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J Interv Card Electrophysiol. 2008 Jul 4;
Morishima I, Nogami A, Tsuboi H, Sone T
Uncommon association of left anterior fascicular ventricular tachycardia (VT) with a healed myocardial infarction (MI) is described. A 55-year-old man with a history of anteroseptal MI had verapamil-sensitive VT. The VT exhibited a right bundle branch block configuration and right-axis deviation. The VT exit was located at the left ventricular anterolateral wall. At the mid-anterior left ventricular septum, delayed Purkinje potentials were seen during sinus rhythm, and the optimal pace map was obtained with pace delay. During the VT, diastolic and systolic Purkinje potentials were simultaneously recorded at the same site. Ablation targeting the delayed potentials during sinus rhythm prolonged the time between QRS onset and the delayed potentials, and the VT no longer became inducible when the delayed potentials were completely eliminated. Left anterior fascicular VT develops in post-MI patients; ischemia-injured His-Purkinje system may be involved in the mechanism of the VT.
Am J Hypertens. 2008 Jul 3;
Hermida RC, Ayala DE, Mojón A, Fernández JR
BackgroundPrevious studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium-channel blockers (CCBs), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the administration-time dependent antihypertensive efficacy of the slow-release, once-a-day nifedipine gastrointestinal-therapeutic-system (GITS) formulation.MethodsWe studied 180 untreated hypertensives (86 men and 94 women), 52.5 +/- 10.7 years of age, randomly assigned to receive nifedipine (30 mg/day) as a monotherapy either upon awakening or at bedtime. BP was measured for 48 h before and after 8 weeks of treatment.ResultsThe BP reduction after treatment was significantly larger with bedtime dosing mainly during night time sleep (P < 0.012). The number of patients with controlled ambulatory BP after treatment was greater with bedtime than morning treatment (P = 0.016). The baseline prevalence of nondipping was unaltered after ingestion of nifedipine on awakening, but reduced from 51 to 35% after bedtime dosing (P = 0.025). The morning surge of BP, a risk factor for stroke, was significantly reduced (P < 0.001) only after bedtime administration of nifedipine. Bedtime in comparison to awakening-time ingestion of nifedipine was also associated with a reduction in the incidence of edema from 13 to 1% (P < 0.001).ConclusionsThe increased efficacy on ambulatory BP as well as the significantly reduced prevalence of edema after bedtime as compared to morning ingestion of nifedipine should be taken into account when prescribing this medication to patients with essential hypertension.American Journal of Hypertension (2008). doi 10.1038/ajh.2008.216American Journal of Hypertension (2008). doi 10.1038/ajh.2008.216.
Am J Hypertens. 2008 Jul 3;
Olivieri O, Pizzolo F, Ciacciarelli A, Corrocher R, Signorelli D, Falcone S, Blengio GS
BackgroundIt has been suggested that hypertensive patients with raised aldosterone-to-renin ratio (ARR) are specifically sensitive to mineralocorticoid receptor antagonists (MRAs). We have previously shown that patients with an elevated ARR are relatively frequent in the setting of primary care. We therefore designed an interventional study to ascertain whether primary care hypertensive patients with an elevated ARR presented a superior response to MRA treatment than subjects with normal ratio.MethodsAccording to the previously observed distribution in general population, 1/3 and 2/3 of hypertensive patients with high or normal ARR, respectively, were treated with kanrenoate 50-100 mg/day for 2 months. To avoid uncontrolled blood pressure (BP), 49% of patients continued also "ARR-neutral" drugs such as verapamil and/or alpha-adrenergic blockers. Patients groups were matched for most features but an elevated ARR was more frequent in female than in male gender; moreover, 90% of women with raised ARR were in menopause.ResultsA clear reduction of BP values was recorded after both the first and the second month of treatment with kanrenoate, with the maximal effect obtained when the dosage titration at 100 mg/day was accomplished. However, patients previously identified by a raised ARR did not have a larger response to MRA treatment than patients with normal ratio. In contrast, MRA was twofold more effective in reducing SBP in women than in men (after 2 months of treatment -16.4 mm Hg vs.-8.2 mm Hg).ConclusionsThese results suggest that postmenopausal hypertension is largely dependent on mineralocorticoid receptor activation and selectively sensitive to MRAs.American Journal of Hypertension (2008). doi 10.1038/ajh.2008.234American Journal of Hypertension (2008). doi 10.1038/ajh.2008.234.
Pharmaceutical Interventions for the Management of No-Reflow.
