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Papers by Jean Barbey

Journal of Clinical Oncology, Oct 1, 2003

Purpose: Arsenic trioxide is an effective treatment for patients with acute promyelocytic leukemi... more Purpose: Arsenic trioxide is an effective treatment for patients with acute promyelocytic leukemia (APL) who have relapsed from or are refractory to all-trans-retinoic acid and anthracycline chemotherapy. Since arsenic can prolong the QT interval and lead to torsade de pointes, a life-threatening ventricular arrhythmia, this retrospective analysis was conducted to determine the degree of QT prolongation in patients treated with arsenic trioxide. Patients and Methods: Clinical data and serial ECGs from 99 patients with advanced malignancies who received 170 courses of arsenic trioxide in either a phase I or phase II investigational study were reviewed. Results: Prolonged QT intervals developed in 38 patients (26 patients had intervals ≥ 500 milliseconds). Compared with baseline, the heart rate—corrected (QTc) interval was prolonged by 30 to 60 milliseconds in 36.6% of treatment courses, and by more than 60 milliseconds in 35.4% of patients. The degree of prolongation was higher in men than in women during the first course of therapy, and in patients with hypokalemia. In patients receiving multiple courses, QTc intervals returned to pretreatment levels before the second course, signifying that arsenic trioxide does not permanently prolong the QTc interval. One hypokalemic, arsenic trioxide–treated patient with relapsed APL developed asymptomatic torsade de pointes, which resolved spontaneously and did not recur after electrolyte replacement. There were no sudden or arrhythmia-related deaths. Conclusion: This analysis shows that arsenic trioxide can prolong the QTc interval. However, with appropriate ECG monitoring and management of electrolytes and concomitant medications, arsenic trioxide can be safely administered in patients with relapsed APL.

Clinical Pharmacology & Therapeutics, Feb 1, 1999

Clinical Pharmacology & Therapeutics (1999) 65, 160–160; doi:

Annals of Internal Medicine, Nov 6, 2001

Recently, arsenic trioxide has increasingly been used for relapsed acute promyelocytic leukemia. ... more Recently, arsenic trioxide has increasingly been used for relapsed acute promyelocytic leukemia. However, it is known to have several adverse effects, including acute cardiac toxicities. To determine cardiac toxicities resulting from arsenic trioxide therapy in patients with relapsed or refractory acute promyelocytic leukemia. Phase II clinical prospective cohort study. A university hospital in Hamamatsu, Japan. 8 patients with relapsed acute promyelocytic leukemia. Arsenic trioxide, 0.15 mg/kg of body weight, administered daily by 2-hour infusion for a maximum of 60 days. Continuous monitoring with ambulatory electrocardiography. Five patients (63%) achieved complete remission. During induction therapy with arsenic trioxide, prolonged QT intervals were observed in all patients. Ventricular premature contractions were noticed during 8 of 12 courses of therapy. Four patients developed nonsustained ventricular tachycardia and required treatment with antiarrhythmic agents. Cardiac toxicity occurs during arsenic trioxide therapy in patients with acute promyelocytic leukemia. Such patients should be monitored for prolonged QT intervals and ventricular arrhythmia.

Circulation-cardiovascular Quality and Outcomes, Nov 1, 2011

Background and Objectives: Anorexia nervosa (AN) carries the highest mortality among psychiatric ... more Background and Objectives: Anorexia nervosa (AN) carries the highest mortality among psychiatric illnesses and disproportionately impacts women. QTc prolongation is believed to underlie this risk but is a subject of controversy as ECG data among patients with advanced AN is inadequately characterized. Moreover, previous studies have utilized non-digitized ECG data and therefore have limited measurement precision. We sought to determine the prevalence of QTc prolongation and assess its relationship to body mass index (BMI) and resting energy expenditure (REE) within a national AN referral center. Methods and analysis: We identified 34 patients hospitalized with severe AN. ECGs were obtained on admission then digitized and read with high-precision calipers by a single blinded electrophysiologist. We evaluated the proportion of patients with marked QTc prolongation defined as exceeding 0.500 seconds. Descriptive statistics were used to summarize continuous normally distributed data. Categorical variables were summarized with frequencies and percentages. Pearson's and Spearman's correlation coefficients were used to determine if there was an association between QTc and admission BMI and REE calculated using the Harris Benedict equation. Findings: A total of 31 of 34 (91.2%) patients were women, and median age was 27 years. The median weight on admission was 81.4 pounds and median BMI was 13.5 kg/m 2 (interquartile range 11.8 - 14.5) Mean heart rate was 58 bpm and mean QTc calculated by the Fridericia formula was 0.421 seconds. A QTc interval exceeding 0.500 seconds was seen in only one patient (4.8%). There was no significant correlation between QTcF and either BMI (-0.20, p=0.39) REE (+0.19, p=0.40) on hospital admission. Conclusions: QTc interval prolongation occurs infrequently among patients with severe anorexia nervosa; most exhibit normal cardiac repolarization even at the height of their illness. Disease severity as assessed by admission BMI and REE is not significantly correlated with the QTc interval. Beyond the need for larger studies, these findings suggest that other markers of sudden death should be investigated within this vulnerable population.

