of the distribution of voltage-gated calcium channels in the renal blood vessels.

    Science.gov (United States)

    Hansen, P B L

    2013-04-01

    Calcium channel blockers are widely used to treat hypertension because they inhibit voltage-gated calcium channels that mediate transmembrane calcium influx in, for example, vascular smooth muscle and cardiomyocytes. The calcium channel family consists of several subfamilies, of which the L-type is usually associated with vascular contractility. However, the L-, T- and P-/Q-types of calcium channels are present in the renal vasculature and are differentially involved in controlling vascular contractility, thereby contributing to regulation of kidney function and blood pressure. In the preglomerular vascular bed, all the three channel families are present. However, the T-type channel is the only channel in cortical efferent arterioles which is in contrast to the juxtamedullary efferent arteriole, and that leads to diverse functional effects of L- and T-type channel inhibition. Furthermore, by different mechanisms, T-type channels may contribute to both constriction and dilation of the arterioles. Finally, P-/Q-type channels are involved in the regulation of human intrarenal arterial contractility. The calcium blockers used in the clinic affect not only L-type but also P-/Q- and T-type channels. Therefore, the distinct effect obtained by inhibiting a given subtype or set of channels under experimental settings should be considered when choosing a calcium blocker for treatment. T-type channels seem to be crucial for regulating the GFR and the filtration fraction. Use of blockers is expected to lead to preferential efferent vasodilation, reduction of glomerular pressure and proteinuria. Therefore, renovascular T-type channels might provide novel therapeutic targets, and may have superior renoprotective effects compared to conventional calcium blockers. Acta Physiologica © 2013 Scandinavian Physiological Society.

  2. HEART FAILURE, DIABETES, BETA-BLOCKERS AND RISK OF HYPOGLYCEMIA

    Directory of Open Access Journals (Sweden)

    A. A. Aleksandrov

    2008-01-01

    Full Text Available Aim. To evaluate an influence of carvedilol on risk of hypoglycemia in patients with diabetes type 2 (D2 and chronic heart failure (CHF treated with angiotensin converting enzyme (ACE inhibitors.Material and methods. 13 patients (10 men, 3 women; aged 59,8±6,7 y.o. with D2 and CHF caused by ischemic heart disease were included in the study. Before inclusion all patients were treated with ACE inhibitors and various beta-blockers (atenolol, metoprolol, bisoprolol. These beta-blockers were changed for carvedilol. Heart ultrasonography, blood pressure control, glycemia monitoring, HbA1c level determination were performed before, during and after carvedilol therapy.Results. Carvedilol reduces frequency and duration of hypoglycaemia episodes. There were not episodes of severe hypoglycaemia during carvedilol therapy.Conclusion. Carvedilol reduces risk of hypoglycemia when it is used in combination with ACE inhiditors in diabetic patients with CHF.

  3. Analysis of solar blocker through portable X-ray fluorescence

    International Nuclear Information System (INIS)

    Ferreira, Diego de Dio; Melquiades, Fabio Luiz; Appoloni, Carlos Roberto; Lopes, Fabio; Lonni, Audrey Stinghen G.; Oliveira, Frederico Minardi de; Duarte, Jose C.

    2009-01-01

    This paper estimates the concentration of TiO 2 by Energy Dispersion X-ray fluorescence (EDXRF) viewing t obtain the FPS due to the physical barrier in the composition of solar blockers, and identifies possible present metals in the samples. A portable EDXRF equipment was used and 27 commercial of different brands and solar protection factors were analysed. Also, three formulations (A, B and C) were prepared and measured estimated in FPS-30 using 5% or TiO 2 . The quantification was performed through calibration curves with 1% to 30% standards of TiO 2 . As result, it was possible to determine the contribution to physical protection in the FPS, associated to the Ti concentration present in some solar blocker samples available in the market. Also, it was possible to detect the presence of various metals in solar protectors, such as Fe, Zn, Br and Sr, and identify chemical elements which were not mentioned and their formulation as well

  4. Beta-blockers and statins in the context of asthma

    Directory of Open Access Journals (Sweden)

    Joanna Pawlak

    2009-12-01

    Full Text Available Asthma is a disease with a complex pathogenesis and differentiated clinical picture with airway inflammation in its background. Many cells and cell-released substances are engaged in the course of the disease. The basic treatment strategy in asthma is based on chronic administration of inhaled glucocorticosteroids (with a strong anti-inflammatory effect and beta2-adrenoreceptor agonists (bronchodilatory effect. Much attention has been recently paid to the effects of other medicines on mechanisms important in the pathogenesis of asthma, including beta-blockers and statins. Many researchers have suggested a potentially useful role of some beta-blockers in chronic asthma therapy, particularly considering their effect on the pharmacodynamics of beta receptors in the bronchi. Moreover, statins, due to their anti-inflammatory and immunomodulatory effects, can also be useful in the management of asthma.

  5. Use of β-Blockers in Pulmonary Hypertension.

    Science.gov (United States)

    Perros, Frédéric; de Man, Frances S; Bogaard, Harm J; Antigny, Fabrice; Simonneau, Gérald; Bonnet, Sébastien; Provencher, Steeve; Galiè, Nazzareno; Humbert, Marc

    2017-04-01

    Contrasting with the major attention that left heart failure has received, right heart failure remains understudied both at the preclinical and clinical levels. However, right ventricle failure is a major predictor of outcomes in patients with precapillary pulmonary hypertension because of pulmonary arterial hypertension, and in patients with postcapillary pulmonary hypertension because of left heart disease. In pulmonary hypertension, the status of the right ventricle is one of the most important predictors of both morbidity and mortality. Paradoxically, there are currently no approved therapies targeting the right ventricle in pulmonary hypertension. By analogy with the key role of β-blockers in the management of left heart failure, some authors have proposed to use these agents to support the right ventricle function in pulmonary hypertension. In this review, we summarize the current knowledge on the use of β-blockers in pulmonary hypertension. © 2017 American Heart Association, Inc.

  6. Effects of gap junction blockers on human neocortical synchronization.

    Science.gov (United States)

    Gigout, S; Louvel, J; Kawasaki, H; D'Antuono, M; Armand, V; Kurcewicz, I; Olivier, A; Laschet, J; Turak, B; Devaux, B; Pumain, R; Avoli, M

    2006-06-01

    Field potentials and intracellular recordings were obtained from human neocortical slices to study the role of gap junctions (GJ) in neuronal network synchronization. First, we examined the effects of GJ blockers (i.e., carbenoxolone, octanol, quinine, and quinidine) on the spontaneous synchronous events (duration = 0.2-1.1 s; intervals of occurrence = 3-27 s) generated by neocortical slices obtained from temporal lobe epileptic patients during application of 4-aminopyridine (4AP, 50 muM) and glutamatergic receptor antagonists. The synchronicity of these potentials (recorded at distances up to 5 mm) was decreased by GJ blockers within 20 min of application, while prolonged GJ blockers treatment at higher doses made them disappear with different time courses. Second, we found that slices from patients with focal cortical dysplasia (FCD) could generate in normal medium spontaneous synchronous discharges (duration = 0.4-8 s; intervals of occurrence = 0.5-90 s) that were (i) abolished by NMDA receptor antagonists and (ii) slowed down by carbenoxolone. Finally, octanol or carbenoxolone blocked 4AP-induced ictal-like discharges (duration = up to 35 s) in FCD slices. These data indicate that GJ play a role in synchronizing human neocortical networks and may implement epileptiform activity in FCD.

  7. Cellular Responses to Beta Blocker Exposures in Marine ...

    Science.gov (United States)

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent activation of adenylate cyclase and increases in blood pressure by limiting cAMP production and protein kinase A activation. After being taken therapeutically, β blockers may make their way to coastal habitats via discharge from waste water treatment plants, posing a potential risk to aquatic organisms. The aim of our research is to evaluate cellular biomarkers of β blocker exposure using two drugs, propranolol and metoprolol, in three commercially important marine bivalves -Crassostrea virginica, Mytilus edulis and Mercenaria mercenaria. Bivalves were obtained from Narragansett Bay (Rhode Island, USA) and acclimated in the laboratory. Following acclimation, gills and hepatopancreas tissues were harvested and separately exposed to 0, 1, 10, 100 and 1000 ng/l of each drug for 24 hours. Samples were preserved for cellular biomarker assays. Elevated cellular damage and changes in enzymatic activities were noted at environmentally relevant concentrations, and M. mercenaria was found to be the most sensitive bivalve out of the three species tested. These studies enhance our understanding of the potential impacts of commonly used prescription medication on organisms in coastal ecosystems, and demonstrate that filter feeders such as marine bivalves may serve as good model organisms to examine the effects of water soluble drugs. Evaluating a suite of biomarkers

  8. Marine Bivalve Cellular Responses to Beta Blocker Exposures ...

    Science.gov (United States)

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent binding of agonists such as catecholamines to β adrenoceptors. In the absence of agonist induced activation of the receptor, adenylate cyclase is not activated which in turn limits cAMP production and protein kinase A activation, preventing increases in blood pressure and arrhythmias. After being taken therapeutically, commonly prescribed β blockers may make their way to coastal habitats via discharge from waste water treatment plants (WWTP) posing a potential risk to aquatic organisms. The aim of our research is to evaluate cellular responses of three commercially important marine bivalves - Eastern oysters, blue mussels and hard clams - upon exposure to two β blocker drugs, propranolol and metoprolol, and to find molecular initiating events (MIEs) indicative of the exposure. Bivalves were obtained from Narragansett Bay (Rhode Island, USA) and acclimated in the laboratory. Following acclimation, gills and hepatopancreas (HP) tissues were harvested and separately exposed to 0, 1, 10, 100 and 1000 ng/l of each drug. Tissues were bathed in 30 parts per thousand (ppt) filtered seawater, antibiotic mix, Leibovitz nutrient media, and the test drug. Exposures were conducted for 24 hours and samples were saved for cellular biomarker assays. A lysosomal destabilization assay, which is a marker of membrane damage, was also performed at the end of each exposure.

  9. Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

    Science.gov (United States)

    Sabourin, Jessica; Bartoli, Fiona; Antigny, Fabrice; Gomez, Ana Maria; Benitah, Jean-Pierre

    2016-01-01

    Store-operated Ca2+ entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that up-regulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidence suggests that the mineralocorticoid hormone aldosterone, through activation of its receptor, MR, might be a key regulator of Ca2+ influx in cardiomyocytes. We thus assessed whether and how SOCE involving transient receptor potential canonical (TRPC) and Orai1 channels are regulated by aldosterone/MR in neonatal rat ventricular cardiomyocytes. Molecular screening using qRT-PCR and Western blotting demonstrated that aldosterone treatment for 24 h specifically increased the mRNA and/or protein levels of Orai1, TRPC1, -C4, -C5, and stromal interaction molecule 1 through MR activation. These effects were correlated with a specific enhancement of SOCE activities sensitive to store-operated channel inhibitors (SKF-96365 and BTP2) and to a potent Orai1 blocker (S66) and were prevented by TRPC1, -C4, and Orai1 dominant negative mutants or TRPC5 siRNA. A mechanistic approach showed that up-regulation of serum- and glucocorticoid-regulated kinase 1 mRNA expression by aldosterone is involved in enhanced SOCE. Functionally, 24-h aldosterone-enhanced SOCE is associated with increased diastolic [Ca2+]i, which is blunted by store-operated channel inhibitors. Our study provides the first evidence that aldosterone promotes TRPC1-, -C4-, -C5-, and Orai1-mediated SOCE in cardiomyocytes through an MR and serum- and glucocorticoid-regulated kinase 1 pathway. PMID:27129253

  10. Management of hypertension: Insights into prescribing behavior with focus on angiotensin receptor blockers

    Directory of Open Access Journals (Sweden)

    S Ramakrishnan

    2017-01-01

    Full Text Available Introduction: Angiotensin receptor blockers (ARBs are emerging as an attractive first choice antihypertensive as recommended by various guidelines. However, choice among the first-line antihypertensive classes and among ARBs differs between practicing physicians. Aims: This survey aimed to understand the usage preferences of ARBs and its place in for treating hypertension (HTN among physicians from various clinical settings in India. Methods: A cross-sectional survey was conducted with a prevalidated survey questionnaire consisting of 25 questions for HTN management. Practicing general physicians and cardiologists were approached for seeking their perception, opinions, and prescribing behavior. Results: Responses of 594 physicians and cardiologists were received. As opined by 90.1% of physicians, newly diagnosed HTN represented more than 10% of their overall patient load. As a monotherapy, 59.9% of the physicians preferred ARB as the first choice in newly diagnosed HTN patients, followed by calcium channel blocker (12.3% and angiotensin-converting-enzyme inhibitor (8.1%. Of all ARBs, telmisartan is preferred by 73% of physicians. Most physicians prefer telmisartan among all ARBs for 24 h blood pressure (BP control, including morning BP surge (76.4% and for prevention of cardiovascular morbidity and mortality (78.8% followed by olmesartan and losartan. Predominantly, majority of physicians (89.1% agreed for the beneficial role of telmisartan in preventing onset of microalbuminuria and nephropathy. Conclusion: Indian physicians prefer ARBs as the first choice in most hypertensive patients, which shows agreement with the guideline recommendations followed globally. Telmisartan has emerged as the most preferred ARB among all, for most of the HTN patients including those with comorbidities.

  11. Entry Threat and Entry Deterrence: The Timing of Broadband Rollout

    OpenAIRE

    Mo Xiao; Peter F. Orazem

    2007-01-01

    Past empirical literature provides strong evidence that competition increases when new firms enter a market. However, rarely have economists been able to examine how competition changes with the threat of entry. This paper uses the evolution of the zip code level market structure of facilities-based broadband providers from 1999 to 2004 to investigate how a firm adjusts its entry strategy when facing the threat of additional entrants. We identify the potential entrant into a local market as t...

  12. Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

    Science.gov (United States)

    Fujiwara, Yuichiro; Arrigoni, Cristina; Domigan, Courtney; Ferrara, Giuseppina; Pantoja, Carlos; Thiel, Gerhard; Moroni, Anna; Minor, Daniel L.

    2009-01-01

    Background Understanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs. Methodology/Principal Findings We used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the T→S mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affect blocker binding. Conclusions/Significance The data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features. PMID:19834614

  13. Corporate Author Entries. Revision 5

    International Nuclear Information System (INIS)

    Hendricks, P.L.

    1986-05-01

    This reference authority has been created and is maintained to provide standard forms for recording the names of organizations consistently in bibliographic citations. This revision includes approximately 42,000 entries established since 1973

  14. Network Competition and Entry Deterrence

    OpenAIRE

    Calzada, Joan; Valletti, Tommaso

    2005-01-01

    We develop a model of logit demand that extends to a multi-firm industry the traditional duopoly framework of network competition with access charges. Firstly, we show that, when incumbents do not face the threat of entry and compete in prices, they inefficiently establish the reciprocal access charge below cost. This inefficiency disappears if incumbents compete in utilities instead of prices. Secondly, we study how incumbents change their choices under the threat of entry when they determin...

  15. Currency union entries and trade

    OpenAIRE

    Nitsch, Volker

    2005-01-01

    Recent research suggests that adopting a common currency increases bilateral trade. In this paper, I explore experiences of currency union entry in the post-war period and find no effect on trade. Previous results derived from a large panel data set (covering more than 200 countries from 1948 through 1997) appear to depend crucially on the assumption of symmetry between currency union exits and entries: While countries leaving a currency union experience significant declines in trade, currenc...

  16. The role of transient receptor potential channels in metabolic syndrome

    DEFF Research Database (Denmark)

    Liu, Daoyan; Zhu, Zhiming; Tepel, Martin

    2008-01-01

    Metabolic syndrome is correlated with increased cardiovascular risk and characterized by several factors, including visceral obesity, hypertension, insulin resistance, and dyslipidemia. Several members of a large family of nonselective cation entry channels, e.g., transient receptor potential (TRP...

  17. Antifungal Effect of Chitosan as Ca²⁺ Channel Blocker

    Directory of Open Access Journals (Sweden)

    Choon Geun Lee

    2016-06-01

    Full Text Available The aim of this study was to investigate antifungal activity of a range of different molecular weight (MW chitosan against Penicillium italicum. Our results demonstrate that the antifungal activity was dependent both the MW and concentration of the chitosan. Among a series of chitosan derived from the hydrolysis of high MW chitosan, the fractions containing various sizes of chitosan ranging from 3 to 15 glucosamine units named as chitooligomers-F2 (CO-F2 was found to show the highest antifungal activity against P. italicum. Furthermore, the effect of CO-F2 toward this fungus was significantly reduced in the presence of Ca²⁺, whereas its effect was recovered by ethylenediaminetetraacetic acid, suggesting that the CO-F2 acts via disruption of Ca²⁺ gradient required for survival of the fungus. Our results suggest that CO-F2 may serve as potential compounds to develop alternatives to synthetic fungicides for the control of the postharvest diseases.

  18. Extracellular Adenosine Triphosphate Associated with Amphibian Erythrocytes: Inhibition of ATP Release by Anion Channel Blockers.

    Science.gov (United States)

    1986-01-01

    Paddle and Burnstock (326), Williams and Forrester (463), Forrester and Williams (151) and Clemens and Forrester (82) provide evidence that hypoxia may...an ATp4 - receptor. Fed. Proc. 45:208, 1986. (abstr) 99. Dahlen , S.E. and Hedqvist, P. ATP, B,y-methylene ATP andN adenosine inhibit non-cholinergic...regulation of skeletal muscle blood low. Circ Res. 29:375-384, 1971. 117. Dodd, J., Jahr, C.E., Hamilton, P.N., Heath, M.J., Matthew , W.P., and Jessell, T.M

  19. Nifedipine--a calcium channel blocker--in asthmatic patients. Interaction with terbutaline.

    Science.gov (United States)

    Svedmyr, K; Löfdahl, C G; Svedmyr, N

    1984-01-01

    Seven asthmatic patients were studied in a single-blind randomized, crossover study after oral administration of 20 mg nifedipine or placebo. Four increasing doses of i.v. terbutaline were then given with 30 min interval. The study was concluded with inhalation of five terbutaline puffs. FEV1 measurements 30 min after intake of nifedipine did not show any difference compared to placebo. During the terbutaline treatment, however, there was a more pronounced bronchodilation after nifedipine than after placebo (P less than 0.05). Terbutaline-induced skeletal muscle tremor was similar after nifedipine and placebo pretreatments. After nifedipine intake there was a decrease of diastolic blood pressure and a reflexogenic tachycardia. Thus, this study showed a small potentiation of the beta 2-adrenoceptor mediated bronchodilation, which is of importance when treating patients with simultaneous asthma and hypertension or angina pectoris.

  20. VKCDB: Voltage-gated potassium channel database

    Directory of Open Access Journals (Sweden)

    Gallin Warren J

    2004-01-01

    Full Text Available Abstract Background The family of voltage-gated potassium channels comprises a functionally diverse group of membrane proteins. They help maintain and regulate the potassium ion-based component of the membrane potential and are thus central to many critical physiological processes. VKCDB (Voltage-gated potassium [K] Channel DataBase is a database of structural and functional data on these channels. It is designed as a resource for research on the molecular basis of voltage-gated potassium channel function. Description Voltage-gated potassium channel sequences were identified by using BLASTP to search GENBANK and SWISSPROT. Annotations for all voltage-gated potassium channels were selectively parsed and integrated into VKCDB. Electrophysiological and pharmacological data for the channels were collected from published journal articles. Transmembrane domain predictions by TMHMM and PHD are included for each VKCDB entry. Multiple sequence alignments of conserved domains of channels of the four Kv families and the KCNQ family are also included. Currently VKCDB contains 346 channel entries. It can be browsed and searched using a set of functionally relevant categories. Protein sequences can also be searched using a local BLAST engine. Conclusions VKCDB is a resource for comparative studies of voltage-gated potassium channels. The methods used to construct VKCDB are general; they can be used to create specialized databases for other protein families. VKCDB is accessible at http://vkcdb.biology.ualberta.ca.

  1. Arachidonic acid-induced Ca2+ entry and migration in a neuroendocrine cancer cell line.

    Science.gov (United States)

    Goswamee, Priyodarshan; Pounardjian, Tamar; Giovannucci, David R

    2018-01-01

    Store-operated Ca 2+ entry (SOCE) has been implicated in the migration of some cancer cell lines. The canonical SOCE is defined as the Ca 2+ entry that occurs in response to near-maximal depletion of Ca 2+ within the endoplasmic reticulum. Alternatively, arachidonic acid (AA) has been shown to induce Ca 2+ entry in a store-independent manner through Orai1/Orai3 hetero-multimeric channels. However, the role of this AA-induced Ca 2+ entry pathway in cancer cell migration has not been adequately assessed. The present study investigated the involvement of AA-induced Ca 2+ entry in migration in BON cells, a model gastro-enteropancreatic neuroendocrine tumor (GEPNET) cell line using pharmacological and gene knockdown methods in combination with live cell fluorescence imaging and standard migration assays. We showed that both the store-dependent and AA-induced Ca 2+ entry modes could be selectively activated and that exogenous administration of AA resulted in Ca 2+ entry that was pharmacologically distinct from SOCE. Also, whereas homomeric Orai1-containing channels appeared to largely underlie SOCE, the AA-induced Ca 2+ entry channel required the expression of Orai3 as well as Orai1. Moreover, we showed that AA treatment enhanced the migration of BON cells and that this migration could be abrogated by selective inhibition of the AA-induced Ca 2+ entry. Taken together, these data revealed that an alternative Orai3-dependent Ca 2+ entry pathway is an important signal for GEPNET cell migration.

  2. An oral Na(V)1.8 blocker improves motor function in mice completely deficient of myelin protein P-0

    DEFF Research Database (Denmark)

    Rosberg, Mette R.; Alvarez Herrero, Susana; Krarup, Christian

    2016-01-01

    Mice deficient of myelin protein P0 are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Dysmyelination in these mice is associated with an ectopic expression of the sensory neuron specific sodium channel isoform NaV1.8 on motor axons. We reported that in P0+/−, a model of CMT......1B, the membrane dysfunction could be acutely improved by a novel oral NaV1.8 blocker referred to as Compound 31 (C31, Bioorg. Med. Chem. Lett. 2010, 20, 6812; AbbVie Inc.). The aim of this study was to investigate the extent to which C31 treatment could also improve the motor axon function in P0......-of-concept that treatment with oral subtype-selective NaV1.8 blockers could be used to improve the motor function in severe forms of demyelinating CMT....

  3. Beta-Blockers for Exams Identify Students at High Risk of Psychiatric Morbidity.

    Science.gov (United States)

    Butt, Jawad H; Dalsgaard, Søren; Torp-Pedersen, Christian; Køber, Lars; Gislason, Gunnar H; Kruuse, Christina; Fosbøl, Emil L

    2017-04-01

    Beta-blockers relieve the autonomic symptoms of exam-related anxiety and may be beneficial in exam-related and performance anxiety, but knowledge on related psychiatric outcomes is unknown. We hypothesized that beta-blocker therapy for exam-related anxiety identifies young students at risk of later psychiatric events. Using Danish nationwide administrative registries, we studied healthy students aged 14-30 years (1996-2012) with a first-time claimed prescription for a beta-blocker during the exam period (May-June); students who were prescribed a beta-blocker for medical reasons were excluded. We matched these students on age, sex, and time of year to healthy and study active controls with no use of beta-blockers. Risk of incident use of antidepressants, incident use of other psychotropic medications, and suicide attempts was examined by cumulative incidence curves for unadjusted associations and multivariable cause-specific Cox proportional hazard analyses for adjusted hazard ratios (HRs). We identified 12,147 healthy students with exam-related beta-blocker use and 12,147 matched healthy students with no current or prior use of beta-blockers (median age, 19 years; 80.3% women). Among all healthy students, 0.14% had a first-time prescription for a beta-blocker during the exam period with the highest proportion among students aged 19 years (0.39%). Eighty-one percent of the students filled only that single prescription for a beta-blocker during follow-up. During follow-up, 2225 (18.3%) beta-blocker users and 1400 (11.5%) nonbeta-blocker users were prescribed an antidepressant (p beta-blocker users and 658 (5.4%) nonbeta-blocker users were prescribed a psychotropic drug (p beta-blocker users and 6 (0.05%) nonbeta-blocker users attempted suicide (p = 0.03). Exam-related beta-blocker use was associated with an increased risk of antidepressant use (adjusted HRs, 1.68 [95% confidence intervals (CIs), 1.57-1.79], p beta-blockers during the exam period was

  4. Effect of Potassium Channel Modulators on Morphine Withdrawal in Mice

    Directory of Open Access Journals (Sweden)

    Vikas Seth

    2010-01-01

    Full Text Available The present study was conducted to investigate the effect of potassium channel openers and blockers on morphine withdrawal syndrome. Mice were rendered dependent on morphine by subcutaneous injection of morphine; four hours later, withdrawal was induced by using an opioid antagonist, naloxone. Mice were observed for 30 minutes for the withdrawal signs ie, the characteristic jumping, hyperactivity, urination and diarrhea. ATP-dependent potassium (K + ATP channel modulators were injected intraperitoneally (i.p. 30 minutes before the naloxone. It was found that a K + ATP channel opener, minoxidil (12.5–50 mg/kg i.p., suppressed the morphine withdrawal significantly. On the other hand, the K + ATP channel blocker glibenclamide (12.5–50 mg/kg i.p. caused a significant facilitation of the withdrawal. Glibenclamide was also found to abolish the minoxidil's inhibitory effect on morphine withdrawal. The study concludes that K + ATP channels play an important role in the genesis of morphine withdrawal and K + ATP channel openers could be useful in the management of opioid withdrawal. As morphine opens K + ATP channels in neurons, the channel openers possibly act by mimicking the effects of morphine on neuronal K + currents.

  5. Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys.

    Science.gov (United States)

    Losen, Mario; Labrijn, Aran F; van Kranen-Mastenbroek, Vivianne H; Janmaat, Maarten L; Haanstra, Krista G; Beurskens, Frank J; Vink, Tom; Jonker, Margreet; 't Hart, Bert A; Mané-Damas, Marina; Molenaar, Peter C; Martinez-Martinez, Pilar; van der Esch, Eline; Schuurman, Janine; de Baets, Marc H; Parren, Paul W H I

    2017-04-20

    Autoantibodies against ion channels are the cause of numerous neurologic autoimmune disorders. Frequently, such pathogenic autoantibodies have a restricted epitope-specificity. In such cases, competing antibody formats devoid of pathogenic effector functions (blocker antibodies) have the potential to treat disease by displacing autoantibodies from their target. Here, we have used a model of the neuromuscular autoimmune disease myasthenia gravis in rhesus monkeys (Macaca mulatta) to test the therapeutic potential of a new blocker antibody: MG was induced by passive transfer of pathogenic acetylcholine receptor-specific monoclonal antibody IgG1-637. The effect of the blocker antibody (IgG4Δhinge-637, the hinge-deleted IgG4 version of IgG1-637) was assessed using decrement measurements and single-fiber electromyography. Three daily doses of 1.7 mg/kg IgG1-637 (cumulative dose 5 mg/kg) induced impairment of neuromuscular transmission, as demonstrated by significantly increased jitter, synaptic transmission failures (blockings) and a decrease in the amplitude of the compound muscle action potentials during repeated stimulations (decrement), without showing overt symptoms of muscle weakness. Treatment with three daily doses of 10 mg/kg IgG4Δhinge-637 significantly reduced the IgG1-637-induced increase in jitter, blockings and decrement. Together, these results represent proof-of principle data for therapy of acetylcholine receptor-myasthenia gravis with a monovalent antibody format that blocks binding of pathogenic autoantibodies.

  6. Voltage-sensing domain of voltage-gated proton channel Hv1 shares mechanism of block with pore domains.

    Science.gov (United States)

    Hong, Liang; Pathak, Medha M; Kim, Iris H; Ta, Dennis; Tombola, Francesco

    2013-01-23

    Voltage-gated sodium, potassium, and calcium channels are made of a pore domain (PD) controlled by four voltage-sensing domains (VSDs). The PD contains the ion permeation pathway and the activation gate located on the intracellular side of the membrane. A large number of small molecules are known to inhibit the PD by acting as open channel blockers. The voltage-gated proton channel Hv1 is made of two VSDs and lacks the PD. The location of the activation gate in the VSD is unknown and open channel blockers for VSDs have not yet been identified. Here, we describe a class of small molecules which act as open channel blockers on the Hv1 VSD and find that a highly conserved phenylalanine in the charge transfer center of the VSD plays a key role in blocker binding. We then use one of the blockers to show that Hv1 contains two intracellular and allosterically coupled gates. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications

    Directory of Open Access Journals (Sweden)

    Miroslav Radenkovic

    2016-01-01

    Full Text Available The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation.

  8. Reappraisal of role of angiotensin receptor blockers in cardiovascular protection

    Directory of Open Access Journals (Sweden)

    Ram CV

    2011-05-01

    Full Text Available C Venkata S RamTexas Blood Pressure Institute, Clinical Research Institute of Dallas Nephrology Associates; and Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USAAbstract: Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin receptor blockers (ARBs have shown cardioprotective and renoprotective properties. These agents are recommended as first-line therapy for the treatment of hypertension and the reduction of cardiovascular risk. Early studies pointed to the cardioprotective and renoprotective effects of ARBs in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET established the clinical equivalence of the cardioprotective and renoprotective effects of telmisartan and ramipril, but did not find an added benefit of the combination over ramipril alone. Similar findings were observed in the Telmisartan Randomized AssessmeNt Study in aCE INtolerant subjects with cardiovascular Disease (TRANSCEND trial conducted in ACEI-intolerant patients. In ONTARGET, telmisartan had a better tolerability profile with similar renoprotective properties compared with ramipril, suggesting a potential clinical benefit over ramipril. The recently completed Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial (ORIENT and Olmesartan and Calcium Antagonists Randomized (OSCAR studies will further define the role of ARBs in cardioprotection and renoprotection for high-risk patients.Keywords: angiotensin receptor blockers, hypertension, outcomes, clinical trials

  9. Calcium channel modulation as a target in chronic pain control.

    Science.gov (United States)

    Patel, Ryan; Montagut-Bordas, Carlota; Dickenson, Anthony H

    2018-06-01

    Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first-in-class synthetic version of ω-conotoxin MVIIA, a peptide blocker of Ca v 2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use-dependent block of Ca v 2.2 channels; activation state-dependent blockers were hypothesized to circumvent the side effects of state-independent blockers by selectively targeting high-frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state-dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus-evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant-based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench-to-bedside translation of calcium channel modulators. This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175

  10. Cell swelling activates separate taurine and chloride channels in Ehrlich mouse ascites tumor cells

    DEFF Research Database (Denmark)

    Lambert, Ian Henry; Hoffmann, Else Kay

    1994-01-01

    The taurine efflux from Ehrlich ascites tumor cells is stimulated by hypotonic cell swelling. The swelling-activated taurine efflux is unaffected by substitution of gluconate for extracellular Cl– but inhibited by addition of MK196 (anion channel blocker) and 4,4 -diisothiocyanostilbene-2......,2 -disulfonic acid (DIDS; anion channel and anion exchange blocker) and by depolarization of the cell membrane. This is taken to indicate that taurine does not leave the osmotically swollen Ehrlich cells in exchange for extracellular Cl–, i.e., via the anion exchanger but via a MK196- and DIDS-sensitive channel...... that is potential dependent. An additional stimulation of the swelling-activated taurine efflux is seen after addition of arachidonic acid and oleic acid. Cell swelling also activates a Mini Cl– channel. The Cl– efflux via this Cl– channel, in contrast to the swelling-activated taurine efflux, is unaffected by DIDS...

  11. SENSITIVE EFFECTS OF POTASSIUM AND CALCIUM CHANNEL BLOCKING AND ATP-SENSITIVE POTASSIUM CHANNEL ACTIVATORS ON SEMINAL VESICLE SMOOTH MUSCLE CONTRACTIONS

    Directory of Open Access Journals (Sweden)

    H SADRAEI

    2000-12-01

    Full Text Available Background. Seminal vesicle smooth muscle contraction is mediated through sympathetic and parasympathetic neurons activity. Although seminal vesicle plays an important role in male fertility, but little attention is given to mechanism involved in contraction of this organ.
    Methods. In this study effects of drugs which activate ATP - sensitive K channels and blockers of K and Ca channels were examined on contraction of guinea - pig isolated seminal vesicle due to electrical filled stimulation (EFS, noradrenaline, carbachol and KCI.
    Results. The K channel blocker tetraethyl ammonium potentate the EFS responses at all frequencies, while, the ATP - sensitive K channel inhibitor glibenclamide and the K channel opener levcromakalim, diazoxide, minoxidil and Ca channel blocker nifedipine all had relaxant effect on guinea - pig seminal vesicle.
    Discussion. This study indicate that activities of K and Ca channels is important in regulation of seminal vesicle contraction due to nerve stimulation, noradrenaline or carbachol.

  12. Building Entry Loss and Delay Spread Measurements on a Simulated HAP-to-Indoor Link at S-Band

    Directory of Open Access Journals (Sweden)

    Delgado-Penín JA

    2008-01-01

    Full Text Available Results from a measurement campaign emulating the high altitude platform (HAP-to-indoor communication channel at S-band are presented in this paper. A link was established between a transmitter carried by a helicopter, representing the HAP, and a receiver placed at several locations in different building types including an airport, an office building, a shopping mall, a residential house, and a skyscraper. A wideband, directive channel sounder was used to measure building entry loss and time delay spread. Results of the building entry loss are presented as a function of building type, elevation, and building entry angle. Results of delay spread for each building are also provided.

  13. Building Entry Loss and Delay Spread Measurements on a Simulated HAP-to-Indoor Link at S-Band

    Directory of Open Access Journals (Sweden)

    P. Valtr

    2008-07-01

    Full Text Available Results from a measurement campaign emulating the high altitude platform (HAP-to-indoor communication channel at S-band are presented in this paper. A link was established between a transmitter carried by a helicopter, representing the HAP, and a receiver placed at several locations in different building types including an airport, an office building, a shopping mall, a residential house, and a skyscraper. A wideband, directive channel sounder was used to measure building entry loss and time delay spread. Results of the building entry loss are presented as a function of building type, elevation, and building entry angle. Results of delay spread for each building are also provided.

