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Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia.
Vanachayangkul, P, Lon, C, Spring, M, Sok, S, Ta-Aksorn, W, Kodchakorn, C, Pann, ST, Chann, S, Ittiverakul, M, Sriwichai, S, et al
Antimicrobial agents and chemotherapy. 2017;(5)
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Abstract
Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.).
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Whole-exome sequencing to identify a novel LMNA gene mutation associated with inherited cardiac conduction disease.
Lai, CC, Yeh, YH, Hsieh, WP, Kuo, CT, Wang, WC, Chu, CH, Hung, CL, Cheng, CY, Tsai, HY, Lee, JL, et al
PloS one. 2013;(12):e83322
Abstract
BACKGROUND Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. OBJECTIVE To investigate the genetic background of a family affected by inherited CCD. METHODS AND RESULTS We used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model. CONCLUSIONS Our results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases.
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Potassium sparing diuretics as adjunct to mannitol therapy in neurocritical care patients with cerebral edema: effects on potassium homeostasis and cardiac arrhythmias.
Bilotta, F, Giovannini, F, Aghilone, F, Stazi, E, Titi, L, Zeppa, IO, Rosa, G
Neurocritical care. 2012;(2):280-5
Abstract
BACKGROUND Mannitol therapy to treat cerebral edema induces osmotic diuresis and electrolyte loss. In neurocritical care patients, potassium is the electrolyte that most often needs replacement. Objective of this study was to evaluate the effects of adding potassium sparing diuretic (canrenone) to mannitol therapy on potassium urinary excretion, potassium plasma levels, and incidence of new cardiac arrhythmias in patients receiving neurocritical care for cerebral edema. METHODS Fifty-six patients were prospectively assigned to mannitol or mannitol plus i.v. canrenone. Potassium urinary excretion, potassium plasma levels, urinary volume, and the incidence of new cardiac arrhythmias were recorded during the first 8 days of therapy. RESULTS In patients treated with mannitol the potassium urinary excretion was stable over the first 3 days and significantly increased, compared to baseline, on day 4th to 8th (baseline 20.3 ± 10.6 mEq/l/die, day 8th 24.6 ± 10.6 mEq/l/die, P < 0.05); while potassium plasma levels significantly decreased. In patients receiving mannitol plus canrenone potassium urinary excretion decreased from day 3rd to 8th (baseline 21.9 ± 11.6 mEq/l/die, day 8th 15.9 ± 10.9 mEq/l/die, P < 0.015) and potassium plasma levels increased but remained within normal values range. The incidence of new cardiac arrhythmias was higher in the mannitol group than the mannitol plus canrenone group (35.7 vs. 10.7%; P < 0.01). Urinary volumes, potassium balance, and sodium plasma concentration were similar in the 2 study groups. CONCLUSION In patients receiving neurocritical care for cerebral edema, the adjunct of a potassium sparing diuretic (canrenone) to mannitol therapy reduces potassium urinary loss, prevents hypokalemia, and reduces the incidence of new cardiac arrhythmias.
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Diagnostic accuracy and image quality of cardiac dual-source computed tomography in patients with arrhythmia.