J Invasive Cardiol. 2008 Jul; 20(7): 374-379
Fischell TA
A common complication of percutaneous coronary intervention (PCI), no-reflow is predominantly encountered during interventions in degenerated saphenous vein grafts and is associated with a marked increase in short-term mortality risk. Etiologically, no-reflow is complex and multifactorial. Microembolic debris from dilated target sites, sustained diffuse microvascular spasm, and pathophysiologic alterations from initial ischemic insults and subsequent reperfusion injuries result in persistence of myocardial ischemia despite angiographic evidence of restored vessel patency. Treatments to prevent or reverse no-reflow include antiplatelet medications to interfere with platelet aggregation. However, insufficient evidence exists demonstrating benefits with their prophylactic use in humans. Distal protection devices target microemboli, but soluble vasoactive factors may elude capture, contributing to downstream vasospasm. Intracoronary administration of vasodilators during PCI address a root cause of no-reflow. Adenosine, nitroprusside, verapamil, nicardipine and others have been evaluated clinically, showing improvements across a range of surrogate TIMI flow grade and frame count and real endpoints (wall motion indices and elevated CPK). Nicardipine may be particularly well-suited for prevention or reversal of no-reflow, demonstrating pharmacologic protection equal or superior to mechanical distal protection devices. The consistent and often dramatic mitigation of no-reflow by adjunctive use of vasodilators supports the role of microvascular spasm as a major, modifiable cause of the syndrome and a critical therapeutic target. A further large-scale, prospective, randomized, controlled clinical study is warranted to confirm prior findings, determine the optimal dosing regimen, and whether treatment or prevention of no-reflow confers clinically relevant outcome benefits.
Auton Autacoid Pharmacol. 2008 Apr; 28(2-3): 69-80
Gmitrov J
1 We studied the effects of verapamil on sudden elevation in blood pressure, microcirculation and arterial baroreflex sensitivity (BRS). 2 Thirty experiments (10 controls and 20 with verapamil) were performed in rabbits sedated using pentobarbital infusion (5 mg kg(-1) h(-1)). 3 BRS, mean femoral artery blood pressure (MAP), heart rate (HR) and ear lobe skin microcirculatory blood flow, estimated using microphotoelectric plethysmography (MPPG), were simultaneously measured during 30 min of verapamil infusion (20 mug kg(-1) min(-1)). BRS was assessed from HR and MAP responses to intravenous phenylephrine (Ph) and by power spectral analysis using transfer function (TF) from MAP to the HR (BRS(Ph,TF)). 4 Verapamil significantly increased microcirculatory blood flow, and decreased BRS(Ph,TF) and phenylephrine-induced abrupt elevation in MAP (MAP(AE)). 5 A significant inverse correlation was found between verapamil-induced changes in MAP(AE), BRS and in microcirculatory blood flow, measured before phenylephrine blood pressure ramps (DeltaMAP(AE) with DeltaBRS(TF), r = -0.47, P < 0.036; DeltaMAP(AE) with DeltaMPPG, r = -0.49, P < 0.025). 6 These results suggest involvement of the arterial baroreflex and vascular blood pressure-buffering mechanisms, their enhancement by verapamil, and thus a potential benefit of verapamil in cardiovascular conditions where patients present with abrupt high elevations in blood pressure.
J Biol Chem. 2008 Jul 2;
Loo TW, Bartlett MC, Clarke DM
A key goal is to correct defective folding of mutant ABC transporters since they cause diseases such as cystic fibrosis. P-glycoprotein (P-gp, ABCB1) is a useful model system because introduction of an arginine at position 65 of the first transmembrane (TM) segment could repair folding defects. To determine the mechanism of arginine-rescue, we first tested the effects of introducing arginines at other positions in TM1 (residues 52-72) of a P-gp processing mutant (G251V) that is defective in folding and trafficking to the cell surface (20% maturation efficiency). We found that arginines introduced into one face of the TM1 helix (positions 52, 55, 56, 59, 60, 62, 63, 66, 67) inhibited maturation whereas, arginines on the opposite face of the helix promoted (positions 64, 65, 68, 71) or had little effect (positions 61, 69) on maturation. Arginines at positions 61, 64, 65, and 68 appeared to lie close to the drug-binding sites as they reduced the apparent affinity for drug substrates such as vinblastine and verapamil. Therefore, arginines that promoted maturation may face an aqueous drug translocation pathway while those that inhibited maturation may face the lipid bilayer. The highest maturation efficiencies (60-85%) were observed with the Arg65 and Arg68 mutants. Mutations that removed hydrogen bond acceptors (Y950F/A or Y953F/A) in TM11 predicted to lie close to Arg65 or Arg68 inhibited maturation but did not affect maturation of the G251V parent. Therefore, arginine may rescue defective folding by promoting packing of the TM segments through hydrogen bond interactions.