  14. Ion channeling

    International Nuclear Information System (INIS)

    Erramli, H.; Blondiaux, G.

    1994-01-01

    Channeling phenomenon was predicted, many years ago, by stark. The first channeling experiments were performed in 1963 by Davies and his coworkers. Parallely Robinson and Oen have investigated this process by simulating trajectories of ions in monocrystals. This technique has been combined with many methods like Rutherford Backscattering Spectrometry (R.B.S.), Particles Induced X-rays Emission (P.I.X.E) and online Nuclear Reaction (N.R.A.) to localize trace elements in the crystal or to determine crystalline quality. To use channeling for material characterization we need data about the stopping power of the incident particle in the channeled direction. The ratios of channeled to random stopping powers of silicon for irradiation in the direction have been investigated and compared to the available theoretical results. We describe few applications of ion channeling in the field of materials characterization. Special attention is given to ion channeling combined with Charged Particle Activation Analysis (C.P.A.A.) for studying the behaviour of oxygen atoms in Czochralski silicon lattices under the influence of internal gettering and in different gaseous atmospheres. Association between ion channeling and C.P.A.A was also utilised for studying the influence of the growing conditions on concentration and position of carbon atoms at trace levels in the MOVPE Ga sub (1-x) Al sub x lattice. 6 figs., 1 tab., 32 refs. (author)

  15. Protonated form: the potent form of potassium-competitive acid blockers.

    Directory of Open Access Journals (Sweden)

    Hua-Jun Luo

    Full Text Available Potassium-competitive acid blockers (P-CABs are highly safe and active drugs targeting H+,K+-ATPase to cure acid-related gastric diseases. In this study, we for the first time investigate the interaction mechanism between the protonated form of P-CABs and human H+,K+-ATPase using homology modeling, molecular docking, molecular dynamics and binding free energy calculation methods. The results explain why P-CABs have higher activities with higher pKa values or at lower pH. With positive charge, the protonated forms of P-CABs have more competitive advantage to block potassium ion into luminal channel and to bind with H+,K+-ATPase via electrostatic interactions. The binding affinity of the protonated form is more favorable than that of the neutral P-CABs. In particular, Asp139 should be a very important binding site for the protonated form of P-CABs through hydrogen bonds and electrostatic interactions. These findings could promote the rational design of novel P-CABs.

  16. Protonated form: the potent form of potassium-competitive acid blockers.

    Science.gov (United States)

    Luo, Hua-Jun; Deng, Wei-Qiao; Zou, Kun

    2014-01-01

    Potassium-competitive acid blockers (P-CABs) are highly safe and active drugs targeting H+,K+-ATPase to cure acid-related gastric diseases. In this study, we for the first time investigate the interaction mechanism between the protonated form of P-CABs and human H+,K+-ATPase using homology modeling, molecular docking, molecular dynamics and binding free energy calculation methods. The results explain why P-CABs have higher activities with higher pKa values or at lower pH. With positive charge, the protonated forms of P-CABs have more competitive advantage to block potassium ion into luminal channel and to bind with H+,K+-ATPase via electrostatic interactions. The binding affinity of the protonated form is more favorable than that of the neutral P-CABs. In particular, Asp139 should be a very important binding site for the protonated form of P-CABs through hydrogen bonds and electrostatic interactions. These findings could promote the rational design of novel P-CABs.

  17. Entry Facilitation by Environmental Groups

    NARCIS (Netherlands)

    van der Made, Allard; Schoonbeek, Lambert

    We consider a model of vertical product differentiation where consumers care about the environmental damage their consumption causes. An environmental group is capable of increasing consumers' environmental concern via a costly campaign. We show that the prospect of such a campaign can induce entry

  18. Ebola virus host cell entry.

    Science.gov (United States)

    Sakurai, Yasuteru

    2015-01-01

    Ebola virus is an enveloped virus with filamentous structure and causes a severe hemorrhagic fever in human and nonhuman primates. Host cell entry is the first essential step in the viral life cycle, which has been extensively studied as one of the therapeutic targets. A virus factor of cell entry is a surface glycoprotein (GP), which is an only essential viral protein in the step, as well as the unique particle structure. The virus also interacts with a lot of host factors to successfully enter host cells. Ebola virus at first binds to cell surface proteins and internalizes into cells, followed by trafficking through endosomal vesicles to intracellular acidic compartments. There, host proteases process GPs, which can interact with an intracellular receptor. Then, under an appropriate circumstance, viral and endosomal membranes are fused, which is enhanced by major structural changes of GPs, to complete host cell entry. Recently the basic research of Ebola virus infection mechanism has markedly progressed, largely contributed by identification of host factors and detailed structural analyses of GPs. This article highlights the mechanism of Ebola virus host cell entry, including recent findings.

  19. Cholesterol modulates Orai1 channel function

    Czech Academy of Sciences Publication Activity Database

    Derler, I.; Jardin, I.; Stathopulos, P.B.; Muik, M.; Fahrner, M.; Zayats, Vasilina; Pandey, Saurabh Kumar; Poteser, M.; Lackner, B.; Absolonova, M.; Schindl, R.; Groschner, K.; Ettrich, Rüdiger; Ikura, M.; Romanin, Ch.

    2016-01-01

    Roč. 9, č. 412 (2016), ra10 ISSN 1945-0877 R&D Projects: GA ČR GA13-21053S Institutional support: RVO:61388971 Keywords : ACTIVATES CRAC CHANNELS * OPERATED CA2+ ENTRY * PLASMA-MEMBRANE Subject RIV: CE - Biochemistry Impact factor: 6.494, year: 2016

  20. Beta-blocker under-use in COPD patients

    Directory of Open Access Journals (Sweden)

    Lim KP

    2017-10-01

    Full Text Available Kuan Pin Lim,1,2 Sarah Loughrey,1 Michael Musk,1,2 Melanie Lavender,1,2 Jeremy P Wrobel1–3 1Advanced Lung Disease Unit, Royal Perth Hospital, Perth, WA, Australia; 2Respiratory Department, Fiona Stanley Hospital, Murdoch, WA, Australia; 3School of Medicine, University of Notre Dame, Fremantle, WA, Australia Background: Cardiovascular (CVS comorbidities are common in COPD and contribute significantly to morbidity and mortality, especially following acute exacerbations of COPD (AECOPD. Beta-blockers (BBs are safe and effective in COPD patients, with demonstrated survival benefit following myocardial infarction. We sought to determine if BBs are under-prescribed in patients hospitalized with AECOPD. We also sought to determine inpatient rates of CVS and cerebrovascular complications, and their impact on patient outcomes. Methods: Retrospective hospital data was collected over a 12-month period. The medical records of all patients >40 years of age coded with a diagnosis of AECOPD were analyzed. Prevalent use and incident initiation of BBs were assessed. Comorbidities including indications and contraindications for BB use were analyzed. Results: Of the 366 eligible patients, 156 patients (42.6% had at least one indication for BB use – of these patients, only 53 (34.0% were on BB therapy and 61 (39.1% were not on BB therapy but had no listed contraindication. Prevalent use of BBs at the time of admission in all 366 patients was 19.7%, compared with 45.6%, 39.6% and 45.9% use of anti-platelets, statins and angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, respectively. CVS and cerebrovascular complications were common in this population (57 patients, 16% and were associated with longer length of stay (p<0.01 and greater inpatient mortality (p=0.02. Conclusions: BBs are under-prescribed in COPD patients despite clear indication(s for their use. Further work is required to explore barriers to BB prescribing in COPD patients

  1. On Biophysical Properties and Sensitivity to Gap Junction Blockers of Connexin 39 Hemichannels Expressed in HeLa Cells

    Science.gov (United States)

    Vargas, Anibal A.; Cisterna, Bruno A.; Saavedra-Leiva, Fujiko; Urrutia, Carolina; Cea, Luis A.; Vielma, Alex H.; Gutierrez-Maldonado, Sebastian E.; Martin, Alberto J. M.; Pareja-Barrueto, Claudia; Escalona, Yerko; Schmachtenberg, Oliver; Lagos, Carlos F.; Perez-Acle, Tomas; Sáez, Juan C.

    2017-01-01

    Although connexins (Cxs) are broadly expressed by cells of mammalian organisms, Cx39 has a very restricted pattern of expression and the biophysical properties of Cx39-based channels [hemichannels (HCs) and gap junction channels (GJCs)] remain largely unknown. Here, we used HeLa cells transfected with Cx39 (HeLa-Cx39 cells) in which intercellular electrical coupling was not detected, indicating the absence of GJCs. However, functional HCs were found on the surface of cells exposed to conditions known to increase the open probability of other Cx HCs (e.g., extracellular divalent cationic-free solution (DCFS), extracellular alkaline pH, mechanical stimulus and depolarization to positive membrane potentials). Cx39 HCs were blocked by some traditional Cx HC blockers, but not by others or a pannexin1 channel blocker. HeLa-Cx39 cells showed similar resting membrane potentials (RMPs) to those of parental cells, and exposure to DCFS reduced RMPs in Cx39 transfectants, but not in parental cells. Under these conditions, unitary events of ~75 pS were frequent in HeLa-Cx39 cells and absent in parental cells. Real-time cellular uptake experiments of dyes with different physicochemical features, as well as the application of a machine-learning approach revealed that Cx39 HCs are preferentially permeable to molecules characterized by six categories of descriptors, namely: (1) electronegativity, (2) ionization potential, (3) polarizability, (4) size and geometry, (5) topological flexibility and (6) valence. However, Cx39 HCs opened by mechanical stimulation or alkaline pH were impermeable to Ca2+. Molecular modeling of Cx39-based channels suggest that a constriction present at the intracellular portion of the para helix region co-localizes with an electronegative patch, imposing an energetic and steric barrier, which in the case of GJCs may hinder channel function. Results reported here demonstrate that Cx39 form HCs and add to our understanding of the functional roles of Cx39 HCs

  2. Effect of Non-specific HCN1 Blocker CsCl on Spatial Learning and Memory in Mouse

    Institute of Scientific and Technical Information of China (English)

    YU Xin; GUO Lianjun; YIN Guangfu; ZONG Xiangang; AI Yongxun

    2006-01-01

    It has been suggested that HCN1 is primarily expressed in hippocampus, however little is known about its effects on spatial learning and memory. In the present study, we investigated the effects of non-specific HCN1 blocker CsCl on spatial learning and memory by using Morris water maze and in situ hybridization in mice. The results showed CsCl 160 mg/kg ip for 4 days, and the mean escape latency was 34 s longer than that of normal control (P<0.01). In hippocampal tissues, staining for the HCN1 mRNA was stronger in the DG and CA1 region of the hippocampus (P <0.05, P<0.05, when CsCl-administration group was compared with normal group). Our results suggested that CsCl could significantly affect the spatial learning and memory in mice, and HCN channel is involved in the process of learning and memory.

  3. Channel box

    International Nuclear Information System (INIS)

    Tanabe, Akira.

    1993-01-01

    In a channel box of a BWR type reactor, protruding pads are disposed in axial position on the lateral side of a channel box opposing to a control rod and facing the outer side portion of the control rod in a reactor core loaded state. In the initial loading stage of fuel assemblies, channel fasteners and spacer pads are abutted against each other in the upper portion between the channel boxes sandwiching the control rod therebetween. Further, in the lower portion, a gap as a channel for the movement of the control rod is ensured by the support of fuel support metals. If the channel box is bent toward the control rod along with reactor operation, the pads are abutted against each other to always ensure the gap through which the control rod can move easily. Further, when the pads are brought into contact with each other, the bending deformation of the channel box is corrected by urging to each other. Thus, the control rod can always be moved smoothly to attain reactor safety operation. (N.H.)

  4. Clinical Outcomes with β-blockers for Myocardial Infarction A Meta-Analysis of Randomized Trials

    DEFF Research Database (Denmark)

    Bangalore, Sripal; Makani, Harikrishna; Radford, Martha

    2014-01-01

    BACKGROUND: Debate exists regarding the efficacy of â-blockers in myocardial infarction and their required duration of usage in contemporary practice. METHODS: We conducted a MEDLINE/EMBASE/CENTRAL search for randomized trials evaluating â-blockers in myocardial infarction enrolling at least 100 ...

  5. Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention

    NARCIS (Netherlands)

    Battes, L.C.; Pedersen, S.S.; Oemrawsingh, R.M.; van Geuns, R.-J.M.; Al Amri, I.; Regar, E.; de Jaegere, P.T.; Serruys, P.W.; van Domburg, R.T.

    2012-01-01

    Background Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose–response

  6. Beta-blocker use and clinical outcomes after primary vascular surgery

    DEFF Research Database (Denmark)

    Høgh, A.; Lindholt, J.S.; Nielsen, Henrik

    2013-01-01

    To explore the associations between beta-blocker use and clinical outcomes (death, hospitalisation with myocardial infarction (MI) or stroke, major amputation and recurrent vascular surgery) after primary vascular reconstruction.......To explore the associations between beta-blocker use and clinical outcomes (death, hospitalisation with myocardial infarction (MI) or stroke, major amputation and recurrent vascular surgery) after primary vascular reconstruction....

  7. Discontinuation of beta-blockers and the risk of myocardial infarction in the elderly.

    NARCIS (Netherlands)

    Teichert, M.; Smet, P.A.G.M. de; Hofman, A.; Witteman, J.C.; Stricker, B.H.C.

    2007-01-01

    BACKGROUND: It has been shown that the abrupt cessation of treatment with beta-adrenoceptor antagonists (beta-blockers) increases the risk of myocardial infarction in patients with hypertension. As beta-blockers differ in their pharmacokinetic and pharmacodynamic properties, this risk of

  8. Endoscopic therapy and beta-blockers for secondary prevention in adults with cirrhosis and oesophageal varices

    DEFF Research Database (Denmark)

    Gluud, Lise Lotte; Morgan, Marsha Y.

    2017-01-01

    This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the beneficial and harmful effects of endoscopic therapy and beta-blockers used as a combination therapy versus monotherapy with either endoscopic therapy or beta-blockers for secondary prevention...

  9. Beta-blockers and depression after myocardial infarction - A multicenter prospective study

    NARCIS (Netherlands)

    van Melle, Joost P.; Verbeek, Danielle E. P.; van den Berg, Maarten P.; Ormel, Johan; van der Linde, Marcel R.; de Jonge, Peter

    2006-01-01

    OBJECTIVES The purpose of this research was to explore the prospective relationship between the use of beta-blockers and depression in myocardial infarction (MI) patients. BACKGROUND Beta-blocker use has been reported to be associated with the development of depression, but the methodological

  10. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices

    DEFF Research Database (Denmark)

    Gluud, Lise L; Klingenberg, Sarah; Nikolova, Dimitrinka

    2007-01-01

    To compare banding ligation versus beta-blockers as primary prophylaxis in patients with esophageal varices and no previous bleeding.......To compare banding ligation versus beta-blockers as primary prophylaxis in patients with esophageal varices and no previous bleeding....

  11. [Elderly heart failure patients and the role of beta-blocker therapy

    NARCIS (Netherlands)

    Middeljans-Tijssen, C.W.; Jansen, R.W.M.M.

    2006-01-01

    In this article different aspects of chronic heart failure in old age are described. We mainly focus on the place of beta-blocker therapy in chronic heart failure. Beta-blockers are recommended for the treatment of stable chronic heart failure with left ventricular systolic dysfunction. There is

  12. Beta-blockers and depression in elderly hypertension patients in primary care

    NARCIS (Netherlands)

    Ringoir, Lianne; Pedersen, Susanne S.; Widdershoven, Jos W. M. G.; Pouwer, Francois; Keyzer, Josephine M. L.; Romeijnders, Arnold C.; Pop, Victor J. M.

    2014-01-01

    Background and Objectives: Previous findings regarding a possible association between beta-blocker use and depression are mixed. To our knowledge there have been no studies investigating the association of beta-blockers with depression in primary care hypertension patients without previous

  13. Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults

    DEFF Research Database (Denmark)

    Gluud, Lise Lotte; Krag, Aleksander

    2012-01-01

    Non-selective beta-blockers are used as a first-line treatment for primary prevention in patients with medium- to high-risk oesophageal varices. The effect of non-selective beta-blockers on mortality is debated and many patients experience adverse events. Trials on banding ligation versus non...

  14. Tolerability to beta-blocker therapy among heart failure patients in clinical practice.

    Science.gov (United States)

    Butler, Javed; Khadim, Ghazanfar; Belue, Rhonda; Chomsky, Don; Dittus, Robert S; Griffin, Marie; Wilson, John R

    2003-06-01

    Although beta-blockers were well-tolerated by heart failure (HF) patients in clinical trials, tolerability of these drugs in a general population of HF patients is not well-described. We studied a total of 308 encounters with beta-blockers therapy in 268 ambulatory HF patients. Side effects and frequency and predictors of discontinuation of therapy were studied. Independent predictors of discontinuation were assessed. Weight gain (59%), fatigue (56%), dizziness (41%), and dyspnea (29%) were the most common side effects. Fifty-one patients (19%) were discontinued on therapy with any 1 particular beta-blocker. Fatigue (30%) and hypotension (28%) were the most common reasons for discontinuation. Forty (78%) of these were given a trial with a different beta-blocker. Of these, 22 (55%) attempts with a different beta-blocker were tolerated. Thus the overall absolute discontinuation rate was only 7% for patients who were given a trial with different beta-blockers or 11% for the entire study population. Independent predictors of discontinuation of therapy included advanced symptoms, nonischemic etiology, history of pulmonary disease, and higher diuretic doses. Side effects with beta-blockers in a general population of HF patients are common; however, with changes in medical management, most patients can tolerate them eventually. In case of intolerance to one kind, a trial with a different beta-blocker is indicated.

  15. Beta-Blocker Use in Pregnancy and Risk of Specific Congenital Anomalies

    DEFF Research Database (Denmark)

    Bergman, Jorieke E H; Lutke, L Renée; Gans, Rijk O B

    2018-01-01

    INTRODUCTION: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy. OBJECTIVE: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the r...

  16. DMPD: Lipopolysaccharide-binding molecules: transporters, blockers and sensors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15241548 Lipopolysaccharide-binding molecules: transporters, blockers and sensors. ...binding molecules: transporters, blockers and sensors. PubmedID 15241548 Title Lipopolysaccharide-binding molecules: transport...Chaby R. Cell Mol Life Sci. 2004 Jul;61(14):1697-713. (.png) (.svg) (.html) (.csml) Show Lipopolysaccharide-

  17. Discontinuation of β-blockers and the risk of myocardial infarction in the elderly

    NARCIS (Netherlands)

    M. Teichert (Martina); P.A. de Smet (Peter); A. Hofman (Albert); J.C.M. Witteman (Jacqueline); B.H.Ch. Stricker (Bruno)

    2007-01-01

    textabstractBackground: It has been shown that the abrupt cessation of treatment with β-adrenoceptor antagonists (β-blockers) increases the risk of myocardial infarction in patients with hypertension. As β-blockers differ in their pharmacokinetic and pharmacodynamic properties, this risk of

  18. Functional Importance of L- and P/Q-Type Voltage-Gated Calcium Channels in Human Renal Vasculature

    DEFF Research Database (Denmark)

    Hansen, Pernille B; Poulsen, Christian B; Walter, Steen

    2011-01-01

    Calcium channel blockers are widely used for treatment of hypertension, because they decrease peripheral vascular resistance through inhibition of voltage-gated calcium channels. Animal studies of renal vasculature have shown expression of several types of calcium channels that are involved......-type subtype (Ca(v) 3.1 and Ca(v) 3.2) voltage-gated calcium channels (Ca(v)s), and quantitative PCR showed highest expression of L-type channels in renal arteries and variable expression between patients of subtypes of calcium channels in intrarenal vessels. Immunohistochemical labeling of kidney sections...

  19. The renin-angiotensin system and its blockers

    Directory of Open Access Journals (Sweden)

    Igić Rajko

    2014-01-01

    Full Text Available Research on the renin-angiotensin system (RAS has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.

  20. Effect of alpha1-blockers on stentless ureteroscopic lithotripsy

    Directory of Open Access Journals (Sweden)

    Jianguo Zhu

    2016-02-01

    Full Text Available ABSTRACT Objective To evaluate the clinical efficiency of alpha1-adrenergic antagonists on stentless ureteroscopic lithotripsy treating uncomplicated lower ureteral stones. Materials and Methods From January 2007 to January 2013, 84 patients who have uncomplicated lower ureteral stones treated by ureteroscopic intracorporeal lithotripsy with the holmium laser were analyzed. The patients were divided into two groups, group A (44 patients received indwelled double-J stents and group B (40 patients were treated by alpha1-adrenergic antagonists without stents. All cases of group B were treated with alpha1 blocker for 1 week. Results The mean operative time of group A was significantly longer than group B. The incidences of hematuria, flank/abdominal pain, frequency/urgency after surgery were statistically different between both groups. The stone-free rate of each group was 100%. Conclusions The effect of alpha1-adrenergic antagonists is more significant than indwelling stent after ureteroscopic lithotripsy in treating uncomplicated lower ureteral stones.

  1. Roselle Polyphenols Exert Potent Negative Inotropic Effects via Modulation of Intracellular Calcium Regulatory Channels in Isolated Rat Heart.

    Science.gov (United States)

    Lim, Yi-Cheng; Budin, Siti Balkis; Othman, Faizah; Latip, Jalifah; Zainalabidin, Satirah

    2017-07-01

    Roselle (Hibiscus sabdariffa Linn.) calyces have demonstrated propitious cardioprotective effects in animal and clinical studies; however, little is known about its action on cardiac mechanical function. This study was undertaken to investigate direct action of roselle polyphenols (RP) on cardiac function in Langendorff-perfused rat hearts. We utilized RP extract which consists of 12 flavonoids and seven phenolic acids (as shown by HPLC profiling) and has a safe concentration range between 125 and 500 μg/ml in this study. Direct perfusion of RP in concentration-dependent manner lowered systolic function of the heart as shown by lowered LVDP and dP/dt max , suggesting a negative inotropic effect. RP also reduced heart rate (negative chronotropic action) while simultaneously increasing maximal velocity of relaxation (positive lusitropic action). Conversely, RP perfusion increased coronary pressure, an indicator for improvement in coronary blood flow. Inotropic responses elicited by pharmacological agonists for L-type Ca 2+ channel [(±)-Bay K 8644], ryanodine receptor (4-chloro-m-cresol), β-adrenergic receptor (isoproterenol) and SERCA blocker (thapsigargin) were all abolished by RP. In conclusion, RP elicits negative inotropic, negative chronotropic and positive lusitropic responses by possibly modulating calcium entry, release and reuptake in the heart. Our findings have shown the potential use of RP as a therapeutic agent to treat conditions like arrhythmia.

  2. Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yoon Jung [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Lee, Jue Yeon [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Lee, Seung Jin [Department of Industrial Pharmacy, College of Pharmacy, Ewha Womans University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Chung, Chong-Pyoung [Department of Periodontology, School of Dentistry, Seoul National University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Park, Yoon Jeong, E-mail: parkyj@snu.ac.kr [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of)

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and

  3. Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

    International Nuclear Information System (INIS)

    Choi, Yoon Jung; Lee, Jue Yeon; Lee, Seung Jin; Chung, Chong-Pyoung; Park, Yoon Jeong

    2011-01-01

    Highlights: ► Doxazocin directly up-regulated bone metabolism at a low dose. ► Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. ► This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor γ, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and according to our data doxazosin might be useful for application in the field of bone

  4. Poor tolerance of beta-blockers by elderly patients with heart failure

    Directory of Open Access Journals (Sweden)

    Satoshi Yanagisawa

    2010-11-01

    Full Text Available Satoshi Yanagisawa, Noriyuki Suzuki, Toshikazu TanakaDepartment of Cardiology, Okazaki City Hospital, Aichi, JapanAbstract: Despite the well-understood importance of beta-blocker therapy in heart failure, it is sometimes not possible to use beta-blockers in elderly patients due to poor tolerance. In this report, we describe the case of an 83-year-old patient with severe systolic heart failure complicated by aortic valve stenosis and atrial fibrillation. A simple therapeutic approach involving discontinuation of beta-blockers remarkably alleviated the symptoms such as left ventricular ejection fraction, and improved the chest radiography and laboratory findings; further, atrial fibrillation converted to sinus rhythm. It is important to carefully administer beta-blocker therapy to elderly patients with heart failure, especially after considering cardiac output.Keywords: elderly, octogenarians, beta-blockers, heart failure

  5. Beta-blockers for exams identify students at high risk of psychiatric morbidity

    DEFF Research Database (Denmark)

    Butt, Jawad H.; Dalsgaard, Søren; Torp-Pedersen, Christian

    2017-01-01

    Objectives: Beta-blockers relieve the autonomic symptoms of exam-related anxiety and may be beneficial in exam-related and performance anxiety, but knowledge on related psychiatric outcomes is unknown. We hypothesized that beta-blocker therapy for exam-related anxiety identifies young students...... at risk of later psychiatric events. Methods: Using Danish nationwide administrative registries, we studied healthy students aged 14-30 years (1996-2012) with a first-time claimed prescription for a beta-blocker during the exam period (May-June); students who were prescribed a beta-blocker for medical...... reasons were excluded. We matched these students on age, sex, and time of year to healthy and study active controls with no use of beta-blockers. Risk of incident use of antidepressants, incident use of other psychotropic medications, and suicide attempts was examined by cumulative incidence curves...

  6. Beta-blockers and depression in elderly hypertension patients in primary care

    DEFF Research Database (Denmark)

    Ringoir, Lianne; Pedersen, Susanne S.; Widdershoven, Jos W M G

    2014-01-01

    BACKGROUND AND OBJECTIVES: Previous findings regarding a possible association between beta-blocker use and depression are mixed. To our knowledge there have been no studies investigating the association of beta-blockers with depression in primary care hypertension patients without previous...... myocardial infarction. The aim of this study was to determine the relation between lipophilic beta-blocker use and depression in elderly primary care patients with hypertension. METHODS: This was a cross-sectional study in primary care practices located in the South of The Netherlands. Primary care...... for potential confounders. CONCLUSIONS: Our findings show that primary care hypertension patients who use a lipophilic beta-blocker are more likely to have higher depression scores than those who do not use a lipophilic beta-blocker....

  7. New Trends in Cancer Therapy: Targeting Ion Channels and Transporters

    Directory of Open Access Journals (Sweden)

    Annarosa Arcangeli

    2010-04-01

    Full Text Available The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. However, ion channel blockers may produce serious side effects, such as cardiac arrhythmias. For instance, Kv11.1 (hERG1 channels are aberrantly expressed in several human cancers, in which they control different aspects of the neoplastic cell behaviour. hERG1 blockers tend to inhibit cancer growth. However they also retard the cardiac repolarization, thus lengthening the electrocardiographic QT interval, which can lead to life-threatening ventricular arrhythmias. Several possibilities exist to produce less harmful compounds, such as developing specific drugs that bind hERG1 channels in the open state or disassemble the ion channel/integrin complex which appears to be crucial in certain stages of neoplastic progression. The potential approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1 targeting specific conformational channel states; (2 finding ever more specific inhibitors, including peptide toxins, for channel subtypes mainly expressed in well-identified tumors; (3 using specific ligands to convey traceable or cytotoxic compounds; (4 developing channel blocking antibodies; (5 designing new molecular tools to decrease channel expression in selected cancer types. Similar concepts apply to ion transporters such as the Na+/K+ pump and the Na+/H+ exchanger. Pharmacological targeting of these transporters is also currently being considered in anti-neoplastic therapy.

  8. New Role of P/Q-type Voltage-gated Calcium Channels

    DEFF Research Database (Denmark)

    Hansen, Pernille B L

    2015-01-01

    Voltage-gated calcium channels are important for the depolarization-evoked contraction of vascular smooth muscle cells (SMCs), with L-type channels being the classical channel involved in this mechanism. However, it has been demonstrated that the CaV2.1 subunit, which encodes a neuronal isoform...... of the voltage-gated calcium channels (P/Q-type), is also expressed and contributes functionally to contraction of renal blood vessels in both mice and humans. Furthermore, preglomerular vascular SMCs and aortic SMCs coexpress L-, P-, and Q-type calcium channels within the same cell. Calcium channel blockers...... are widely used as pharmacological treatments. However, calcium channel antagonists vary in their selectivity for the various calcium channel subtypes, and the functional contribution from P/Q-type channels as compared with L-type should be considered. Confirming the presence of P/Q-type voltage...

  9. Surface channeling

    International Nuclear Information System (INIS)

    Sizmann, R.; Varelas, C.

    1976-01-01

    There is experimental evidence that swift light ions incident at small angles towards single crystalline surfaces can lose an appreciable fraction of their kinetic energy during reflection. It is shown that these projectiles penetrate into the bulk surface region of the crystal. They can travel as channeled particles along long paths through the solid (surface channeling). The angular distribution and the depth history of the re-emerged projectiles are investigated by computer simulations. A considerable fraction of the penetrating projectiles re-emerges from the crystal with constant transverse energy if the angle of incidence is smaller than the critical angle for axial channeling. Analytical formulae are derived based on a diffusion model for surface channeling. A comparison with experimental data exhibits the relevance of the analytical solutions. (Auth.)

  10. Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention.

    Science.gov (United States)

    Battes, Linda C; Pedersen, Susanne S; Oemrawsingh, Rohit M; van Geuns, Robert J; Al Amri, Ibtihal; Regar, Evelyn; de Jaegere, Peter P T; Serruys, Patrick; van Domburg, Ron T

    2012-02-01

    Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose-response relationship between beta blocker dose and depressive symptoms. Patients treated with PCI (N=685) completed the depression scale of the Hospital Anxiety and Depression Scale 1 and 12 months post PCI. Information about type and dose of beta blocker use was extracted from medical records. Of all patients, 68% (466/685) were on beta blocker therapy at baseline. In adjusted analysis, beta blocker use at 1 month post PCI (OR: 0.82; 95% CI: 0.53-1.26) was not significantly associated with depressive symptoms. At 12 months post PCI, there was a significant relationship between beta blocker use and depressive symptoms (OR: 0.51; 95% CI: 0.31-0.84), with beta blocker therapy associated with a 49% risk reduction in depressive symptoms. There was a dose-response relationship between beta blocker dose and depressive symptoms 12 months post PCI, with the risk reduction in depressive symptoms in relation to a low dose being 36% (OR: 0.64; 95% CI: 0.37-1.10) and 58% (OR: 0.42; 95% CI: 0.24-0.76) in relation to a high dose. Patients treated with beta blocker therapy were less likely to experience depressive symptoms 12 months post PCI, with there being a dose-response relationship with a higher dose providing a more pronounced protective effect. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Spark Channels

    Energy Technology Data Exchange (ETDEWEB)

    Haydon, S. C. [Department of Physics, University of New England, Armidale, NSW (Australia)

    1968-04-15

    A brief summary is given of the principal methods used for initiating spark channels and the various highly time-resolved techniques developed recently for studies with nanosecond resolution. The importance of the percentage overvoltage in determining the early history and subsequent development of the various phases of the growth of the spark channel is discussed. An account is then given of the recent photographic, oscillographic and spectroscopic investigations of spark channels initiated by co-axial cable discharges of spark gaps at low [{approx} 1%] overvoltages. The phenomena observed in the development of the immediate post-breakdown phase, the diffuse glow structure, the growth of the luminous filament and the final formation of the spark channel in hydrogen are described. A brief account is also given of the salient features emerging from corresponding studies of highly overvolted spark gaps in which the spark channel develops from single avalanche conditions. The essential differences between the two types of channel formation are summarized and possible explanations of the general features are indicated. (author)

  12. Flavivirus Entry Receptors: An Update

    Directory of Open Access Journals (Sweden)

    Manuel Perera-Lecoin

    2013-12-01

    Full Text Available Flaviviruses enter host cells by endocytosis initiated when the virus particles interact with cell surface receptors. The current model suggests that flaviviruses use at least two different sets of molecules for infectious entry: attachment factors that concentrate and/or recruit viruses on the cell surface and primary receptor(s that bind to virions and direct them to the endocytic pathway. Here, we present the currently available knowledge regarding the flavivirus receptors described so far with specific attention to C-type lectin receptors and the phosphatidylserine receptors, T-cell immunoglobulin and mucin domain (TIM and TYRO3, AXL and MER (TAM. Their role in flavivirus attachment and entry as well as their implication in the virus biology will be discussed in depth.

  13. Inhibition of T cell proliferation by selective block of Ca(2+)-activated K(+) channels

    DEFF Research Database (Denmark)

    Jensen, B S; Odum, Niels; Jorgensen, N K

    1999-01-01

    cell activation and proliferation has been investigated by using various blockers of IK channels. The Ca(2+)-activated K(+) current in human T cells is shown by the whole-cell voltage-clamp technique to be highly sensitive to clotrimazole, charybdotoxin, and nitrendipine, but not to ketoconazole...

  14. Binding of ArgTX-636 in the NMDA receptor ion channel

    DEFF Research Database (Denmark)

    Poulsen, Mette H; Andersen, Jacob; Christensen, Rune

    2015-01-01

    of NMDAR activity and have therapeutic potential for treatment of a variety of brain diseases or as pharmacological tools for studies of the neurobiological role of NMDARs. We have performed a kinetic analysis of the blocking mechanism of the prototypical polyamine toxin NMDAR ion channel blocker...

  15. Molecular and functional characterization of Kv7 K+ channel in murine gastrointestinal smooth muscles

    DEFF Research Database (Denmark)

    Jepps, Thomas Andrew; Greenwood, Iain A; Moffatt, James D

    2009-01-01

    that K(v)7.x especially K(v)7.4 and K(v)7.5 are expressed in different regions of the murine gastrointestinal tract and blockers of K(v)7 channels augment inherent contractile activity. Drugs that selectively block K(v)7.4/7.5 might be promising therapeutics for the treatment of motility disorders...

