Effects of Celecoxib on the QTc Interval: A Thorough QT/QTc Study

PurposeCelecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go–related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines.MethodsThis randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method–corrected QT intervals (QTcF) were calculated and evaluated.FindingsTwenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were <5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of >450 ms or a change from baseline in QTcI of >60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 μg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects.ImplicationsCelecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.     

QTc prolongation and torsades de pointes associated with methadone therapy

Oral methadone therapy is an effective and increasingly popular treatment for opioid dependency and chronic pain. Although it is not typically considered pro-dysrhythmic, we present the unique case of a 52-year-old HIV-positive woman without underlying cardiac disease who developed QTc prolongation and pulseless Torsades secondary to high dose methadone therapy.     

QTc interval in patients with changing edematous states: implications on interpreting repeat QTc interval measurements in patients with anasarca of varying etiology and those undergoing hemodialysis

Associations have been described among weight, amplitude of QRS complexes, and QRS duration (QRSd) in patients with anasarca (AN), and changes in the amplitude of the QRS complexes, QRSd, and QTc after hemodialysis (HD) and in patients with heart failure with associated peripheral edema congestive heart failure. The objective of this study was to evaluate the hypothesis that changes in QTc in patients with AN and after HD are at least partially apparent, due to changing edematous states, and not totally due to altered electrophysiology. QTc was measured in patients with AN on admission, at peak weight (N = 28), and at their subsequent lowest weight (N = 12), in 28 control patients without change in weight during hospitalization, and in one patient before and after 26 HD sessions. In the patients with AN, the QTc was 451 +/- 36 ms on admission and dropped to 423 +/- 46 ms at peak weight (P = 0.005). QTc was 421 +/- 44 ms at peak weight and raised to 434 +/- 30 at subsequent lowest weight (P = 0.32). In the controls, QTc on admission and at discharge were 435 +/- 34 and 428 +/- 23 ms, correspondingly (P = 0.18). QTc increased from 472 +/- 18 ms before to 489 +/- 36 ms after HD (P = 0.017). Alterations in QTc in AN, or HD suggest that the changes in the QTc may be partially only apparent, and due to the electrocardiogram machine-based measurement of the attenuated/augmented QRST complexes resulting from fluid shifts.     

Assessment of ventricular repolarization in a large group of children with early onset deafness

This study examined the ECG traces of 397 deaf children (age 12.5 +/- 2.9 years, range 6-19 years), after exclusion of cases with Jervell and Lange-Nielsen syndrome (JLNS), and compared them to those of 361 normal hearing counterparts (age 12.5 +/- 2.7 years; range 7-18 years). An observer, who was unaware of the hearing status of the subjects, measured QT and QTc intervals and calculated dispersions of QT and QTc from standard 12-lead ECGs recorded at a speed of 25 mm/s at rest. Although the mean QT was found to be longer in deaf children than that observed in the control group (P < 0.0001), the mean QTc was significantly shorter (P < 0.0001). The mean heart rate was significantly lower in deaf children. When QT and QTc data were recompared after the children were grouped according to the heart rate, the observed difference became less significant or disappeared. In conclusion, there are no major abnormalities for repolarization parameters in children with congenital sensorineural deafness, when compared to hearing counterparts, if heart rates are similar. Based on these results, routine ECG screening of deaf children for repolarization abnormalities may be unnecessary unless they have a history of syncope or positive family history of syncope and/or early sudden death.     