Journal of Cardiovascular Pharmacology, 1991

Annals of Noninvasive Electrocardiology, May 4, 2015

Background: Electrocardiographic (ECG) safety evaluation is a required element of drug developmen... more Background: Electrocardiographic (ECG) safety evaluation is a required element of drug development. Performance characteristics of ECG measurement methodologies have rarely been studied prospectively. Methods: We conducted a randomized, placebo-controlled, crossover study in 24 subjects to evaluate effects of moxifloxacin on the Fridericia rate-corrected QT (QTcF) interval. Five ECG replicates were obtained at 30 time points. Change from baseline QTcF (QTcF) was fit by mixed-model analysis of variance to evaluate residual standard deviation. Precision was defined as intrasubject QTcF variance. Two core lab approaches were compared: QTinno, fully automated, 5 replicates and HeartSignals, computer-assisted manual, 3 replicates. Core lab values were then compared to an automated commercial algorithm (VERITAS). Results: Twenty-three subjects provided 3450 ECGs potentially available for analysis. QTinno QTcF values were based upon 3419 ECGs, HeartSignals data on 2028 ECGs. Variance was similar between the QTinno and HeartSignals approaches (41.5 and 44 ms 2). After excluding VERITAS QTcF measurements that deviated by >40 ms on visual review, variance in a set of 1907 common ECGs was lowest for HeartSignal, followed by QTinno and VERITAS (43.8, 52.6, 89.4 ms 2) P = 0.02 HeartSignals versus QTinno, P < 0.0001 for both HeartSignals and QTinno versus VERITAS. Conclusions: A fully automated core lab approach using 5 replicates and a computer-assisted manual approach using 3 replicates were equally precise. When an identical number of ECGs were compared, the computer-assisted manual method was most precise, while the commercial algorithm was relatively imprecise. Although suitable for clinical assessment the standard commercial algorithm cannot be recommended for regulated safety research.

Blood, Sep 1, 2001

different concentrations. Consistent with our earlier report, incubation of Karpas 299 cells with... more different concentrations. Consistent with our earlier report, incubation of Karpas 299 cells with immobilized antibodies to CD30 was found to potently induce cell death, whereas in the same experiment the addition of these antibodies in their soluble form did not induce cell death and actually slightly enhanced viability (Figure 1). Also noteworthy is the fact that, in the earlier report by Gruss et al 4 in which the cytotoxic effects of M44 and M67 were originally described, plate-bound antibodies were used. In preliminary experiments using plate-bound HeFi-1, we have also observed a proapoptotic effect (data not shown). In summary, we suggest that apparently different experimental methods are the most likely explanation for the discrepancies between our report and that of Levi et al, in particular the use of immobilized antibody versus plate-bound antibody. The different effects of soluble and immobilized antibody are suggestive of an intriguing physiologic mechanism by which low levels of CD30 activation may induce cell-cycle arrest, activation of NF-B, and the concomitant induction of antiapoptotic genes, whereas a stronger CD30-activation signal may result in a transient and more limited activation of NF-B and ultimately cell death. The strength of the CD30 signal may be determined by numerous factors, including the density of CD30 receptors on the cell and the form of ligand (ie, membrane-bound or soluble). The threshold sensitivity of a given cell may also be determined by additional factors, such as the stability of intracellular signaling intermediates, particularly TRAF2. Thus, the apparent discrepancies between our data and those of Levi et al may reflect a novel physiologic function of CD30.