  16. Use of Ion-Channel Modulating Agents to Study Cyanobacterial Na+ - K+ Fluxes

    Directory of Open Access Journals (Sweden)

    Pomati Francesco

    2004-01-01

    Full Text Available Here we describe an experimental design aimed to investigate changes in total cellular levels of Na+ and K+ ions in cultures of freshwater filamentous cyanobacteria. Ion concentrations were measured in whole cells by flame photometry. Cellular Na+ levels increased exponentially with rising alkalinity, with K+ levels being maximal for optimal growth pH (~8. At standardized pH conditions, the increase in cellular Na+, as induced by NaCl at 10 mM, was coupled by the two sodium channel-modulating agents lidocaine hydrochloride at 1 &mgr;M and veratridine at 100 &mgr;M. Both the channel-blockers amiloride (1 mM and saxitoxin (1 &mgr;M, decreased cell-bound Na+ and K+ levels. Results presented demonstrate the robustness of well-defined channel blockers and channel-activators in the study of cyanobacterial Na+- K+ fluxes.

  17. Installaton of a fish migration channel for spawning at Itaipu

    International Nuclear Information System (INIS)

    Borghetti, J.R.; Perez Chena, D.; Nogueira, S.V.G.

    1993-01-01

    The objective of installing a fish migration channel for spawning at the Itaipu hydroelectric station on the Parana river between Brazil and Paraguay is to improve fish recovery downstream from the dam. Preliminary data from the first phase has proved the efficiency of an experimental project, with the entry and ascendancy of fish in a migration channel ladder. These data now provide the technical basis for implementation of the complementary spawning channel stage. (author)

  18. Beta-blockers for preventing aortic dissection in Marfan syndrome.

    Science.gov (United States)

    Koo, Hyun-Kyoung; Lawrence, Kendra Ak; Musini, Vijaya M

    2017-11-07

    Marfan syndrome is a hereditary disorder affecting the connective tissue and is caused by a mutation of the fibrillin-1 (FBN1) gene. It affects multiple systems of the body, most notably the cardiovascular, ocular, skeletal, dural and pulmonary systems. Aortic root dilatation is the most frequent cardiovascular manifestation and its complications, including aortic regurgitation, dissection and rupture are the main cause of morbidity and mortality. To assess the long-term efficacy and safety of beta-blocker therapy as compared to placebo, no treatment or surveillance only in people with Marfan syndrome. We searched the following databases on 28 June 2017; CENTRAL, MEDLINE, Embase, Science Citation Index Expanded and the Conference Proceeding Citation Index - Science in the Web of Science Core Collection. We also searched the Online Metabolic and Molecular Bases of Inherited Disease (OMMBID), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 June 2017. We did not impose any restriction on language of publication. All randomised controlled trials (RCTs) of at least one year in duration assessing the effects of beta-blocker monotherapy compared with placebo, no treatment or surveillance only, in people of all ages with a confirmed diagnosis of Marfan syndrome were eligible for inclusion. Two review authors independently screened titles and abstracts for inclusion, extracted data and assessed trial quality. Trial authors were contacted to obtain missing data. Dichotomous outcomes will be reported as relative risk and continuous outcomes as mean differences with 95% confidence intervals. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. One open-label, randomised, single-centre trial including 70 participants with Marfan syndrome (aged 12 to 50 years old) met the inclusion criteria. Participants were randomly assigned to

  19. Impact of beta-blockers on cardiopulmonary exercise testing in patients with advanced liver disease.

    Science.gov (United States)

    Wallen, M P; Hall, A; Dias, K A; Ramos, J S; Keating, S E; Woodward, A J; Skinner, T L; Macdonald, G A; Arena, R; Coombes, J S

    2017-10-01

    Patients with advanced liver disease may develop portal hypertension that can result in variceal haemorrhage. Beta-blockers reduce portal pressure and minimise haemorrhage risk. These medications may attenuate measures of cardiopulmonary performance, such as the ventilatory threshold and peak oxygen uptake measured via cardiopulmonary exercise testing. To determine the effect of beta-blockers on cardiopulmonary exercise testing variables in patients with advanced liver disease. This was a cross-sectional analysis of 72 participants who completed a cardiopulmonary exercise test before liver transplantation. All participants remained on their usual beta-blocker dose and timing prior to the test. Variables measured during cardiopulmonary exercise testing included the ventilatory threshold, peak oxygen uptake, heart rate, oxygen pulse, the oxygen uptake efficiency slope and the ventilatory equivalents for carbon dioxide slope. Participants taking beta-blockers (n = 28) had a lower ventilatory threshold (P advanced liver disease taking beta-blockers compared to those not taking the medication. This may incorrectly risk stratify patients on beta-blockers and has implications for patient management before and after liver transplantation. The oxygen uptake efficiency slope was not influenced by beta-blockers and may therefore be a better measure of cardiopulmonary performance in this patient population. © 2017 John Wiley & Sons Ltd.

  20. The review of identification and assay methods of β-blockers

    Directory of Open Access Journals (Sweden)

    Ольга Олександрівна Віслоус

    2015-10-01

    Full Text Available Every year the number of β-blockers on the pharmaceutical market is increasing, requiring systematization of their standardization methods.Aim of research. The aim of our research is to study literature data about identification and assay methods of β-blockers with different direction of action – selective (praktolol, metoprolol, atenolol, acebutolol, betaxolol, bevantolol, bisoprolol, celiprolol, esmolol, epanolol, esatenolol, nebivolol, Talinolol, non-selective (alprenolol, Oxprenololum, pindolol, propranolol, timolol, sotalol, nadolol, mepindolol, karteol, tertatolol, bopindolol, bupranolol, penbutolol, kloranolol and combined (labetalol, carvedilol.Methods. The analytical review of literature sources about β-blockers analysis by physical, chemical, and physicochemical methods.Results. After literature sources’ analyzing it was found that physical and physicochemical constants are basically used for β-blockers pharmacopoeial analysis; both physicochemical values and chemical reactions are used in forensic analysis, resulting in the article.It was founded that titration methods, mostly acid-base titration method, are used for β-blockers assay in the analysis of substances. For β-blockers detection in biological fluids and dosage forms, active pharmaceutical ingredients and metabolites mixture separation one should prefer physicochemical methods, such as gas chromatography and liquid chromatography, absorption UV-Visible spectroscopy, fluorometry, etc.Conclusion. The results have shown can be used for the further search of the identification and assay optimal methods of β-blockers both pure and mixed with other active substances and excipients

  1. Prevalence of major depressive disorder in patients receiving beta-blocker therapy versus other medications.

    Science.gov (United States)

    Carney, R M; Rich, M W; teVelde, A; Saini, J; Clark, K; Freedland, K E

    1987-08-01

    Depression is believed to be a common side effect in patients receiving beta-blocker therapy. However, diagnoses of depression defined by current diagnostic criteria may not be more common in patients receiving beta-blockers than in patients with the same medical disorder receiving other medications. Seventy-seven patients undergoing elective cardiac catheterization for evaluation of chest pain received a semi-structured diagnostic psychiatric interview. Twenty-one percent of the patients receiving beta-blockers and 33 percent of the patients receiving medications other than beta-blockers met the current American Psychiatric Association criteria for major depressive disorder (DSM-III) (p = NS). The mean heart rate and state anxiety scores for patients taking beta-blockers were significantly lower than those measured in patients taking medications other than beta-blockers. No other medical or demographic differences were observed between the two groups. Despite the methodologic limitations of the study, there does not appear to be a difference in the point prevalence of depression between patients receiving beta-blockers and those receiving other medications.

  2. Combinatorial Strategies and High Throughput Screening in Drug Discovery Targeted to the Channel of Botulinum Neurotoxin

    National Research Council Canada - National Science Library

    Montal, Mauricio

    2006-01-01

    .... The major focus thus far has been the implementation of a reliable and robust high-throughput screen for blockers specific for BoNT using Neuro 2A cells in which BoNTA forms channels with similar properties to those previously characterized in lipid bilayers. The immediate task during the present reporting period involved the detailed characterization of the channel and chaperone activity of BoNTA on Neuro2A cells.

  3. Feasibility and Association of Neurohumoral Blocker Up-titration After Cardiac Resynchronization Therapy.

    Science.gov (United States)

    Martens, Pieter; Verbrugge, Frederik H; Nijst, Petra; Bertrand, Philippe B; Dupont, Matthias; Tang, Wilson H; Mullens, Wilfried

    2017-08-01

    Cardiac resynchronization therapy (CRT) improves mortality and morbidity on top of optimal medical therapy in heart failure with reduced ejection fraction (HFrEF). This study aimed to elucidate the association between neurohumoral blocker up-titration after CRT implantation and clinical outcomes. Doses of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta-blockers were retrospectively evaluated in 650 consecutive CRT patients implanted from October 2008 to August 2015 and followed in a tertiary multidisciplinary CRT clinic. All 650 CRT patients were on a maximal tolerable dose of ACE-I/ARB and beta-blocker at the time of CRT implantation. However, further up-titration was successful in 45.4% for ACE-I/ARB and in 56.8% for beta-blocker after CRT-implantation. During a mean follow-up of 37 ± 22 months, a total of 139 events occurred for the combined end point of heart failure admission and all-cause mortality. Successful, versus unsuccessful, up-titration was associated with adjusted hazard ratios of 0.537 (95% confidence interval 0.316-0.913; P = .022) for ACE-I/ARB and 0.633 (0.406-0.988; P = .044) for beta-blocker on the combined end point heart failure admission and all-cause mortality. Patients in the up-titration group exhibited a similar risk for death or heart failure admission as patients treated with the maximal dose (ACE-I/ARB: P = .133; beta-blockers: P = .709). After CRT, a majority of patients are capable of tolerating higher dosages of neurohumoral blockers. Up-titration of neurohumoral blockers after CRT implantation is associated with improved clinical outcomes, similarly to patients treated with the guideline-recommended target dose at the time of CRT implantation. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Predicting the Diversity of Foreign Entry Modes

    DEFF Research Database (Denmark)

    Hashai, Niron; Geisler Asmussen, Christian; Benito, Gabriel

    2007-01-01

    diversity across value chain activities and host markets. Analyzing a sample of Israeli based firms we show that larger firms exhibit a higher degree of entry mode diversity both across value chain activities and across host markets. Higher levels of knowledge intensity are also associated with more......This paper expands entry mode literature by referring to multiple modes exerted in different value chain activities within and across host markets, rather than to a single entry mode at the host market level. Scale of operations and knowledge intensity are argued to affect firms' entry mode...... diversity in firms' entry modes across both dimensions....

  5. Entry decisions in the generic pharmaceutical industry.

    Science.gov (United States)

    Morton, F M

    1999-01-01

    Data on all generic drug entries in the period 1984-1994 are used to estimate which markets heterogeneous potential entrants will decide to enter. I find that organizational experience predicts entry. Firms tend to enter markets with supply and demand characteristics similar to the firm's existing drugs. Larger revenue markets, markets with more hospital sales, and products that treat chronic conditions attract more entry. The simultaneous nature of entry leads to an additional interpretation: specialization is profitable because of the severe risk to profits when a market is "overentered." However, I am unable to make any conclusions about the efficiency of entry decisions.

  6. [Assessment of the utilization of angiotensin receptor blockers in hypertension].

    Science.gov (United States)

    Peña Cabia, S; Ricote Lobera, I; Santos Mena, B; Hidalgo Correas, F J; Climent Florez, B; García Díaz, B

    2013-01-01

    To assess the degree in which the utilization of angiotensin receptor blockers (ARBs) in our Healthcare Area fits the criteria proposed by the Autonomous Community of Madrid (CAM) before setting «Plan de Actuación de ARA-II» («Action Plan ARA-II»). To study the indications for which are prescribed and to identify those factors that can show influence in prescription. Drug utilization study of the type indication-prescription, descriptive and transversal, for which ARBs-treated and hypertensive patients admitted to a University General Hospital for a study period of 3 months were selected. Based on the clinical situations summarized in the CAM Document «Criterios para establecer el lugar en la terapéutica de los antagonistas de los receptores de la angiotensina II» («Criteria for the place of angiotensin receptor blockers in the therapeutic»), a percentage of patients with «appropriate prescription» and «inadequate prescription« of ARBs was calculated and analyzed in order to determine if the age and the sex were related to the type of prescription or the main indications for which they had been prescribed. Out of the 153 patients included in the study, 67.3% had a «inadequate prescription«, 47.6% of them due to an ARBs prescription as the first drug inhibitor of the reninangiotensin- aldosterone system and 34.0% owing to a poor control of blood pressure with angiotensin-converting enzyme inhibitors (ACEi). There were no statistically significant differences found either by age or sex in the type of prescription or in the main indications for which they were prescribed. The adequacy of the criteria for the utilisation of ARBs Document occurred in 32.7% of cases. In addition, factors such as age and sex did not seem to affect the type of prescription. Misconceptions of superiority of ARBs versus ACEi were evidenced as well. Copyright © 2013 SEFH. Published by AULA MEDICA. All rights reserved.

  7. Bladder contractility is modulated by Kv7 channels in pig detrusor

    DEFF Research Database (Denmark)

    Svalø, Julie; Bille, Michala; Parameswaran Theepakaran, Neeraja

    2013-01-01

    Kv7 channels are involved in smooth muscle relaxation, and accordingly we believe that they constitute potential targets for the treatment of overactive bladder syndrome. We have therefore used myography to examine the function of Kv7 channels in detrusor, i.e. pig bladder, with a view...... relaxation, suggesting that Kv7.2 and/or Kv7.4 channels constitute the subtypes that are relevant to bladder contractility. The effects of retigabine and ML213 were attenuated by pre-incubation with 10µM XE991 (Kv7.1-7.5 channel blocker) (P...

  8. MARKETING CHANNELS

    Directory of Open Access Journals (Sweden)

    Ljiljana Stošić Mihajlović

    2014-07-01

    Full Text Available Marketing channel is a set of entities and institutions, completion of distribution and marketing activities, attend the efficient and effective networking of producers and consumers. Marketing channels include the total flows of goods, money and information taking place between the institutions in the system of marketing, establishing a connection between them. The functions of the exchange, the physical supply and service activities, inherent in the system of marketing and trade. They represent paths which products and services are moving after the production, which will ultimately end up buying and eating by the user.

  9. Atmospheric Entry Experiments at IRS

    Science.gov (United States)

    Auweter-Kurtz, M.; Endlich, P.; Herdrich, G.; Kurtz, H.; Laux, T.; Löhle, S.; Nazina, N.; Pidan, S.

    2002-01-01

    Entering the atmosphere of celestial bodies, spacecrafts encounter gases at velocities of several km/s, thereby being subjected to great heat loads. The thermal protection systems and the environment (plasma) have to be investigated by means of computational and ground facility based simulations. For more than a decade, plasma wind tunnels at IRS have been used for the investigation of TPS materials. Nevertheless, ground tests and computer simulations cannot re- place space flights completely. Particularly, entry mission phases encounter challenging problems, such as hypersonic aerothermodynamics. Concerning the TPS, radiation-cooled materials used for reuseable spacecrafts and ablator tech- nologies are of importance. Besides the mentioned technologies, there is the goal to manage guidance navigation, con- trol, landing technology and inflatable technologies such as ballutes that aim to keep vehicles in the atmosphere without landing. The requirement to save mass and energy for planned interplanetary missions such as Mars Society Balloon Mission, Mars Sample Return Mission, Mars Express or Venus Sample Return mission led to the need for manoeuvres like aerocapture, aero-breaking and hyperbolic entries. All three are characterized by very high kinetic vehicle energies to be dissipated by the manoeuvre. In this field flight data are rare. The importance of these manoeuvres and the need to increase the knowledge of required TPS designs and behavior during such mission phases point out the need of flight experiments. As result of the experience within the plasma diagnostic tool development and the plasma wind tunnel data base, flight experiments like the PYrometric RE-entry EXperiment PYREX were developed, fully qualified and successfully flown. Flight experiments such as the entry spectrometer RESPECT and PYREX on HOPE-X are in the conceptual phase. To increase knowledge in the scope of atmospheric manoeuvres and entries, data bases have to be created combining both

  10. An Analysis of Forensic Imaging in the Absence of Write-Blockers

    Directory of Open Access Journals (Sweden)

    Gary C Kessler

    2014-09-01

    Full Text Available Best practices in digital forensics demand use of write-blockers when creating forensic copies of digital media and this has been a core of computer forensics training for decades. The practice is so in-grained that images created without a write-blocker are immediate suspect for integrity. This paper describes a research framework to examine what occurs when a forensic image is acquired without benefit of a write-blocker in order to understand the true impact of such an eventuality. The initial tests document the changes made to a hard drive and flash drive when imaged and examined with a Windows-based forensics workstation.

  11. Multi drug resistance to cancer chemotherapy: Genes involved and blockers

    International Nuclear Information System (INIS)

    Sayed-Ahmed, Mohamed M.

    2007-01-01

    During the last three decades, important and considerable research efforts had been performed to investigate the mechanism through which cancer cells overcome the cytotoxic effects of a variety of chemotherapeutic drugs. Most of the previously published work has been focused on the resistance of tumor cells to those anticancer drugs of natural source. Multidrug resistance (MDR) is a cellular cross-resistance to a broad spectrum of natural products used in cancer chemotherapy and is believed to be the major cause of the therapeutic failures of the drugs belonging to different naturally obtained or semisynthetic groups including vinca alkaloids, taxans, epipodophyllotoxins and certain antibiotics. This phenomenon results from overexpression of four MDR genes and their corresponding proteins that act as membrane-bound ATP consuming pumps. These proteins mediate the efflux of many structurally and functionally unrelated anticancer drugs of natural source. MDR may be intrinsic or acquired following exposure to chemotherapy. The existence of intrinsically resistant tumor cell clone before and following chemotherapeutic treatment has been associated with a worse final outcome because of increased incidence of distant metasis. In view of irreplaceability of natural product anticancer drugs as effective chemotherapeutic agents, and in view of MDR as a major obstacle to successful chemotherapy, this review is aimed to highlight the genes involved in MDR, classical MDR blockers and gene therapy approaches to overcome MDR. (author)

  12. Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint

    Directory of Open Access Journals (Sweden)

    Fitzgerald PJ

    2012-06-01

    Full Text Available Paul J FitzgeraldThe Zanvyl Krieger Mind/Brain Institute, Solomon H Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USAAbstract: There is growing evidence that the neurotransmitter norepinephrine (NE and its sister molecule epinephrine (EPI (adrenaline affect some types of cancer. Several recent epidemiological studies have shown that chronic use of beta blocking drugs (which antagonize NE/EPI receptors results in lower recurrence, progression, or mortality of breast cancer and malignant melanoma. Preclinical studies have shown that manipulation of the levels or receptors of NE and EPI with drugs affects experimentally induced cancers. Psychological stress may play an etiological role in some cases of cancer (which has been shown epidemiologically, and this could be partly mediated by NE and EPI released by the sympathetic nervous system as part of the body’s “fight or flight” response. A less well-appreciated phenomenon is that the genetic tone of NE/EPI may play a role in cancer. NE and EPI may affect cancer by interacting with molecular pathways already implicated in abnormal cellular replication, such as the P38/MAPK pathway, or via oxidative stress. NE/EPI-based drugs other than beta blockers also may prevent or treat various types of cancer, as may cholinesterase inhibitors that inhibit the sympathetic nervous system, which could be tested epidemiologically.Keywords: clonidine, guanfacine, aspirin, acetylcholine, epinephrine, adrenaline, sympathetic nervous system, parasympathetic nervous system, inflammation

  13. Angiotensin Receptor Blockers: Cardiovascular Protection in the Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Prakash C Deedwania

    2006-03-01

    Full Text Available It is well recognised that the metabolic syndrome, a constellation of risk factors including obesity, hypertension, insulin resistance and dyslipidaemia, is associated with an increased risk of cardiovascular complications and the development of Type 2 diabetes. Consequently, timely identification and management of all components of the metabolic syndrome is warranted. In particular, guidelines have emphasised the importance of targeting elevated blood pressure (BP and dyslipidaemia as a method of reducing global cardiovascular risk.Findings from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE trial show that the angiotensin receptor blocker, valsartan, reduces cardiovascular events and the development of Type 2 diabetes in high-risk individuals. This profile is being further explored in the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR trial.Given the potential advantages to patients and physicians of tackling more than one of the components of the metabolic syndrome, antihypertensive agents such as valsartan would appear to be an important addition to the management of vulnerable patients at high risk of cardiovascular events.

  14. Role of analgesics, sedatives, neuromuscular blockers, and delirium.

    Science.gov (United States)

    Hall, Jesse B; Schweickert, William; Kress, John P

    2009-10-01

    A major focus on critical care medicine concerns the institution of life-support therapies, such as mechanical ventilation, during periods of organ failure to permit a window of opportunity to diagnose and treat underlying disorders so that patients may be returned to their prior functional status upon recovery. With the growing success of these intensive care unit-based therapies and longer-term follow-up of patients, severe weakness involving the peripheral nervous system and muscles has been identified in many recovering patients, often confounding the time course or magnitude of recovery. Mechanical ventilation is often accompanied by pharmacologic treatments including analgesics, sedatives, and neuromuscular blockers. These drugs and the encephalopathies accompanying some forms of critical illness result in a high prevalence of delirium in mechanically ventilated patients. These drug effects likely contribute to an impaired ability to assess the magnitude of intensive care unit-acquired weakness, to additional time spent immobilized and mechanically ventilated, and to additional weakness from the patient's relative immobility and bedridden state. This review surveys recent literature documenting these relationships and identifying approaches to minimize pharmacologic contributions to intensive care unit-acquired weakness.

  15. Angiotensin receptor blockers: Focus on cardiac and renal injury.

    Science.gov (United States)

    Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Krishnamurthy, Prasanna; Suzuki, Kenji; Nakamura, Masahiko; Watanabe, Kenichi

    2016-04-01

    Angiotensin II, an important component of renin angiotensin system, is a potent vasopressor and its actions are mostly mediated via angiotensin II type 1 receptor (AT1R) and role of AT2R in counterbalancing the actions of AT1R stimulation are under extensive research. In addition to its physiological actions, angiotensin II plays important roles in the pathogenesis of atherosclerosis, hypertension, left ventricular hypertrophy, and heart failure. The effects of angiotensin II can be blocked by either suppressing its production by blocking angiotensin converting enzyme or by antagonizing its actions on AT1R using angiotensin II receptor blockers (ARBs). Instead of the extensive use of ARBs in the treatment of various cardiovascular diseases, proper selection of a particular ARB is crucial as the clinical condition of individual patient is different and also their economic status would play an essential role in medication compliance. Thus a critical review of the proven and promising actions of ARBs against various pathological conditions will be of great importance for the clinicians as well as for the researchers. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Minoxidil opens mitochondrial KATP channels and confers cardioprotection

    Science.gov (United States)

    Sato, Toshiaki; Li, Yulong; Saito, Tomoaki; Nakaya, Haruaki

    2003-01-01

    ATP-sensitive potassium channel in the mitochondrial inner membrane (mitoKATP channel) rather than in the sarcolemma (sarcKATP channel) appears to play an important role in cardioprotection. We examined the effect of minoxidil, a potent antihypertensive agent and hair growth stimulator, on sarcKATP and mitoKATP channels in guinea-pig ventricular myocytes. Minoxidil activated a glybenclamide-sensitive sarcKATP channel current in the whole-cell recording mode with an EC50 of 182.6 μM. Minoxidil reversibly increased the flavoprotein oxidation, an index of mitoKATP channel activity, in a concentration-dependent manner. The EC50 for mitoKATP channel activation was estimated to be 7.3 μM; this value was notably ≈25-fold lower than that for sarcKATP channel activation. Minoxidil (10 μM) significantly attenuated the ouabain-induced increase of mitochondrial Ca2+ concentration, which was measured by loading cells with rhod-2 fluorescence. Furthermore, pretreatment with minoxidil (10 μM) before 20-min no-flow ischaemia significantly improved the recovery of developed tension measured after 60 min of reperfusion in coronary perfused guinea-pig ventricular muscles. These cardioprotective effects of minoxidil were completely abolished by the mitoKATP channel blocker 5-hydroxydecanoate (500 μM). Our results indicate that minoxidil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by the selective activation of mitoKATP channels. PMID:14691056

  17. A computational design approach for virtual screening of peptide interactions across K+ channel families

    Directory of Open Access Journals (Sweden)

    Craig A. Doupnik

    2015-01-01

    Full Text Available Ion channels represent a large family of membrane proteins with many being well established targets in pharmacotherapy. The ‘druggability’ of heteromeric channels comprised of different subunits remains obscure, due largely to a lack of channel-specific probes necessary to delineate their therapeutic potential in vivo. Our initial studies reported here, investigated the family of inwardly rectifying potassium (Kir channels given the availability of high resolution crystal structures for the eukaryotic constitutively active Kir2.2 channel. We describe a ‘limited’ homology modeling approach that can yield chimeric Kir channels having an outer vestibule structure representing nearly any known vertebrate or invertebrate channel. These computationally-derived channel structures were tested in silico for ‘docking’ to NMR structures of tertiapin (TPN, a 21 amino acid peptide found in bee venom. TPN is a highly selective and potent blocker for the epithelial rat Kir1.1 channel, but does not block human or zebrafish Kir1.1 channel isoforms. Our Kir1.1 channel-TPN docking experiments recapitulated published in vitro findings for TPN-sensitive and TPN-insensitive channels. Additionally, in silico site-directed mutagenesis identified ‘hot spots’ within the channel outer vestibule that mediate energetically favorable docking scores and correlate with sites previously identified with in vitro thermodynamic mutant-cycle analysis. These ‘proof-of-principle’ results establish a framework for virtual screening of re-engineered peptide toxins for interactions with computationally derived Kir channels that currently lack channel-specific blockers. When coupled with electrophysiological validation, this virtual screening approach may accelerate the drug discovery process, and can be readily applied to other ion channels families where high resolution structures are available.

  18. The roles of KCa, KATP, and KV channels in regulating cutaneous vasodilation and sweating during exercise in the heat.

    Science.gov (United States)

    Louie, Jeffrey C; Fujii, Naoto; Meade, Robert D; McNeely, Brendan D; Kenny, Glen P

    2017-05-01

    We recently showed the varying roles of Ca 2+ -activated (K Ca ), ATP-sensitive (K ATP ), and voltage-gated (K V ) K + channels in regulating cholinergic cutaneous vasodilation and sweating in normothermic conditions. However, it is unclear whether the respective contributions of these K + channels remain intact during dynamic exercise in the heat. Eleven young (23 ± 4 yr) men completed a 30-min exercise bout at a fixed rate of metabolic heat production (400 W) followed by a 40-min recovery period in the heat (35°C, 20% relative humidity). Cutaneous vascular conductance (CVC) and local sweat rate were assessed at four forearm skin sites perfused via intradermal microdialysis with: 1 ) lactated Ringer solution (control); 2 ) 50 mM tetraethylammonium (nonspecific K Ca channel blocker); 3 ) 5 mM glybenclamide (selective K ATP channel blocker); or 4 ) 10 mM 4-aminopyridine (nonspecific K V channel blocker). Responses were compared at baseline and at 10-min intervals during and following exercise. K Ca channel inhibition resulted in greater CVC versus control at end exercise ( P = 0.04) and 10 and 20 min into recovery (both P exercise (all P ≤ 0.04), and 10 min into recovery ( P = 0.02). No differences in CVC were observed with K V channel inhibition during baseline ( P = 0.15), exercise (all P ≥ 0.06), or recovery (all P ≥ 0.14). With the exception of K V channel inhibition augmenting sweating during baseline ( P = 0.04), responses were similar to control with all K + channel blockers during each time period (all P ≥ 0.07). We demonstrated that K Ca and K ATP channels contribute to the regulation of cutaneous vasodilation during rest and/or exercise and recovery in the heat. Copyright © 2017 the American Physiological Society.

  19. Pilot-Reported Beta-Blockers Identified by Forensic Toxicology Analysis of Postmortem Specimens

    Science.gov (United States)

    2017-01-01

    This study compared beta-blockers reported by pilots with the medications found by postmortem toxicology analysis of specimens received from fatal aviation accidents between 1999 and 2015. Several studies have compared drugs using the standard approa...

  20. Effect of glucose infusion on endurance performance after beta-adrenoceptor blocker administration

    NARCIS (Netherlands)

    van Baak, M.A.; Mooij, J.M.

    1994-01-01

    Effect of glucose infusion on endurance performance after beta-adrenoceptor blocker administration. Van Baak MA, Mooij JM. Department of Human Biology, University of Limburg, Maastricht, The Netherlands. To investigate the effect of glucose (Glc) infusion on endurance performance after

  1. Use of angiotensin II receptor blockers in children- a review of ...

    African Journals Online (AJOL)

    2015-05-19

    May 19, 2015 ... sex and height, whereas hypertension is defined as SBP and/or DBP persistently ... strated the efficacy of angiotensin receptor blockers in ... An open-label, multicenter, single-dose study was ..... sure among school children of.

  2. Dutch pediatricians' views on the use of neuromuscular blockers for dying neonates: a qualitative study

    NARCIS (Netherlands)

    ten Cate, K.; van de Vathorst, S.

    2015-01-01

    To assess Dutch pediatricians' views on neuromuscular blockers for dying neonates. Qualitative study involving in-depth interviews with 10 Dutch pediatricians working with severely ill neonates. Data were analyzed using appropriate qualitative research techniques. Participants explained their view

  3. β-Blocker-Associated Risks in Patients With Uncomplicated Hypertension Undergoing Noncardiac Surgery

    DEFF Research Database (Denmark)

    Jørgensen, Mads E; Hlatky, Mark A; Køber, Lars Valeur

    2015-01-01

    IMPORTANCE: Perioperative β-blocker strategies are important to reduce risks of adverse events. Effectiveness and safety may differ according to patients' baseline risk. OBJECTIVE: To determine the risk of major adverse cardiovascular events (MACEs) associated with long-term β-blocker therapy...... antihypertensive drugs (β-blockers, thiazides, calcium antagonists, or renin-angiotensin system [RAS] inhibitors) undergoing noncardiac surgery between 2005 and 2011. INTERVENTIONS: Various antihypertensive treatment regimens, chosen as part of usual care. MAIN OUTCOMES AND MEASURES: Thirty-day risk of MACEs...... (cardiovascular death, nonfatal ischemic stroke, nonfatal myocardial infarction) and all-cause mortality, assessed using multivariable logistic regression models and adjusted numbers needed to harm (NNH). RESULTS: The baseline characteristics of the 14,644 patients who received β-blockers (65% female, mean [SD...

  4. Beta-blocker subtype and risks of perioperative adverse events following non-cardiac surgery

    DEFF Research Database (Denmark)

    Jørgensen, Mads E.; Sanders, Robert D.; Køber, Lars

    2017-01-01

    Aims Beta-blockers vary in pharmacodynamics and pharmacokinetic properties. It is unknown whether specific types are associated with increased perioperative risks. We evaluated perioperative risks associated with beta-blocker subtypes, overall and in patient subgroups. Methods and results We...... performed a Danish Nationwide cohort study, 2005-2011, of patients treated chronically with beta blocker (atenolol, bisoprolol, carvedilol, metoprolol, propranolol, or other) prior to non-cardiac surgery. Risks of 30-day all-cause mortality (ACM) and 30-day major adverse cardiovascular events (MACE) were...... in analyses stratified by age, surgery priority, duration of anaesthesia or surgery risk (all P for interaction >0.05). Conclusion Risks of ACM and MACE did not systematically differ by beta-blocker subtype. Findings may guide clinical practice and future trials....

  5. Comparison of the clinical outcome of different beta-blockers in heart failure patients

    DEFF Research Database (Denmark)

    Bølling, Rasmus; Scheller, Nikolai Madrid; Køber, Lars

    2014-01-01

    AIM: To compare survival on different beta-blockers in heart failure. METHODS AND RESULTS: We identified all Danish patients ≥35 years of age who were hospitalized with a first admission for heart failure and who initiated treatment with a beta-blocker within 60 days of discharge. The study period....... In an unadjusted model carvedilol was associated with a lower mortality [hazard ratio (HR) 0.737, 0.714-0.761] compared with metoprolol (reference) while bisoprolol was not associated with an increased mortality (HR 1.020, 0.973-1.069). In a model adjusted for possible confounders and stratified according to beta-blocker...... receiving high-dose carvedilol (≥50 mg daily) showed significantly lower all-cause mortality risk and hospitalization risk, compared with other beta-blockers....

  6. Endogenous endophthalmitis in a rheumatoid patient on tumor necrosis factor alpha blocker

    Directory of Open Access Journals (Sweden)

    Agarwal Pankaj

    2007-01-01

    Full Text Available The development of anti-tumor necrosis factor (TNF therapies is a milestone in the therapy of rheumatic diseases. It is of concern whether all potential undesired complications of therapy have been evaluated within clinical trials which have led to treatment approval. Specialists prescribing TNF blockers should be aware of the unusual and severe complications that can occur. We describe a case of endogenous endophthalmitis in a rheumatoid patient on TNF alpha blocker.

  7. A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure.

    Science.gov (United States)

    Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

    2016-10-01

    Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease.