Tsiflikas, I, Drosch, T, Brodoefel, H, Thomas, C, Reimann, A, Till, A, Nittka, D, Kopp, AF, Schroeder, S, Heuschmid, M, et al
International journal of cardiology. 2010;(1):79-85
Abstract
BACKGROUND Cardiac multi-detector computed tomography (MDCT) permits accurate visualization of high-grade coronary artery stenosis. However, in patients with heart rate irregularities, MDCT was found to have limitations. Thus, the aim of the present study was to evaluate the diagnostic accuracy of a new dual-source computed tomography (DSCT) scanner generation with 83 ms temporal resolution in patients without stable sinus rhythm. METHODS 44 patients (31 men, mean age 67.5+/-9.2 years) without stable sinus rhythm and scheduled for invasive coronary angiography (ICA) because of suspected (n=17) or known coronary artery disease (CAD, n=27) were included in this study. All patients were examined with DSCT (Somatom Definition, Siemens). Besides assessment of total calcium score, all coronary segments were analyzed with regard to the presence of significant coronary artery lesions (>50%). The findings were compared to ICA in a blinded fashion. RESULTS During CT examination, heart rhythm was as follows: 25 patients (57%) atrial fibrillation, 7 patients (16%) ventricular extrasystoles (two of them with atrial fibrillation), 4 patients (9%) supraventricular extrasystoles, 10 patients (23%) sinus arrhythmia (heart rate variability>10 bpm). Mean heart rate was 69+/-14 bpm, median 65 bpm. Mean Agatston score equivalent (ASE) was 762, ranging from 0 to 4949.7 ASE. Prevalence of CAD was 68% (30/44). 155 segments (27%) showed "step-ladder" artifacts and 28 segments (5%) could not be visualized by DSCT. Only 70 segments (12%) were completely imaged without any artifacts. Based on a coronary segment model, sensitivity was 73%, specificity 91%, positive predictive value 63%, and negative predictive value 94% for the detection of significant lesions (>or=50% diameter stenosis). Overall accuracy was 88%. CONCLUSIONS In patients with heart rate irregularities, including patients with atrial fibrillation and a high prevalence of coronary artery disease, the diagnostic yield of dual-source computed tomography is still hampered due to a high number of segments with "step-ladder" artifacts.
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123 I-mIBG scintigraphy to predict inducibility of ventricular arrhythmias on cardiac electrophysiology testing: a prospective multicenter pilot study.
Bax, JJ, Kraft, O, Buxton, AE, Fjeld, JG, Parízek, P, Agostini, D, Knuuti, J, Flotats, A, Arrighi, J, Muxi, A, et al
Circulation. Cardiovascular imaging. 2008;(2):131-40
Abstract
BACKGROUND Disturbances of autonomic function after infarction are associated with both total mortality and sudden death. Although many imaging techniques for assessing the cardiac autonomic nervous system have been studied, the clinical usefulness of these techniques remains uncertain. This exploratory pilot study examined the relationship between abnormalities of ventricular sympathetic innervation delineated by scintigraphic imaging with (123)I-mIBG and inducible ventricular tachyarrhythmias in patients with left ventricular dysfunction and previous myocardial infarction. METHODS AND RESULTS Fifty patients underwent electrophysiological (EP) testing and 15-minute and 4-hour planar and single photon emission computed tomography (SPECT) imaging with (123)I-mIBG and SPECT imaging with (99m)Tc-tetrofosmin. The primary efficacy variables were the 4-hour heart:mediastinum ratio (H/M) and the (123)I-mIBG/(99m)Tc-tetrofosmin SPECT mismatch score. EP studies were categorized as positive (EP(+)) or negative (EP(-)) for inducibility of sustained (>30 seconds) ventricular tachyarrhythmias. Thirty patients were EP(+), and 20 were EP(-). There were no significant differences in the 4-hour H/M ratios or (123)I-mIBG/(99m)Tc-tetrofosmin SPECT mismatch scores between the two groups. In a multivariable analysis using all (123)I-mIBG and (99m)Tc-tetrofosmin SPECT measurements, the only variable that showed a significant difference between EP(+) and EP(-) patients was the 4-hour (123)I-mIBG SPECT defect score. A 4-hour (123)I-mIBG SPECT defect score of > or =37 yielded a sensitivity of 77% and specificity of 75% for predicting EP results. CONCLUSIONS The standard indices of (123)I-mIBG imaging (H/M and innervation-perfusion mismatch score) are not predictive of EP test results. The association of (123)I-mIBG SPECT defect severity with EP test inducibility in this exploratory study will require confirmation in a larger cohort of patients.
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Discrimination of Brugada syndrome patients from individuals with the saddle-back type ST-segment elevation using a marker of the standard 12-lead electrocardiography.