Clinical Pharmacology & Therapeutics, Aug 1, 1995

The plasma concentration-response relationship of the antihistamine chlorpheniramine is poorly ch... more The plasma concentration-response relationship of the antihistamine chlorpheniramine is poorly characterized. This study examined concurrently the concentrations of chlorpheniramine and presence of H1-receptor antagonist in plasma after administration of 8 mg chlorpheniramine in normal volunteers. Six extensive metabolizers and five poor metabolizers, as judged by CYP2D6 phenotype (dextromethorphan metabolic ratio), were enrolled in the study. More than 80% occupancy of H1-receptors by antagonist in plasma was observed for 12 hours after the dose in extensive metabolizers and greater than 60% from 12 to 30 hours in poor metabolizers, when plasma concentrations had fallen below those that should result in 50% occupancy of receptors. The results suggest that (+/-)-chlorpheniramine plasma concentrations do not predict H1-receptor antagonist in plasma. In addition, a role is suggested for CYP2D6 in formation of a potent active metabolite of chlorpheniramine.

Circulation, Feb 1, 1988

Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic ... more Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic effects are not well correlated. One explanation is the generation of active metabolites: while in most patients (extensive metabolizers; EMs) concentrations of the metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3MODE) are higher than those of encainide, a small subset (poor metabolizers; PMs) lack the ability to extensively biotransform encainide. Considerable data from studies in vitro and animal studies, as well as indirect evidence in patients, indicate that ODE and 3MODE produce the effects seen during long-term encainide therapy in EMs. We now report the initial direct evaluation of the pharmacologic actions of these metabolites of encainide in man. Nine patients with ventricular arrhythmias, seven of the EM phenotype and two of the PM phenotype, were studied. Chronic high-frequency ventricular arrhythmias were suppressed by encainide therapy in seven of nine; monitoring arrhythmia frequency during withdrawal of encainide allowed definition of plasma concentrations of encainide and metabolites associated with arrhythmia suppression. Intravenous infusions of both ODE and 3MODE suppressed chronic ventricular arrhythmias, while infusions ofplacebo had no effect. ODE clearance was a function of metabolizer phenotype, with higher clearance (mean 914 ml/min; range 554 to 1314) in EMs than in PMs (434, 298 ml/min); moreover, 3MODE was detected during ODE infusions in all seven EMs but in neither PM. 3MODE clearance was more uniform (mean 289 ml/min in EMs [range 180-410] vs 300 and 78 ml/min in the two PMs) and ODE was not detected in any subject during 3MODE infusion. Encainide itself was not detected after any infusion of ODE or 3MODE. During withdrawal of encainide therapy, ODE plasma concentration at the time of arrhythmia recurrence was 55 + 40 ng/ml (mean ± SD), while ODE by infusion was effective at a concentration of 37 + 15 ng/ml. Similarly, plasma concentration of 3MODE at the time of arrhythmia recurrence after withdrawal of chronic encainide was 116 ± 35 ng/ml and that during 3MODE infusion was 105 ± 50 ng/ml. While both compounds prolonged QRS duration, ODE was the more potent, increasing QRS by 9.2 ± 1.6% per 100 ng/ml vs 1.2 ± 0.5% per 100 ng/ml for 3MODE. On the other hand, 3MODE prolonged the corrected JT interval by 1.9 ± 0.6% per 100 ng/ml, while ODE shortened it by 2.7 ± 1.9% per 100 ng/ml. These data indicate that ODE and 3MODE are potent sodium channel-blockers that suppress arrhythmias at the low concentrations noted during long-term encainide therapy in EMs. The disposition of ODE was itself a function of metabolizer phenotype, while that of 3MODE was not strongly associated with metabolizer phenotype. These findings suggest that therapy with ODE would result in variable plasma concentrations, with particularly high values in PMs. 3MODE, however, appears to be a promising agent with different electrocardiographic characteristics than ODE and more uniform disposition, and it therefore merits further evaluation in man.