  8. Channel Power in Multi-Channel Environments

    NARCIS (Netherlands)

    M.G. Dekimpe (Marnik); B. Skiera (Bernd)

    2004-01-01

    textabstractIn the literature, little attention has been paid to instances where companies add an Internet channel to their direct channel portfolio. However, actively managing multiple sales channels requires knowing the customers’ channel preferences and the resulting channel power. Two key

  9. Beta-blocker use and COPD mortality: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Etminan Mahyar

    2012-09-01

    Full Text Available Abstract Background Despite the benefits of beta-blockers in patients with established or sub-clinical coronary artery disease, their use in patients with chronic obstructive pulmonary disease (COPD has been controversial. Currently, no systematic review has examined the impact of beta-blockers on mortality in COPD. Methods We systematically searched electronic bibliographic databases including MEDLINE, EMBASE and Cochrane Library for clinical studies that examine the association between beta-blocker use and all cause mortality in patients with COPD. Risk ratios across studies were pooled using random effects models to estimate a pooled relative risk across studies. Publication bias was assessed using a funnel plot. Results Our search identified nine retrospective cohort studies that met the study inclusion criteria. The pooled relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%. Conclusion The results of this review are consistent with a protective effect of beta-blockers with respect to all cause mortality. Due to the observational nature of the included studies, the possibility of confounding that may have affected these results cannot be excluded. The hypothesis that beta blocker therapy might be of benefit in COPD needs to be evaluated in randomised controlled trials.

  10. Risk of Cardiovascular Events in Patients With Diabetes Mellitus on β-Blockers.

    Science.gov (United States)

    Tsujimoto, Tetsuro; Sugiyama, Takehiro; Shapiro, Martin F; Noda, Mitsuhiko; Kajio, Hiroshi

    2017-07-01

    Although the use of β-blockers may help in achieving maximum effects of intensive glycemic control because of a decrease in the adverse effects after severe hypoglycemia, they pose a potential risk for the occurrence of severe hypoglycemia. This study aimed to evaluate whether the use of β-blockers is effective in patients with diabetes mellitus and whether its use is associated with the occurrence of severe hypoglycemia. Using the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) data, we performed Cox proportional hazards analyses with a propensity score adjustment. The primary outcome was the first occurrence of a cardiovascular event during the study period, which included nonfatal myocardial infarction, unstable angina, nonfatal stroke, and cardiovascular death. The mean follow-up periods (±SD) were 4.6±1.6 years in patients on β-blockers (n=2527) and 4.7±1.6 years in those not on β-blockers (n=2527). The cardiovascular event rate was significantly higher in patients on β-blockers than in those not on β-blockers (hazard ratio, 1.46; 95% confidence interval, 1.24-1.72; P diabetes mellitus was associated with an increased risk for cardiovascular events. © 2017 The Authors.

  11. An ERG channel inhibitor from the scorpion Buthus eupeus

    DEFF Research Database (Denmark)

    Korolkova, Y.V.; Kozlov, S.A.; Lipkin, A.V.

    2001-01-01

    and the three mutants partly inhibited the native M-like current in NG108-15 at 100 nm. The effect of the recombinant BeKm-1 on different K(+) channels was also studied. BeKm-1 inhibited hERG1 channels with an IC(50) of 3.3 nm, but had no effect at 100 nm on hEAG, hSK1, rSK2, hIK, hBK, KCNQ1/KCNE1, KCNQ2/KCNQ3......, KCNQ4 channels, and minimal effect on rELK1. Thus, BeKm-1 was shown to be a novel specific blocker of hERG1 potassium channels....

  12. Nicorandil directly and cyclic GMP-dependently opens K+ channels in human bypass grafts

    Directory of Open Access Journals (Sweden)

    Marija Marinko

    2015-06-01

    Full Text Available As we previously demonstrated the role of different K+ channels in the action of nicorandil on human saphenous vein (HSV and human internal mammary artery (HIMA, this study aimed to analyse the contribution of the cGMP pathway in nicorandil-induced vasorelaxation and to determine the involvement of cGMP in the K+ channel-activating effect of nicorandil. An inhibitor of soluble guanylate cyclase (GC, ODQ, significantly inhibited nicorandil-induced relaxation, while ODQ plus glibenclamide, a selective ATP-sensitive K+ (KATP channel inhibitor, produced a further inhibition of both vessels. In HSV, ODQ in combination with 4-aminopyridine, a blocker of voltage-gated K+ (KV channels, did not modify the concentration-response to nicorandil compared with ODQ, whereas in HIMA, ODQ plus iberiotoxin, a selective blocker of large-conductance Ca2+-activated K+ (BKCa channels, produced greater inhibition than ODQ alone. We showed that the cGMP pathway plays a significant role in the vasorelaxant effect of nicorandil on HSV and HIMA. It seems that nicorandil directly opens KATP channels in both vessels and BKCa channels in HIMA, although it is possible that stimulation of GC contributes to KATP channels activation in HIMA. Contrary, the activation of KV channels in HSV is probably due to GC activation and increased levels of cGMP.

  13. Automated entry control system for nuclear facilities

    International Nuclear Information System (INIS)

    Ream, W.K.; Espinoza, J.

    1985-01-01

    An entry control system to automatically control access to nuclear facilities is described. The design uses a centrally located console, integrated into the regular security system, to monitor the computer-controlled passage into and out of sensitive areas. Four types of entry control points are used: an unmanned enclosed portal with metal and SNM detectors for contraband detection with positive personnel identification, a bypass portal for contraband search after a contraband alarm in a regular portal also with positive personnel identification, a single door entry point with positive personnel identification, and a single door entry point with only a magnetic card-type identification. Security force action is required only as a response to an alarm. The integration of the entry control function into the security system computer is also described. The interface between the entry control system and the monitoring security personnel utilizing a color graphics display with touch screen input is emphasized. 2 refs., 7 figs

  14. Fusion-activated Ca(2+ entry: an "active zone" of elevated Ca(2+ during the postfusion stage of lamellar body exocytosis in rat type II pneumocytes.

    Directory of Open Access Journals (Sweden)

    Pika Miklavc

    2010-06-01

    Full Text Available Ca(2+ is essential for vesicle fusion with the plasma membrane in virtually all types of regulated exocytoses. However, in contrast to the well-known effects of a high cytoplasmic Ca(2+ concentration ([Ca(2+](c in the prefusion phase, the occurrence and significance of Ca(2+ signals in the postfusion phase have not been described before.We studied isolated rat alveolar type II cells using previously developed imaging techniques. These cells release pulmonary surfactant, a complex of lipids and proteins, from secretory vesicles (lamellar bodies in an exceptionally slow, Ca(2+- and actin-dependent process. Measurements of fusion pore formation by darkfield scattered light intensity decrease or FM 1-43 fluorescence intensity increase were combined with analysis of [Ca(2+](c by ratiometric Fura-2 or Fluo-4 fluorescence measurements. We found that the majority of single lamellar body fusion events were followed by a transient (t(1/2 of decay = 3.2 s rise of localized [Ca(2+](c originating at the site of lamellar body fusion. [Ca(2+](c increase followed with a delay of approximately 0.2-0.5 s (method-dependent and in the majority of cases this signal propagated throughout the cell (at approximately 10 microm/s. Removal of Ca(2+ from, or addition of Ni(2+ to the extracellular solution, strongly inhibited these [Ca(2+](c transients, whereas Ca(2+ store depletion with thapsigargin had no effect. Actin-GFP fluorescence around fused LBs increased several seconds after the rise of [Ca(2+](c. Both effects were reduced by the non-specific Ca(2+ channel blocker SKF96365.Fusion-activated Ca(2+entry (FACE is a new mechanism that leads to [Ca(2+](c transients at the site of vesicle fusion. Substantial evidence from this and previous studies indicates that fusion-activated Ca(2+ entry enhances localized surfactant release from type II cells, but it may also play a role for compensatory endocytosis and other cellular functions.

  15. Entry Mode Choice in Emerging Markets

    OpenAIRE

    Gundersen, Anne Kathrine Navestad

    2012-01-01

    As the mature markets of developed economies have become increasingly saturated, firms are turning their attention towards emerging markets for further enterprise growth. However, these countries often present significant challenges for foreign entrants, forcing firms to adapt their strategies to the new context. While MNEs? entry mode choice is an extensively studied field, there is a deficit in the entry mode research on SMEs, and even more so when it comes to entry into emerging markets in...

  16. Optimal firm growth under the threat of entry

    Science.gov (United States)

    Kort, Peter M.; Wrzaczek, Stefan

    2015-01-01

    The paper studies the incumbent-entrant problem in a fully dynamic setting. We find that under an open-loop information structure the incumbent anticipates entry by overinvesting, whereas in the Markov perfect equilibrium the incumbent slightly underinvests in the period before the entry. The entry cost level where entry accommodation passes into entry deterrence is lower in the Markov perfect equilibrium. Further we find that the incumbent’s capital stock level needed to deter entry is hump shaped as a function of the entry time, whereas the corresponding entry cost, where the entrant is indifferent between entry and non-entry, is U-shaped. PMID:26435573

  17. Strategic Entry Deterrence Modeling: Literature Review

    OpenAIRE

    D. A. Seliverstov

    2017-01-01

    The prime focus in this article is on key findings concerning theoretical aspects of strategic behavior by incumbents to deter market entry of new firms. The author summarizes main lines of scientific research in the topic which give an insight into the patterns of the incumbent’s impact on the behavior of the entrants, the entry deterrence instruments and the consequences of these actions. Today the free entry markets are considered to be a rare phenomenon. The market entry of new firms is a...

  18. Energy Information Data Base: corporate author entries

    International Nuclear Information System (INIS)

    1980-06-01

    One of the controls for information entered into the data bases created and maintained by the DOE Technical Information Center is the standardized name for the corporate entity or the corporate author. The purpose of Energy Information Data Base: Corporate Author Entries is to provide a means for the consistent citing of the names of organizations in bibliographic records. These entries serve as guides for users of the DOE/RECON computerized data bases who want to locate information originating in particular organizations. The entries in this revision include the corporate entries used in report bibliographic citations since 1973 and list approximately 28,000 corporate sources

  19. Cutting through - open entries require proper support

    Energy Technology Data Exchange (ETDEWEB)

    Peng, S.S. [West Virginia University, Morgantown, WV (USA). Mining Engineering Dept.

    2000-06-01

    The paper explains the applications of open entries in mining and different roof techniques to relieve longwall abutment pressures. The primary support for the open (or cut-through) entries and recovery rooms are normally similar to other development entries in the same mines. The supplementary supports installed can be divided into the following three types: complete backfill of open entries, supplemental roof and/or rib-bolt reinforcement only - no standing support and rows of standing support with or without supplemental roof and/or rib-bolt reinforcement. 3 figs.

  20. The selective A-type K+ current blocker Tx3-1 isolated from the Phoneutria nigriventer venom enhances memory of naïve and Aβ(25-35)-treated mice.

    Science.gov (United States)

    Gomes, Guilherme M; Dalmolin, Gerusa D; Cordeiro, Marta do Nascimento; Gomez, Marcus V; Ferreira, Juliano; Rubin, Maribel A

    2013-12-15

    Potassium channels regulate many neuronal functions, including neuronal excitability and synaptic plasticity, contributing, by these means, to mnemonic processes. In particular, A-type K(+) currents (IA) play a key role in hippocampal synaptic plasticity. Therefore, we evaluated the effect of the peptidic toxin Tx3-1, a selective blocker of IA currents, extracted from the venom of the spider Phoneutria nigriventer, on memory of mice. Administration of Tx3-1 (i.c.v., 300 pmol/site) enhanced both short- and long-term memory consolidation of mice tested in the novel object recognition task. In comparison, 4-aminopyridine (4-AP; i.c.v., 30-300 pmol/site), a non-selective K(+) channel blocker did not alter long-term memory and caused toxic side effects such as circling, freezing and tonic-clonic seizures. Moreover, Tx3-1 (i.c.v., 10-100 pmol/site) restored memory of Aβ25-35-injected mice, and exhibited a higher potency to improve memory of Aβ25-35-injected mice when compared to control group. These results show the effect of the selective blocker of IA currents Tx3-1 in both short- and long-term memory retention and in memory impairment caused by Aβ25-35, reinforcing the role of IA in physiological and pathological memory processes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. New Conotoxin SO-3 Targeting N-type Voltage-Sensitive Calcium Channels

    Directory of Open Access Journals (Sweden)

    Lei Wen

    2006-04-01

    Full Text Available Selective blockers of the N-type voltage-sensitive calcium (CaV channels are useful in the management of severe chronic pain. Here, the structure and function characteristics of a novel N-type CaV channel blocker, SO-3, are reviewed. SO-3 is a 25-amino acid conopeptide originally derived from the venom of Conus striatus, and contains the same 4-loop, 6-cysteine framework (C-C-CC-C-C as O-superfamily conotoxins. The synthetic SO-3 has high analgesic activity similar to ω-conotoxin MVIIA (MVIIA, a selective N-type CaV channel blocker approved in the USA and Europe for the alleviation of persistent pain states. In electrophysiological studies, SO-3 shows more selectivity towards the N-type CaV channels than MVIIA. The dissimilarity between SO-3 and MVIIA in the primary and tertiary structures is further discussed in an attempt to illustrate the difference in selectivity of SO-3 and MVIIA towards N-type CaV channels.

  2. Gene Therapy Targeting HIV Entry

    Directory of Open Access Journals (Sweden)

    Chuka Didigu

    2014-03-01

    Full Text Available Despite the unquestionable success of antiretroviral therapy (ART in the treatment of HIV infection, the cost, need for daily adherence, and HIV-associated morbidities that persist despite ART all underscore the need to develop a cure for HIV. The cure achieved following an allogeneic hematopoietic stem cell transplant (HSCT using HIV-resistant cells, and more recently, the report of short-term but sustained, ART-free control of HIV replication following allogeneic HSCT, using HIV susceptible cells, have served to both reignite interest in HIV cure research, and suggest potential mechanisms for a cure. In this review, we highlight some of the obstacles facing HIV cure research today, and explore the roles of gene therapy targeting HIV entry, and allogeneic stem cell transplantation in the development of strategies to cure HIV infection.

  3. Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology.

    Science.gov (United States)

    Wu, Wei; Sanguinetti, Michael C

    2016-06-01

    Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Voltage-dependent ion channels in the mouse RPE: comparison with Norrie disease mice.

    Science.gov (United States)

    Wollmann, Guido; Lenzner, Steffen; Berger, Wolfgang; Rosenthal, Rita; Karl, Mike O; Strauss, Olaf

    2006-03-01

    We studied electrophysiological properties of cultured retinal pigment epithelial (RPE) cells from mouse and a mouse model for Norrie disease. Wild-type RPE cells revealed the expression of ion channels known from other species: delayed-rectifier K(+) channels composed of Kv1.3 subunits, inward rectifier K(+) channels, Ca(V)1.3 L-type Ca(2+) channels and outwardly rectifying Cl(-) channels. Expression pattern and the ion channel characteristics current density, blocker sensitivity, kinetics and voltage-dependence were compared in cells from wild-type and Norrie mice. Although no significant differences were observed, our study provides a base for future studies on ion channel function and dysfunction in transgenic mouse models.

  5. Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review

    NARCIS (Netherlands)

    Brewster, Lizzy M.; Seedat, Yackoob K.

    2013-01-01

    Clinicians are encouraged to take an individualized approach when treating hypertension in patients of African ancestry, but little is known about why the individual patient may respond well to calcium blockers and diuretics, but generally has an attenuated response to drugs inhibiting the

  6. Effect of beta-blockers on exacerbation rate and lung function in chronic obstructive pulmonary disease (COPD).

    Science.gov (United States)

    Duffy, Sean; Marron, Robert; Voelker, Helen; Albert, Richard; Connett, John; Bailey, William; Casaburi, Richard; Cooper, J Allen; Curtis, Jeffrey L; Dransfield, Mark; Han, MeiLan K; Make, Barry; Marchetti, Nathaniel; Martinez, Fernando; Lazarus, Stephen; Niewoehner, Dennis; Scanlon, Paul D; Sciurba, Frank; Scharf, Steven; Reed, Robert M; Washko, George; Woodruff, Prescott; McEvoy, Charlene; Aaron, Shawn; Sin, Don; Criner, Gerard J

    2017-06-19

    Beta-blockers are commonly prescribed for patients with cardiovascular disease. Providers have been wary of treating chronic obstructive pulmonary disease (COPD) patients with beta-blockers due to concern for bronchospasm, but retrospective studies have shown that cardio-selective beta-blockers are safe in COPD and possibly beneficial. However, these benefits may reflect symptom improvements due to the cardiac effects of the medication. The purpose of this study is to evaluate associations between beta-blocker use and both exacerbation rates and longitudinal measures of lung function in two well-characterized COPD cohorts. We retrospectively analyzed 1219 participants with over 180 days of follow up from the STATCOPE trial, which excluded most cardiac comorbidities, and from the placebo arm of the MACRO trial. Primary endpoints were exacerbation rates per person-year and change in spirometry over time in association with beta blocker use. Overall 13.9% (170/1219) of participants reported taking beta-blockers at enrollment. We found no statistically significant differences in exacerbation rates with respect to beta-blocker use regardless of the prevalence of cardiac comorbidities. In the MACRO cohort, patients taking beta-blockers had an exacerbation rate of 1.72/person-year versus a rate of 1.71/person-year in patients not taking beta-blockers. In the STATCOPE cohort, patients taking beta-blockers had an exacerbation rate of 1.14/person-year. Patients without beta-blockers had an exacerbation rate of 1.34/person-year. We found no detrimental effect of beta blockers with respect to change in lung function over time. We found no evidence that beta-blocker use was unsafe or associated with worse pulmonary outcomes in study participants with moderate to severe COPD.

  7. Border Crossing/Entry Data - Border Crossing/Entry Data Time Series tool

    Data.gov (United States)

    Department of Transportation — The dataset is known as “Border Crossing/Entry Data.” The Bureau of Transportation Statistics (BTS) Border Crossing/Entry Data provides summary statistics to the...

  8. Beta blockers and chronic heart failure patients: prognostic impact of a dose targeted beta blocker therapy vs. heart rate targeted strategy.

    Science.gov (United States)

    Corletto, Anna; Fröhlich, Hanna; Täger, Tobias; Hochadel, Matthias; Zahn, Ralf; Kilkowski, Caroline; Winkler, Ralph; Senges, Jochen; Katus, Hugo A; Frankenstein, Lutz

    2018-05-17

    Beta blockers improve survival in patients with chronic systolic heart failure (CHF). Whether physicians should aim for target dose, target heart rate (HR), or both is still under debate. We identified 1,669 patients with systolic CHF due to ischemic heart disease or idiopathic dilated cardiomyopathy from the University Hospital Heidelberg and the Clinic of Ludwigshafen, Germany. All patients were treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker and had a history of CHF known for at least 6 months. Target dose was defined as treatment with ≥ 95% of the respective published guideline-recommended dose. Target HR was defined as 51-69 bpm. All-cause mortality during the median follow-up of 42.8 months was analysed with respect to beta blocker dosing and resting HR. 201 (12%) patients met the dose target (group A), 285 (17.1%) met the HR target (group B), 627 (37.6%) met no target (group C), and 556 (33.3%) did not receive beta blockers (Group D). 5-year mortality was 23.7, 22.7, 37.6, and 55.6% for group A, B, C, and D, respectively (p <  0.001). Survival for group A patients with a HR ≥ 70 bpm was 28.8% but 14.8% if HR was 50-70 bpm (p = 0.054). Achieving guidelines recommended beta blocker dose or to HR control has a similar positive impact on survival. When on target dose, supplemental HR control additionally improves survival.

  9. Mechanism of HERG potassium channel inhibition by tetra-n-octylammonium bromide and benzethonium chloride

    International Nuclear Information System (INIS)

    Long, Yan; Lin, Zuoxian; Xia, Menghang; Zheng, Wei; Li, Zhiyuan

    2013-01-01

    Tetra-n-octylammonium bromide and benzethonium chloride are synthetic quaternary ammonium salts that are widely used in hospitals and industries for the disinfection and surface treatment and as the preservative agent. Recently, the activities of HERG channel inhibition by these compounds have been found to have potential risks to induce the long QT syndrome and cardiac arrhythmia, although the mechanism of action is still elusive. This study was conducted to investigate the mechanism of HERG channel inhibition by these compounds by using whole-cell patch clamp experiments in a CHO cell line stably expressing HERG channels. Tetra-n-octylammonium bromide and benzethonium chloride exhibited concentration-dependent inhibitions of HERG channel currents with IC 50 values of 4 nM and 17 nM, respectively, which were also voltage-dependent and use-dependent. Both compounds shifted the channel activation I–V curves in a hyperpolarized direction for 10–15 mV and accelerated channel activation and inactivation processes by 2-fold. In addition, tetra-n-octylammonium bromide shifted the inactivation I–V curve in a hyperpolarized direction for 24.4 mV and slowed the rate of channel deactivation by 2-fold, whereas benzethonium chloride did not. The results indicate that tetra-n-octylammonium bromide and benzethonium chloride are open-channel blockers that inhibit HERG channels in the voltage-dependent, use-dependent and state-dependent manners. - Highlights: ► Tetra-n-octylammonium and benzethonium are potent HERG channel inhibitors. ► Channel activation and inactivation processes are accelerated by the two compounds. ► Both compounds are the open-channel blockers to HERG channels. ► HERG channel inhibition by both compounds is use-, voltage- and state dependent. ► The in vivo risk of QT prolongation needs to be studied for the two compounds

  10. Mechanism of HERG potassium channel inhibition by tetra-n-octylammonium bromide and benzethonium chloride

    Energy Technology Data Exchange (ETDEWEB)

    Long, Yan; Lin, Zuoxian [Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 (China); Xia, Menghang; Zheng, Wei [National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892 (United States); Li, Zhiyuan, E-mail: li_zhiyuan@gibh.ac.cn [Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 (China)

    2013-03-01

    Tetra-n-octylammonium bromide and benzethonium chloride are synthetic quaternary ammonium salts that are widely used in hospitals and industries for the disinfection and surface treatment and as the preservative agent. Recently, the activities of HERG channel inhibition by these compounds have been found to have potential risks to induce the long QT syndrome and cardiac arrhythmia, although the mechanism of action is still elusive. This study was conducted to investigate the mechanism of HERG channel inhibition by these compounds by using whole-cell patch clamp experiments in a CHO cell line stably expressing HERG channels. Tetra-n-octylammonium bromide and benzethonium chloride exhibited concentration-dependent inhibitions of HERG channel currents with IC{sub 50} values of 4 nM and 17 nM, respectively, which were also voltage-dependent and use-dependent. Both compounds shifted the channel activation I–V curves in a hyperpolarized direction for 10–15 mV and accelerated channel activation and inactivation processes by 2-fold. In addition, tetra-n-octylammonium bromide shifted the inactivation I–V curve in a hyperpolarized direction for 24.4 mV and slowed the rate of channel deactivation by 2-fold, whereas benzethonium chloride did not. The results indicate that tetra-n-octylammonium bromide and benzethonium chloride are open-channel blockers that inhibit HERG channels in the voltage-dependent, use-dependent and state-dependent manners. - Highlights: ► Tetra-n-octylammonium and benzethonium are potent HERG channel inhibitors. ► Channel activation and inactivation processes are accelerated by the two compounds. ► Both compounds are the open-channel blockers to HERG channels. ► HERG channel inhibition by both compounds is use-, voltage- and state dependent. ► The in vivo risk of QT prolongation needs to be studied for the two compounds.

  11. Risk of insomnia attributable to β-blockers in elderly patients with newly diagnosed hypertension.

    Science.gov (United States)

    Chang, Chia-Hsien; Yang, Yea-Huei Kao; Lin, Swu-Jane; Su, Jyun-Jhong; Cheng, Ching-Lan; Lin, Li-Jen

    2013-01-01

    Use of β-blockers may cause insomnia and central nervous system and/or psychological side effects, but data are limited on the relative risks of insomnia among β-blockers. This retrospective cohort study used Taiwan's National Health Insurance claims database from 2003 to 2007, where 4,063 patients aged above 65 years with newly diagnosed hypertension and treated with β-blockers were followed for 1 year. The primary endpoint was a new insomnia event within 30 days of treatment initiation. Adjusted odds ratios of insomnia were obtained by logistic regressions, controlling for baseline risk factors of insomnia. Using propranolol therapy as the reference, the adjusted odds ratio (95% confidence interval) for the insomnia risk was 0.47 (0.35-0.63) for non-propranolol users, 0.31 (0.19-0.50) for bisoprolol, and 0.46 (0.33-0.66) for atenolol. Compared to the patients using non-selective β-blockers, the adjusted odds ratio was 0.48 (0.36-0.34) for those using selective β(1)-blockers. Additionally, the adjusted odds ratio was 0.72 (0.53-0.96) for β-blockers with low lipophilicity when compared to those with high lipophilicity. The use of bisoprolol and atenolol was associated with the lowest risk of insomnia in elderly patients, as compared to propranolol. β-Blockers with high selectivity in β(1)-receptors and/or low lipophilicity were associated with a lower risk of insomnia.

  12. Influence of beta blockers on survival in dogs with severe subaortic stenosis.

    Science.gov (United States)

    Eason, B D; Fine, D M; Leeder, D; Stauthammer, C; Lamb, K; Tobias, A H

    2014-01-01

    Subaortic stenosis (SAS) is one of the most common congenital cardiac defects in dogs. Severe SAS frequently is treated with a beta adrenergic receptor blocker (beta blocker), but this approach largely is empirical. To determine the influence of beta blocker treatment on survival time in dogs with severe SAS. Retrospective review of medical records of dogs diagnosed with severe, uncomplicated SAS (pressure gradient [PG] ≥80 mmHg) between 1999 and 2011. Fifty dogs met the inclusion criteria. Twenty-seven dogs were treated with a beta blocker and 23 received no treatment. Median age at diagnosis was significantly greater in the untreated group (1.2 versus 0.6 years, respectively; P = .03). Median PG at diagnosis did not differ between the treated and untreated groups (127 versus 121 mmHg, respectively; P = .2). Cox proportional hazards regression was used to identify the influence of PG at diagnosis, age at diagnosis, and beta blocker treatment on survival. In the all-cause multivariate mortality analysis, only age at diagnosis (P = .02) and PG at diagnosis (P = .03) affected survival time. In the cardiac mortality analysis, only PG influenced survival time (P = .03). Treatment with a beta blocker did not influence survival time in either the all-cause (P = .93) or cardiac-cause (P = .97) mortality analyses. Beta blocker treatment did not influence survival in dogs with severe SAS in our study, and a higher PG at diagnosis was associated with increased risk of death. Copyright © 2014 by the American College of Veterinary Internal Medicine.

  13. Beta-blocker withdrawal among patients presenting for surgery from home

    Science.gov (United States)

    Schonberger, Robert B.; Lukens, Carrie L.; Turkoglu, O. Dicle; Feinleib, Jessica L.; Haspel, Kenneth L.; Burg, Matthew M.

    2012-01-01

    Structured Abstract Objective This study sought to measure the incidence of perioperative beta-blocker non-compliance by patients who were prescribed chronic beta blocker therapy and presented for surgery from home. The effect of patient non-compliance on day of surgery presenting heart rate was also examined. Design Prospective observational study with outcome data obtained from review of the medical record. Setting The preoperative clinic and operating rooms of a Veterans Administration hospital. Participants Patients on chronic beta blocker therapy who presented from home for surgery. Interventions None. Measurements and Main Results Demographic and comorbidity data as well as data on self-reported compliance to beta-blocker therapy, initial day of surgery vital signs, and recent ambulatory vital signs were collected. Ten out of fifty subjects (20%; 95% CI = 9-31%) reported not taking their day of surgery beta-blocker. These self-reported non-adherers demonstrated a higher presenting heart rate on the day of surgery vs. adherent subjects (median of 78 beats per minute vs. 65 beats per minute, p=0.02 by Wilcoxon Rank-Sum Test). The difference-in-difference between baseline primary care and day of surgery heart rate was also statistically significant between compliant and non-compliant subjects (-7 beats per minute vs. +12.5 beats per minute, p<0.00001). Conclusions Patient self-report and physiologic data documented failure to take beta-blockers and possible beta-blocker withdrawal in 20% of patients who presented for surgery from home. If these findings are confirmed in larger studies, improved patient understanding of and compliance with medication instructions during preoperative visits should be a focus of future quality improvement initiatives. PMID:22418043

  14. Energy Data Base: corporate author entries

    International Nuclear Information System (INIS)

    Hendricks, P.L.

    1982-08-01

    Corporate author entries provide a means for consistent citing of the names of organizations in bibliographic records in the data bases of the DOE Technical Information Center. These entries serve as guides for users of the DOE/RECON computerized data bases who want to locate information originating in particular organizations

  15. Strategic Entry Deterrence Modeling: Literature Review

    Directory of Open Access Journals (Sweden)

    D. A. Seliverstov

    2017-01-01

    Full Text Available The prime focus in this article is on key findings concerning theoretical aspects of strategic behavior by incumbents to deter market entry of new firms. The author summarizes main lines of scientific research in the topic which give an insight into the patterns of the incumbent’s impact on the behavior of the entrants, the entry deterrence instruments and the consequences of these actions. Today the free entry markets are considered to be a rare phenomenon. The market entry of new firms is associated with significant entry costs, which allow the incumbents to take advantage of their dominant position and derive positive economic profits. In case of entry threat by potential competitors the incumbents take strategic actions aimed at deterring entry and preserving their dominant position. Among the most efficient strategic actions one can emphasize the erection of additional barriers to entry for the newcomers through producing the limit output and price, investments in sunk assets, capacity expansion and product differentiation. Meanwhile by taking strategic actions the incumbents are not always trying to affect the entrant’s costs and profit directly, they often aim at changing the entrant’s expectations regarding future intentions of the incumbents to preserve dominant position.

  16. 40 CFR 170.112 - Entry restrictions.

    Science.gov (United States)

    2010-07-01

    ...-entry interval applies, including, but not limited to, soil, water, air, or surfaces of plants; and (2...-entry activity, the agricultural employer shall provide a decontamination site in accordance with § 170... running water for routine and emergency decontamination and mechanical devices that would reduce the...

  17. Entry and Competition in Differentiated Products Markets

    NARCIS (Netherlands)

    Schaumans, C.B.C.; Verboven, F.L.

    2011-01-01

    We propose a methodology for estimating the competition effects from entry when firms sell differentiated products. We first derive precise conditions under which Bres- nahan and Reiss'entry threshold ratios (ETRs) can be used to test for the presence and to measure the magnitude of competition

  18. On Entry Deterrence and Imperfectly Observable Commitment

    DEFF Research Database (Denmark)

    Poulsen, Anders

    2001-01-01

    We analyse a simple entry-deterrence game, where a `Potential Intruder' only imperfectly observes the decision of an `Incumbent' to commit or to not commit to fight any entry by the Potential Intruder. Our game generalises the one studied in Bonanno (1992) by allowing for a richer information tec...

  19. Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure.

    Science.gov (United States)

    Zugck, Christian; Haunstetter, Armin; Krüger, Carsten; Kell, Robert; Schellberg, Dieter; Kübler, Wolfgang; Haass, Markus

    2002-05-15

    This prospective study tested the impact of beta-blocker treatment on currently used risk predictors in congestive heart failure (CHF). Given the survival benefit obtained by beta-blockade, risk stratification by factors established in the "pre-beta-blocker era" may be questioned. The study included 408 patients who had CHF with left ventricular ejection fraction (LVEF) 2.24 nmol/l (18% vs. 40%) and NT-proBNP >364 pmol/l (27% vs. 45%), although patients with beta-blocker treatment received only 37 +/- 21% of the maximal recommended beta-blocker dosages. The prognostic value of variables used for risk stratification of patients with CHF is markedly influenced by beta-blocker treatment. Therefore, in the beta-blocker era, a re-evaluation of the selection criteria for heart transplantation is warranted.

  20. Foreign Entry and Heterogeneous Growth of Firms

    DEFF Research Database (Denmark)

    Deng, Paul Duo; Jefferson, Gary H.

    We adopt the framework of Schumpeterian creative destruction formalized by Aghion et al. (2009) to analyze the impact of foreign entry on the productivity growth of domestic firms. In the face of foreign entry, domestic firms exhibit heterogeneous patterns of growth depending on their technologic...... manufacturing. Our empirical results confirm that foreign entry indeed generates strong heterogeneous growth patterns among domestic firms.......We adopt the framework of Schumpeterian creative destruction formalized by Aghion et al. (2009) to analyze the impact of foreign entry on the productivity growth of domestic firms. In the face of foreign entry, domestic firms exhibit heterogeneous patterns of growth depending on their technological...... distance from foreign firms. Domestic firms with smaller technological distance from their foreign counterparts tend to experience faster productivity growth, while firms with larger technological distance tend to lag further behind. We test this hypothesis using a unique firm-level data of Chinese...

  1. Adaptive Text Entry for Mobile Devices

    DEFF Research Database (Denmark)

    Proschowsky, Morten Smidt

    The reduced size of many mobile devices makes it difficult to enter text with them. The text entry methods are often slow or complicated to use. This affects the performance and user experience of all applications and services on the device. This work introduces new easy-to-use text entry methods...... for mobile devices and a framework for adaptive context-aware language models. Based on analysis of current text entry methods, the requirements to the new text entry methods are established. Transparent User guided Prediction (TUP) is a text entry method for devices with one dimensional touch input. It can...... be touch sensitive wheels, sliders or similar input devices. The interaction design of TUP is done with a combination of high level task models and low level models of human motor behaviour. Three prototypes of TUP are designed and evaluated by more than 30 users. Observations from the evaluations are used...

  2. Ionic channels underlying the ventricular action potential in zebrafish embryo.

    Science.gov (United States)

    Alday, Aintzane; Alonso, Hiart; Gallego, Monica; Urrutia, Janire; Letamendia, Ainhoa; Callol, Carles; Casis, Oscar

    2014-06-01

    Over the last years zebrafish has become a popular model in the study of cardiac physiology, pathology and pharmacology. Recently, the application of the 3Rs regulation and the characteristics of the embryo have reduced the use of adult zebrafish use in many studies. However, the zebrafish embryo cardiac physiology is poorly characterized since most works have used indirect techniques and direct recordings of cardiac action potential and ionic currents are scarce. In order to optimize the zebrafish embryo model, we used electrophysiological, pharmacological and immunofluorescence tools to identify the characteristics and the ionic channels involved in the ventricular action potentials of zebrafish embryos. The application of Na(+) or T-type Ca(+2) channel blockers eliminated the cardiac electrical activity, indicating that the action potential upstroke depends on Na(+) and T-type Ca(+2) currents. The plateau phase depends on L-type Ca(+2) channels since it is abolished by specific blockade. The direct channel blockade indicates that the action potential repolarization and diastolic potential depends on ERG K(+) channels. The presence in the embryonic heart of the Nav1.5, Cav1.2, Cav3.2 and ERG channels was also confirmed by immunofluorescence, while the absence of effect of specific blockers and immunostaining indicate that two K(+) repolarizing currents present in human heart, Ito and IKs, are absent in the embryonic zebrafish heart. Our results describe the ionic channels present and its role in the zebrafish embryo heart and support the use of zebrafish embryos to study human diseases and their use for drug testing. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Channelling and electromagnetic radiation of channelling particles

    International Nuclear Information System (INIS)

    Kalashnikov, N.