Effects of adrenaline and potassium on QTc interval and QT dispersion in man

BACKGROUND: Hypoglycaemia alters cardiac repolarization acutely, with increases in rate-corrected QT (QTc) interval and QT dispersion (QTd) on the electrocardiogram (ECG); such changes are related to the counterregulatory sympatho-adrenal response. Adrenaline produces both QTc lengthening and a fall in plasma potassium (K+) when infused into healthy volunteers. Hypokalaemia prolongs cardiac repolarization independently however, and therefore our aim was to determine whether adrenaline-induced repolarization changes are mediated directly or through lowered plasma K+. MATERIALS AND METHODS: Ten healthy males were studied on two occasions. At both visits they received similar l-adrenaline infusions but on one occasion potassium was also administered; infusion rates were adjusted to maintain circulating K+ at baseline. The QTc interval, QTd, peripheral physiological responses and plasma adrenaline and potassium concentrations were measured during both visits. RESULTS: The QTc interval and QTd increased both with and without potassium clamping. Without K+ replacement, mean (SE) QTc lengthened from 378 (5) ms to a final maximum value of 433 (10) ms, and QTd increased from 36 (5) ms to 69 (8) ms (both P < 0.001). During K+ replacement, QTc duration at baseline and study end was 385 (7) ms and 423 (11) ms, respectively (P < 0.001), and QTd 38 was (4) ms and 63 (5) ms (P = 0.001). CONCLUSIONS: These data suggest that disturbed cardiac repolarization as a result of increases in circulating adrenaline occurs independently of extracellular potassium. A direct effect of adrenaline upon the myocardium appears the most likely mechanism.     

Safety of ondansetron loading doses in children with cancer

Introduction In highly emetogenic chemotherapy, the recommended dose of the serotonin-receptor antagonist ondansetron (5 mg/m² q8h) may be insufficient to prevent chemotherapy-induced nausea and vomiting. In adults, ondansetron-loading doses (OLD) of 32 mg are safe. We aimed to evaluate in children the safety of an OLD of 16 mg/m² (top, 24 mg) i.v., followed by two doses of 5 mg/m² q8h. Materials and methods This retrospective single-center study included all pediatric oncology patients having received ≥1 OLD between 2002 and 2005. Adverse events (AE) definitely, probably, or possibly related to OLD were studied, excluding AE not or unlikely related to the OLD. Associations between potential predictors and at least moderate AE were analyzed by mixed logistic regression. Results Of 167 patients treated with chemotherapy, 37 (22%) received 543 OLD. The most common AE were hypotension, fatigue, injection site reaction, headache, hot flashes/flushes, and dizziness. At least mild AE were described in 139 OLD (26%), at least moderate AE in 23 (4.2%), and severe AE in 5 (0.9%; exact 95% confidence interval [CI], 0.4–2.1). Life-threatening or lethal AE were not observed (0.0%; 0.0–0.6). At least moderate AE were significantly more frequent in female patients (odds ratio [OR] 3.5; 95% CI 1.4–8.8; p = 0.010), after erroneously given second OLD (17.0; 1.9–154; p = 0.012) and higher 24 h cumulative surface corrected dose (1.26 per mg/m²; 1.06–1.51; p = 0.009). OLD given to infants below 2 years were not associated with more frequent AE. Conclusions Ondansetron-loading doses of 16 mg/m² (top, 24 mg) i.v. seem to be safe in infants, children, and adolescents. Results presented in part at the 20th Symposium of the Multinational Association of Supportive Care in Cancer, St. Gallen, Switzerland, June 27–30, 2007.     

Correlation between QTc interval and clinical severity of subarachnoid hemorrhage depends on the QTc formula used