Pflugers Arch. 2008 Jul 2;
Koyama T, Kimura C, Hayashi M, Watanabe M, Karashima Y, Oike M
Mechanical stresses regulate physiological and pathological functions of vascular endothelial cells. We examined, in this study, the effects of hypergravity on endothelial functions. Hypergravity (3 G) applied by low speed centrifuge immediately induced a membrane translocation of small G-protein RhoA and tyrosine phosphorylation of 125 kDa FAK in bovine aortic endothelial cells (BAECs). Hypergravity also induced a transient reorganization of actin fibers in 3 min, which was inhibited by Rho-kinase inhibitor (Y27632) and tyrosine kinase inhibitors (herbimycin A and tyrphostin 46). Furthermore, the extracellular ATP concentration ([ATP](o)) was increased by 2 G and 3 G hypergravity in 5 min, and the inhibitors of Rho-kinase, tyrosine kinase, and volume-regulated anion channels (VRAC; verapamil, tamoxifen and fluoxetine) significantly suppressed [ATP](o) elevation. Application of 3 G hypergravity for 1 h increased the nuclear uptake of BrdU, which was inhibited by Rho-kinase inhibitor and VARC inhibitors. Furthermore, intermittent application of 3 G hypergravity for 1 or 2 h/day stimulated endothelial migration in 5 days, and this was inhibited by suramin, a P(2) antagonist. Collectively, these results indicate that hypergravity induces ATP release and actin reorganization via RhoA activation and FAK phosphorylation, thereby activating cell proliferation and migration in BAECs. These also suggest that gravity can be regarded as an extracorporeal signal that could significantly affect endothelial functions.
J Biomol Screen. 2008 Jul 1;
Gao J, Xu Y, Yang Y, Yang Y, Zheng Z, Jiang W, Hong B, Yan X, Si S
The ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that directly contributes to high-density lipoprotein (HDL) biogenesis by mediating the cellular efflux of cholesterol and phospholipids to lipid-poor apolipoprotein A-I. Therefore, identification of a novel upregulator of ABCA1 would be beneficial for atherosclerosis prevention and/or therapy because of its pivotal role in cholesterol homeostasis and HDL metabolism. In this study, a high-throughput assay method for ABCA1 upregulators was developed and used for screening a synthetic and natural compound library. The cell-based high-throughput screen is conducted in a 96-well format using the human hepatoma HepG2 cells stably transfected with ABCA1 promoter-luciferase construct and calibrated with reference ABCA1 upregulators (oxysterols, 9-cis-retinoic acid, thiazolidinediones, cyclic adenosine monophosphate, verapamil, fenofibrate, and oncostatin M). Among 2600 compounds, 4 microbial compounds (pyrromycin, aclarubicin, daidzein, and pratensein) were picked up as hits by the high-throughput screening assay, and those compounds were further identified as upregulators of ABCA1 expression by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis. (Journal of Biomolecular Screening 2008:xx-xx).
Int Urol Nephrol. 2008 Jul 1;
Tuygun C, Ozok UH, Gucuk A, Halil Bozkurt I, Abdurrahim Imamoglu M
AIM: To determine the effectiveness of transdermal electromotive administration (TEA) of verapamil and dexamethasone in the treatment of Peyronie's disease (PD). METHOD: Totally, 51 patients with PD were prospectively included in the study. All patients were evaluated by history, subjective score scales, physical examination, photographs, and penile USG, before and after therapy. All patients were treated with TEA of the combination of verapamil and dexamethasone. The treatment plan included a total of 20 sessions (at 3-day intervals for a period of 2 months), each with a duration of 20 min. At the end of the study, improvements in penile plaques, penile deviation, pain on erection, and erectile dysfunction were determined. RESULTS: The findings in 41 of the 51 patients were eligible to present. Median patient age was 52 years. Median duration of disease at presentation was 8 months. Remarkable reduction in palpable plaques and in penile angulation was observed in 10 patients (24%) and 11 (26%) patients, respectively. There were significant decreases in median plaque volume from 72 mm(2) to 45 mm(2) (P < 0.001), and in median penile angulation from 25 masculine to 15 masculine (P < 0.001). Impaired sexual activity and pain on erection had completely resolved in 11 (55%) patients and in 16 (80%), respectively. CONCLUSION: The results of our study have shown that TEA of the combination of verapamil and dexamethasone is a more effective therapy for improving subjective symptoms rather than objective symptoms. Therefore, we think that this treatment can be individualized according to the clinical features of PD patients.
P-glycoprotein down-regulates expression of breast cancer resistance protein in a drug-free state.
FEBS Lett. 2008 Jun 24;
Xu HD, Bark H, Kim SH, Yun J, Choi CH
This study investigated whether P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are linked in terms of expression. RT-PCR and Western blot analyses showed that the lung cancer cell line SK-MES-1/WT expressed BCRP. In a drug-free state, BCRP expression was significantly down-regulated in doxorubicin-resistant SK-MES-1/DX1000 cells overexpressing Pgp. Pharmacological inhibitors (PSC833 or verapamil) or siRNA for Pgp inhibited the down-regulation of BCRP, which was confirmed by confocal microscopy. PSC833-induced the phosphorylation of c-Jun NH2-terminal kinase (JNK) and c-Jun, while the JNK inhibitor SP600125 inhibited this effect. Dominant negative c-Jun increased the expression of BCRP, but decreased that of Pgp. These results indicate that Pgp down-regulates BCRP expression in a drug-free state in which JNK/c-Jun is involved.