    1983-01-01

    A brief description is presented of the channelling of charged particles between atoms in the crystal lattice. The specificities are discussed of the transverse motion of channelling particles as are the origin and properties of quasi-characteristic radiation of channelling particles which accompany transfers from one band of permissible energies of the transverse motion of channelling particles to the other. (B.S.)

  4. Optimal use of β-blockers in high-risk hypertension: A guide to dosing equivalence

    Directory of Open Access Journals (Sweden)

    Janet B McGill

    2010-05-01

    Full Text Available Janet B McGillDepartment of Medicine, Washington University School of Medicine, St. Louis, Missouri, USAAbstract: Hypertension is the number one diagnosis made by primary care physicians, placing them in a unique position to prescribe the antihypertensive agent best suited to the individual patient. In individuals with diabetes mellitus, blood pressure (BP levels > 130/80 mmHg confer an even higher risk for cardiovascular and renal disease, and these patients will benefit from aggressive antihypertensive treatment using a combination of agents. β‑blockers are playing an increasingly important role in the management of hypertension in high-risk patients. β‑blockers are a heterogeneous class of agents, and this review presents the differences between β‑blockers and provides evidence-based protocols to assist in understanding dose equivalence in the selection of an optimal regimen in patients with complex needs. The clinical benefits provided by β‑blockers are only effective if patients adhere to medication treatment long term. β‑blockers with proven efficacy, once-daily dosing, and lower side effect profiles may become instrumental in the treatment of hypertensive diabetic and nondiabetic patients.Keywords: antihypertensive, blood pressure, atenolol, carvedilol, labetalol, metoprolol, nebivolol

  5. Computerized provider order entry systems.

    Science.gov (United States)

    2001-01-01

    Computerized provider order entry (CPOE) systems are designed to replace a hospital's paper-based ordering system. They allow users to electronically write the full range of orders, maintain an online medication administration record, and review changes made to an order by successive personnel. They also offer safety alerts that are triggered when an unsafe order (such as for a duplicate drug therapy) is entered, as well as clinical decision support to guide caregivers to less expensive alternatives or to choices that better fit established hospital protocols. CPOE systems can, when correctly configured, markedly increase efficiency and improve patient safety and patient care. However, facilities need to recognize that currently available CPOE systems require a tremendous amount of time and effort to be spent in customization before their safety and clinical support features can be effectively implemented. What's more, even after they've been customized, the systems may still allow certain unsafe orders to be entered. Thus, CPOE systems are not currently a quick or easy remedy for medical errors. ECRI's Evaluation of CPOE systems--conducted in collaboration with the Institute for Safe Medication Practices (ISMP)--discusses these and other related issues. It also examines and compares CPOE systems from three suppliers: Eclipsys Corp., IDX Systems Corp., and Siemens Medical Solutions Health Services Corp. Our testing focuses primarily on the systems' interfacing capabilities, patient safeguards, and ease of use.

  6. Channel Modeling

    Science.gov (United States)

    Schmitz, Arne; Schinnenburg, Marc; Gross, James; Aguiar, Ana

    For any communication system the Signal-to-Interference-plus-Noise-Ratio of the link is a fundamental metric. Recall (cf. Chapter 9) that the SINR is defined as the ratio between the received power of the signal of interest and the sum of all "disturbing" power sources (i.e. interference and noise). From information theory it is known that a higher SINR increases the maximum possible error-free transmission rate (referred to as Shannon capacity [417] of any communication system and vice versa). Conversely, the higher the SINR, the lower will be the bit error rate in practical systems. While one aspect of the SINR is the sum of all distracting power sources, another issue is the received power. This depends on the transmitted power, the used antennas, possibly on signal processing techniques and ultimately on the channel gain between transmitter and receiver.

  7. Channeling experiment

    International Nuclear Information System (INIS)

    Abelin, H.; Birgersson, L.; Widen, H.; Aagren, T.; Moreno, L.; Neretnieks, I.

    1990-07-01

    Channeling of water flow and tracer transport in real fractures in a granite body at Stripa have been investigated experimentally. The experimental site was located 360 m below the ground level. Two kinds of experiments were performed. In the single hole experiments, 20 cm diameter holes were drilled about 2.5 m into the rock in the plane of the fracture. Specially designed packers were used to inject water into the fracture in 5 cm intervals all along the fracture trace in the hole. The variation of the injection flowrates along the fracture were used to determine the transmissivity variations in the fracture plane. Detailed photographs were taken from inside the hole and the visual fracture aperture was compared with the injection flowrates in the same locations. Geostatistical methods were used to evaluate the results. Five holes were measured in great detail. In addition 7 holes were drilled and scanned by simpler packer systems. A double hole experiment was performed where two parallel holes were drilled in the same fracture plane at nearly 2 m distance. Pressure pulse tests were made between the holes in both directions. Tracers were injected in 5 locations in one hole and monitored for in many locations in the other hole. The single hole experiment and the double hole experiment show that most of the fracture planes are tight but that there are open sections which form connected channels over distances of at least 2 meters. It was also found in the double hole experiment that the investigated fracture was intersected by at least one fracture between the two holes which diverted a large amount of the injected tracers to several distant locations at the tunnel wall. (authours)

  8. Functional and pharmacological consequences of the distribution of voltage-gated calcium channels in the renal blood vessels

    DEFF Research Database (Denmark)

    Hansen, P B L

    2013-01-01

    Calcium channel blockers are widely used to treat hypertension because they inhibit voltage-gated calcium channels that mediate transmembrane calcium influx in, for example, vascular smooth muscle and cardiomyocytes. The calcium channel family consists of several subfamilies, of which the L......-type is usually associated with vascular contractility. However, the L-, T- and P-/Q-types of calcium channels are present in the renal vasculature and are differentially involved in controlling vascular contractility, thereby contributing to regulation of kidney function and blood pressure. In the preglomerular...... vascular bed, all the three channel families are present. However, the T-type channel is the only channel in cortical efferent arterioles which is in contrast to the juxtamedullary efferent arteriole, and that leads to diverse functional effects of L- and T-type channel inhibition. Furthermore...

  9. Electrochemical cell apparatus having axially distributed entry of a fuel-spent fuel mixture transverse to the cell lengths

    Science.gov (United States)

    Reichner, Philip; Dollard, Walter J.

    1991-01-01

    An electrochemical apparatus (10) is made having a generator section (22) containing axially elongated electrochemical cells (16), a fresh gaseous feed fuel inlet (28), a gaseous feed oxidant inlet (30), and at least one gaseous spent fuel exit channel (46), where the spent fuel exit channel (46) passes from the generator chamber (22) to combine with the fresh feed fuel inlet (28) at a mixing apparatus (50), reformable fuel mixture channel (52) passes through the length of the generator chamber (22) and connects with the mixing apparatus (50), that channel containing entry ports (54) within the generator chamber (22), where the axis of the ports is transverse to the fuel electrode surfaces (18), where a catalytic reforming material is distributed near the reformable fuel mixture entry ports (54).

  10. Improving the prognosis of diabetic patients: evaluating the role of intensive versus moderate blood pressure control with selective angiotensin II receptor blocker (ARB therapy

    Directory of Open Access Journals (Sweden)

    Martin P Bedigian

    2000-06-01

    Full Text Available The ABCD (Appropriate Blood Pressure Control in Diabetes and ABCD-2V (Part 2 with Valsartan are prospective, randomised clinical trials which will provide important data on the impact of intensive vs. moderate blood pressure (BP control on microvascular and macrovascular complications in normotensive and hypertensive patients with type 2 diabetes mellitus (DM. The ABCD trial was a five-year study that compared the effects of intensive vs. moderate BP control on the endpoints of nephropathy, retinopathy, neuropathy, and cardiovascular disease events using a calcium channel blocker (CCB and an angiotensin-converting enzyme (ACE inhibitor as the primary antihypertensive agents. The recently published results of the hypertensive cohort of ABCD are reviewed herein. The follow-up study, ABCD-2V, is ongoing and was designed to compare intensive vs. moderate BP control on the same endpoints as the ABCD study, using the highly selective angiotensin II receptor blocker (ARB valsartan as the primary antihypertensive agent. First results of ABCD-2V are expected in 2004. The baseline characteristics for the patients enrolled thus far in the hypertensive cohort of ABCD-2V are reviewed. These studies will provide insight into the role of intensive vs. moderate BP control in the management of normotensive and hypertensive patients with type 2 DM.

  11. Use of statins and beta-blockers after acute myocardial infarction according to income and education

    DEFF Research Database (Denmark)

    Rasmussen, Jeppe Nørgaard; Gislason, Gunnar H; Rasmussen, Søren

    2007-01-01

    OBJECTIVE: To study the initiation of and long-term refill persistency with statins and beta-blockers after acute myocardial infarction (AMI) according to income and education. DESIGN AND SETTING: Linkage of individuals through national registers of hospitalisations, drug dispensation, income...... and education. PARTICIPANTS: 30 078 patients aged 30-74 years surviving first hospitalisation for AMI in Denmark between 1995 and 2001. MAIN OUTCOME MEASURES: Initiation of statin or beta-blocker treatment (out-patient claim of prescriptions within 6 months of discharge) and refill persistency (first break.......66-0.82) and medium (HR 0.82; 95% CI 0.74-0.92) income compared with low income, whereas there was a trend in the opposite direction concerning a break in beta-blocker treatment. There was no gradient in re-initiation of treatment. CONCLUSION: Patients with low compared with high income less frequently initiated...

  12. USE OF BETA-BLOCKERS IN THE PERIOPERATIVE PERIOD: HOW STRONG ARE THE EVIDENCES?

    Directory of Open Access Journals (Sweden)

    V. V. Samoylenko

    2015-09-01

    Full Text Available Optimization of the pharmacotherapy in preoperative period is the cornerstone of the concept of risk modification of cardiovascular complications in the perioperative period. Therefore, special attention has recently been focused on the use of beta-blockers in the postoperative period. Nowadays convincing evidence base for the use of this class of drugs in the perioperative period that was the basis for the development of clinical guidelines is accumulated. Moreover, results of large randomized trials of beta-blockers are controversial. This has resulted in significant differences in the classes of recommendations and levels of evidence.Analysis of the results of basic researches and the provisions of recommendations of the international and national professional medical societies on the use of beta-blockers in patients with cardiovascular disease to reduce the risk of cardiac complications in the perioperative period for planned extracardiac surgical procedures is presented.

  13. Combination monoamine oxidase inhibitor and beta-blocker treatment of migraine, with anxiety and depression.

    Science.gov (United States)

    Merikangas, K R; Merikangas, J R

    1995-11-01

    This paper presents the results of a study comparing the effectiveness of a beta-adrenergic blocking agent, atenolol, a monoamine oxidase inhibitor (MAO-I), phenelzine, and the combination in treatment of 61 adults with migraine headache. The goals of the study are (1) to investigate the safety of concomitant treatment of migraine with beta-blockers and phenelzine, (2) to assess whether orthostatic hypertension and other side effects would be relieved, and (3) to compare the results of this open trial of phenelzine to those of a previous study using similar methods. Phenelzine was associated with a large decrease in the frequency and severity of migraine attacks. Anxiety and depression were also reduced by phenelzine both alone, and in combination with a beta-blocker. The results show that the combination of MAO-I's and beta-blockers can be administered safely, and can lead to the reduction in the side effects with either drug alone.

  14. Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium.

    Science.gov (United States)

    Pattnaik, Bikash R; Hughes, Bret A

    2012-03-01

    Recently, we demonstrated the expression of KCNQ1, KCNQ4, and KCNQ5 transcripts in monkey retinal pigment epithelium (RPE) and showed that the M-type current in RPE cells is blocked by the specific KCNQ channel blocker XE991. Using patch-clamp electrophysiology, we investigated the pharmacological sensitivity of the M-type current in isolated monkey RPE cells to elucidate the subunit composition of the channel. Most RPE cells exhibited an M-type current with a voltage for half-maximal activation of approximately -35 mV. The M-type current activation followed a double-exponential time course and was essentially complete within 1 s. The M-type current was inhibited by micromolar concentrations of the nonselective KCNQ channel blockers linopirdine and XE991 but was relatively insensitive to block by 10 μM chromanol 293B or 135 mM tetraethylammonium (TEA), two KCNQ1 channel blockers. The M-type current was activated by 1) 10 μM retigabine, an opener of all KCNQ channels except KCNQ1, 2) 10 μM zinc pyrithione, which augments all KCNQ channels except KCNQ3, and 3) 50 μM N-ethylmaleimide, which activates KCNQ2, KCNQ4, and KCNQ5, but not KCNQ1 or KCNQ3, channels. Application of cAMP, which activates KCNQ1 and KCNQ4 channels, had no significant effect on the M-type current. Finally, diclofenac, which activates KCNQ2/3 and KCNQ4 channels but inhibits KCNQ5 channels, inhibited the M-type current in the majority of RPE cells but activated it in others. The results indicate that the M-type current in monkey RPE is likely mediated by channels encoded by KCNQ4 and KCNQ5 subunits.

  15. The role of voltage-gated potassium channels in the regulation of mouse uterine contractility

    Directory of Open Access Journals (Sweden)

    Abel Peter W

    2007-11-01

    Full Text Available Abstract Background Uterine smooth muscle cells exhibit ionic currents that appear to be important in the control of uterine contractility, but how these currents might produce the changes in contractile activity seen in pregnant myometrium has not been established. There are conflicting reports concerning the role of voltage-gated potassium (Kv channels and large-conductance, calcium-activated potassium (BK channels in the regulation of uterine contractility. In this study we provide molecular and functional evidence for a role for Kv channels in the regulation of spontaneous contractile activity in mouse myometrium, and also demonstrate a change in Kv channel regulation of contractility in pregnant mouse myometrium. Methods Functional assays which evaluated the effects of channel blockers and various contractile agonists were accomplished by quantifying contractility of isolated uterine smooth muscle obtained from nonpregnant mice as well as mice at various stages of pregnancy. Expression of Kv channel proteins in isolated uterine smooth muscle was evaluated by Western blots. Results The Kv channel blocker 4-aminopyridine (4-AP caused contractions in nonpregnant mouse myometrium (EC50 = 54 micromolar, maximal effect at 300 micromolar but this effect disappeared in pregnant mice; similarly, the Kv4.2/Kv4.3 blocker phrixotoxin-2 caused contractions in nonpregnant, but not pregnant, myometrium. Contractile responses to 4-AP were not dependent upon nerves, as neither tetrodotoxin nor storage of tissues at room temperature significantly altered these responses, nor were responses dependent upon the presence of the endometrium. Spontaneous contractions and contractions in response to 4-AP did not appear to be mediated by BK, as the BK channel-selective blockers iberiotoxin, verruculogen, or tetraethylammonium failed to affect either spontaneous contractions or 4-AP-elicited responses. A number of different Kv channel alpha subunit proteins were

  16. Chloride channels in myotonia congenita assessed by velocity recovery cycles.

    Science.gov (United States)

    Tan, S Veronica; Z'Graggen, Werner J; Boërio, Delphine; Rayan, Dipa Raja; Norwood, Fiona; Ruddy, Deborah; Howard, R; Hanna, Michael G; Bostock, Hugh

    2014-06-01

    Myotonia congenita (MC) is caused by congenital defects in the muscle chloride channel CLC-1. This study used muscle velocity recovery cycles (MVRCs) to investigate how membrane function is affected. MVRCs and responses to repetitive stimulation were compared between 18 patients with genetically confirmed MC (13 recessive, 7 dominant) and 30 age-matched, normal controls. MC patients exhibited increased early supernormality, but this was prevented by treatment with sodium channel blockers. After multiple conditioning stimuli, late supernormality was enhanced in all MC patients, indicating delayed repolarization. These abnormalities were similar between the MC subtypes, but recessive patients showed a greater drop in amplitude during repetitive stimulation. MVRCs indicate that chloride conductance only becomes important when muscle fibers are depolarized. The differential responses to repetitive stimulation suggest that, in dominant MC, the affected chloride channels are activated by strong depolarization, consistent with a positive shift of the CLC-1 activation curve. Copyright © 2013 Wiley Periodicals, Inc.

  17. Heart rate and use of beta-blockers in stable outpatients with coronary artery disease.

    Directory of Open Access Journals (Sweden)

    Ph Gabriel Steg

    Full Text Available BACKGROUND: Heart rate (HR is an emerging risk factor in coronary artery disease (CAD. However, there is little contemporary data regarding HR and the use of HR-lowering medications, particularly beta-blockers, among patients with stable CAD in routine clinical practice. The goal of the present analysis was to describe HR in such patients, overall and in relation to beta-blocker use, and to describe the determinants of HR. METHODS AND FINDINGS: CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis of >50%, or chest pain associated with proven myocardial ischemia. A total of 33,438 patients from 45 countries in Europe, the Americas, Africa, Middle East, and Asia/Pacific were enrolled between November 2009 and July 2010. Most of the 33,177 patients included in this analysis were men (77.5%. Mean (SD age was 64.2 (10.5 years, HR by pulse was 68.3 (10.6 bpm, and by electrocardiogram was 67.2 (11.4 bpm. Overall, 44.0% had HR ≥ 70 bpm. Beta-blockers were used in 75.1% of patients and another 14.4% had intolerance or contraindications to beta-blocker therapy. Among 24,910 patients on beta-blockers, 41.1% had HR ≥ 70 bpm. HR ≥ 70 bpm was independently associated with higher prevalence and severity of angina, more frequent evidence of myocardial ischemia, and lack of use of HR-lowering agents. CONCLUSIONS: Despite a high rate of use of beta-blockers, stable CAD patients often have resting HR ≥ 70 bpm, which was associated with an overall worse health status, more frequent angina and ischemia. Further HR lowering is possible in many patients with CAD. Whether it will improve symptoms and outcomes is being tested.

  18. Effects of beta-blockers on heart failure with preserved ejection fraction: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Feng Liu

    Full Text Available BACKGROUND: Effects of beta-blockers on the prognosis of the heart failure patients with preserved ejection fraction (HFpEF remain controversial. The aim of this meta-analysis was to determine the impact of beta-blockers on mortality and hospitalization in the patients with HFpEF. METHODS: A search of MEDLINE, EMBASE, and the Cochrane Library databases from 2005 to June 2013 was conducted. Clinical studies reporting outcomes of mortality and/or hospitalization for patients with HFpEF (EF ≥ 40%, being assigned to beta-blockers treatment and non-beta-blockers control group were included. RESULTS: A total of 12 clinical studies (2 randomized controlled trials and 10 observational studies involving 21,206 HFpEF patients were included for this meta-analysis. The pooled analysis demonstrated that beta-blocker exposure was associated with a 9% reduction in relative risk for all-cause mortality in patients with HFpEF (95% CI: 0.87 - 0.95; P < 0.001. Whereas, the all-cause hospitalization, HF hospitalization and composite outcomes (mortality and hospitalization were not affected by this treatment (P=0.26, P=0.97, and P=0.88 respectively. CONCLUSIONS: The beta-blockers treatment for the patients with HFpEF was associated with a lower risk of all-cause mortality, but not with a lower risk of hospitalization. These finding were mainly obtained from observational studies, and further investigations are needed to make an assertion.

  19. Late Pregnancy β Blocker Exposure and Risks of Neonatal Hypoglycemia and Bradycardia.

    Science.gov (United States)

    Bateman, Brian T; Patorno, Elisabetta; Desai, Rishi J; Seely, Ellen W; Mogun, Helen; Maeda, Ayumi; Fischer, Michael A; Hernandez-Diaz, Sonia; Huybrechts, Krista F

    2016-09-01

    β blockers are widely used in the treatment of hypertensive disorders during pregnancy. These medications cross the placenta and may cause physiologic changes in neonates exposed in utero. We sought to define the risks of neonatal hypoglycemia and bradycardia associated with maternal exposure to β blockers at the time of delivery in a large, nationwide cohort of Medicaid beneficiaries. We used a cohort of 2 292 116 completed pregnancies linked to liveborn infants of Medicaid-enrolled women from 2003 to 2007. We examined the risks of neonatal hypoglycemia and neonatal bradycardia associated with maternal exposure to β blockers at the time of delivery. Propensity score matching was used to control for potential confounders including maternal demographics, obstetric and medical conditions, and exposure to other medications. There were 10 585 (0.5%) pregnancies exposed to β blockers at the time of delivery. The risk of neonatal hypoglycemia was 4.3% in the β blocker-exposed neonates versus 1.2% in the unexposed; the risk of neonatal bradycardia was 1.6% in the exposed versus 0.5% in the unexposed. After controlling for confounders, risk remained elevated for both neonatal hypoglycemia and bradycardia among exposed pregnancies versus unexposed (adjusted odds ratio, 1.68, 95% confidence interval, 1.50-1.89 and adjusted odds ratio, 1.29, 95% confidence interval, 1.07-1.55, respectively). Our findings suggest that neonates born to mothers exposed to β blockers in late pregnancy, including labetalol, are at elevated risk for neonatal hypoglycemia and bradycardia. Copyright © 2016 by the American Academy of Pediatrics.

  20. Entry, Descent, and Landing With Propulsive Deceleration

    Science.gov (United States)

    Palaszewski, Bryan

    2012-01-01

    The future exploration of the Solar System will require innovations in transportation and the use of entry, descent, and landing (EDL) systems at many planetary landing sites. The cost of space missions has always been prohibitive, and using the natural planetary and planet s moons atmospheres for entry, descent, and landing can reduce the cost, mass, and complexity of these missions. This paper will describe some of the EDL ideas for planetary entry and survey the overall technologies for EDL that may be attractive for future Solar System missions.

  1. Technical Area 55 Entry Control System (ECS)

    International Nuclear Information System (INIS)

    Beaumont, A.; Brundige, E.; DesJardin, R.; Rivera, R.

    1984-01-01

    The exchange badge system which was used at the Plutonium Facility located in Technical Area 55 was replaced on a trial basis with an automated Entry Control System. As a result of the success of the trial system, a new system incorporating expanded features and increased reliability is being implemented. The new Entry Control System incorporates several features not previously available in relatively inexpensive entry systems. The reliability of the system is enhanced by redundant microprocessors incorporating bubble memory for nonvolatile storage of the system data base. The badge readers incorporate dual communication lines to two different controllers to further increase the total system reliability

  2. Physical security workshop summary: entry control

    International Nuclear Information System (INIS)

    Eaton, M.J.

    1982-01-01

    Entry control hardware has been used extensively in the past to assist security forces in separating the authorized from the unauthorized at the plant perimeter. As more attention is being focused on the insider threat, these entry control elements are being used to extend the security inspectors' presence into the plant by compartmentalizing access and monitoring vital components. This paper summarizes the experiences expressed by the participants at the March 16 to 19, 1982 INMM Physical Protection Workshop in utilizing access control and contraband detection hardware for plant wide entry control applications

  3. Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review

    Science.gov (United States)

    2013-01-01

    Background Clinicians are encouraged to take an individualized approach when treating hypertension in patients of African ancestry, but little is known about why the individual patient may respond well to calcium blockers and diuretics, but generally has an attenuated response to drugs inhibiting the renin-angiotensin system and to β-adrenergic blockers. Therefore, we systematically reviewed the factors associated with the differential drug response of patients of African ancestry to antihypertensive drug therapy. Methods Using the methodology of the systematic reviews narrative synthesis approach, we sought for published or unpublished studies that could explain the differential clinical efficacy of antihypertensive drugs in patients of African ancestry. PUBMED, EMBASE, LILACS, African Index Medicus and the Food and Drug Administration and European Medicines Agency databases were searched without language restriction from their inception through June 2012. Results We retrieved 3,763 papers, and included 72 reports that mainly considered the 4 major classes of antihypertensive drugs, calcium blockers, diuretics, drugs that interfere with the renin-angiotensin system and β-adrenergic blockers. Pharmacokinetics, plasma renin and genetic polymorphisms did not well predict the response of patients of African ancestry to antihypertensive drugs. An emerging view that low nitric oxide and high creatine kinase may explain individual responses to antihypertensive drugs unites previous observations, but currently clinical data are very limited. Conclusion Available data are inconclusive regarding why patients of African ancestry display the typical response to antihypertensive drugs. In lieu of biochemical or pharmacogenomic parameters, self-defined African ancestry seems the best available predictor of individual responses to antihypertensive drugs. PMID:23721258

  4. DOGMAS AND UPDATES ON THE USE OF BETA-BLOCKERS IN SECONDARY PREVENTION. FIRST PART.

    Directory of Open Access Journals (Sweden)

    Alberto Morales Salinas

    2011-08-01

    Full Text Available There is consensus on clinical guidelines that beta-blockers (BB provide unquestionable benefits in several environments of secondary prevention, such as heart failure and myocardial infarction. However, in everyday practice they are underused in contexts where they are not contraindicated. Such is the case of heart failure with ejection fraction. This article presents an analysis on the available evidence of beta blockers’ effectiveness in heart failure with ejection fraction. It is concluded that overwhelming evidence favours the use of beta-blockers in chronic heart failure with ejection fraction, whereas in episodes of acute decompensated heart failure, their suspension should be avoided whenever it is possible.

  5. Relationship between heart failure, concurrent chronic obstructive pulmonary disease and beta-blocker use

    DEFF Research Database (Denmark)

    Sessa, Maurizio; Mascolo, Annamaria; Mortensen, Rikke Nørmark

    2018-01-01

    Aims: To compare the hazard of all-cause, chronic obstructive pulmonary disease (COPD) and heart failure (HF) hospitalization in carvedilol vs. metoprolol/bisoprolol/nebivolol users with COPD and concurrent HF from 2009 to 2012, and to evaluate the use and persistence in treatment of these β-blockers...... with COPD and concurrent HF. Additionally, we found a widespread phenomenon of carvedilol prescription at variance with the European Society of Cardiology guidelines and potential for improving the proportion of patients treated with β-blockers....

  6. Transport of beta-blockers and calcium antagonists by diffusion in cat myocardium

    DEFF Research Database (Denmark)

    Haunsø, Stig; Sejrsen, Per; Svendsen, Jesper Hastrup

    1991-01-01

    Beta-blockers and calcium antagonists have been claimed to possess cardioprotective properties. This study addresses the question of whether a significant amount of these drugs will reach the cardiac myocytes during no-flow ischemia, where solute transport depends solely on diffusion. In anesthet......Beta-blockers and calcium antagonists have been claimed to possess cardioprotective properties. This study addresses the question of whether a significant amount of these drugs will reach the cardiac myocytes during no-flow ischemia, where solute transport depends solely on diffusion...

  7. The value of β-blockers administration during recovery phase of dobutamine stress echocardiography: a review.

    Science.gov (United States)

    Nguyen, James; Juneman, Elizabeth; Movahed, Mohammad Reza

    2013-07-01

    Dobutamine stress echocardiography (DSE) is a successful technique for detection of ischemia in patients with suspected coronary artery disease (CAD). There are some data that administration of β-blocker after peak infusion of dobutamine can improve sensitivity. The goal of this manuscript is to review the current literature in regard to the mechanism and accuracy of post-dobutamine β-blocker administration for ischemia detection. In this review, we present 2 case reports followed by detailed review of the literature. © 2013. This article is a U.S. Government work and is in the public domain in the USA.

  8. Texting while driving: is speech-based text entry less risky than handheld text entry?

    Science.gov (United States)

    He, J; Chaparro, A; Nguyen, B; Burge, R J; Crandall, J; Chaparro, B; Ni, R; Cao, S

    2014-11-01

    Research indicates that using a cell phone to talk or text while maneuvering a vehicle impairs driving performance. However, few published studies directly compare the distracting effects of texting using a hands-free (i.e., speech-based interface) versus handheld cell phone, which is an important issue for legislation, automotive interface design and driving safety training. This study compared the effect of speech-based versus handheld text entries on simulated driving performance by asking participants to perform a car following task while controlling the duration of a secondary text-entry task. Results showed that both speech-based and handheld text entries impaired driving performance relative to the drive-only condition by causing more variation in speed and lane position. Handheld text entry also increased the brake response time and increased variation in headway distance. Text entry using a speech-based cell phone was less detrimental to driving performance than handheld text entry. Nevertheless, the speech-based text entry task still significantly impaired driving compared to the drive-only condition. These results suggest that speech-based text entry disrupts driving, but reduces the level of performance interference compared to text entry with a handheld device. In addition, the difference in the distraction effect caused by speech-based and handheld text entry is not simply due to the difference in task duration. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Entry Mode and Performance of Nordic Firms

    DEFF Research Database (Denmark)

    Wulff, Jesper

    2015-01-01

    including the proposed moderating effect, on average, yield higher post-entry performance. This study sheds light on inconsistent results found in previous research investigating the impact of international experience and has practical implications for managerial decision-making.......This study investigates whether the relationship between mode of international market entry and non-location bound international experience is weaker for firms that are large or have a high foreign to total sales ratio, labeled multinational experience. Empirical evidence based on 250 foreign...... market entries made by Norwegian, Danish and Swedish firms suggests that the association between equity mode choice and non-location bound international experience diminishes in the presence of higher levels of multinational experience. Furthermore, firms whose entry mode choice is predicted by the model...

  10. Border Crossing/Entry Data - Boarder Crossing

    Data.gov (United States)

    Department of Transportation — Border Crossing/Entry Data provides summary statistics for incoming crossings at the U.S.-Canadian and the U.S.-Mexican border at the port level. Data are available...

  11. Market entry strategies into the BRIC countries

    DEFF Research Database (Denmark)

    Boyd, Britta; Dyhr Ulrich, Anna Marie

    2014-01-01

    Based on a sample of 177 exporting SMEs, this study investigates what market entry strategy is used by Danish family and non-family businesses. From a resource-based view, three critical internal factors (risk, flexibility and control) affecting the entry mode choice into the BRIC markets...... are analysed. The effective management of firms’ resources and capabilities is influenced by the perception of these internal factors when expanding into foreign markets. Our results confirmed that family firms build up longer lasting relationships in the host country by choosing high commitment entry modes...... when entering the BRIC markets. In contrast, family firms choose high commitment entry modes which involve high risk and low flexibility when entering the BRIC markets. Further implications discuss the suitability of export strategies to BRIC markets for managers of Danish family and non-family firms....

  12. Energy Information Data Base: corporate author entries

    International Nuclear Information System (INIS)

    1980-03-01

    One of the controls for information entered into the data bases created and maintained by the DOE Technical Information Center is the standardized name for the corporate entity or the corporate author. The purpose of Energy Information Data Base: Corporate Author Entries (TID-4585-R1) and this supplemental list of authorized or standardized corporate entries is to provide a means for the consistent citing of the names of organizations in bibliographic records. In general, an entry in Corporate Author Entries consists of the seven-digit code number assigned to the particular corporate entity, the two-letter country code, the largest element of the corporate name, the location of the corporate entity, and the smallest element of the corporate name (if provided). This supplement [DOE/TIC-4585-R1(Suppl.5)] contains additions to the base document (TID-4585-R1) and is intended to be used with that publication

  13. Tactile Data Entry System, Phase II

    Data.gov (United States)

    National Aeronautics and Space Administration — Building on our successful Phase I Tactile Data Entry program, Barron Associates proposes development of a Glove-Enabled Computer Operations (GECO) system to permit...

  14. "Exclusive Dealing Contract and Inefficient Entry Threat"

    OpenAIRE

    Noriyuki Yanagawa; Ryoko Oki

    2008-01-01

    This paper examines the effects of exclusive dealing contracts in a simple model with manufacturers-distributors relations. We consider entrants in both manufacturing and distribution sectors. It is well-known that a potential entry threat is welfare increasing under homogenous price competition, even though the potential entrant is less productive. This paper reexamines this intuition by employing the above model. We show that the entry threat of a less-productive manufacturer is welfare dec...

  15. Entry and exit decisions under uncertainty

    DEFF Research Database (Denmark)

    Kongsted, Hans Christian

    1996-01-01

    This paper establishes the general deterministic limit that corresponds to Dixit's model of entry and exit decisions under uncertainty. The interlinked nature of decisions is shown to be essential also in the deterministic limit. A numerical example illustrates the result......This paper establishes the general deterministic limit that corresponds to Dixit's model of entry and exit decisions under uncertainty. The interlinked nature of decisions is shown to be essential also in the deterministic limit. A numerical example illustrates the result...

  16. Evaluation of risk of falls and orthostatic hypotension in older, long-term topical beta-blocker users

    NARCIS (Netherlands)

    Ramdas, Wishal D.; van der Velde, Nathalie; van der Cammen, Tischa J. M.; Wolfs, Roger C. W.