OBJECTIVES: Subarachnoid hemorrhage (SAH) frequently prolongs QT interval in the acute phase. The purpose of our study is to investigate whether the correlation between electrocardiographic corrected QT interval and the clinical severity of SAH depends on QTc formula used. METHODS: We retrospectively studied 52 consecutive subjects with nontraumatic SAH (extravasation of blood into the spaces covering the central nervous system that are filled with cerebrospinal fluid) who were admitted within the first day of SAH. QT intervals were measured on a standard 12-lead electrocardiography and corrected by Bazett and Hodges formulae. All patients were evaluated according to clinical condition on admission by Hunt-Hess grades. The patients were grouped in two different categories according to QT interval corrected by Bazett and Hodges and scored by Hunt-Hess (HH) grades. RESULTS: Mean age of the study patients was 54 +/- 12 years and of those 31 (60%) were female. Mean values of heart rate and RR interval were 82 +/- 21 bpm and 777 +/- 163 msec, respectively. The mean QTc interval by Bazett and Hodges were 456 +/- 59 msec and 438 +/- 48 msec, respectively (P < 0.001). Twenty-three patients according to Bazett and fifteen according to Hodges had prolonged QTc. Correlation analyses showed relation between HH and QTc and prolonged QTc by Bazett (r = 0.278, P = 0.04 and r = 0.314, P = 0.024; respectively). There was no correlation between HH and QTc and prolonged QTc by Hodges (r = 0.204, P = 0.14 and r = 0.115, P = 0.41; respectively). CONCLUSIONS: In our study, correlation between QTc interval and clinical severity of SAH depended on the QTc formula used.     

PTCA+支架治疗对冠心病患者QTc离散度的影响

目的探讨行PTCA+支架治疗对冠心病患者QTc离散度(QTcd)是否有影响.方法对60例成功地行单支或多支PTCA+支架治疗患者术前及术后24h分别作12导联心电图测量QTc,并计算出QTcd.结果60例患者中,术后QTcd改善44例,恶化6例,无变化10例,术前QTcd为52±18 ms,术后QTcd为43±17 ms,提示QTcd明显降低(P＜0.01).结论有效的PTCA+支架治疗可显著降低冠心病的QTcd,QTcd改善可能是由于PTCA+支架术后增加心肌灌注,从而降低心律失常的危险性.     

Systematic decrements in QTc between the first and second day of contiguous daily ECG recordings under controlled conditions

Background: Many thorough QT (TQT) studies use a baseline day and double delta analysis to account for potential diurnal variation in QTc. However, little is known about systematic changes in the QTc across contiguous days when normal volunteers are brought into a controlled inpatient environment. Methods: Two separate crossover TQT studies included 2 days of no treatment lead‐in days with ECG collection preceding periods of drug treatment . In the first study, there were two pairs of such contiguous days with 10 replicate electrocardiograms (ECGs) collected at six time points, and in the second study, there were four pairs of contiguous days with nine replicate ECGs collected at five time points. These lead‐in day pairs provided the opportunity to evaluate any systematic changes across contiguous first and second days of an inpatient environment. Within‐patient consistency of change across pairs of days as well as within day, diurnal variation could also be evaluated. Results: Modest (4.2 ms [range 1.9–6.5 ms]) but consistent decreases (significant [P < 0.05] for all 32 comparisons) were observed (probability: ≤5.4 × 10^?16). Although group behavior with respect to QTc was consistent, individual subjects demonstrated substantial variability across pairs of days. Evidence of diurnal variation was weak and inconsistent. Magnitude of any diurnal variation was less than magnitude of change across days. Conclusions: Subjects show a systematic decrease in QTc from first day to second day of inpatient status and do not demonstrate a significant diurnal pattern. The magnitude of this systematic change is sufficient to influence QTc study interpretation. (PACE 2011; 34:1116–1127)     

Effects of Nemonoxacin on Thorough ECG QT/QTc Interval: A Randomized,Placebo- and Positive-controlled Crossover Study in Healthy Chinese Adults

Purpose

Nemonoxacin, a nonfluorinated quinolone, has been approved in Taiwan and mainland China for the treatment of bacterial infection. Whether nemonoxacin is associated with the adverse events of other quinolones, such as the risk for QT-interval prolongation, which has led to the withdrawal of several fluoroquinolones from the market, needs to be elucidated.

