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Myocardial protective effect of intracoronary administration of nicorandil and alprostadil via targeted perfusion microcatheter in patients undergoing elective percutaneous coronary intervention: A randomized controlled trial.
Zhang, W, Dai, J, Zheng, X, Xu, K, Yang, X, Shen, L, Wang, X, Hao, Z, Qiu, X, Jiang, L, et al
Medicine. 2021;(15):e25551
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BACKGROUND The aim of the study was to evaluate the efficacy of nicorandil and alprostadil on myocardial protection in patients undergoing elective percutaneous coronary intervention (PCI). METHODS In this prospective, single-blinded, randomized controlled study, 90 consecutive patients scheduled for elective PCI for de novo coronary lesions were assigned to the nicorandil, alprostadil, and nitroglycerin groups in a 1:1:1 ratio. Drugs were administered intracoronary via a targeted perfusion microcatheter. The primary endpoint was the thrombolysis in myocardial infarction (TIMI) myocardial perfusion frame count (TMPFC). Additionally, the corrected TIMI frame count (cTFC), TIMI myocardial perfusion grade (TMPG), and incidence of periprocedural myocardial injury (PMI) were assessed. RESULTS Both nicorandil and alprostadil were significantly effective in reducing TMPFC (114.6 ± 33.7 vs 93.4 ± 30.9, P = .016; 114.3 ± 34.3 vs 94.7 ± 33.3, P = .029, respectively). Similar findings were observed in the improvement of cTFC (20.3 ± 10.5 vs 13.5 ± 5.0, P = .003; 20.2 ± 7.4 vs 15.2 ± 5.2, P = .003, respectively) and percentage of TMPG 3 (100% vs 82.8%, P = .052; 83.3% vs 96.7%, P = .196, respectively); whereas, nitroglycerin produced a limited effect on TMPFC (114.4 ± 30.9 vs 112.1 ± 31.9, P = .739), cTFC (19.4 ± 7.2 vs 19.3 ± 7.2, P = .936), and percentage of TMPG 3 (86.7% vs 86.7%, P = 1.000). No significant difference was found in the incidence of PMI (16.7% vs 16.0% vs 27.6%, P = .537), though it was comparatively lower in the nicorandil and alprostadil groups. Furthermore, the intracoronary administration of nicorandil and alprostadil had a mild effect on blood pressure and heart rate. CONCLUSIONS The intracoronary administration of nicorandil and alprostadil via a targeted perfusion microcatheter was more effective in improving myocardial perfusion in patients undergoing elective PCI than nitroglycerin.
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Theobromine consumption does not improve fasting and postprandial vascular function in overweight and obese subjects.
Smolders, L, Mensink, RP, van den Driessche, JJ, Joris, PJ, Plat, J
European journal of nutrition. 2019;(3):981-987
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BACKGOUND Theobromine, a component of cocoa, may favorably affect conventional lipid-related cardiovascular risk markers, but effects on flow-mediated dilation (FMD) and other vascular function markers are not known. OBJECTIVE To evaluate the effects of 4-week theobromine consumption (500 mg/day) on fasting and postprandial vascular function markers. DESIGN In a randomized, double-blind crossover study, 44 apparently healthy overweight (N = 30) and obese (N = 14) men and women with low HDL-C concentrations, consumed daily 500 mg theobromine or placebo for 4 weeks. After 4 weeks, FMD, peripheral arterial tonometry (PAT), augmentation index (AIx), pulse wave velocity (PWV), blood pressure (BP) and retinal microvasculature measurements were performed. These measurements were carried out under fasting conditions and 2.5 h after a high-fat mixed meal challenge. RESULTS 4-week theobromine consumption did not change fasting vascular function markers, except for a decrease in central AIx (cAIx, - 1.7 pp, P = 0.037) and a trend towards smaller venular calibers (- 2 µm, P = 0.074). Consuming a high-fat mixed meal decreased FMD (0.89 pp, P = 0.002), reactive hyperemia index (RHI, - 0.30, P < 0.001), peripheral systolic BP (SBP, - 3 mmHg, P ≤ 0.001), peripheral diastolic BP (DBP, - 2 mmHg, P ≤ 0.001), central SBP (- 6 mmHg, P ≤ 0.001) and central DBP (- 2 mmHg, P ≤ 0.001), but increased heart rate (HR, 2 bpm, P < 0.001). Theobromine did not modify these postprandial effects, but increased postprandially the brachial artery diameter (0.03 cm, P = 0.015), and decreased the cAIx corrected for a HR of 75 (cAIx75, - 5.0 pp, P = 0.004) and peripheral AIx (pAIx, - 6.3 pp, P = 0.017). CONCLUSION Theobromine consumption did not improve fasting and postprandial endothelial function, but increased postprandial peripheral arterial diameters and decreased the AIx. These findings do not suggest that theobromine alone contributes to the proposed cardioprotective effects of cocoa. This trial was registered on clinicaltrials.gov under study number NCT02209025.