    2009-01-01

    Falls are a serious problem in the elderly, and have recently been described as cardiovascular-mediated side effects of beta-blocker eye drops. Therefore, we investigated the possible association between the long-term use of beta-blockers, prostaglandins and their combinations in eye drops, and

  17. Evaluation of risk of falls and orthostatic hypotension in older, long-term topical beta-blocker users

    NARCIS (Netherlands)

    W.D. Ramdas (Wishal); N. van der Velde (Nathalie); T.J.M. van der Cammen (Tischa); R.C.W. Wolfs (Roger)

    2009-01-01

    textabstractBackground: Falls are a serious problem in the elderly, and have recently been described as cardiovascular-mediated side effects of beta-blocker eye drops. Therefore, we investigated the possible association between the long-term use of beta-blockers, prostaglandins and their

  18. Beta-blocker use and fall risk in older individuals: Original results from two studies with meta-analysis

    NARCIS (Netherlands)

    Ham, Annelies C.; van Dijk, Suzanne C.; Swart, Karin M. A.; Enneman, Anke W.; van der Zwaluw, Nikita L.; Brouwer-Brolsma, Elske M.; van Schoor, Natasja M.; Carola Zillikens, M.; Lips, Paul; de Groot, Lisette C. P. G. M.; Hofman, Albert; Witkamp, Renger F.; Uitterlinden, André G.; Stricker, Bruno H.; van der Velde, Nathalie

    2017-01-01

    Aims To investigate the association between use of -blockers and beta-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Methods Data from two prospective studies were used, including community-dwelling

  19. Beta-1-Selective Beta-Blockers and Cognitive Functions in Patients With Coronary Artery Disease: A Cross-Sectional Study.

    Science.gov (United States)

    Burkauskas, Julius; Noreikaite, Aurelija; Bunevicius, Adomas; Brozaitiene, Julija; Neverauskas, Julius; Mickuviene, Narseta; Bunevicius, Robertas

    2016-01-01

    The association between current beta-1-selective beta-blocker use and cognitive function was evaluated in 722 patients with coronary artery disease without dementia. Beta-1-selective beta-blocker use was associated with worse incidental learning independently of sociodemographic characteristics, clinical coronary artery disease severity, and depression/anxiety.

  20. We are what we eat: An economic tool for tracing the origins of nutrients with entry points for action

    NARCIS (Netherlands)

    Rutten, M.M.; Tabeau, A.A.; Godeschalk, F.E.

    2014-01-01

    We develop a methodology for incorporating nutrition impacts in economy-wide analyses, providing entry points for where, when and how to act. It accounts for three channels of consumption, directly via primary commodities and indirectly via processed foods and food-related services, and produces

  1. Nipah virus entry can occur by macropinocytosis

    International Nuclear Information System (INIS)

    Pernet, Olivier; Pohl, Christine; Ainouze, Michelle; Kweder, Hasan; Buckland, Robin

    2009-01-01

    Nipah virus (NiV) is a zoonotic biosafety level 4 paramyxovirus that emerged recently in Asia with high mortality in man. NiV is a member, with Hendra virus (HeV), of the Henipavirus genus in the Paramyxoviridae family. Although NiV entry, like that of other paramyxoviruses, is believed to occur via pH-independent fusion with the host cell's plasma membrane we present evidence that entry can occur by an endocytic pathway. The NiV receptor ephrinB2 has receptor kinase activity and we find that ephrinB2's cytoplasmic domain is required for entry but is dispensable for post-entry viral spread. The mutation of a single tyrosine residue (Y304F) in ephrinB2's cytoplasmic tail abrogates NiV entry. Moreover, our results show that NiV entry is inhibited by constructions and drugs specific for the endocytic pathway of macropinocytosis. Our findings could potentially permit the rapid development of novel low-cost antiviral treatments not only for NiV but also HeV.

  2. Models of radon entry: A review

    International Nuclear Information System (INIS)

    Gadgil, A.J.

    1991-08-01

    This paper reviews existing models of radon entry into houses. The primary mechanism of radon entry in houses with high indoor concentrations is, in most cases, convective entry of radon bearing soil-gas from the surrounding soil. The driving force for this convective entry is the small indoor-outdoor pressure difference arising from the stack effect and other causes. Entry points for the soil-gas generally are the cracks or gaps in the building substructure, or though other parts of the building shell in direct contact with the soil, although entry may also occur by flow though permeable concrete or cinder block walls of the substructure. Models using analytical solutions to idealized geometrical configurations with simplified boundary conditions obtain analytical tractability of equations to be solved at the cost of severe approximations; their strength is in the insights they offer with their solutions. Models based on lumped parameters attempt to characterize the significant physical behavioral characteristics of the soil-gas and radon flow. When realistic approximations are desired for the boundary conditions and terms in the governing equations, numerical models must be used; these are usually based on finite difference or finite element solutions to the governing equations. Limited data are now available for experimental verification of model predictions. The models are briefly reviewed and their strengths and limitations are discussed

  3. (Patho)physiological implications of the novel epithelial Ca2+ channels TRPV5 and TRPV6.

    NARCIS (Netherlands)

    Nijenhuis, T.; Hoenderop, J.G.J.; Nilius, B.; Bindels, R.J.M.

    2003-01-01

    The epithelial Ca(2+) channels TRPV5 and TRPV6 constitute the apical Ca(2+) entry mechanism in active Ca(2+) (re)absorption. These two members of the superfamily of transient receptor potential (TRP) channels were cloned from the vitamin-D-responsive epithelia of kidney and small intestine and

  4. Effect of beta-blocker therapy on functional status in patients with heart failure--a meta-analysis

    DEFF Research Database (Denmark)

    Abdulla, Jawdat; Køber, Lars; Christensen, Erik

    2005-01-01

    BACKGROUND: The results of randomised control trials (RCTs) evaluating the effect of beta-blockers on functional status in patients with chronic heart failure are conflicting. AIM: To perform a systematic review and meta-analysis of RCTs evaluating the effect of beta-blockers on New York Heart...... Association (NYHA) classification and exercise tolerance in chronic heart failure. METHODS AND RESULTS: We selected 28 RCTs evaluating beta-blocker versus placebo in addition to ACE inhibitor therapy. Combined results of 23 RCTs showed that beta-blockers improved NYHA class by at least one class with odds...... ratio (OR) 1.80 (1.33-2.43) pbeta-blockers had no significant effect...

  5. Preadmission use of renin-angiotensin blockers and rupture of abdominal aortic aneurysm

    DEFF Research Database (Denmark)

    Wemmelund, Holger; Høgh, Annette; Hundborg, Heidi H.

    2016-01-01

    PURPOSE: Rupture of abdominal aortic aneurysms (rAAA) is associated with high mortality. Use of angiotensin converting enzyme inhibitors (ACE-inhibitors) and angiotensin receptor blockers (ARBs) has been suggested to reduce the risk of rAAA. This nationwide, combined case-control and follow-up st...

  6. Systemic delivery of β-blockers via transdermal route for hypertension

    Science.gov (United States)

    Ahad, Abdul; Al-Jenoobi, Fahad I.; Al-Mohizea, Abdullah M.; Akhtar, Naseem; Raish, Mohammad; Aqil, Mohd.

    2014-01-01

    Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later. PMID:26702253

  7. Conversion to Silodosin in Men on Conventional α1 -Blockers for Symptomatic Benign Prostatic Hyperplasia.

    Science.gov (United States)

    Tanaka, Masahiko; Niimi, Aya; Tomita, Kyoichi; Homma, Yukio

    2010-04-01

    α1 -blockers have commonly been used as first-line medical therapy for symptomatic benign prostatic hyperplasia (BPH). Recently, a highly selective α1A -adrenoceptor antagonist, silodosin, was developed in Japan. We examined the efficacy and safety of conversion from conventional α1 -blockers to silodosin in men with BPH. Conversion to silodosin was proposed to consecutive patients on conventional α1 -blockers for symptomatic BPH for at least 6 months. The effects of conversion were examined by the International Prostate Symptom Score, quality of life index, overactive bladder symptom score, peak flow rate, residual urine volume, and adverse events at 12 weeks. The efficacy of silodosin was also evaluated by patients' impression. Eighty-one men underwent conversion, for the most part because of dissatisfaction with the efficacy of their current treatment in improving nocturia or weak stream. The International Prostate Symptom Score total score significantly improved from 12.7 ± 5.9 at baseline to 10.6 ± 5.4 at 4 weeks (P silodosin. Efficacy as judged by patients' impression was 76% (37/49) at 12 weeks of treatment. None of the overactive bladder symptom score, peak flow rate, and residual urine volume exhibited significant change. No serious adverse events were observed during the study period. Conversion to silodosin may be beneficial in men who are dissatisfied with conventional α1 -blockers for BPH, and be particularly useful in improving voiding symptoms. © 2010 Blackwell Publishing Asia Pty Ltd.

  8. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers

    DEFF Research Database (Denmark)

    Lambers Heerspink, Hiddo J; Holtkamp, Frank A; Parving, Hans-Henrik

    2012-01-01

    Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of...

  9. Polymer membrane electrodes for sensitive potentiometric determination of beta-blockers.

    Science.gov (United States)

    Wassil, Anwar A; Farag, Abd El-Ftaah Bastawy; Moukdad, Fatma A

    2007-01-01

    The construction of PVC matrix-type beta-blockers (sotalol, carvedilol, and betaxolol) ion selective electrodes and their use for direct potentiometry of their respective species are described. The proposed sensors are based on the complex ion associates of beta-blockers with tungstophosphate (TP) and Ammonium Reineckate (Rein) ionophoris in poly vinyl chloride membrane (PVC) with Dioctylphthalate (DOP) plasticizer. The four electrodes (Beta-TP), (Sota-TP), (Carve-TP), and (Cave-Rein) show stable potential response with near Nernstian slope of 50.8, 33.7, 32.35, and 33 mv per decade, range of concentration 10-2-10-7 M beta-blockers. Selectivity coefficients data obtained for 11 different organic and inorganic ions are presented. The electrodes have fast response time (30 and 40 s) and were used over wide range of pH 4.5-8.5. Validation of the method according to the quality assurance standers shows suitability of proposed sensors for use in the quality control assessment of these drugs. The results obtained for the determination of beta-blockers with the proposed electrodes show average recoveries of 100.78% and a mean standard deviation of +/-1.2. The nominal are obtained. The data agree well with those obtained by standard methods.

  10. The use of guideline recommended beta-blocker therapy in primary prevention implantable cardioverter defibrillator patients

    DEFF Research Database (Denmark)

    Ruwald, Anne Christine; Gislason, Gunnar Hilmar; Vinther, Michael

    2017-01-01

    Aims: We aimed to examine the use of guideline recommended beta-blocker therapy prior to and after primary prevention implantable cardioverter defibrillator (ICD) implantation in a 'real-life' setting. Methods and results: From the Danish Pacemaker and ICD Registry we identified all 1st-time prim......Aims: We aimed to examine the use of guideline recommended beta-blocker therapy prior to and after primary prevention implantable cardioverter defibrillator (ICD) implantation in a 'real-life' setting. Methods and results: From the Danish Pacemaker and ICD Registry we identified all 1st......-time primary prevention ICD and cardiac resynchronization therapy defibrillator (CRT-D) implantations in Denmark from 2007-12 (n = 2935). Use of beta-blocker, type and dose was acquired through the Danish Prescription Registry. According to guideline recommendations, we defined target daily doses as ≥50 mg...... carvedilol and ≥200 mg metoprolol. Prior to implantation 2427 of 2935 (83%) patients received beta-blocker therapy, with 2166 patients (89%) having initiated treatment 3 months or more prior to implantation. The majority of patients was prescribed carvedilol (52%) or metoprolol (41%). Patients on carvedilol...

  11. Structural adaptation to ischemia in skeletal muscle: effects of blockers of the renin-angiotensin system

    NARCIS (Netherlands)

    Scheidegger, K. J.; Nelissen-Vrancken, M. H.; Leenders, P. J.; Daemen, M. J.; Smits, J. F.; Wood, J. M.

    1997-01-01

    To investigate the effects of long-term treatment with blockers of the renin-angiotensin system on capillarization and growth of fibers in ischemic hind-limb muscles and in muscles under normal growth conditions. Ischemia was induced by partial ligation of the left common iliac artery. Ischemia

  12. Trends in co-prescribing of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in Ireland.

    LENUS (Irish Health Repository)

    Wan Md Adnan, Wan A H

    2011-03-01

    (i) To examine the trends in co-prescribing of angiotensin converting enzyme inhibitor (ACEI) and angiotensin-II receptor blocker (ARB) therapy and (ii) to examine the influence of major clinical trials (CALM, COOPERATE, VALIANT and ONTARGET) on co-prescribing.

  13. Non-selective beta-blockers may reduce risk of hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Thiele, Maja; Albillos, Agustín; Abazi, Rozeta

    2015-01-01

    BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB...

  14. Remission of post-transplant focal segmental glomerulosclerosis with angiotensin receptor blockers

    Directory of Open Access Journals (Sweden)

    S B Bansal

    2017-01-01

    Full Text Available Recurrence of focal segmental glomerulosclerosis (FSGS is common after kidney transplantation. Plasmapheresis (PP is considered to be the most effective treatment; however, results are variable and relapse is common after stopping plasmapheresis. Here, we report an unusual case of recurrent FSGS, who achieved complete remission with angiotensin receptor blocker therapy.

  15. Beta-blockers do not impair the cardiovascular benefits of endurance training in hypertensives.

    Science.gov (United States)

    Westhoff, T H; Franke, N; Schmidt, S; Vallbracht-Israng, K; Zidek, W; Dimeo, F; van der Giet, M

    2007-06-01

    Aerobic physical exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension. Beta-blockade interacts with heart rate, sympathetic tone, maximal workload and local lactate production. In the present randomized-controlled study, we compared the cardiovascular effects of an endurance training programme in elderly hypertensives with or without beta-blockers and developed a first approach to determine a lactate-based training heart rate in presence of beta-blockade. Fifty-two patients (23 with beta-blocker, 29 without beta-blocker) > or =60 years with systolic 24-h ambulatory blood pressure (ABP) > or =140 mm Hg and/or antihypertensive treatment were randomly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme (lactate 2.0 mmol/l). In the exercise group, the training significantly decreased systolic and diastolic 24-h ABP, blood pressure on exertion (100 W) and increased endothelium-dependent vasodilation (flow-mediated vasodilation, FMD) and physical performance both in the presence and absence of beta-blockade (Pendurance training evokes comparable cardiovascular benefits in the presence and absence of beta-blockade including a marked improvement of endothelial function. In the present study, target training heart rate with beta-blockers is about 18% lower than without.

  16. Bed blockers: A study on the elderly patients in a teaching hospital in India

    Directory of Open Access Journals (Sweden)

    Praveen Kumar N

    2010-07-01

    Full Text Available A cross-sectional study of in-patients over the age of 60 years was conducted at district McGann Hospital, Shimoga on patients who were classified as bed blockers. Level of dependency and cognitive function of these patients were assessed using Barthel scale and Abbreviated mental test (AMT respectively. Median age of the study population was 67 years; majority of them were men. Most of them were admitted in the medical ward and the median time to be labeled as bed blocker was 32 days. These bed blockers were a weak group of patients with an average 3.1 pathology per case. Majority of them suffered from neurological disorders and cardiovascular disease. High level of dependence was noted with a mean Barthel score of 29.68 (Range 0 -100. Low levels of cognitive function was also noted among these patients with a mean AMT of 4.76 (Range 0 -10.These findings demonstrate that the bed blockers in McGann hospital suffer not only from genuine health problems but also have a high dependency level in activities of daily living which hamper their discharge to the community. Community based rehabilitation using an intersectoral approach may help at least the less dependent to return home.

  17. Pilot-Reported Beta-Blockers Identified by Forensic Toxicology Analysis of Postmortem Specimens.

    Science.gov (United States)

    Canfield, Dennis V; Dubowski, Kurt M; Whinnery, James M; Forster, Estrella M

    2018-01-01

    This study compared beta-blockers reported by pilots with the medications found by postmortem toxicology analysis of specimens received from fatal aviation accidents between 1999 and 2015. Several studies have compared drugs using the standard approach: Compare the drug found by toxicology analysis with the drug reported by the pilot. This study uniquely examined first the pilot-reported medication and then compared it to that detected by toxicology analysis. This study will serve two purposes: (i) to determine the capability of a toxicology laboratory to detect reported medications, and (ii) to identify pilots with medications below detectable limits. All information required for this study was extracted from the Toxicology Data Base system and was searched using ToxFlo or SQL Server Management Studio. The following information was collected and analyzed: pilot-reported trade and/or generic drug, date specimens received, time of accident, type of aviation operations (CFR), state, pilot level, age, class of medical, specimen type, specimen concentration, dose reported, frequency reported associated with the accident, quantity reported, National Transportation Safety Board (NTSB) accident event number, and all NTSB reports. There were 319 pilots that either reported taking a beta-blocker or were found to be taking a beta-blocker by postmortem toxicology analysis. Time of death, therapeutic concentration and specimen type were found to be factors in the ability of the laboratory to detect beta-blockers. Beta-blockers taken by pilots will, in most cases, be found by a competent postmortem forensic toxicology laboratory at therapeutic concentrations. The dose taken by the pilot was not found to be a factor in the ability of the laboratory to identify beta-blockers. Time of dose, route of administration, specimen tested and therapeutic concentration of the drug were found to be factors in the ability of the laboratory to identify beta-blockers in postmortem specimens

  18. CFD analyses of coolant channel flowfields

    Science.gov (United States)

    Yagley, Jennifer A.; Feng, Jinzhang; Merkle, Charles L.

    1993-01-01

    The flowfield characteristics in rocket engine coolant channels are analyzed by means of a numerical model. The channels are characterized by large length to diameter ratios, high Reynolds numbers, and asymmetrical heating. At representative flow conditions, the channel length is approximately twice the hydraulic entrance length so that fully developed conditions would be reached for a constant property fluid. For the supercritical hydrogen that is used as the coolant, the strong property variations create significant secondary flows in the cross-plane which have a major influence on the flow and the resulting heat transfer. Comparison of constant and variable property solutions show substantial differences. In addition, the property variations prevent fully developed flow. The density variation accelerates the fluid in the channels increasing the pressure drop without an accompanying increase in heat flux. Analyses of the inlet configuration suggest that side entry from a manifold can affect the development of the velocity profile because of vortices generated as the flow enters the channel. Current work is focused on studying the effects of channel bifurcation on the flow field and the heat transfer characteristics.

  19. The broad-spectrum cation channel blocker pinokalant (LOE 908 MS) reduces brain infarct volume in rats

    DEFF Research Database (Denmark)

    Christensen, Thomas; Wienrich, Marion; Ensinger, Helmut A

    2005-01-01

    this period and the spontaneous temperature after course in control rats established in other experiments was imitated. Seven days later histological brain sections were prepared and the infarct volumes measured. Body temperature did not differ between the groups. Mean arterial blood pressure was slightly...... higher in the pinokalant group. Pinokalant treatment significantly reduced cortical infarct volume from 33.8+/-15.8 mm3 to 24.5+/-13.1 mm3 (control group versus pinokalant group, P=0.017, t-test). Taking the effective drug plasma concentration established in other experiments into account revealed...... and electrophysiologic status of the ischemic penumbra and to reduce lesion size on magnetic resonance images in the acute phase following middle cerebral artery occlusion in rats. The purpose of the present study was to investigate whether these beneficial effects of pinokalant are translated into permanent...

  20. Effect of sodium channel blocker, pilsicainide hydrochloride, on net inward current of atrial myocytes in thyroid hormone toxicosis rats.

    Science.gov (United States)

    Yamakawa, Munesada; Sunagawa, Masanori; Shimabukuro, Michio; Higa, Namio; Takasu, Nobuyuki; Kosugi, Tadayoshi

    2005-07-01

    To investigate effect of pilsicainide hydrochloride (pilsicainide) on electrocardiogram (ECG) signals and action potentials (APs) of atrial myocytes, levo-thyroxine (T4, 500 microg/kg body weight) was daily injected into peritoneal cavity of Sprague-Dawley rats for 14 days. T4-treatment significantly shortened RR interval, P wave, and QRS complex durations on ECG. Although pilsicainide did not affect the heart rate, P wave and corrected QT interval (QTc) was increased in T4-treated rats. AP recordings revealed that AP durations at 20%, 50%, and 90% repolarization were significantly shortened and maximal rate of rise (Max dV/dt) was significantly increased in T4-treated rat atrial cells. Pilsicainide significantly decreased AP amplitude (APA) and Max dV/dt in both control and T4-treated rat atrial cells. Concentration-inhibition study demonstrated that pilsicainide significantly inhibited net inward current of T4-treated rats at lower concentration (IC50 of 29.2 microg/mL) than that of control rats (133 microg/mL). In conclusion, pilsicainide could decrease the conduction velocity in T4-treated rat atrium by decreasing the Max dV/dt and net inward current, which could be a possible treatment of thyrotoxicosis-induced arrhythmia.

  1. Preoperative depression symptom severity and its impact on adherence to preoperative beta-blocker therapy.

    Science.gov (United States)

    Schonberger, Robert B; Feinleib, Jessica; Holt, Natalie; Dai, Feng; Brandt, Cynthia; Burg, Matthew M

    2014-12-01

    To test the association among depression symptoms, distressed personality type, and preoperative beta-blocker nonadherence and to estimate the prevalence of untreated major depression in this population. Prospective observational study. A veterans hospital. One hundred twenty patients on outpatient beta-blocker therapy presenting for surgery. The Patient Health Questionnaire (PHQ)-9, the D-Scale-14 (DS14), and Modified Morisky Scale (MMS) questionnaires. Of 99 participants who presented for surgery, the incidence of preoperative nonadherence was 14.1% (95% confidence interval 7%-21%), consistent with prior research. Nonadherence was 9.5% among those with no depression, 27.8% among those with mild depression, and 28.6% among those with moderate-to-severe depression (Cochran-Armitage test for trend p = 0.03). Distressed personality type was found in 35% of the cohort (95% confidence interval 26-45%) and was not associated with beta-blocker nonadherence (Fisher's exact test, p = 0.24). Among participants with symptoms of major depressive disorder (n = 25, 25.3%), more than half (n = 14, 56%) had no indication of depression listed at their most recent primary care visit. Patients with symptoms of depression on chronic beta-blocker therapy are susceptible to medication nonadherence on the day of surgery. Most surgical patients with symptoms of major depression lack a diagnosis of depression. Preoperative depression screening may thus (1) identify a population at increased risk of beta-blocker withdrawal, and (2) identify patients who may benefit from anesthesiologist-initiated referral for this treatable condition. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Medical student satisfaction, coping and burnout in direct-entry versus graduate-entry programmes.

    Science.gov (United States)

    DeWitt, Dawn; Canny, Benedict J; Nitzberg, Michael; Choudri, Jennifer; Porter, Sarah

    2016-06-01

    There is ongoing debate regarding the optimal length of medical training, with concern about the cost of prolonged training. Two simultaneous tracks currently exist in Australia: direct entry from high school and graduate entry for students with a bachelor degree. Medical schools are switching to graduate entry based on maturity, academic preparedness and career-choice surety. We tested the assumption that graduate entry is better by exploring student preferences, coping, burnout, empathy and alcohol use. From a potential pool of 2188 participants, enrolled at five Australian medical schools, a convenience sample of 688 (31%) first and second year students completed a survey in the middle of the academic year. Participants answered questions about demographics, satisfaction and coping and completed three validated instruments. Over 90% of students preferred their own entry-type, though more graduate-entry students were satisfied with their programme (82.4% versus 65.3%, p students in self-reported coping or in the proportion of students meeting criteria for burnout (50.7% versus 51.2%). Direct-entry students rated significantly higher for empathy (concern, p = 0.022; personal distress, p = 0.031). Graduate-entry students reported significantly more alcohol use and hazardous drinking (30.0% versus 22.8%; p = 0.017). Our multi-institution data confirm that students are generally satisfied with their choice of entry pathway and do not confirm significant psychosocial benefits of graduate entry. Overall, our data suggest that direct-entry students cope with the workload and psychosocial challenges of medical school, in the first 2 years, as well as graduate-entry students. Burnout and alcohol use should be addressed in both pathways. Despite studies showing similar academic outcomes, and higher total costs, more programmes in Australia are becoming graduate entry. Further research on non-cognitive issues and outcomes is needed so that universities, government

  3. Does Erythropoietin Regulate TRPC Channels in Red Blood Cells?

    Directory of Open Access Journals (Sweden)

    Jens Danielczok

    2017-03-01

    Full Text Available Background: Cation channels play an essential role in red blood cells (RBCs ion homeostasis. One set of ion channels are the transient receptor potential channels of canonical type (TRPC channels. The abundance of these channels in primary erythroblasts, erythroid cell lines and RBCs was associated with an increase in intracellular Ca2+ upon stimulation with Erythropoietin (Epo. In contrast two independent studies on Epo-treated patients revealed diminished basal Ca2+ concentration or reduced phosphatidylserine exposure to the outer membrane leaflet. Methods: To resolve the seemingly conflicting reports we challenged mature human and mouse RBCs of several genotypes with Epo and Prostaglandin E2 (PGE2 and recorded the intracellular Ca2+ content. Next Generation Sequencing was utilised to approach a molecular analysis of reticulocytes. Results/Conclusions: Our results allow concluding that Epo and PGE2 regulation of the Ca2+ homeostasis is distinctly different between murine and human RBCs and that changes in intracellular Ca2+ upon Epo treatment is a primary rather than a compensatory effect. In human RBCs, Epo itself has no effect on Ca2+ fluxes but inhibits the PGE2-induced Ca2+ entry. In murine mature RBCs functional evidence indicates TRPC4/C5 mediated Ca2+ entry activated by Epo whereas PGE2 leads to a TRPC independent Ca2+ entry.

  4. Venom-derived peptides inhibiting Kir channels: Past, present, and future.

    Science.gov (United States)

    Doupnik, Craig A

    2017-12-01

    Inwardly rectifying K + (Kir) channels play a significant role in vertebrate and invertebrate biology by regulating the movement of K + ions involved in membrane transport and excitability. Yet unlike other ion channels including their ancestral K + -selective homologs, there are very few venom toxins known to target and inhibit Kir channels with the potency and selectivity found for the Ca 2+ -activated and voltage-gated K + channel families. It is unclear whether this is simply due to a lack of discovery, or instead a consequence of the evolutionary processes that drive the development of venom components towards their targets based on a collective efficacy to 1) elicit pain for defensive purposes, 2) promote paralysis for prey capture, or 3) facilitate delivery of venom components into the circulation. The past two decades of venom screening has yielded three venom peptides with inhibitory activity towards mammalian Kir channels, including the discovery of tertiapin, a high-affinity pore blocker from the venom of the European honey bee Apis mellifera. Venomics and structure-based computational approaches represent exciting new frontiers for venom peptide development, where re-engineering peptide 'scaffolds' such as tertiapin may aid in the quest to expand the palette of potent and selective Kir channel blockers for future research and potentially new therapeutics. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Effects of Voltage-Gated K+ Channel on Cell Proliferation in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Wei Wang

    2014-01-01

    Full Text Available Objective. To study the effects and underlying mechanisms of voltage-gated K+ channels on the proliferation of multiple myeloma cells. Methods. RPMI-8226 MM cell line was used for the experiments. Voltage-gated K+ currents and the resting potential were recorded by whole-cell patch-clamp technique. RT-PCR detected Kv channel mRNA expression. Cell viability was analyzed with MTT assay. Cell counting system was employed to monitor cell proliferation. DNA contents and cell volume were analyzed by flow cytometry. Results. Currents recorded in RPMI-8226 cells were confirmed to be voltage-gated K+ channels. A high level of Kv1.3 mRNA was detected but no Kv3.1 mRNA was detected in RPMI-8226 cells. Voltage-gated K+ channel blocker 4-aminopyridine (4-AP (2 mM depolarized the resting potential from −42 ± 1.7 mV to −31.8 ± 2.8 mV (P0.05. Conclusions. In RPMI-8226, voltage-gated K+ channels are involved in proliferation and cell cycle progression its influence on the resting potential and cell volume may be responsible for this process; the inhibitory effect of the voltage-gated K+ channel blocker on RPMI-8226 cell proliferation is a phase-specific event.

  6. Delayed rectifier potassium channels are involved in SO2 derivative-induced hippocampal neuronal injury.

    Science.gov (United States)

    Li, Guangke; Sang, Nan

    2009-01-01

    Recent studies implicate the possible neurotoxicity of SO(2), however, its mechanisms remain unclear. In the present study, we investigated SO(2) derivative-induced effect on delayed rectifier potassium channels (I(K)) and cellular death/apoptosis in primary cultured hippocampal neurons. The results demonstrate that SO(2) derivatives (NaHSO(3) and Na(2)SO(3), 3:1M/M) effectively augmented I(K) and promoted the activation of delayed rectifier potassium channels. Also, SO(2) derivatives increased neuronal death percentage and contributed to the formation of DNA ladder in concentration-dependent manners. Interestingly, the neuronal death and DNA ladder formation, caused by SO(2) derivatives, could be attenuated by the delayed rectifier potassium channel blocker (tetraethylammonium, TEA), but not by the transient outward potassium channel blocker (4-aminopyridine, 4-AP). It implies that stimulating delayed rectifier potassium channels were involved in SO(2) derivative-caused hippocampal neuronal insults, and blocking these channels might be one of the possibly clinical treatment for SO(2)-caused neuronal dysfunction.

  7. Beta-blocker therapy is not associated with symptoms of depression and anxiety in patients receiving an implantable cardioverter-defibrillator

    DEFF Research Database (Denmark)

    Hoogwegt, Madelein T; Kupper, Nina; Theuns, Dominic A M J

    2012-01-01

    Beta-blockers are frequently prescribed to implantable cardioverter-defibrillator (ICD) patients. Beta-blocker therapy has been proposed to induce emotional distress such as depression and anxiety, but a paucity of studies has examined the relationship between beta-blockers and distress. We...... investigated the association between beta-blocker therapy, including type and dosage, and symptoms of anxiety and depression in a consecutive cohort of patients receiving an ICD....

  8. Adrenaline reveals the torsadogenic effect of combined blockade of potassium channels in anaesthetized guinea pigs.

    Science.gov (United States)

    Michael, G; Kane, K A; Coker, S J

    2008-08-01

    Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.

  9. David J. Triggle: Medicinal chemistry, to pharmacology, calcium channels, and beyond.

    Science.gov (United States)

    Walker, Michael J A

    2015-11-15

    David Triggle's scientific career began as a chemist, went through medicinal chemistry into pharmacology, and finally on to somewhat more philosophical interests in later years. It was a career marked by many contributions to all of those aspects of science. Chief amongst his many contributions, in addition to those in medicinal chemistry, was his work on the drugs known as calcium ion channel blockers or (calcium antagonists). In the calcium ion channel field he was a particularly instrumental figure in sorting out the mechanisms, actions and roles of the class of calcium channel blockers, known chemical and pharmacologically as the dihydropyridines (DHPs) in particular, as well as other calcium blockers of diverse structures. During the course of a long career, and extensive journeys into medicinal chemistry and pharmacology, he published voluminously in terms of papers, reviews, conference proceedings and books. Notably, many of his papers often had limited authorship where, as senior author it reflected his deep involvement in all aspects of the reported work. His work always helped clarify the field while his incisive reviews, together with his role in coordinating and running scientific meetings, were a great help in clarifying and organizing various fields of study. He has had a long and illustrious career, and is wellknown in the world of biomedical science; his contributions are appreciated, and well recognized everywhere. The following article attempts to chart a path through his work and contributions to medicinal chemistry, pharmacology, science, academia and students. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Localization and pharmacological characterization of voltage dependent calcium channels in cultured neocortical neurons

    DEFF Research Database (Denmark)

    Timmermann, D B; Lund, Trine Meldgaard; Belhage, B

    2001-01-01

    The physiological significance and subcellular distribution of voltage dependent calcium channels was defined using calcium channel blockers to inhibit potassium induced rises in cytosolic calcium concentration in cultured mouse neocortical neurons. The cytosolic calcium concentration was measured...... channels were differentially distributed in somata, neurites and nerve terminals. omega-conotoxin MVIIC (omega-CgTx MVIIC) inhibited approximately 40% of the Ca(2+)-rise in both somata and neurites and 60% of the potassium induced [3H]GABA release, indicating that the Q-type channel is the quantitatively...... most important voltage dependent calcium channel in all parts of the neuron. After treatment with thapsigargin the increase in cytosolic calcium was halved, indicating that calcium release from thapsigargin sensitive intracellular calcium stores is an important component of the potassium induced rise...

  11. Beta-blocker use and fall risk in older individuals: Original results from two studies with meta-analysis.

    Science.gov (United States)

    Ham, Annelies C; van Dijk, Suzanne C; Swart, Karin M A; Enneman, Anke W; van der Zwaluw, Nikita L; Brouwer-Brolsma, Elske M; van Schoor, Natasja M; Zillikens, M Carola; Lips, Paul; de Groot, Lisette C P G M; Hofman, Albert; Witkamp, Renger F; Uitterlinden, André G; Stricker, Bruno H; van der Velde, Nathalie

    2017-10-01

    To investigate the association between use of β-blockers and β-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Data from two prospective studies were used, including community-dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B-PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time-varying β-blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β-blocker use, their characteristics - selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism - and fall risk. The results of the studies were combined using meta-analyses. In total 2917 participants encountered a fall during a total follow-up time of 89 529 years. Meta-analysis indicated no association between use of any β-blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 [95% confidence interval (CI) 0.88-1.06]. Use of a selective β-blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83-1.01). Use of a nonselective β-blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01-1.48). Other β-blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk. Our study suggests that use of a nonselective β-blocker, contrary to selective β-blockers, is associated with an increased fall risk in an older population. In clinical practice, β-blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β-blocker in this age group, and the pros and cons for β-blocker classes should be taken into consideration. © 2017 The British Pharmacological Society.

  12. 19 CFR 151.41 - Information on entry summary.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 2 2010-04-01 2010-04-01 false Information on entry summary. 151.41 Section 151... Products § 151.41 Information on entry summary. On the entry summary for petroleum or petroleum products in.... If the exact volumetric quantity cannot be determined in advance, the entry summary may be made for...

  13. Entry control system for large populations

    International Nuclear Information System (INIS)

    Merillat, P.D.