Clinical Pharmacology & Therapeutics, Jul 1, 1993

Immediate-versus controlled-release disopyrarnide: Importance of saturable 1 1 binding Objective:... more Immediate-versus controlled-release disopyrarnide: Importance of saturable 1 1 binding Objective: To examine the effects of saturable plasma binding on the pharmacokinetics of immediaterelease (IR) and controlled-release (CR) disopyramide. Backflround: Saturable binding causes a lack of correspondence between the pharmacokinetics of total and unbound plasma disopyramide. Levels of total drug may therefore be insensitive to important differences between formulations. Methods: Patients receiving long-term disopyramide underwent serial blood sampling during withdrawal of equivalent doses of IR and CR disopyramide, and during accumulation of I R disopyramide. Plasma disopyramide was measured by enzyme-multiplied immunoassay technique, protein binding by ultrafiltration, and a,-acid glycoprotein by radial immunodiffusion. Pharmacologic effect was assessed by use of high-speed ECGs. Values for plasma area under the concentration-time curve and elimination half-life were determined from the log-plasma concentration data; rate of plasma drug accumulation was determined by nonlinear modeling. Results: Saturable plasma binding was evident in all patients. Comparison of total to unbound drug showed that peak-to-trough ratios during steady state were smaller (1.45 versus 2.39; p < 0.001), elimination half-life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steadystate levels during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0.05). Comparison of IR and CR disopyramide showed that unbound drug levels for CR disopyramide revealed lower peak plasma concentrations (0.75 versus 0.96 pglml) and peak-to-trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in ECG intervals during usual dosing were observed only with IR disopyramide. Conclusimts: Because of saturable plasma binding, total plasma concentrations underestimate fluctuations in unbound disopyramide during usual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects. (CLIN P-COL THER 1993;54:16-22.

General Hospital Psychiatry, Mar 1, 2012

Background: Anorexia nervosa (AN) carries the highest mortality of any psychiatric disorder large... more Background: Anorexia nervosa (AN) carries the highest mortality of any psychiatric disorder largely attributable to sudden cardiac death and suicide. Controversy exists regarding the underlying mechanism of cardiac risk, whether QT prolongation is a consistent feature of the disorder and whether repolarization varies by disease severity. Some of the uncertainty may relate to a lack of standardized electrocardiography (ECG). To date, studies have not utilized centrally adjudicated digital ECG, and most have relied on the Bazett formula for rate-correction, which is suboptimal at the extremes of heart rate often observed in AN. Methods: We evaluated a hospitalized cohort of medically compromised, very-low-body mass index (BMI) AN patients. The QT interval was measured with high-precision calipers by a single, blinded electrophysiologist and rate corrected (QTc) using the Fridericia formula. Anatomically corrected left ventricular (LV) mass and resting energy expenditure (REE) were calculated as proxies for disease severity. Proportions exceeding categorical thresholds for QTc prolongation and correlations between admission QTc and disease severity were performed. Results: Among 19 patients, mean BMI was 12.3 kg/m 2 , and 95% were female. The majority (68%) of patients were receiving QTprolonging drugs. Four patients (21%) had QTc prolongation. Two of these patients (10.5%) exceeded the 500 ms threshold for marked QTcprolongation, though each had concomitant factors contributing to delayed repolarization. The QTc interval was not significantly correlated with LV mass, LV mass index, BMI or REE. Conclusions: Although delayed cardiac repolarization was observed among a medically compromised cohort of patients with anorexia nervosa, the QTc interval was not a reliable correlate of disease severity despite digital ECG adjudication and optimal rate correction.

Clinical Pharmacology & Therapeutics, May 1, 2002

British Journal of Clinical Pharmacology, Mar 1, 2001

Aims 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time ... more Aims 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)-and (x)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults. Methods Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained. Results Mean accumulation half-times (days) for halofantrine were: 7.0t4.8 [(+)halofantrine] and 7.3t4.8 [(x)-halofantrine]. Mean steady-state concentrations were: 97.6t52.0 ng ml x1 [(+)-halofantrine] and 48.5t20.8 [(x)-halofantrine]. Steadystate oral clearance was: 139t73 l h x1 [(+)-halofantrine] and 265t135 l h x1 [(x)-halofantrine]. Peak plasma concentrations of both (+)-and (x)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4±8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)-and (x)-halofantrine concentration. The ®ve subjects who received placebo had no demonstrable change in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.