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Route of Feeding as a Proxy for Dysphagia After Stroke and the Effect of Transdermal Glyceryl Trinitrate: Data from the Efficacy of Nitric Oxide in Stroke Randomised Controlled Trial.
Woodhouse, LJ, Scutt, P, Hamdy, S, Smithard, DG, Cohen, DL, Roffe, C, Bereczki, D, Berge, E, Bladin, CF, Caso, V, et al
Translational stroke research. 2018;(2):120-129
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Post-stroke dysphagia is common, associated with poor outcome and often requires non-oral feeding/fluids. The relationship between route of feeding and outcome, as well as treatment with glyceryl trinitrate (GTN), was studied prospectively. The Efficacy of Nitric Oxide in Stroke (ENOS) trial assessed transdermal GTN (5 mg versus none for 7 days) in 4011 patients with acute stroke and high blood pressure. Feeding route (oral = normal or soft diet; non-oral = nasogastric tube, percutaneous endoscopic gastrostomy tube, parenteral fluids, no fluids) was assessed at baseline and day 7. The primary outcome was the modified Rankin Scale (mRS) measured at day 90. At baseline, 1331 (33.2%) patients had non-oral feeding, were older, had more severe stroke and more were female, than 2680 (66.8%) patients with oral feeding. By day 7, 756 patients had improved from non-oral to oral feeding, and 119 had deteriorated. Non-oral feeding at baseline was associated with more impairment at day 7 (Scandinavian Stroke Scale 29.0 versus 43.7; 2p < 0.001), and worse mRS (4.0 versus 2.7; 2p < 0.001) and death (23.6 versus 6.8%; 2p = 0.014) at day 90. Although GTN did not modify route of feeding overall, randomisation ≤6 h of stroke was associated with a move to more oral feeding at day 7 (odds ratio = 0.61, 95% confidence intervals 0.38, 0.98; 2p = 0.040). As a proxy for dysphagia, non-oral feeding is present in 33% of patients with acute stroke and associated with more impairment, dependency and death. GTN moved feeding route towards oral intake if given very early after stroke. Clinical Trial Registration Clinical Trial Registration-URL: http://www.controlled-trials.com . Unique identifier: ISRCTN99414122.
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Topical diltiazem for pain after closed hemorrhoidectomy.
Rodríguez-Wong, U, Ocharán-Hernández, ME, Toscano-Garibay, J
Revista de gastroenterologia de Mexico. 2016;(2):74-9
Abstract
BACKGROUND Anal sphincter spasm contributes to the appearance of postoperative pain following hemorrhoidectomy. AIM: To determine the efficacy of topical diltiazem in the control of post-hemorrhoidectomy pain. MATERIAL AND METHODS A randomized, prospective, experimental, double-blind study was conducted on 2 groups of patients in the postoperative period of closed hemorrhoidectomy. Each group consisted of 17 patients. Group A received topical diltiazem in the anal region 3 times a day and group B received a placebo. Ketorolac was administered to both groups as rescue therapy. RESULTS In group A, the mean score on the visual analog scale was 2.97±1.18cm at 24h, 1.51±1.18cm at 48h, and 0.84±0.92cm at 72h. In group B, it was 6.82±1.9cm at 24h, 5.3±1.66cm at 48h, and 4.32±2.13cm at 72h (P<.001, 95% CI). The mean number of analgesic doses in group A was 2.41±0.87 at 24h, 1.11±0.85 at 48h, and 0.94±0.96 at 72h. In group B, it was 3.82±0.52 at 24h, 3.64±0.70 at 48h, and 2.88±1.26 at 72h (P<.001, 95% CI). CONCLUSIONS In this study, topical administration of diltiazem resulted in a statistically significant reduction of postoperative pain in patients that underwent closed hemorrhoidectomy.