Nakazawa, K, Sakurai, T, Kishi, R, Takagi, A, Osada, K, Ryu, S, Fujita, S, Matsuda, H, Ishikawa, Y, Miyake, F
Circulation journal : official journal of the Japanese Circulation Society. 2007;(4):546-9
Abstract
BACKGROUND In the clinical situation, the saddle-back (S-B) type is more frequently detected than the coved type. In the present study, the discrimination of Brugada syndrome from the S-B type individuals using a marker of the standard 12-lead electrocardiography (ECG) was attempted. METHODS AND RESULTS The study group consisted of 55 individuals with the S-B type in whom pilsicainide provocation test (PLC test) was carried out. The time from the onset of the QRS wave in lead V(2) (IV (2)) to the peak of the late R-like wave in the QRS wave (PV(2)), and the time from IV(2) to the offset of the QRS wave in lead V(5) (EV(5)) were measured. The coved type was induced by the PLC test in 29 cases (N-C group), but not in the remaining 26 cases (N-N group). The (IV(2) -PV(2)) - (IV(2) - EV(5)) value before the PLS test was greater in the N-C group than in the N-N group. The negative predictive value of ;(IV(2) - PV(2)) - (IV(2) - EV(5)) > or =0' was 76.4% for the prediction of a positive PLC test. CONCLUSIONS A ;(IV(2) - PV(2)) - (IV(2) - EV(5)) > or =0' is a useful ECG marker for the discrimination of Brugada syndrome in the S-B type individuals.
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Cardiac monitoring of patients receiving arsenic trioxide therapy.
Unnikrishnan, D, Dutcher, JP, Garl, S, Varshneya, N, Lucariello, R, Wiernik, PH
British journal of haematology. 2004;(5):610-7
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Abstract
Arsenic trioxide (ATO) is approved for the treatment of acute promyelocytic leukaemia and is under investigation for other malignancies. We report the cardiac findings in 18 patients with haematologic malignancies treated with ATO and assess the role of cardiac factors in fluid retention syndrome observed during ATO therapy. Based on initial observations in 10 patients treated with ATO, cardiac functions in the subsequent eight patients were evaluated prospectively. Evaluation included pre- and during-treatment electrocardiograms, Holter monitoring, echocardiograms, multigated acquisition scan and cardiac stress tests if indicated. All eight patients developed fluid retention during ATO, evidenced by pulmonary congestion, oedema and pleural/pericardial effusions. No cardiac factors were identified that contributed to fluid retention. Six patients had prolonged corrected QT (QTc) compared with baseline, three developed ventricular tachycardia. Sinus tachycardia, ventricular premature contractions, and non-sustained ventricular/supraventricular tachycardia were seen during ATO treatment. Fluid retention and cardiac events did not correlate with the dose or total amount of ATO or prior anthracycline therapy. In summary, fluid overload during ATO therapy does not appear to be cardiac in origin but appears to be drug-related, and may reflect cytokine-induced capillary leak. QTc prolongation, transient arrhythmias and clinically significant arrhythmias were seen with therapeutic doses of ATO.
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Randomised trial on the influence of continuous magnesium infusion on arrhythmias following cardiopulmonary bypass surgery for congenital heart disease.
Dittrich, S, Germanakis, J, Dähnert, I, Stiller, B, Dittrich, H, Vogel, M, Lange, PE
Intensive care medicine. 2003;(7):1141-4
Abstract
OBJECTIVES To check the hypothesis that continuous magnesium infusion protects the heart from arrhythmias following cardiopulmonary bypass surgery for congenital heart disease. DESIGN A prospective randomised placebo-controlled study, with patients stratified in three weight groups. PATIENTS AND PARTICIPANTS The study group ( n=65) postoperatively received a magnesium infusion (1 mmol/kg), the control group ( n=66) received placebo. In both groups serum and ionised magnesium values were followed, and all postoperative arrhythmias were documented for 24 h. MEASUREMENTS AND RESULTS Serum and ionised magnesium in the blood was elevated after the end of bypass (0.54+/-0.15 mmol l(-1) pre-operatively, 0.88+/-0.24 mmol l(-1) postoperatively), where a cardioplegia solution containing magnesium was used. Magnesium values remained at this elevated level in the magnesium therapy group, and decreased to normal pre-operative values within 24 h in controls ( P<0.001). The incidence of postoperative arrhythmias was lower in the study group: 8/65 in the study group and 17/66 in the control group, respectively (chi-squared test, P=0.05). Lower patient weight (32.7 kg versus 22.6 kg), longer cardiopulmonary bypass time (128.7 min versus 87.9 min) and deeper body temperature during extracorporeal circulation (29.2 degrees C versus 32.6 degrees C) were identified as risk factors for postoperative arrhythmias ( P<0.05). CONCLUSIONS Continuous magnesium infusion effectively reduces the rate of arrhythmias following cardiopulmonary bypass surgery for congenital heart disease and should, therefore, be routinely used.