Intravenous conivaptan: Effects on the QTc interval and other electrocardiographic parameters in healthy volunteers

Prolongation of the QT interval is clinically important because it may be associated with torsade de pointes, a potentially fatal arrhythmia. The objective of this study was to define the effects on electrocardiogram (ECG) of intravenous conivaptan, the first arginine vasopressin V_1A/V₂-receptor antagonist indicated for the treatment of euvolemic hyponatremia, on hospitalized patients without congestive heart failure. After a placebo run-in period, participants in this randomized, single-blind, placebo- and positive-controlled, parallel-group study received an intravenous 20-mg loading dose of conivaptan (day 1), followed by a 40-mg/d continuous infusion (days 1–4); a 20-mg loading dose of conivaptan (day 1), followed by an 80-mg/d continuous infusion (days 1–4); or moxifloxacin 400 mg (positive control) or placebo from day 1 to day 4. The primary ECG endpoint was QTc interval duration, which was determined by the individually corrected QT interval for each subset; secondary endpoints included QT intervals corrected with Bazett’s formula and Fridericia’s formula. No clinically notable changes in ECG parameters were associated with conivaptan, suggesting that conivaptan did not affect cardiac repolarization or cardiac conduction.     

恩丹西酮不同时机用药对曲马多静脉术后自控镇痛恶心、呕吐的影响

目的探讨恩丹两酮不同时机用药对曲马多静脉术后自控镇痛恶心、呕吐的预防作用。方法 将90例ASAⅠ～Ⅱ级、住连续硬膜外麻醉下行下肢手术的病人随机均分为三组：Ⅰ组（不用恩丹西酮）、Ⅱ组（先用恩丹西酮再用曲马多）、Ⅲ组（先用曲马多冉用恩丹西酮）。术毕接PCIA。观察病人术后48h恶心、呕吐情况。结果Ⅱ组恶心、呕吐发生率显著低于Ⅰ组、Ⅲ组（P〈0．05）,Ⅰ组、Ⅲ组两者相比差异无统计学意义（P〉0．05）。结论曲马多负荷剂量前先应用恩丹曲酮可有效顶防曲马多静脉术后镇痛恶心、呕吐,而曲马多负荷剂量后应用恩丹西酮效果不明显。     

Corrected QT interval in relation to the severity of diabetic autonomic neuropathy

The aim of this study was to investigate to what extent the existence of objective signs of diabetic autonomic neuropathy affects the corrected QT interval (QTc) in diabetic subjects. A total of 105 diabetic subjects (type 1, n  = 53; type 2, n  = 52) as well as 40 matched (by age and sex) control subjects were studied. All subjects underwent the battery of five Ewing tests. Autonomic neuropathy was diagnosed if two of the five tests were abnormal. In addition, the result of each test was considered as normal (grade = 0), borderline (grade = 1) or abnormal (grade = 2), and on the basis of the sum of the scores we calculated a total score for autonomic neuropathy. The QTc interval was measured at rest, and a value > 440 ms was considered abnormal. The QTc interval was significantly more prolonged in diabetic persons with autonomic neuropathy than in those without neutopathy and in control subjects: 408.4 ± 24.2 ms vs. 394.6 ± 27.9 ms and 393.6 ± 25.5 ms respectively ( P  = 0.001). Furthermore, multivariate analysis controlling for age, sex, systolic and diastolic blood pressure, body mass index (BMI), waist–hip ratio (WHR), smoking, type and duration of diabetes, type of treatment, HBA_1c and total score of autonomic neuropathy eliminated the role of all these factors as potential confounders except for the total score of autonomic neuropathy, which was found to affect QTc interval independently and significantly ( P  = 0.012). In summary, the present study confirmed the well-known relation between autonomic neuropathy and QTc interval; in addition, it showed that QTc prolongation is associated with major degrees of autonomic neuropathy.     