    1982-01-01

    An Entry Control System has been developed which is appropriate for use at an installation with a large population requiring access over a large area. This is accomplished by centralizing the data base management and enrollment functions and decentralizing the guard-assisted, positive personnel identification and access functions. Current information pertaining to all enrollees is maintained through user-friendly enrollment stations. These stations may be used to enroll individuals, alter their area access authorizations, change expiration dates, and other similar functions. An audit trail of data base alterations is provided to the System Manager. Decentrailized systems exist at each area to which access is controlled. The central system provides these systems with the necessary entry control information to allow them to operate microprocessor-driven entry control devices. The system is comprised of commercially available entry control components and is structured such that it will be able to incorporate improved devices as technology porogresses. Currently, access is granted to individuals who possess a valid credential, have current access authorization, can supply a memorized personal identification number, and whose physical hand dimensions match their profile obtained during enrollment. The entry control devices report misuses as security violations to a Guard Alarm Display and Assessment System

  14. Financial Performance of Entry Mode Decisions

    DEFF Research Database (Denmark)

    Boyd, Britta; Dyhr Ulrich, Anna Marie; Hollensen, Svend

    2012-01-01

    Based on a survey of 170 Danish SMEs the paper examines influences on entry mode choices and the financial outcome of these decisions. The main research objectives are divided into two steps: Step 1: To determine the factors influencing the choice of foreign entry modes by Danish companies. Step ...... and implications are provided for companies willing to invest more into foreign markets in order to achieve a higher degree of control and better financial results.......Based on a survey of 170 Danish SMEs the paper examines influences on entry mode choices and the financial outcome of these decisions. The main research objectives are divided into two steps: Step 1: To determine the factors influencing the choice of foreign entry modes by Danish companies. Step 2......: To determine the relationship between the choice of entry mode and export performance, measured in terms of financial outcome. Drawing from transaction cost theory the authors develop and test a model where different factors affect the level of control chosen by the parent company. This study contributes...

  15. Beta-blocker therapy is not associated with symptoms of depression and anxiety in patients receiving an implantable cardioverter-defibrillator

    NARCIS (Netherlands)

    M.T. Hoogwegt (Madelein); N. Kupper (Nina); D.A.M.J. Theuns (Dominic); L.J.L.M. Jordaens (Luc); S.S. Pedersen (Susanne)

    2012-01-01

    textabstractBeta-blockers are frequently prescribed to implantable cardioverter-defibrillator (ICD) patients. Beta-blocker therapy has been proposed to induce emotional distress such as depression and anxiety, but a paucity of studies has examined the relationship between beta-blockers and distress.

  16. Atmospheric Entry Studies for Venus Missions: 45 Sphere-Cone Rigid Aeroshells and Ballistic Entries

    Science.gov (United States)

    Prabhu, Dinesh K.; Spilker, Thomas R.; Allen, Gary A., Jr.; Hwang, Helen H.; Cappuccio, Gelsomina; Moses, Robert W.

    2013-01-01

    The present study considers direct ballistic entries into the atmosphere of Venus using a 45deg sphere-cone rigid aeroshell, a legacy shape that has been used successfully in the past in the Pioneer Venus Multiprobe Mission. For a number of entry mass and heatshield diameter combinations (i.e., various ballistic coefficients) and entry velocities, the trajectory space in terms of entry flight path angles between skip out and -30deg is explored with a 3DoF trajectory code, TRAJ. From these trajectories, the viable entry flight path angle space is determined through the use of mechanical and thermal performance limits on the thermal protection material and science payload; the thermal protection material of choice is entry-grade carbon phenolic, for which a material thermal response model is available. For mechanical performance, a 200 g limit is placed on the peak deceleration load experienced by the science instruments, and 10 bar is assumed as the pressure limit for entry-grade carbon-phenolic material. For thermal performance, inflection points in the total heat load distribution are used as cut off criteria. Analysis of the results shows the existence of a range of critical ballistic coefficients beyond which the steepest possible entries are determined by the pressure limit of the material rather than the deceleration load limit.

  17. HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

    International Nuclear Information System (INIS)

    András, Ibolya E.; Toborek, Michal

    2014-01-01

    Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ

  18. HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

    Energy Technology Data Exchange (ETDEWEB)

    András, Ibolya E., E-mail: iandras@med.miami; Toborek, Michal, E-mail: mtoborek@med.miami.edu

    2014-04-15

    Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ.

  19. Beta-blockers for prevention and treatment of retinopathy of prematurity in preterm infants.

    Science.gov (United States)

    Kaempfen, Siree; Neumann, Roland P; Jost, Kerstin; Schulzke, Sven M

    2018-03-02

    Retinopathy of prematurity (ROP) is a vision-threatening disease of preterm neonates. The use of beta-adrenergic blocking agents (beta-blockers), which modulate the vasoproliferative retinal process, may reduce the progression of ROP or even reverse established ROP. To determine the effect of beta-blockers on short-term structural outcomes, long-term functional outcomes, and the need for additional treatment, when used either as prophylaxis in preterm infants without ROP, stage 1 ROP (zone I), or stage 2 ROP (zone II) without plus disease or as treatment in preterm infants with at least prethreshold ROP. We searched the Cochrane Neonatal Review Group Specialized Register; CENTRAL (in the Cochrane Library Issue 7, 2017); Embase (January 1974 to 7 August 2017); PubMed (January 1966 to 7 August 2017); and CINAHL (January 1982 to 7 August 2017). We checked references and cross-references and handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings. We considered for inclusion randomised or quasi-randomised clinical trials that used beta-blockers for prevention or treatment of ROP in preterm neonates of less than 37 weeks' gestational age. We used the standard methods of Cochrane and the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. We included three randomised trials (N = 366) in this review. Two of these studies were at high risk of bias. All studies reported on prevention of ROP and compared oral propranolol with placebo or no treatment. We found no trials assessing beta-blockers in infants with established stage 2 or higher ROP with plus disease.In one trial, study medication was started after one week of life, i.e. prior to the first ROP screening. The other two trials included preterm infants if they had stage 2 or lower ROP without plus disease. Based on the GRADE assessment, we considered evidence to be of low quality for the following outcomes: rescue treatment with anti-VEGF or

  20. Modeling the Effects of β1-Adrenergic Receptor Blockers and Polymorphisms on Cardiac Myocyte Ca2+ Handling

    Science.gov (United States)

    Amanfu, Robert K.

    2014-01-01

    β-Adrenergic receptor blockers (β-blockers) are commonly used to treat heart failure, but the biologic mechanisms governing their efficacy are still poorly understood. The complexity of β-adrenergic signaling coupled with the influence of receptor polymorphisms makes it difficult to intuit the effect of β-blockers on cardiac physiology. While some studies indicate that β-blockers are efficacious by inhibiting β-adrenergic signaling, other studies suggest that they work by maintaining β-adrenergic responsiveness. Here, we use a systems pharmacology approach to test the hypothesis that in ventricular myocytes, these two apparently conflicting mechanisms for β-blocker efficacy can occur concurrently. We extended a computational model of the β1-adrenergic pathway and excitation-contraction coupling to include detailed receptor interactions for 19 ligands. Model predictions, validated with Ca2+ and Förster resonance energy transfer imaging of adult rat ventricular myocytes, surprisingly suggest that β-blockers can both inhibit and maintain signaling depending on the magnitude of receptor stimulation. The balance of inhibition and maintenance of β1-adrenergic signaling is predicted to depend on the specific β-blocker (with greater responsiveness for metoprolol than carvedilol) and β1-adrenergic receptor Arg389Gly polymorphisms. PMID:24867460

  1. Prevalence and prognostic significance of adrenergic escape during chronic beta-blocker therapy in chronic heart failure.

    Science.gov (United States)

    Frankenstein, Lutz; Zugck, Christian; Schellberg, Dieter; Nelles, Manfred; Froehlich, Hanna; Katus, Hugo; Remppis, Andrew

    2009-02-01

    Like aldosterone escape to ACE-inhibitors, adrenergic escape (AE) to beta-blockers appears conceivable in chronic heart failure (CHF), as generalized systemic neurohumoral activation has been described as the pathophysiological basis of this syndrome. The aim of this study was to examine the prevalence and prognostic value of AE with respect to different beta-blocker agents and doses. This was a prospective, observational study of 415 patients with systolic CHF receiving chronic stable beta-blocker therapy. AE was defined by norepinephrine levels above the upper limit of normal. Irrespective of the individual beta-blocker agents used and the dose equivalent taken, the prevalence of AE was 31-39%. Norepinephrine levels neither correlated with heart rate (r=0.02; 95% CI: -0.08-0.11; P=0.74) nor were they related to underlying rhythm (P=0.09) or the individual beta-blocker agent used (P=0.87). The presence of AE was a strong and independent indicator of mortality (adjusted HR: 1.915; 95% CI: 1.387-2.645; chi2: 15.60). We verified the presence of AE in CHF patients on chronic stable beta-blocker therapy, irrespective of the individual beta-blocker agent and the dose equivalent. As AE might indicate therapeutic failure, the determination of AE could help to identify those patients with CHF that might benefit from more aggressive treatment modalities. Heart rate, however, is not a surrogate for adrenergic escape.

  2. Citizens and service channels: channel choice and channel management implications

    NARCIS (Netherlands)

    Pieterson, Willem Jan

    2010-01-01

    The arrival of electronic channels in the 1990s has had a huge impact on governmental service delivery. The new channels have led to many new opportunities to improve public service delivery, not only in terms of citizen satisfaction, but also in cost reduction for governmental agencies. However,

  3. Modes and orders of market entry

    DEFF Research Database (Denmark)

    Ulhøi, John Parm

    2012-01-01

    (first-mover or follower). Invention is understood as the conversion of human creativity, time and financial resources into new ideas. Innovation in turn reflects the practical and financial return on such investments. While there is little disagreement about what an innovator strategy is, imitative......This paper focuses on the initial questions of how and when to enter a market from the perspective of a firm. By entry mode is meant a firm’s strategy (innovation or imitation) for entering the market in response to environmental changes. Entry order refers to the related issue of market timing...... strategies are more ambiguous. Based on a corporate technology and innovation strategy perspective, the paper reconceptualises and extends existing modes and orders of market entry, and in particular clarifies the ambiguity associated with imitative strategies. Four distinct imitator strategies...

  4. ATP-modulated K+ channels sensitive to antidiabetic sulfonylureas are present in adenohypophysis and are involved in growth hormone release.

    OpenAIRE

    Bernardi, H; De Weille, J R; Epelbaum, J; Mourre, C; Amoroso, S; Slama, A; Fosset, M; Lazdunski, M

    1993-01-01

    The adenohypophysis contains high-affinity binding sites for antidiabetic sulfonylureas that are specific blockers of ATP-sensitive K+ channels. The binding protein has a M(r) of 145,000 +/- 5000. The presence of ATP-sensitive K+ channels (26 pS) has been demonstrated by electrophysiological techniques. Intracellular perfusion of adenohypophysis cells with an ATP-free medium to activate ATP-sensitive K+ channels induces a large hyperpolarization (approximately 30 mV) that is antagonized by an...

  5. Surfen is a broad-spectrum calcium channel inhibitor with analgesic properties in mouse models of acute and chronic inflammatory pain

    Czech Academy of Sciences Publication Activity Database

    Rivas-Ramirez, Paula; Gadotti, V. M.; Zamponi, G. W.; Weiss, Norbert

    2017-01-01

    Roč. 469, č. 10 (2017), s. 1325-1334 ISSN 0031-6768 R&D Projects: GA ČR GA15-13556S; GA MŠk 7AMB15FR015 Institutional support: RVO:61388963 Keywords : calcium channel * pain * inflammatory pain * calcium channel blocker * surfen * DRG neuron Subject RIV: ED - Physiology OBOR OECD: Physiology (including cytology) Impact factor: 3.156, year: 2016

  6. Involvement of plasma membrane Ca2+ channels, IP3 receptors, and ryanodine receptors in the generation of spontaneous rhythmic contractions of the cricket lateral oviduct.

    Science.gov (United States)

    Tamashiro, Hirotake; Yoshino, Masami

    2014-12-01

    In the present study, the isolated cricket (Gryllus bimaculatus) lateral oviduct exhibited spontaneous rhythmic contractions (SRCs) with a frequency of 0.29±0.009 Hz (n=43) and an amplitude of 14.6±1.25 mg (n=29). SRCs completely disappeared following removal of extracellular Ca2+ using a solution containing 5mM EGTA. Application of the non-specific Ca2+ channel blockers Co2+, Ni2+, and Cd2+ also decreased both the frequency and amplitude of SRCs in dose-dependent manners, suggesting that Ca2+ entry through plasma membrane Ca2+ channels is essential for the generation of SRCs. Application of ryanodine (30 μM), which depletes intracellular Ca2+ by locking ryanodine receptor (RyR)-Ca2+ channels in an open state, gradually reduced the frequency and amplitude of SRCs. A RyR antagonist, tetracaine, reduced both the frequency and amplitude of SRCs, whereas a RyR activator, caffeine, increased the frequency of SRCs with a subsequent increase in basal tonus, indicating that RyRs are essential for generating SRCs. To further investigate the involvement of phospholipase C (PLC) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in SRCs, we examined the effect of a PLC inhibitor, U73122, and an IP3R antagonist, 2-aminoethoxydiphenyl borate (2-APB), on SRCs. Separately, U73122 (10 μM) and 2-APB (30-50 μM) both significantly reduced the amplitude of SRCs with little effect on their frequency, further indicating that the PLC/IP3R signaling pathway is fundamental to the modulation of the amplitude of SRCs. A hypotonic-induced increase in the frequency and amplitude of SRCs and a hypertonic-induced decrease in the frequency and amplitude of SRCs indicated that mechanical stretch of the lateral oviduct is involved in the generation of SRCs. The sarcoplasmic reticulum Ca2+-pump ATPase inhibitors thapsigargin and cyclopiazonic acid impaired or suppressed the relaxation phase of SRCs. Taken together, the present results indicate that Ca2+ influx through plasma membrane Ca2

  7. Stanniocalcin 2 Regulates Non-capacitative Ca2+ Entry and Aggregation in Mouse Platelets

    Directory of Open Access Journals (Sweden)

    Esther López

    2018-03-01

    Full Text Available Stanniocalcin 2 (STC2 is a fish protein that controls body Ca2+ and phosphate metabolism. STC2 has also been described in mammals, and as platelet function highly depends on both extracellular and intracellular Ca2+, we have explored its expression and function in these cells. STC2−/− mice exhibit shorter tail bleeding time than WT mice. Platelets from STC2-deficient mice showed enhanced aggregation, as well as enhanced Ca2+ mobilization in response to the physiological agonist thrombin (Thr and the diacylglycerol analog, OAG, a selective activator of the non-capacitative Ca2+ entry channels. Interestingly, platelets from STC2−/− mice exhibit attenuated interaction between STIM1 and Orai1 in response to Thr, thus suggesting that STC2 is required for Thr-evoked STIM1-Orai1 interaction and the subsequent store-operated Ca2+ entry (SOCE. We have further assessed possible changes in the expression of the most relevant channels involved in non-capacitative Ca2+ entry in platelets. Then, protein expression of Orai3, TRPC3 and TRPC6 were evaluated by Western blotting, and the results revealed that while the expression of Orai3 was enhanced in the STC2-deficient mice, others like TRPC3 and TRPC6 remains almost unaltered. Summarizing, our results provide for the first time evidence for a role of STC2 in platelet physiology through the regulation of agonist-induced Ca2+ entry, which might be mediated by the regulation of Orai3 channel expression.

  8. Comparison the Efficacy of Four Different Alpha Blockers in the Treatment of Benign Prostatic Hyperplasia

    Directory of Open Access Journals (Sweden)

    Fatih Fırat

    2011-05-01

    Full Text Available Aim: Benign prostatic hyperplasia (BPH also known as nodular hyperplasia, benign enlargement of the prostate refers to the increase in size of the prostate in middle aged and elderly men. Although four different types of specific alpha blocker have been used in the treatment of BPH it remains controversial that which alpha adrenergic blocker is effective than others. The aim of this study is to compare the efficacy of 4 different alpha blockers agents on the treatment of BPH. Material and Methods: Between June 2005 and December 2008 a total of 135 consecutive patients with diagnosed of BPH were evaluated in our clinic. Patients were randomized into four groups according to alpha blocker types as fallows: group I, doxazosin 4 mg; group II, tamsulosin 0.4 mg; group III, terazosin 5 mg; and group IV, alfuzosin 10 mg. All patients were followed up with International Prostatic Symptom Score (IPSS, maximal urinary flow rates (Qmax and adverse effects were determined at baseline and again at least 3 months as efficacy parameters. Results: The mean age of the patients were 59.8±5.4 years, 58.9±6.4 years, 58.7±5.1 years, and 59.2±5.5 years in group I, group II, group III, and group IV, respectively (p>0.05. After 3 months treatment with alpha blockers the improvements in IPSS were found as 2.73, 3.73, 3.55 and 4.44 in group I, group II, group III, and group IV, respectively. Maximum urine flow rates increased as 2.81 ml/sec, 3.24 ml/sec, 3.88 ml/sec and 4.49 ml/sec in group I, group II, group III, and group IV, respectively. However, among 4 alpha blockers statistically significant difference was found only between doxazosin and alfuzosin groups according to uroflowmetry and IPSS results. According to these results, when compared adverse effect, the significant difference was observed only in tamsulosine group. Conclusions: As a result we can say that except retrograde ejaculation in tamsulosine group, adverse effects are not different between the

  9. Role of TRP channels in the cardiovascular system.

    Science.gov (United States)

    Yue, Zhichao; Xie, Jia; Yu, Albert S; Stock, Jonathan; Du, Jianyang; Yue, Lixia

    2015-02-01

    The transient receptor potential (TRP) superfamily consists of a large number of nonselective cation channels with variable degree of Ca(2+)-permeability. The 28 mammalian TRP channel proteins can be grouped into six subfamilies: canonical, vanilloid, melastatin, ankyrin, polycystic, and mucolipin TRPs. The majority of these TRP channels are expressed in different cell types including both excitable and nonexcitable cells of the cardiovascular system. Unlike voltage-gated ion channels, TRP channels do not have a typical voltage sensor, but instead can sense a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, lipid environment alterations, hypertrophic signals, and inflammation products. By integrating multiple stimuli and transducing their activity to downstream cellular signal pathways via Ca(2+) entry and/or membrane depolarization, TRP channels play an essential role in regulating fundamental cell functions such as contraction, relaxation, proliferation, differentiation, and cell death. With the use of targeted deletion and transgenic mouse models, recent studies have revealed that TRP channels are involved in numerous cellular functions and play an important role in the pathophysiology of many diseases in the cardiovascular system. Moreover, several TRP channels are involved in inherited diseases of the cardiovascular system. This review presents an overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases. Ultimately, TRP channels may become potential therapeutic targets for cardiovascular diseases. Copyright © 2015 the American Physiological Society.

  10. Form, its meaning, and dictionary entries

    Directory of Open Access Journals (Sweden)

    Violetta Koseska-Toszewa

    2015-11-01

    It is worth stressing that distinguishing between the form and its meaning in comparing the material 6 languages belonging to three different groups of Slavic languages (as is the case in the MONDILEX Project will allow us to avoid numeorus substantiva mistakes and erroneous conclusions. Hence dictionary entries should be verified and made uniform in that respect before they are “digitalized”... Distinction between the form and its meaning in a dictionary entry is fully possible, as shown by works of Z. Saloni (2002 and A.Przepiórkowski (2008.

  11. Automated Re-Entry System using FNPEG

    Science.gov (United States)

    Johnson, Wyatt R.; Lu, Ping; Stachowiak, Susan J.

    2017-01-01

    This paper discusses the implementation and simulated performance of the FNPEG (Fully Numerical Predictor-corrector Entry Guidance) algorithm into GNC FSW (Guidance, Navigation, and Control Flight Software) for use in an autonomous re-entry vehicle. A few modifications to FNPEG are discussed that result in computational savings -- a change to the state propagator, and a modification to cross-range lateral logic. Finally, some Monte Carlo results are presented using a representative vehicle in both a high-fidelity 6-DOF (degree-of-freedom) sim as well as in a 3-DOF sim for independent validation.

  12. Predicting the effects on patients with dilated cardiomyopathy of {beta}-blocker therapy, by using iodine-123 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) myocardial scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Yoshinaga, Keiichiro; Tahara, Minoru; Torii, Hiroyuki [Kagoshima City Medical Association Hospital (Japan); Kihara, Koichi

    1998-12-01

    We examined whether the iodine-123 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) myocardial scintigraphy was useful for predicting the treatment response to {beta}-blocker in patients with dilated cardiomyopathy (DCM). Sixteen patients with DCM were studied. BMIPP single photon emission computed tomography (SPECT) was performed before {beta}-blocker therapy. The count ratio of the heart (H) to the upper mediastinum (M) (H/M ratio) was calculated. Several measurements including the BMIPP H/M ratio before the administration of metoprorol were retrospectively compared among the 10 ``good responders`` (showing improvement by at least one NYHA class or an increase in the ejection fraction of {>=}0.10, 6 months after the start of the drug therapy) and the 6 ``poor responders.`` The bull`s eye map of BMIPP was divided into 17 areas. Each segmental score was analyzed quantitatively by means of a two-point scoring system (good uptake {>=}67%, poor uptake <67%). The total score was regarded as the uptake score. The H/M ratio was significantly higher in the good responders than in the poor responders (2.41{+-}0.24 vs. 1.86{+-}0.17 p<0.01). There were no significant differences between the two groups in any other variable data at entry. The uptake score was also a good index for predicting the therapeutic effect. When a relative uptake of 67% or higher was scored as 1, uptake scores of 9 to 17 corresponded to good responses (sensitivity=100%, specificity=100%, accuracy=100%, positive and negative predictive value=100%). Although the number of patients studied is small, our results suggest that BMIPP myocardial scintigraphy can predict the response to a {beta}-blocker in patients with DCM. (author)

  13. Ca2+ influx insensitive to organic Ca2+ entry blockers contributes to noradrenaline-induced contractions of the isolated guinea pig aorta

    NARCIS (Netherlands)

    Gouw, M. A.; Wilffert, B.; Wermelskirchen, D.; van Zwieten, P. A.

    1990-01-01

    We determined the contribution of intracellular Ca2+ to the noradrenaline (NA, 3 X 10(-5) mmol/l)-induced contraction of the isolated guinea pig aorta. Since only about 55% of the NA-induced contraction could be attributed to intracellular Ca2+ release, we assumed that a Ca2+ influx component

  14. Ca2+influx insensitive to organic Ca2+entry blockers contributes to noradrenaline-induced contractions of the isolated guinea pig aorta

    NARCIS (Netherlands)

    Gouw, M.A.M.; Wilffert, B.; Wermelskirchen, D.; Van Zwieten, P.A.

    1990-01-01

    We determined the contribution of intracellular Ca2+to the noradrenaline (NA, 3 x 10-5mmol/l)-induced contraction of the isolated guinea pig aorta. Since only about 55% of the NA-induced contraction could be attributed to intracellular Ca2+release, we assumed that a Ca2+influx component contributes

  15. ACTION OF CHEMICALLY DIFFERENT PROSTAGLANDIN BLOCKERS ON THE ADRENAL HORMONES IN PIGEONS DURING STRESS.

    Science.gov (United States)

    Sarkar, S; Ghosh, S; Sengupta, S; Dasadhikari, S; Ghosh, A

    1999-01-01

    The effect of prostaglandin (PG) inhibitors differing in their chemical nature, viz. Aspirin (acetylsalicylic acid), Mefenamic acid (fenamates), Diclofenac (phenylacetic acid derivative) and Piroxicam (oxicam derivative) on the adrenal hormones was studied in acutely stressed pigeons. None of these PG blockers exerted any significant effect on the catecholamine and corticosterone content of the control, i.e. unstressed pigeon adrenal gland excepting mefenamic acid which caused a release of epinephrine. Aspirin, diclofenac and piroxicam did not modulate the catecholamine or corticosterone secretion whereas mefenamic acid caused a released of both epinephrine and norepinephrine and increased the adrenal corticosterone content in the acutely stressed pigeons. These results were compared with those obtained from studies on the effects of other chemically different PG blockers, indomethacin (a methylated indole derivative) and ibuprofen (a propionic acid derivative). It is suggested that chemically and structurally different PG inhibitors show diverse action in the same species under similar stress conditions.

  16. Early initiation of beta blockers following primary endoscopic therapy for bleeding esophageal varices in cirrhotics

    International Nuclear Information System (INIS)

    Salim, A.; Malik, K.; Farooq, M.O.; Butt, U.; Butt, A.K.

    2017-01-01

    Beta-blockers provide secondary prophylaxis following endoscopic therapy for variceal bleeding. Guidelines recommend starting beta-blockers 6 days after endoscopy to prevent masking hemodynamic signs of rebleeding. We aimed to see safety of earlier initiation of beta-blockers. Methods: Cirrhotic patients with upper GI bleed were given I.V vasoactive agents until undergoing endoscopy. Patients with only esophageal varices as source of bleed were recruited. Vasoactive agents were discontinued following variceal banding. The patients were observed for 12-18 hours, discharged on oral carvedilol 6.25 mg BID and monitored for 6 weeks for rebleeding and mortality. Results: 50 patients were included, 27 (54%) male and 23 (46%) female. Average age was 43+3 years. Etiology of cirrhosis was HCV in 42 (84%), HBV in 6 (12%), HCV and HBV in 2 (4%) and indeterminate in 1 (2%) patient. 17 (34%) patients had Child A, 22 (44%) Child B and 11 (22%) had Child C disease. Hospital stay was under 24 hours in 24 (48%), 24-48 hours in 15 (30%) and 48-72 hours in 11 (22%) patients. 5 (10%) patients underwent EGD within 6 hours of admission, 28 (56%) within 12 hours, 14 (28%) within 24 hours and 3 (6%) within 36 hours. No rebleeding, mortality or drug related adverse effects were noted during 6 weeks after discharge. Conclusions:Our study proves possibility of shorter management of variceal bleeding by having a 12-18 hour monitoring after endoscopic banding, followed by beta-blocker initiation and discharge. This will safely reduce physical and financial burden on health services. Background: Beta-blockers provide secondary prophylaxis following endoscopic therapy for variceal bleeding. Guidelines recommend starting beta-blockers 6 days after endoscopy to prevent masking hemodynamic signs of re-bleeding. We aimed to see safety of earlier initiation of beta-blockers. Methods: Cirrhotic patients with upper GI bleed were given intravenous vasoactive agents until undergoing endoscopy. Patients

  17. The role of nitrates, beta blockers, and calcium antagonists in stable angina pectoris.

    Science.gov (United States)

    Chan, P K; Heo, J Y; Garibian, G; Askenase, A; Segal, B L; Iskandrian, A S

    1988-09-01

    Numerous controlled studies have shown that nitrates, beta blockers, and calcium antagonists are effective in the treatment of stable angina pectoris. The pharmacokinetics, pharmacodynamics, and hemodynamic effects of these agents are different, and thus combination therapy offers additive improvement and also counterbalancing of the undesirable side effects of each drug. The choice of therapy depends on the severity of symptoms, associated diseases, compliance, side effects, and status of left ventricular function. The main mechanism of improvement is a decrease in myocardial oxygen consumption, though an increase in coronary blood flow is another potential reason for the use of calcium blockers. This review considers the properties of these drugs, their mechanism of action, and the results of randomized studies.

  18. Alpha 1-blockers vs 5 alpha-reductase inhibitors in benign prostatic hyperplasia. A comparative review

    DEFF Research Database (Denmark)

    Andersen, J T

    1995-01-01

    During recent years, pharmacological treatment of symptomatic benign prostatic hyperplasia (BPH) has become the primary treatment choice for an increasing number of patients. The 2 principal drug classes employed are alpha 1-blockers and 5 alpha-reductase inhibitors. Current information from...... of patients who will respond well to alpha 1-blockers have yet to be identified, and data concerning the long term effects of these drugs are not yet available. 5 alpha-Reductase inhibitors have a slow onset of effect, but treatment leads to improvement in symptoms, reduction of the size of the prostate gland...... and improvement in objective parameters for bladder outflow obstruction. Approximately 30 to 50% of patients will respond to treatment with 5 alpha-reductase inhibitors. The definitive role of pharmacological treatment in symptomatic BPH remains to be established, although it seems that patients unfit...

  19. Potassium channels as drugs targets in therapy of cardiovascular diseases: 25 years later

    Directory of Open Access Journals (Sweden)

    Protić Dragana

    2013-03-01

    Full Text Available Potassium channels are the most variable ion channel group. They participate in numerous cardiovascular functions, for example regulation of vascular tone, maintenance of resting cardiac membrane potential and excitability of cardiac conduction tissue. Both drugs and endogenous ligands could modulate potassium channel function, belonging to the potassium channel blockers or openers. Modulation of potassium channels could be a therapeutic or adverse drug action. Class III antiarrhythmic agents block the potassium channels, thereby prolonging repolarization phase of action potential with resulting prolongation of effective refractory period. Their effectiveness against supraventricular and ventricular arrhythmias should be weighted against their proarrhythmogenic potential. In addition, numerous other antiarrhythmic agents could modulate potassium channels as well. Diazoxide, minoxidil and nicorandil (well known arterial vasodilators, as well as numerous newly synthesized substances with still unknown therapeutic potential, belong to the potassium channel activators/openers. Therapeutic use of such vasodilators may involve treatment of hypertension (diazoxide, minoxidil and stable angina (nicorandil. Their use might be accompanied with side effects, such as vasodilation, edema, hypotension and reflex tachycardia. Potassium channel openers have also an important role in the treatment of peripheral vascular disease and pulmonary hypertension. In the future, drugs with selective effects on the vascular or cardiac potassium channels could be useful therapeutic agents.

  20. POTASSIUM CHANNELS AS DRUGS TARGETS IN THERAPY OF CARDIOVASCULAR DESEASES: 25 YEARS LATER

    Directory of Open Access Journals (Sweden)

    Protić Dragana

    2013-01-01

    Full Text Available Potassium channels are the most variable ion channel group. They participate in numerous cardiovascular functions, for example regulation of vascular tone, maintenance of resting cardiac membrane potential and excitability of cardiac conduction tissue. Both drugs and endogenous ligands could modulate potassium channel function, belonging to the potassium channel blockers or openers. Modulation of potassium channels could be a therapeutic or adverse drug action. Class III antiarrhythmic agents block the potassium channels, thereby prolonging repolarization phase of action potential with resulting prolongation of effective refractory period. Their effectiveness against supraventricular and ventricular arrhythmias should be weighted against their proarrhythmogenic potential. In addition, numerous other antiarrhythmic agents could modulate potassium channels as well. Diazoxide, minoxidil and nicorandil (well known arterial vasodilators, as well as numerous newly synthesized substances with still unknown therapeutic potential, belong to the potassium channel activators/ openers. Therapeutic use of such vasodilators may involve treatment of hypertension (diazoxide, minoxidil and stable angina (nicorandil. Their use might be accompanied with side effects, such as vasodilation, edema, hypotension and reflex tachycardia. Potassium channel openers have also an important role in the treatment of peripheral vascular disease and pulmonary hypertension. In the future, drugs with selective effects on the vascular or cardiac potassium channels could be useful therapeutic agents.

  1. Foreign entry, cultural barriers and learning

    NARCIS (Netherlands)

    H.G. Barkema (Harry); J.H.J. Bell (John); J.M.E. Pennings

    1996-01-01

    textabstractThis paper examines the longevity of foreign entries. Hypotheses are developed on the mode (start-ups vs. acquisitions) and ownership structure (wholly owned vs. joint ventures) in relation to cultural distance. The hypotheses are tested within a framework of organizational learning,

  2. Entry modes of European firms in Vietnam

    Directory of Open Access Journals (Sweden)

    Daniel Simonet

    2012-09-01

    Full Text Available Purpose: The purpose of the paper is to explore the entry modes of EU firms setting up operations in Vietnam. Design/methodology/approach: we use a case study approach on Haymarket, Cadbury, Creative Education, Fairchild, Aventis and Artemisinin and Farming International using interviews from managerial professionals in Vietnam. Findings: Despite the fact that Vietnam has been opening up for more than 20 years, licensing is the preferred entry mode because of the risks involved in venturing with local firms; that preference signals a low level commitment and a high perception of risk and state interference. In line with Vietnam transition to state - rather than private market - capitalism, a foreign company opting for a joint-venture will do so with a state-owned rather than privately-owned company. The choice of a subsidiary can be explained by the lack of trust in partners and institutions, not by improvement in the socio-political environment. Limitations: In determining the entry mode strategy, the paper focuses on the Uppsala school’s “psychic distance” (e.g. cultural distance, lack of trust rather than on firm-specific advantages (Rugman, 1980; 2006. Key-words: international entry mode; emerging markets; subsidiary; joint-venture; India; Vietnam

  3. Correlation Between Entry Requirements and Academic ...

    African Journals Online (AJOL)

    In this study, the investigator examines the correlation between entry requirements and academic performance of undergraduate students at the University of Buea. The quality of performance on the Cameroon General Certificate Examination at the Advanced Level is the predictor while the criterion is the cumulative grade ...

  4. Flavivirus cell entry and membrane fusion

    NARCIS (Netherlands)

    Smit, Jolanda M.; Moesker, Bastiaan; Rodenhuis-Zybert, Izabela; Wilschut, Jan

    2011-01-01

    Flaviviruses, such as dengue virus and West Nile virus, are enveloped viruses that infect cells through receptor-mediated endocytosis and fusion from within acidic endosomes. The cell entry process of flaviviruses is mediated by the viral E glycoprotein. This short review will address recent

  5. Women's Entry into Teaching: Myths and Realities.

    Science.gov (United States)

    Russell, Dorothy S.

    1979-01-01

    The author reviews the entry of women into the teaching profession in nineteenth-century America, noting that, while the primary motivation for encouraging women to teach was that they could be paid less than men, this economic justification was obscured by sentimental pronouncements about women's superior moral and nurturant power. (SJL)

  6. Perceptions regarding strategic and structural entry barriers

    NARCIS (Netherlands)

    Lutz, C.H.M.; Kemp, R.G.M.; Dijkstra, S.G.