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Efficacy of intravenous nicorandil for fractional flow reserve assessment: study protocol for a crossover randomised trial.
Nishi, T, Kitahara, H, Fujimoto, Y, Nakayama, T, Sugimoto, K, Nagashima, K, Hanaoka, H, Kobayashi, Y
BMJ open. 2016;(11):e012737
Abstract
INTRODUCTION Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. Intravenous administration of nicorandil can be applicable for fractional flow reserve (FFR) measurement as a hyperaemic agent and a possible alternative to adenosine. However, the effectiveness of intravenous nicorandil infusion for FFR measurement is largely unclear. METHODS AND ANALYSIS This crossover randomised study is being performed to investigate the efficacy of intravenous administration of nicorandil for FFR measurement. Patients with an intermediate coronary artery stenosis who satisfy the eligibility criteria undergo FFR measurement with a consecutive randomised order of patient-blind infusions of continuous intravenous administration of adenosine and a single bolus intravenous administration of nicorandil. The primary end point of the study is the agreement between the FFR values obtained by the intravenous nicorandil and those obtained by the intravenous adenosine. Recruitment of this trial started in November 2015 and will end in March 2017, or until a total of 50 participants have been recruited. ETHICS AND DISSEMINATION The protocol was approved by the Institutional Review Board at Chiba University Hospital. Study findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER UMIN000019309; Pre-results.
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A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major.
Fernandes, JL, Loggetto, SR, Veríssimo, MP, Fertrin, KY, Baldanzi, GR, Fioravante, LA, Tan, DM, Higa, T, Mashima, DA, Piga, A, et al
Blood. 2016;(12):1555-61
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Cardiovascular disease resulting from iron accumulation is still a major cause of death in patients with thalassemia major (TM). Voltage-gated calcium-channel blockade prevents iron entry into cardiomyocytes and may provide an adjuvant treatment to chelation, reducing myocardial iron uptake. We evaluated whether addition of amlodipine to chelation strategies would reduce myocardial iron overload in TM patients compared with placebo. In a multicenter, double-blind, randomized, placebo-controlled trial, 62 patients were allocated to receive oral amlodipine 5 mg/day or placebo in addition to their current chelation regimen. The main outcome was change in myocardial iron concentration (MIC) determined by magnetic resonance imaging at 12 months, with patients stratified into reduction or prevention groups according to their initial T2* below or above the normal human threshold of 35 ms (MIC, 0.59 mg/g dry weight). At 12 months, patients in the reduction group receiving amlodipine (n = 15) had a significant decrease in MIC compared with patients receiving placebo (n = 15) with a median of -0.26 mg/g (95% confidence interval, -1.02 to -0.01) vs 0.01 mg/g (95% confidence interval, -0.13 to 0.23), P = .02. No significant changes were observed in the prevention group (treatment-effect interaction with P = .005). The same findings were observed in the subgroup of patients with T2* <20 ms. Amlodipine treatment did not cause any serious adverse events. Thus, in TM patients with cardiac siderosis, amlodipine combined with chelation therapy reduced cardiac iron more effectively than chelation therapy alone. Because this conclusion is based on subgroup analyses, it needs to be confirmed in ad hoc clinical trials. This trial was registered at www.clinicaltrials.gov identifier as #NCT01395199.
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A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children.
Brousseau, DC, Scott, JP, Badaki-Makun, O, Darbari, DS, Chumpitazi, CE, Airewele, GE, Ellison, AM, Smith-Whitley, K, Mahajan, P, Sarnaik, SA, et al
Blood. 2015;(14):1651-7
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Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sβ(0) thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417.
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Cardioprotective effects of single oral dose of nicorandil before selective percutaneous coronary intervention.