A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N-of-1 trials design

Goals of work Chemotherapy-induced nausea and vomiting is problematic in paediatric brain tumour treatment protocols which often discourage the use of corticosteroids as anti-emetics. The dopamine receptor antagonist, metopimazine, is an effective anti-emetic in combination with ondansetron in adults. The present study was designed to assess its efficacy in children with cancer, a group in which it has not been studied previously.Patients and methods We conducted a series of randomized, multiple-crossover, double-blind, placebo-controlled N-of-1 trials comparing ondansetron/metopimazine with ondansetron monotherapy in children with brain tumours receiving highly emetogenic therapy and combined the individual results using Bayesian statistical modeling.Main results Ten of twelve enrolled patients completed at least one chemotherapy cycle on study (median=2.5 cycles, range 1–11). Two patients were unable to complete any cycles, and a further three patients withdrew from the study prior to completing all cycles because of an inability to tolerate the taste of the study drug. Combination therapy increased the proportion of days during which patients had no emesis (overall odds ratio=1.52, 95% credible region=0.32–6.40, probability of odds ratio>1=72%), decreased the number of emetic episodes per day (overall rate ratio=0.67, 95% credible region=0.15–3.14, probability of rate ratio<1=75%) and decreased parents ratings of their childs distress. The drug was more effective during the delayed chemotherapy phase than the acute phase. No adverse events were attributed to metopimazine.Conclusions Based on this pilot study, we believe that the high likelihood that metopimazine is an effective adjunct to ondansetron monotherapy suggests that this combination therapy is worthy of further study in children receiving emetogenic chemotherapy.     

Acute effect of methylphenidate on QT interval duration and dispersion in children with attention deficit hyperactivity disorder

Among childhood psychiatric disorders, attention deficit hyperactivity disorder (ADHD) is of greatest interest to practitioners. Methylphenidate (MPH) is a drug that is widely used in the treatment of children in whom ADHD has been diagnosed. Although this treatment has been used for years, its effects on the heart remain the subject of debate. The QT interval comprises the ventricular activation and recovery periods as seen on electrocardiogram (ECG). The acute effect of MPH on QT interval dispersion is unknown. Researchers in the present study sought to investigate the acute effects of MPH on QT interval as seen on ECG. A total of 25 patients with ADHD (mean age, 9.4±2.1 y) who were treated with MPH were enrolled in the study. Twelve-lead derivation ECGs were taken before and 2 h after administration of 10 mg of MPH. Maximum QT interval, minimum QT interval, and interval durations were measured, and QT dispersion was calculated, for each ECG. QT dispersion measured after medication administration decreased significantly from 59.6±16.3 ms to 50.8±10.9 ms (P=.016); corrected QT dispersion decreased significantly from 70.9±17.6 ms to 61.3±13.3 ms (P=.011). Maximum QT interval duration decreased from 373.7±21.8 ms to 361.8±29.0 ms (P=.006); minimum QT interval duration rose from 317.0±23.3 ms to 322.3±21.6 ms (P=.312). In conclusion, the findings of this study show that MPH reduces QT dispersion during the acute period shortly after its administration.     

QTc Dispersion in Hyperthyroidism and Its Association with Pulmonary Hypertension

Background: Several studies have reported that hyperthyroidism is associated with prolonged QT interval corrected by the heart rate (QTc) and pulmonary hypertension (PHT). Methods: Forty‐seven patients with newly diagnosed overt hyperthyroidism and 20 healthy people were enrolled in the study. Transthoracic echocardiography, 12‐lead surface electrocardiogram, and thyroid hormone levels were studied at the time of enrollment and after achievement of euthyroid state with propylthiouracil treatment. Results: Baseline clinical characteristics were similar. However, heart rate (90.5±19.6 vs 79.2±13.7 bpm, P = 0.024), pulmonary artery systolic pressure (PASP) (26.0±12.0 vs 10.6±4.0 mmHg, P < 0.001), E deceleration time (DT) (191.8±25.6 vs 177.0±10.7 ms, P = 0.016), isovolumetric relaxation time (IVRT) (91.38±12.3 vs 79.6±10.5 ms, P < 0.001), and QTc dispersion (QTcD) (50.3±17.2 vs 38.9±11.6 ms, P = 0.009) were significantly higher in hyperthyroid patients compared to control group. Heart rate (to 74.1±13.8, P < 0.001), QTcD (to 37.3±10.1 ms, P < 0.001), DT (to 185.3±19.7 ms, P = 0.008), IVRT (to 88.6±10.3 ms, P = 0.056), and PASP (23.1±10.1 mmHg P < 0.001) were significantly decreased after achievement of euthyroid state. Although PHT was present in 16 patients before treatment only six patients still had PHT during euyhyroid state. Compared to patients with normal PASP, QTcD was significantly longer in patients with PHT (56.5±15.8 vs 37.9±12.8 mmHg P < 0.001). There were also significant correlations between QTcD and presence of PHT (r = 0.516, P < 0.001) and PASP (r = 0.401, P = 0.009). Conclusions: Hyperthyroidism is a reversible cause of PHT and diastolic dysfunction. Increased QTcD observed in hyperthyroidism may be associated with PHT and diastolic dysfunction. These abnormal findings in hyperthyroidism often normalize with the achievement of euthyroid state.     