Clinical Pharmacology & Therapeutics, Feb 1, 1999

Clinical Pharmacology & Therapeutics (1999) 65, 150–150; doi:

European Heart Journal Supplements, Sep 1, 2001

In 1996 the Committee for Proprietary Medicinal Products published their 'Points to consider' whi... more In 1996 the Committee for Proprietary Medicinal Products published their 'Points to consider' which have been used as unofficial guidelines by drug companies developing new pharmacologic compounds. Recommendaitons endorsed by the CPMP regarding hand measurement of the QT interval, QT dispersion, the Bazett QT interval correction for heart rate and the use of signal values for QTc changes compared to baseline are discussed in this paper.

Gastroenterology, Apr 1, 2000

Adverse cardiac events have been reported in patients receiving cisapride. We conducted an indepe... more Adverse cardiac events have been reported in patients receiving cisapride. We conducted an independent case review of all spontaneous adverse event reports of serious ventricular arrhythmias (SVAs) and QT prolongation (t QT) and of clinical events possibly due to SVAs in patients treated with the prokinetic agent, classifying cases by confidence in diagnosis (dx) and presence of cofactors. We assigned confidence in dx conservatively (erring on side of dx of LQTS), and decisions were made solely by us, without company involvement. Of 471 cases reported worldwide from December 1990 through March 1999, 327 (69%) cases of LQTS or t QT were identified; in 83 (18%) no LQTS or t QT was identified and in 61 (13%) there were insufficient data to assess LQTS. In most of the 327 LQTS or t QTcases, we had high (122,51% ofLQTS cases) or medium (77, 32%) confidence in LQTS dx; 86 (26%) had only t QT. Recognized cofactors were present in 222 (68%) t QT or LQTS cases. The percentage of LQTS cases with cofactors rose with confidence level (P<.OOI): Recognized cofactors were present in 100 (82%) cases with high confidence LQTS and 54 (70%) with medium confidence, versus 14 (33%) with low confidence. The most common recognized cofactors in t QT or LQTS were coadministration of medications that increase cisapride levels by inhibiting cytochrome P450 3A4 (97 cases, 44%), electrolyte disturbances (69, 31%), and concomitant QT prolonging drugs (54, 24%). Of cases in which cytochrome P450 3A4 inhibitors were coadministered, clarithromycin, erythromycin, or fluconazole, or a combination of these drugs, was administered in 79 (81%). Other medical conditions cited as contraindications in labeling (eg, heart failure) were uncommon sole cofactors (45,14%). Of 34 (14%) LQTS cases without cofactors, 9 (4%) were designated high-confidence. Most patients with high confidence dx LQTS and no cofactors or other labeled conditions had complex medical histories. We conclude that in the vast majority of cases of LQTS in patients receiving cisapride, recognizable and often preventable cofactors are present and that LQTS risk diminishes when this drug is used appropriately. Additional data and analysis from this ongoing study will be presented. GASTROENTEROLOGY Vol. 118, No.4

American Journal of Cardiology, 1990

OfpdiMtSWith vMtrkulartisupravenbicub arrhythmias. Un-fikeotber~bhckers,sotaMalso~classIII ~ythnk... more OfpdiMtSWith vMtrkulartisupravenbicub arrhythmias. Un-fikeotber~bhckers,sotaMalso~classIII ~ythnkactian,evHencedbyprdoneationof the myouudial action potential duatlan. This addi-tionalacthpmbabtyaccountsfortlKfgreaterantianlmythnkeffkacyofsotalodcmnparedwitbother /3 blockers. kmgathm of ratecocrected QT (QTc) (a measure of dassIIIacth)andttwdegreeofj+recept~blodcade (assessed by the redutii of the maximal exerciseinducedhecvtrate), 11 of 17patiemtshadan aMytbmk~. Eightofthesellre-had-tamqedve to camventbn8l j9receptormtagodsts. The plasma txnmntration associated wnfl signmad QTC p#tAongation (2.55 pg/ml)warfomdtobemuchgreaterthanthatas-soc&tedwith90%inmaximalslowingof beart rate (0.9 &ml). As with other @-receptor antagonists, the activHles of sotabl's 2 stereoisomers differ,withtlbel-bomcK having far more @bckhg activity. However, both isomers have equal dau Ill antlaMlytluniiactivHy.wheniMeasbBgdoses0f thedkomerofsotalol(SOto4OOmgevery12 hours) were evahated in patients wltb clue& ventrkdar a&ytlmnias, arrbytbmii trequency was ruppnnred>9O%h3patientsand9O%inlpatient. with 900 n&day, QTc was ptdonged by 12.3 f 7% (p <O.Ol) and the &crease in heart rate at rest by 19.3 f 8.4% (p <0.09) and during peak exercise by 12.3 f 7% (p <trzed wftbp4acebo.Onehterpratrtion sIowtngofthehaclrtrateco&lbetbatd-sotaklber