    2010-01-01

    This article uses factor analysis to identify the underlying dimensions of strategic and structural entry barriers. We find that, in the perception of firms, both types of barriers are important and that the effectiveness of strategic barriers depends on attributes of the market structure. Based on

  7. Perceptions regarding strategic and structural entry barriers

    NARCIS (Netherlands)

    Lutz, Clemens H. M.; Kemp, Ron G. M.; Dijkstra, S. Gerhard

    This article uses factor analysis to identify the underlying dimensions of strategic and structural entry barriers. We find that, in the perception of firms, both types of barriers are important and that the effectiveness of strategic barriers depends on attributes of the market structure. Based on

  8. Infectious Entry Pathway of Enterovirus B Species

    Directory of Open Access Journals (Sweden)

    Varpu Marjomäki

    2015-12-01

    Full Text Available Enterovirus B species (EV-B are responsible for a vast number of mild and serious acute infections. They are also suspected of remaining in the body, where they cause persistent infections contributing to chronic diseases such as type I diabetes. Recent studies of the infectious entry pathway of these viruses revealed remarkable similarities, including non-clathrin entry of large endosomes originating from the plasma membrane invaginations. Many cellular factors regulating the efficient entry have recently been associated with macropinocytic uptake, such as Rac1, serine/threonine p21-activated kinase (Pak1, actin, Na/H exchanger, phospholipace C (PLC and protein kinase Cα (PKCα. Another characteristic feature is the entry of these viruses to neutral endosomes, independence of endosomal acidification and low association with acidic lysosomes. The biogenesis of neutral multivesicular bodies is crucial for their infection, at least for echovirus 1 (E1 and coxsackievirus A9 (CVA9. These pathways are triggered by the virus binding to their receptors on the plasma membrane, and they are not efficiently recycled like other cellular pathways used by circulating receptors. Therefore, the best “markers” of these pathways may be the viruses and often their receptors. A deeper understanding of this pathway and associated endosomes is crucial in elucidating the mechanisms of enterovirus uncoating and genome release from the endosomes to start efficient replication.

  9. Energy Information Data Base: corporate author entries

    International Nuclear Information System (INIS)

    1978-06-01

    The DOE Energy Information Data Base has been created and is maintained by the DOE Technical Information Center. One of the controls for information entered into the base is the standardized name of the corporate entity or the corporate author. The purpose of this list of authorized or standardized corporate entries is to provide a means for the consistent citing of the names of organizations in bibliographic records. It also serves as a guide for users who retrieve information from a bibliographic data base and who want to locate information originating in particular organizations. This authority is a combination of entries established by the Technical Information Center and the International Atomic Energy Agency's International Nuclear Information System (INIS). The format calls, in general, for the name of the organization represented by the literature being cataloged to be cited as follows: the largest element, the place, the smallest element, e.g., Brigham Young Univ., Provo, Utah (USA), Dept. of Chemical Engineering. Code numbers are assigned to each entry to provide manipulation by computer. Cross references are used to reflect name changes and invalid entries

  10. Radiation Database for Earth and Mars Entry

    Science.gov (United States)

    2008-11-17

    state which mainly determines its polarizability . ∆r2 = r2u− r2l is the difference between Radiation Database for Earth and Mars Entry RTO-EN-AVT...NO A← X (0,0) band in the presence of argon and nitrogen. Journal of Quantitative Spectroscopy and Radiative Transfer, 47:375–390, 1992. Radiation

  11. 76 FR 15841 - Entry of Merchandise

    Science.gov (United States)

    2011-03-22

    ... DEPARTMENT OF HOMELAND SECURITY Bureau of Customs and Border Protection DEPARTMENT OF THE TREASURY 19 CFR Part 141 Entry of Merchandise CFR Correction In Title 19 of the Code of Federal Regulations, Parts 141 to 199, revised as of April 1, 2010, on page 6, the second general authority citation for part...

  12. Anthropologists and Broadcasting: Roles and Entry Strategies

    Science.gov (United States)

    Eiselein, E. B.; Topper, Martin

    1976-01-01

    The article describes some of the roles open to anthropologists in radio and television. Entry strategies for occupying these roles include taking the first step in approaching the broadcast station, learning about broadcasting, and communicating anthropology to the broadcasters. (Author/NQ)

  13. Ramelteon combined with an ?1-blocker decreases nocturia in men with benign prostatic hyperplasia

    OpenAIRE

    Kawahara, Takashi; Morita, Satoshi; Ito, Hiroki; Terao, Hideyuki; Sakata, Ryoko; Ishiguro, Hitoshi; Tanaka, Katsuyuki; Miyamoto, Hiroshi; Matsuzaki, Junichi; Kubota, Yoshinobu; Uemura, Hiroji

    2013-01-01

    Background Nocturia is defined as waking one or more times during the night due to the urge to void. Recently, the effectiveness of several sedatives and analgesics for nocturia has been reported. We herein investigated the effects of ramelteon, an antioxidant and sleep inducer, on nocturia unresponsive to ?1-blocker monotherapy in males with lower urinary tract symptoms (LUTS) as a pilot study. Methods Subjects were 19 patients who had LUTS suggestive of benign prostate hyperplasia, received...

  14. Ramelteon combined with an α1-blocker decreases nocturia in men with benign prostatic hyperplasia.

    Science.gov (United States)

    Kawahara, Takashi; Morita, Satoshi; Ito, Hiroki; Terao, Hideyuki; Sakata, Ryoko; Ishiguro, Hitoshi; Tanaka, Katsuyuki; Miyamoto, Hiroshi; Matsuzaki, Junichi; Kubota, Yoshinobu; Uemura, Hiroji

    2013-06-12

    Nocturia is defined as waking one or more times during the night due to the urge to void. Recently, the effectiveness of several sedatives and analgesics for nocturia has been reported. We herein investigated the effects of ramelteon, an antioxidant and sleep inducer, on nocturia unresponsive to α1-blocker monotherapy in males with lower urinary tract symptoms (LUTS) as a pilot study. Subjects were 19 patients who had LUTS suggestive of benign prostate hyperplasia, received α1-blockers (tamsulosin, silodosin, or naftopidil), and continued to have two or more episodes of nocturia per night before starting ramelteon. Ramelteon at 8 mg once daily for one month was added to the α1-blocker. A self-administered questionnaire including the International Prostate Symptom Score (IPSS), quality of life (QoL) index, Overactive Bladder Symptom Score (OABSS), and Nocturia Quality-of-Life Questionnaire (N-QOL) were assessed before and one month after starting ramelteon. The mean score on IPSS question 7 (nocturia) decreased significantly from 2.88 before starting ramelteon to 2.41 one month after starting the medication (P = 0.03). The mean total OABSS decreased significantly from 6.31 to 5.38 (P = 0.03), and the mean for OABSS question 2 (nighttime frequency of nocturia) also significantly decreased from 2.63 to 2.13 (P = 0.01). The mean total N-QOL score did not change significantly. Two patients had dizziness; the remaining patients had no adverse drug-related events. Ramelteon in combination with an α1-blocker could be a treatment option for reducing nocturia in men with BPH.

  15. Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

    Science.gov (United States)

    Thiele, Maja; Wiest, Reiner; Gluud, Lise Lotte; Albillos, Agustín; Krag, Aleksander

    2013-11-01

    Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of β-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of β-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The meta-analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. 47 CFR 90.713 - Entry criteria.

    Science.gov (United States)

    2010-10-01

    ... MOBILE RADIO SERVICES Regulations Governing Licensing and Use of Frequencies in the 220-222 MHz Band § 90... channels in the emergency medical category may not have any interest in another pending application in the same geographic area for channels in the emergency medical category. [62 FR 15994, Apr. 3, 1997, as...

  17. β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon.

    Science.gov (United States)

    Richards, John R; Hollander, Judd E; Ramoska, Edward A; Fareed, Fareed N; Sand, I Charles; Izquierdo Gómez, María Manuela; Lange, Richard A

    2017-05-01

    Cocaine abuse remains a significant worldwide health problem. Patients with cardiovascular toxicity from cocaine abuse frequently present to the emergency department for treatment. These patients may be tachycardic, hypertensive, agitated, and have chest pain. Several pharmacological options exist for treatment of cocaine-induced cardiovascular toxicity. For the past 3 decades, the phenomenon of unopposed α-stimulation after β-blocker use in cocaine-positive patients has been cited as an absolute contraindication, despite limited and inconsistent clinical evidence. In this review, the authors of the original studies, case reports, and systematic review in which unopposed α-stimulation was believed to be a factor investigate the pathophysiology, pharmacology, and published evidence behind the unopposed α-stimulation phenomenon. We also investigate other potential explanations for unopposed α-stimulation, including the unique and deleterious pharmacologic properties of cocaine in the absence of β-blockers. The safety and efficacy of the mixed β-/α-blockers labetalol and carvedilol are also discussed in relation to unopposed α-stimulation.

  18. The challenge of analyzing beta-blocker drugs in sludge and wastewater.

    Science.gov (United States)

    Scheurer, Marco; Ramil, Maria; Metcalfe, Chris D; Groh, Stefanie; Ternes, Thomas A

    2010-01-01

    In this study, different approaches were used to assess and overcome the severe effects of interference from the sample matrix from different types of sludges and wastewater on the analysis of nine beta-blockers and the beta sympathomimetic clenbuterol. The partitioning of the target compounds into sludge was investigated in wastewater treatment plants (WWTPs) in both Canada and Germany to evaluate whether this is an important mechanism for removal from sewage. Due to ion suppression in the electro spray interface, absolute recoveries were for certain compounds even lower than 20%. By using surrogate standards, acceptable relative recoveries of >75% were achieved for WWTP influents and effluents and for sludges. These matrix effects underline the need to use appropriate surrogate standards to aid in analyte quantitation. Using the developed methods, beta-blockers were detected at concentrations up to 2 microg/L in WWTP effluents, with metoprolol, sotalol, and atenolol present as the dominant compounds. Removal rates within WWTPs were highly inconsistent and ranged from 1-69%. Propranolol showed the greatest degree of partitioning into sludge with solid/water partition coefficients of one order of magnitude higher than those for all other compounds. However, even for propranolol, sorption did not contribute significantly to the overall elimination in WWTPs. It is likely that the removal of beta-blockers during waste water treatment can be attributed primarily to microbial biodegradation.

  19. Recent developments in HPLC analysis of β-blockers in biological samples.

    Science.gov (United States)

    Saleem, Kishwar; Ali, Imran; Kulsum, Umma; Aboul-Enein, Hassan Y

    2013-09-01

    β-Adrenergic blockers represent a very important class of drugs that are used worldwide for treating various cardiac diseases. The present article describes the state-of-the art of analyses of β-adrenergic blockers using high-performance liquid chromatography (HPLC). Sample preparation techniques such as liquid-liquid extraction, solid-phase extraction and solid-phase microextraction have been discussed, which are essential prior to HPLC analysis. Additionally, applications of liquid chromatography coupled with tandem mass spectrometry are included. HPLC methods have been reported to include 0.6-26 min as the run times and 0.01 ng/mL to 25 µg/mL as detection limits. The most commonly used columns were C18 with various buffers as the mobile phases, along with various organic modifiers. The optimization of HPLC conditions has been discussed. It has been observed that the reported methods are quite satisfactory for the analyses of β-adrenergic blockers in biological samples. Future perspectives in the hyphenation of solid-phase microextraction-nano-liquid chromatography-tandem mass spectrometry have also been highlighted to achieve detections at nanogram and picogram levels. The present article is very useful for academicians, scientists, drug and pharmaceutical personnel and government regulatory authorities.

  20. Shaker-related voltage-gated K+ channel expression and vasomotor function in human coronary resistance arteries.

    Science.gov (United States)

    Nishijima, Yoshinori; Korishettar, Ankush; Chabowski, Dawid S; Cao, Sheng; Zheng, Xiaodong; Gutterman, David D; Zhang, David X

    2018-01-01

    K V channels are important regulators of vascular tone, but the identity of specific K V channels involved and their regulation in disease remain less well understood. We determined the expression of K V 1 channel subunits and their role in cAMP-mediated dilation in coronary resistance arteries from subjects with and without CAD. HCAs from patients with and without CAD were assessed for mRNA and protein expression of K V 1 channel subunits with molecular techniques and for vasodilator response with isolated arterial myography. Assays of mRNA transcripts, membrane protein expression, and vascular cell-specific localization revealed abundant expression of K V 1.5 in vascular smooth muscle cells of non-CAD HCAs. Isoproterenol and forskolin, two distinct cAMP-mediated vasodilators, induced potent dilation of non-CAD arterioles, which was inhibited by both the general K V blocker 4-AP and the selective K V 1.5 blocker DPO-1. The cAMP-mediated dilation was reduced in CAD and was accompanied by a loss of or reduced contribution of 4-AP-sensitive K V channels. K V 1.5, as a major 4-AP-sensitive K V 1 channel expressed in coronary VSMCs, mediates cAMP-mediated dilation in non-CAD arterioles. The cAMP-mediated dilation is reduced in CAD coronary arterioles, which is associated with impaired 4-AP-sensitive K V channel function. © 2017 John Wiley & Sons Ltd.

  1. Mortality and Reinfarction among Patients Using Different Beta-Blockers for Secondary Prevention after a Myocardial Infarction

    DEFF Research Database (Denmark)

    Andersen, Søren Skøtt; Hansen, Morten Lock; Gislason, Gunnar H

    2009-01-01

    Objectives: To study differences in the clinical efficacy of various brands of beta-blocker in secondary prevention after a myocardial infarction (MI). Methods: All patients hospitalized with a first MI between 1995 and 2002 who were still alive 30 days after discharge and had had at least one...... prescription for a beta-blocker filled were identified by individual-level linkage of nationwide registries of hospitalizations and drugs dispensed from pharmacies. A total of 32,259 MI patients were included in the study. Multivariable Cox proportional hazard models were used to analyze the risks of death...... and recurrent MI related to treatment with different beta-blockers. Results: The risks for death and recurrent MI were similar in patients using different beta-blockers, except that mortality from all causes among patients with a prescription for sotalol was higher. Subgroup analyses of high-risk patients...

  2. The Role of KCNQ1 Mutations and Maternal Beta Blocker Use During Pregnancy in the Growth of Children With Long QT Syndrome

    Directory of Open Access Journals (Sweden)

    Heta Huttunen

    2018-04-01

    Full Text Available ObjectiveTwo missense mutations in KCNQ1, an imprinted gene that encodes the alpha subunit of the voltage-gated potassium channel Kv7.1, cause autosomal dominant growth hormone deficiency and maternally inherited gingival fibromatosis. We evaluated endocrine features, birth size, and subsequent somatic growth of patients with long QT syndrome 1 (LQT1 due to loss-of-function mutations in KCNQ1.DesignMedical records of 104 patients with LQT1 in a single tertiary care center between 1995 and 2015 were retrospectively reviewed.MethodsClinical and endocrine data of the LQT1 patients were included in the analyses.ResultsAt birth, patients with a maternally inherited mutation (n = 52 were shorter than those with paternal inheritance of the mutation (n = 29 (birth length, −0.70 ± 1.1 SDS vs. −0.2 ± 1.0 SDS, P < 0.05. Further analyses showed, however, that only newborns (n = 19 of mothers who had received beta blockers during pregnancy were shorter and lighter at birth than those with paternal inheritance of the mutation (n = 29 (−0.89 ± 1.0 SDS vs. −0.20 ± 1.0 SDS, P < 0.05; and 3,173 ± 469 vs. 3,515 ± 466 g, P < 0.05. Maternal beta blocker treatment during the pregnancy was also associated with lower cord blood TSH levels (P = 0.011 and significant catch-up growth during the first year of life (Δ0.08 SDS/month, P = 0.004. Later, childhood growth of the patients was unremarkable.ConclusionLoss-of-function mutations in KCNQ1 are not associated with abnormalities in growth, whereas maternal beta blocker use during pregnancy seems to modify prenatal growth of LQT1 patients—a phenomenon followed by catch-up growth after birth.

  3. Protective effect of Na(+)/Ca (2+) exchange blocker KB-R7943 on myocardial ischemia-reperfusion injury in hypercholesterolemic rats.

    Science.gov (United States)

    Lv, Yan; Ren, Yongkui; Sun, Lufan; Wang, Shaojun; Wei, Minjie; Jia, Dalin

    2013-06-01

    Reverse-mode activation of the Na(+)/Ca(2+) exchanger (NCX) during reperfusion following ischemia contributes to Ca(2+) overload and cardiomyocyte injury. KB-R7943, a selective reverse-mode NCX inhibitor, reduces lethal reperfusion injury under non-ischemic conditions. However, the effectiveness of this compound under ischemic conditions is unclear. In the present study, we studied the effects of KB-R7943 in an animal model of hyperlipidemia. We further assessed whether the K ATP (+) channels are involved in potential protective mechanisms of KB-R7943. Twelve rats were fed normal chow, while 48 animals were fed a high cholesterol diet. The hearts from the control and hypercholesterolemic rats were subjected to 25 min of global ischemia followed by a 120-min reperfusion. Before this, hearts from hypercholesterolemic rats either received no intervention (cholesterol control group) or were pre-treated with 1 μM KB-R7943 and 0.3 μM of K ATP (+) blocker glibenclamide or glibenclamide alone. The infarction sizes (triphenyltetrazolium assay) were 35 ± 5.0 % in the control group, 46 ± 8.7 % in the cholesterol control group (p KB-R7943 group (p KB-R7943 and glibenclamide group, and 47 ± 8.5 % in the glibenclamide group (p KB-R7943 attenuated the magnitude of cell apoptosis (p KB-R7943 reduces the infarction size and apoptosis in hyperlipidemic animals through the activation of K ATP (+) channels.

  4. Effect of propionyl-L-carnitine on L-type calcium channels in human heart sarcolemma

    International Nuclear Information System (INIS)

    Bevilacqua, M.; Vago, T.; Norbiato, G.

    1991-01-01

    Propionyl-L-carnitine (PC) protects perfused rat hearts against damage by ischemia-reperfusion. Activation of L-type calcium channel play a role on ischemia-reperfusion damage. Therefore, we studied the effect of PC on some properties of L-type calcium channels in an in vitro preparation from human myocardium sarcolemma (from patients with idiopathic dilated cardiomyopathy). Binding of the L-type calcium channel blockers isradipine [ 3 H]-PN 200-110 (PN) to plasma membrane preparations revealed a single population of binding sites (total number: Bmax = 213 +/- 34 fM/mg protein and affinity: Kd = 152 +/- 19 nM; n = 6). The characteristics of these binding sites were evaluated in the presence and in the absence of Ca 2+ and of calcium blockers (D-888, a verapamillike drug, and diltiazem). Incubation in a Ca 2+ -containing buffer increased the affinity of PN binding sites. Binding sites for PN were modulated by organic calcium channel blockers; in competition isotherms at 37 degree C, D-888 (desmethoxyverapamil) decreased the PN binding, whereas diltiazem increased it. These results strongly suggest that the site labelled by PN is the voltage-operated calcium channel of the human myocardium. The addition of PC (1 mM) to plasma membranes labelled with PN at 37 degree C decreased the affinity of the binding; this effect was counteracted by the addition of Ca 2+ to the medium. This result was consistent with a competition between Ca 2+ and PC. The effect of PC incubation at 4 degree C was the opposite; at this temperature PC increased the affinity of the binding sites and the effect was obscured by Ca 2+

  5. Prospective direct comparison of antihypertensive effect and safety between high-dose amlodipine or indapamide in hypertensive patients uncontrolled by standard doses of angiotensin receptor blockers and amlodipine.

    Science.gov (United States)

    Okamura, Keisuke; Shirai, Kazuyuki; Totake, Nao; Okuda, Tetsu; Urata, Hidenori

    2018-01-01

    When hypertension is uncontrolled by routine treatment with an angiotensin II receptor blocker (ARB) and the calcium channel blocker amlodipine (5 mg), the dose of amlodipine can be increased or a diuretic can be added. We investigated the more effective option in a prospective multicenter open-label study. Hypertensive patients were recruited if the target blood pressure (BP) in The Japanese Society of Hypertension 2009 guideline could not be achieved with standard-dose ARB therapy and amlodipine (5 mg). Patients were divided into three groups. Group-1 was switched to a combination of irbesartan (100 mg) and amlodipine (10 mg). Group-2A was changed to a combination of irbesartan (100 mg), amlodipine (5 mg), and indapamide, while Group-2B received a standard-dose ARB and amlodipine (5 mg) plus indapamide. Patients were assigned by their attending physicians and were followed for 6 months. The primary endpoint was the antihypertensive effect of each regimen. Group-1 contained 85 patients, Group-2A had 49 patients, and Group-2B had 4 patients. We only analyzed Group-1 and Group-2A due to the small size of Group-2B. In both groups, systolic BP and diastolic BP were significantly decreased up to 6 months (all p < 0.001). Reduction of systolic BP was greater in Group-1 than Group-2A after 1 month and 6 months (both p < 0.05). Uric acid was increased in Group-2A after 3 months, but not at 6 months. Although both regimens were effective for reducing BP, increasing amlodipine to 10 mg daily controlled hypertension without elevation of serum uric acid.

  6. Effect of angiotensin II receptor blocker, olmesartan, on turnover of bone metabolism in bedridden elderly hypertensive women with disuse syndrome.

    Science.gov (United States)

    Aoki, Motokuni; Kawahata, Hirohisa; Sotobayashi, Daisuke; Yu, Hisahiro; Moriguchi, Atsushi; Nakagami, Hironori; Ogihara, Toshio; Morishita, Ryuichi

    2015-08-01

    Although recent studies suggest that several antihypertensive drugs could reduce the risk of bone fracture, it is still unclear how these drugs act on bone remodeling, especially in elderly women with severe osteoporosis with disuse syndrome. In the present study, we investigated the effects of a calcium channel blocker (CCB) and an angiotensin II receptor blocker (ARB) on bone metabolism in elderly bedridden women with hypertension and disuse syndrome. Elderly bedridden women (aged >75 years) receiving antihypertensive therapy treated with CCB were recruited in the present study. The participants were divided into two groups--CCB group and ARB group--and followed up to 12 months. Markers of bone resorption were markedly increased, suggesting accelerated bone resorption in the participants of the present study. In the follow-up period, the patients treated with a CCB showed a significant decrease in bone mineral density in a time-dependent manner, accompanied by a significant increase in bone resorption markers, whereas treatment with olmesartan inhibited bone loss, associated with attenuation of increased bone resorption markers. Bone mineral density of femoral neck in the CCB group was significantly lower than that in the ARB group at 6 months. The present study showed inhibitory effects of an ARB on bone resorption in hypertensive patients with accelerated bone resorption, such as elderly bedridden women, and indicated an important role of the renin-angiotensin system in bone metabolism. In elderly hypertensive patients, ARB might be expected to have additional beneficial potential to maintain bone health in bedridden patients. © 2014 Japan Geriatrics Society.

  7. Beta Blockers Suppress Dextrose-Induced Endoplasmic Reticulum Stress, Oxidative Stress, and Apoptosis in Human Coronary Artery Endothelial Cells.

    Science.gov (United States)

    Haas, Michael J; Kurban, William; Shah, Harshit; Onstead-Haas, Luisa; Mooradian, Arshag D

    Beta blockers are known to have favorable effects on endothelial function partly because of their capacity to reduce oxidative stress. To determine whether beta blockers can also prevent dextrose-induced endoplasmic reticulum (ER) stress in addition to their antioxidative effects, human coronary artery endothelial cells and hepatocyte-derived HepG2 cells were treated with 27.5 mM dextrose for 24 hours in the presence of carvedilol (a lipophilic beta blockers with alpha blocking activity), propranolol (a lipophilic nonselective beta blockers), and atenolol (a water-soluble selective beta blockers), and ER stress, oxidative, stress and cell death were measured. ER stress was measured using the placental alkaline phosphatase assay and Western blot analysis of glucose regulated protein 78, c-Jun-N-terminal kinase (JNK), phospho-JNK, eukaryotic initiating factor 2α (eIF2α), and phospho-eIF2α and measurement of X-box binding protein 1 (XBP1) mRNA splicing using reverse transcriptase-polymerase chain reaction. Superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride (MCLA) chemiluminescence. Cell viability was measured by propidium iodide staining method. The ER stress, SO production, and cell death induced by 27.5 mM dextrose were inhibited by all 3 beta blockers tested. The antioxidative and ER stress reducing effects of beta blockers were also observed in HepG2 cells. The salutary effects of beta blockers on endothelial cells in reducing both ER stress and oxidative stress may contribute to the cardioprotective effects of these agents.

  8. Effects of treatment with β-blocker and aldosterone antagonist on central and peripheral haemodynamics and oxygenation in cirrhosis

    DEFF Research Database (Denmark)

    Winkler, Christine; Hobolth, Lise; Krag, Aleksander

    2011-01-01

    Patients with cirrhosis often exhibit abnormalities in cardiovascular regulation and oxygenation. Many of these patients are treated with β-blockers and aldosterone antagonists that may influence the regulation of systemic haemodynamics, but the specific effects on systemic haemodynamics and oxyg......Patients with cirrhosis often exhibit abnormalities in cardiovascular regulation and oxygenation. Many of these patients are treated with β-blockers and aldosterone antagonists that may influence the regulation of systemic haemodynamics, but the specific effects on systemic haemodynamics...

  9. Barriers to Beta-Blocker Use and Up-Titration Among Patients with Heart Failure with Reduced Ejection Fraction.

    Science.gov (United States)

    Levitan, Emily B; Van Dyke, Melissa K; Loop, Matthew Shane; O'Beirne, Ronan; Safford, Monika M

    2017-12-01

    For patients with heart failure with reduced ejection fraction (HFrEF), guidelines recommend use of beta-blockers with gradual up-titration. However, many patients with HFrEF do not use beta-blockers and up-titration is rare. Our purpose was to identify and rank barriers to beta-blocker use and up-titration from the perspective of primary care physicians. We conducted 4 moderated, structured group discussions among 19 primary care physicians using the nominal group technique; 16 participants also completed a survey. Participants generated lists of barriers to beta-blocker use and up-titration among patients with HFrEF. Each participant had six votes with three votes assigned to the item ranked most important, two to the second most important item, and one to the third most important item. Investigators characterized items into themes. The percentage of available votes was calculated for each theme. Fifteen of 16 participating primary care physicians who completed the survey reported that management of beta-blockers was their responsibility. Treatment/side effects, particularly hypotension, were identified as the most important barrier for beta-blocker use (72% of available votes) followed by polypharmacy (11%), healthcare system barriers (10%), and comorbidities (6%). Barriers to up-titration included treatment/side effects (49% of available votes), patient communication/buy-in (21%), polypharmacy (13%), and healthcare system barriers (8%). Many barriers to guideline concordant use of beta-blockers among patients with HFrEF identified by primary care providers are not readily modifiable. Addressing these barriers may require development, testing, and dissemination of protocols for beta-blocker initiation and up-titration that are safe and appropriate in primary care.

  10. An Analysis of the Feasible Entry Mode for Tottenham Hotspur’s Entry into China

    OpenAIRE

    Zhang, Lei

    2013-01-01

    An increasing number of European football clubs has developed global strategies with an emphasis on the Chinese market, which seems to be a shortcut to their global success. In order to achieve an effective expansion, the selection of appropriate entry modes should be conducted cautiously. This paper aims to select feasible entry modes for Tottenham Hotspur F.C., an emerging power in the Premier League, to enter into the Chinese market. A framework that combines different theories based ...

  11. Market Entry Strategies : Case: McDonald's entry on the Russian market

    OpenAIRE

    Karataev, Oleg

    2015-01-01

    The thesis considers the entry strategy and development of the company McDonald's into international markets. The theoretical aspects of the entry strategy of the company into the international markets. Analyzes the key features of the development of McDonald's in Russia. Investigated the prospects of the company in international markets. In theoretic part there was regarded some important aspects of international strategic management, such as: strategic alternatives, elements and levels o...

  12. Variable Entry Biased Paracentric Hemispherical Deflector: Experimental results on energy resolution for different entry positions

    Science.gov (United States)

    Dogan, Mevlut; Ulu, Melike; Gennerakis, Giannis; Zouros, Theo J. M.

    2014-04-01

    A new hemispherical deflector analyzer (HDA) which is designed for electron energy analysis in atomic collisions has been constructed and tested. Using the crossed beam technique at the electron spectrometer, test measurements were performed for electron beam (200 eV) - Helium atoms interactions. These first experimental results show that the paracentric entries give almost twice as good resolution as that for the conventional entry. Supporting simulations of the entire lens+HDA spectrometer are found in relatively good agreement with experiment.

  13. Study on entry criteria for severe accident management during hot leg LBLOCAs in a PWR

    International Nuclear Information System (INIS)

    Zhang, Longfei; Zhang, Dafa; Wang, Shaoming

    2007-01-01

    The risk of Large Break Loss of Coolant Accidents (LBLOCA) has been considered an important safety issue since the beginning of the nuclear power industry. The rapid depressurization occurs in the primary coolant circuit when a large break appears in a Pressurized Water Reactors (PWR).Then the coolant temperature reaches saturation at a very low pressure. The core outlet fluid temperatures maybe not reliable indicators of the core damage states at a such lower pressure. The problem is how to decide the time for water injection in the SAM (Severe Accident Management). An alternative entry criterion is the fluid temperature just above the hot channel in which the fluid temperature showed maximum among all the channels. For that reason, a systematic study of entry criterion of SAM for different hot leg break sizes in a 3-loop PWR has been started using the detailed system thermal hydraulic and severe accident analysis code package, RELAP/SCDAPSIM. Best estimate calculations of the large break LOCA of 15 cm, 20 cm and 25 cm without accident managements and in the case of high-pressure safety injection as the accident management were performed in this paper. The analysis results showed that the core exit temperatures are not reliable indicators of the peak core temperatures and core damage states once peak core temperatures reach 1500 K, and the proposed entry criteria for SAM at the time when the core outlet temperature reaches 900 K is not effective to prevent core melt. Then other analyses were performed with a parameter of fluid temperature just above the hot channel. The latter analysis showed that earlier water injection when the fluid temperature just above the hot channel reaches 900 K is effective to prevent further core melt. Since fuel surface and hot channel have spatial distribution and depend on a period of cycle operation, a series of thermocouples are required to install just above the fuel assembly. The maximum exit temperature of 900 K that captured by

  14. USACE Navigation Channels 2012

    Data.gov (United States)

    California Natural Resource Agency — This dataset represents both San Francisco and Los Angeles District navigation channel lines. All San Francisco District channel lines were digitized from CAD files...

  15. The genetic background affects the vascular response in T-type calcium channels 3.2 deficient mice

    DEFF Research Database (Denmark)

    Svenningsen, Per; Hansen, Pernille B L

    2016-01-01

    -type channels are the dominant Ca(2+) entry pathway in vascular smooth muscle cells, however, T-type calcium channels are also expressed in the cardiovascular system where they play a functional role in the regulation of both contraction and vasodilation in (Chen et al. 2003; Hansen et al. 2001). This article...... is protected by copyright. All rights reserved....

  16. Regulation of the epithelial Ca2+ channels in small intestine as studied by quantitative mRNA detection.

    NARCIS (Netherlands)

    Abel, M. van; Hoenderop, J.G.J.; Kemp, J.W.C.M. van der; Leeuwen, J.P.P.M. van; Bindels, R.J.M.

    2003-01-01

    The epithelial Ca2+ channels TRPV5 and TRPV6 are localized to the brush border membrane of intestinal cells and constitute the postulated rate-limiting entry step of active Ca2+ absorption. The aim of the present study was to investigate the hormonal regulation of these channels. To this end, the

  17. Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

    Science.gov (United States)

    Blessberger, Hermann; Kammler, Juergen; Domanovits, Hans; Schlager, Oliver; Wildner, Brigitte; Azar, Danyel; Schillinger, Martin; Wiesbauer, Franz; Steinwender, Clemens

    2018-03-13

    Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. The objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia. We identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, Embase , the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature. We included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia. Two review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers. We included 88 randomized controlled trials with 19,161 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple-blinded design with a placebo group, intention-to-treat analysis

  18. Quantum Channels With Memory

    International Nuclear Information System (INIS)

    Rybar, T.

    2012-01-01

    Quantum memory channels represent a very general, yet simple and comprehensible model for causal processes. As such they have attracted considerable research interest, mostly aimed on their transfer capabilities and structure properties. Most notably it was shown that memory channels can be implemented via physically naturally motivated collision models. We also define the concept of repeatable channels and show that only unital channels can be implemented repeat ably with pure memory channels. In the special case of qubit channels we also show that every unital qubit channel has a repeatable implementation. We also briefly explore the possibilities of stroboscopical simulation of channels and show that all random unitary channels can be stroboscopically simulated. Particularly in qubit case, all indivisible qubit channels are also random unitary, hence for qubit all indivisible channels can be stroboscopically simulated. Memory channels also naturally capture the framework of correlated experiments. We develop methods to gather and interpret data obtained in such setting and in detail examine the two qubit case. We also show that for control unitary interactions the measured data will never contradict a simple unitary evolution. Thus no memory effects can be spotted then. (author)

  19. Eight channel fast scalar

    Energy Technology Data Exchange (ETDEWEB)

    Waddoup, W D; Stubbs, R J [Durham Univ. (UK)

    1977-11-01

    An eight channel 64-bit scaler has been constructed with a static CMOS memory. Scaling frequencies are independently variable, at each channel, as are the number of bits/channel. The scaler, when used in conjunction with a multichannel charge to time converter results in a very flexible, gated multichannel ADC.

  20. KV7 potassium channels

    DEFF Research Database (Denmark)

    Stott, Jennifer B; Jepps, Thomas Andrew; Greenwood, Iain A

    2014-01-01

    Potassium channels are key regulators of smooth muscle tone, with increases in activity resulting in hyperpolarisation of the cell membrane, which acts to oppose vasoconstriction. Several potassium channels exist within smooth muscle, but the KV7 family of voltage-gated potassium channels have been...