儿童血管迷走性晕厥QT间期离散度及P波离散度研究

目的　探讨儿童血管迷走性晕厥 (VVS)QT间期离散度 (QTd)及P波离散度 (Pd)的变化。方法　不明原因晕厥(UPS)患儿 5 5例 (研究组 ) ,均进行基础直立倾斜试验 (BHUTT)或 (和 )舌下含服硝酸甘油倾斜试验 (SNTTT)。匹配健康儿童 5 5例为对照 (对照组 )。于BHUTT前一天描记 12导联同步体表心电图 (12ECG)。选择波形清晰的 12ECG 3个心动周期 ,测量心率 (HR)、QTd 与Pd。结果　与对照组比较 ,研究组HR减慢 (P <0 0 1) ,QTmax、QTmin、QTd 延长 (P <0 0 1) ,QTcmax、QTcd增大 (P <0 0 1或P <0 0 5 ) ;Pcmax、Pcmin缩短 (P <0 0 1) ,Pd 及Pcd稍延长 (P >0 0 5 )。QTd、QTcd及Pd、Pcd在VVS患儿男女性别之间无差异(P >0 0 5 ) ,HUTT阳性组与阴性组之间亦未见差异 (P >0 0 5 )。结论　QTd 及Pd 在VVS患儿男女性别及HUTT阳性组与阴性组间未见差异。VVS患儿QTd 及QTcd增大 ,Pd 及Pcd延长不明显 ,临床上要警惕VVS患儿发生室性心律失常。     

Effect of telmisartan on QT interval variability and autonomic control in hypertensive patients with left ventricular hypertrophy

Objectives

The aim of the study was to examine the effect of the antihypertensive AT1 receptors antagonist telmisartan on cardiovascular autonomic function and QT dispersion in hypertensive patients with LVH.

Methods

Twenty-five patients (18 males and seven women, mean age 49.8 ± 5.2 years) with mild essential arterial hypertension and LVH were compared with 25 age-matched healthy controls. All the participants underwent a complete clinical examination, including electrocardiogram for QT interval measurements and 24 h ambulatory ECG monitoring for measurement of heart rate variability. The ECG, 24 h ambulatory ECG, and echocardiogram were repeated after eight weeks of treatment.

Results

At baseline, hypertensive patients showed QT dispersion (p < 0.001) and QTc dispersion (p < 0.001) significantly higher than control subjects. An eight-week telmisartan treatment significantly reduced blood pressure (p < 0.0001), without significant change in left ventricular mass. Telmisartan-based treatment induced an increased vagal activity without significant change of sympathetic activity and a reduction of QT dispersion (p < 0.001) and QTc dispersion (p < 0.001).

Conclusions

These data suggest that therapy with telmisartan significantly improves the sympathovagal balance increasing parasympathetic activity, and cardiac electrical stability reducing the heterogeneity of ventricular repolarization in hypertensive subjects. These effects could contribute to reduce arrhythmias as well as sudden cardiac death in at-risk hypertensive patients.