Journal of Cardiovascular Pharmacology and Therapeutics, Jun 1, 2002

Adverse cardiac events, typically long QT syndrome, have been reported in patients treated with t... more Adverse cardiac events, typically long QT syndrome, have been reported in patients treated with the gastrointestinal prokinetic agent cisapride. To analyze cases of cisapride-associated long QT syndrome and ascertain the degree of confidence in the diagnosis of long QT syndrome and the presence of risk factors. Review of all cases reported to the manufacturer, health authorities, or in the medical literature as of October 1999. Before review, specific definitions and a classification scheme were agreed upon. Each case was classified by confidence in the long QT syndrome diagnosis and the presence of recognized risk factors (cofactors) or other medical conditions that were listed as contraindications in the June 1998 United States labeling (labeled conditions). Of 574 cases reviewed, 391 cases of long QT syndrome or isolated QT prolongation were confirmed. Most of these were classified as long QT syndrome with high (145, 37%) or medium (92, 23.5%) confidence in the diagnosis. Recognized cofactors were present in 262 (67%) cases. The proportion of cases with recognized cofactors rose with confidence in the diagnosis (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) from 42.2% in the low-confidence group to 68.5% and 82.1% in the medium- and high-confidence groups, respectively. Conversely, the proportion of cases with other labeled conditions decreased with confidence in the diagnosis, from 33.3% for low confidence to 13% and 8.3% for medium and high confidence, respectively. Analysis of cases and prescribing data showed reporting rates decreased in studied months in 1999 compared with the average study period. In most cases with high or medium confidence in the diagnosis of cisapride-associated long QT syndrome, recognized cofactors for long QT syndrome were present. The risk of cisapride-related long QT syndrome may be minimized by avoiding cofactors.

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Clinical Pharmacology & Therapeutics, May 27, 2002

Cardiology Clinics, May 1, 1997

Vasodepressor syncope is a common medical problem that can be diagnosed through an accurate histo... more Vasodepressor syncope is a common medical problem that can be diagnosed through an accurate history and upright tilt testing. In most cases, patients experience a striking decrease in syncopal episodes following a tilt test, and long-term therapy is not necessary. In the rare patient who experiences no prodrome and continues to experience injury-causing syncope, empiric therapy with drugs or dual-chamber pacing has to be considered despite the lack of controlled trials establishing the efficacy of such therapies.

Journal of Clinical Oncology, Oct 1, 2003

Purpose: Arsenic trioxide is an effective treatment for patients with acute promyelocytic leukemi... more Purpose: Arsenic trioxide is an effective treatment for patients with acute promyelocytic leukemia (APL) who have relapsed from or are refractory to all-trans-retinoic acid and anthracycline chemotherapy. Since arsenic can prolong the QT interval and lead to torsade de pointes, a life-threatening ventricular arrhythmia, this retrospective analysis was conducted to determine the degree of QT prolongation in patients treated with arsenic trioxide. Patients and Methods: Clinical data and serial ECGs from 99 patients with advanced malignancies who received 170 courses of arsenic trioxide in either a phase I or phase II investigational study were reviewed. Results: Prolonged QT intervals developed in 38 patients (26 patients had intervals ≥ 500 milliseconds). Compared with baseline, the heart rate—corrected (QTc) interval was prolonged by 30 to 60 milliseconds in 36.6% of treatment courses, and by more than 60 milliseconds in 35.4% of patients. The degree of prolongation was higher in men than in women during the first course of therapy, and in patients with hypokalemia. In patients receiving multiple courses, QTc intervals returned to pretreatment levels before the second course, signifying that arsenic trioxide does not permanently prolong the QTc interval. One hypokalemic, arsenic trioxide–treated patient with relapsed APL developed asymptomatic torsade de pointes, which resolved spontaneously and did not recur after electrolyte replacement. There were no sudden or arrhythmia-related deaths. Conclusion: This analysis shows that arsenic trioxide can prolong the QTc interval. However, with appropriate ECG monitoring and management of electrolytes and concomitant medications, arsenic trioxide can be safely administered in patients with relapsed APL.