Yang, J, Zhang, J, Cui, W, Liu, F, Xie, R, Yang, X, Gu, G, Zheng, H, Lu, J, Yang, X, et al
Anatolian journal of cardiology. 2015;(2):125-31
Abstract
OBJECTIVE Nicorandil, an opener of ATP-sensitive K+ channels, was used to treat angina in patients with coronary artery disease. In this study, we aim to investigate the cardioprotective effects of single oral dose of nicorandil in patients undergoing selective percutaneous coronary intervention (PCI). METHODS One hundred and thirty-eight patients with acute coronary syndrome undergoing PCI from July 2011 to October 2012 were randomly divided into control group (group 1, n = 47), 10 mg oral nicorandil group (group 2, n = 45), and 20 mg oral nicorandil group (group 3, n = 46) about 2 hours before procedure, respectively. Cardiac troponin I (cTnI) levels were determined at 20 ~ 24 hours after PCI. RESULTS There was a significant difference in the rate of any cTnI elevation among the three groups (group 1: 36.17%, group 2: 20.00%, group 3: 15.22%, p = 0.0176). With respect to the frequency of cTnI elevation ≥ 3 and 5 × the upper limit of normal (ULN), there also had statistical difference among the three groups (17.02% in group 1, 8.89% in group 2, and 4.35% in group 3, respectively for cTnI elevation ≥ 3 × ULN, p = 0.0428; 12.77% in group 1, 6.67% in group 2, and 2.17% in group 3, respectively, for cTnI elevation ≥ 5 × ULN, p = 0.0487). Logistic regression analysis showed that LVEF (OR = 0.915, 95% CI = 0.853-0.981) and the use of nicorandil (OR = 0.516, 95% CI = 0.267-0.996) before PCI were independent protective factors of myocardial injury. CONCLUSION Single oral dose of nicorandil (10 mg, 20 mg) 2 hours before the PCI procedure could decrease the incidence of peri-procedure myocardial injury and PCI-related myocardial infarction.
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Augmented reflex cutaneous vasodilatation following short-term dietary nitrate supplementation in humans.
Levitt, EL, Keen, JT, Wong, BJ
Experimental physiology. 2015;(6):708-18
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What is the central question of this study? Nitrate supplementation via beetroot juice has been shown to have several benefits in healthy humans, including reduced blood pressure and increased blood flow to exercising muscle. Whether nitrate supplementation can improve blood flow to the skin in heat-stressed humans has not been investigated. What is the main finding and its importance? Similar to previous studies, we found that nitrate supplementation reduces blood pressure. Nitrate supplementation increased vasodilatation in the skin of heat-stressed humans but did not directly increase skin blood flow. Nitrate supplementation has been shown to increase NO-dependent vasodilatation through both NO synthase (NOS)-dependent and NOS-independent pathways. We hypothesized that nitrate supplementation would augment reflex cutaneous active vasodilatation. Subjects were equipped with two microdialysis fibres on the forearm randomly assigned as control (Ringer solution) or NOS inhibition (20 mm l-NAME). Whole-body heating was performed to raise core temperature by 0.8°C above baseline core temperature. Maximal cutaneous vasodilatation was achieved via 54 mm sodium nitroprusside and local heating to 43°C. Skin blood flow (measured by laser-Doppler flowmetry) and blood pressure were measured. Cutaneous vascular conductance (CVC) was calculated as skin blood flow divided by mean arterial pressure (MAP) and expressed as a percentage of maximal CVC (%CVCmax ). Subjects underwent heat stress before and after nitrate supplementation (3 days of beetroot juice; 5 mm, 0.45 g nitrates per day). During heat stress, MAP was reduced following nitrate supplementation compared with the control conditions (before 88 ± 3 mmHg versus after 78 ± 2 mmHg; P < 0.05); however, resting MAP was not different between conditions (before 88 ± 3 mmHg versus after 83 ± 2 mmHg; P = 0.117). Nitrate supplementation increased plateau CVC at control sites (before 67 ± 2%CVCmax versus after 80 ± 5%CVCmax ; P = 0.01) but not at l-NAME-treated sites (before 45 ± 4%CVCmax versus after 40 ± 5%CVCmax ; P = 0.617). There was no change in the calculated percentage of NOS-dependent vasodilatation before and after supplementation (before 59 ± 4% versus after 64 ± 6%; P = 0.577). These data suggest that nitrate supplementation augments CVC and reduces MAP during heat stress.
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Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms.
Stanhewicz, AE, Alexander, LM, Kenney, WL
Clinical science (London, England : 1979). 2015;(2):159-67
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Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22 ± 1 years) and 11 older (O: 71 ± 3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 ± 3 vs Y = 96 ± 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 ± 6% vs Y = 49 ± 5, P = 0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax = 91 ± 2, P = 0.03) and NO-dependent (%CVCmax = 43 ± 9%, P = 0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O = 31 ± 8 vs Y = 44 ± 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 ± 2 vs Y = 21 ± 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 47 ± 5%, P = 0.001) and NO-dependent vasodilatation (20 ± 3%, P = 0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.