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Magnesium-flush infusion into the aortic root just before reperfusion reduces the requirement for internal defibrillation and early post-perfusion arrhythmias.
Beşoğul, Y, Tünerir, B, Ozdemir, C, Aslan, R
The Journal of international medical research. 2003;(3):202-9
Abstract
Pre- and post-operative administration of magnesium has beneficial effects on post-operative ischaemia and reperfusion arrhythmias, but few studies have examined whether intra-operatively administered magnesium can prevent the effects of intra-operative arrhythmias. The aim of this randomized, double-blind study was to compare the effects of intra-operative magnesium or placebo on intra-operative arrhythmias in patients undergoing coronary bypass grafting. Patients received a flush infusion of magnesium or placebo into the aortic root before cross-clamp removal. The results showed that rate of spontaneous resumption of a cardiac rhythm was significantly higher, and number of shocks for defibrillation, energy requirement for defibrillation and rate of intra-operative ventricular tachyarrhythmias were significantly lower in the magnesium group, compared with the placebo group. The differences in need for temporary pacing, and in serum magnesium levels, were not significant. Intra-operative administration of magnesium has beneficial effects on the outcome of surgery. Larger, multicentre clinical investigations should now be undertaken.
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First clinical experience with the rapid-, short-acting amiodarone derivative E 047/1 after cardiac surgery.
Gombotz, H, Vicenzi, M, Mahla, E, Rehak, P, Metzler, H
European journal of anaesthesiology. 2002;(1):23-31
Abstract
BACKGROUND AND OBJECTIVE Amiodarone is very effective against a variety of dysrhythmias but has poor pharmacodynamic properties and many undesired side-effects. Its short- and rapid-acting derivative E 047/1 may circumvent some of these drawbacks. It is easier to titrate while retaining the high efficacy of amiodarone and may have acceptable influences on haemodynamics and cardiac conduction in patients who develop serious, destabilizing ventricular tachydysrhythmias after cardiac surgery. METHODS Testing E 047/1 was performed prospectively in two consecutive phase II open, clinical studies. Out of 504 patients scheduled for surgery using cardiopulmonary bypass for coronary artery grafting and/or valve repair, 35 developed serious, haemodynamically destabilizing ventricular dysrhythmias (Lown 2-Lown 4b) after surgery and were treated with a 1 mg kg(-1) (pilot study, n = 15) or randomized to a 2 or 3 mg kg(-1) bolus of E 047/1, followed by a 1 mg kg(-1) h(-1) continuous infusion for 2 h (n = 10 in each group). Dysrhythmias, PQ, QTc intervals and haemodynamics using the thermodilution technique were evaluated for up to 24 h after drug initiation. RESULTS At the time of final inclusion the patients had between 6 and 12 (or more) ventricular ectopics per minute. Within the first 2-3 min of application in the pilot trial E 047/1 induced a decrease of ventricular dysrhythmias to between 0 and 4 per min, a decrease that held for the duration of treatment. The area under the curve decreased from 434 (322, 855; median, quartiles) to 114 (9, 477, P < 0.01) events per hour. In the randomized trial, E 047/1 administered in either dose rapidly reduced ventricular dysrhythmias at least as effectively as in the pilot trial 565 (478, 701) to 33 (8, 238, P < 0.05) after a 2 mg bolus; 482 (339, 482) to 95 (13, 540, P < 0.01) events per hour after a 3 mg bolus. Approximately 4-6 h after drug termination, dysrhythmias reappeared in the majority of patients. In only three patients did the incidence of dysrhythmias return to inclusion criteria levels. In contrast to the pilot trial, in the randomized trial there was a slight increase of mean pulmonary artery pressure, central venous pressure and pulmonary arterial wedge pressure and a slight decrease of LCWI in both groups. E 047/1 did not cause QTc prolongation. CONCLUSIONS E 047/1 appears to be a safe alternative to amiodarone in the perioperative setting of cardiac surgery when serious, destabilizing dysrhythmias occur.