Clinical Pharmacology & Therapeutics, Feb 1, 1999

Clinical Pharmacology & Therapeutics (1999) 65, 160–160; doi:

Annals of Internal Medicine, Nov 6, 2001

Recently, arsenic trioxide has increasingly been used for relapsed acute promyelocytic leukemia. ... more Recently, arsenic trioxide has increasingly been used for relapsed acute promyelocytic leukemia. However, it is known to have several adverse effects, including acute cardiac toxicities. To determine cardiac toxicities resulting from arsenic trioxide therapy in patients with relapsed or refractory acute promyelocytic leukemia. Phase II clinical prospective cohort study. A university hospital in Hamamatsu, Japan. 8 patients with relapsed acute promyelocytic leukemia. Arsenic trioxide, 0.15 mg/kg of body weight, administered daily by 2-hour infusion for a maximum of 60 days. Continuous monitoring with ambulatory electrocardiography. Five patients (63%) achieved complete remission. During induction therapy with arsenic trioxide, prolonged QT intervals were observed in all patients. Ventricular premature contractions were noticed during 8 of 12 courses of therapy. Four patients developed nonsustained ventricular tachycardia and required treatment with antiarrhythmic agents. Cardiac toxicity occurs during arsenic trioxide therapy in patients with acute promyelocytic leukemia. Such patients should be monitored for prolonged QT intervals and ventricular arrhythmia.

Circulation-cardiovascular Quality and Outcomes, Nov 1, 2011

Background and Objectives: Anorexia nervosa (AN) carries the highest mortality among psychiatric ... more Background and Objectives: Anorexia nervosa (AN) carries the highest mortality among psychiatric illnesses and disproportionately impacts women. QTc prolongation is believed to underlie this risk but is a subject of controversy as ECG data among patients with advanced AN is inadequately characterized. Moreover, previous studies have utilized non-digitized ECG data and therefore have limited measurement precision. We sought to determine the prevalence of QTc prolongation and assess its relationship to body mass index (BMI) and resting energy expenditure (REE) within a national AN referral center. Methods and analysis: We identified 34 patients hospitalized with severe AN. ECGs were obtained on admission then digitized and read with high-precision calipers by a single blinded electrophysiologist. We evaluated the proportion of patients with marked QTc prolongation defined as exceeding 0.500 seconds. Descriptive statistics were used to summarize continuous normally distributed data. Categorical variables were summarized with frequencies and percentages. Pearson&amp;amp;#39;s and Spearman&amp;amp;#39;s correlation coefficients were used to determine if there was an association between QTc and admission BMI and REE calculated using the Harris Benedict equation. Findings: A total of 31 of 34 (91.2%) patients were women, and median age was 27 years. The median weight on admission was 81.4 pounds and median BMI was 13.5 kg/m 2 (interquartile range 11.8 - 14.5) Mean heart rate was 58 bpm and mean QTc calculated by the Fridericia formula was 0.421 seconds. A QTc interval exceeding 0.500 seconds was seen in only one patient (4.8%). There was no significant correlation between QTcF and either BMI (-0.20, p=0.39) REE (+0.19, p=0.40) on hospital admission. Conclusions: QTc interval prolongation occurs infrequently among patients with severe anorexia nervosa; most exhibit normal cardiac repolarization even at the height of their illness. Disease severity as assessed by admission BMI and REE is not significantly correlated with the QTc interval. Beyond the need for larger studies, these findings suggest that other markers of sudden death should be investigated within this vulnerable population.

Journal of Cardiovascular Pharmacology, 1991

Annals of Noninvasive Electrocardiology, May 4, 2015

Background: Electrocardiographic (ECG) safety evaluation is a required element of drug developmen... more Background: Electrocardiographic (ECG) safety evaluation is a required element of drug development. Performance characteristics of ECG measurement methodologies have rarely been studied prospectively. Methods: We conducted a randomized, placebo-controlled, crossover study in 24 subjects to evaluate effects of moxifloxacin on the Fridericia rate-corrected QT (QTcF) interval. Five ECG replicates were obtained at 30 time points. Change from baseline QTcF (QTcF) was fit by mixed-model analysis of variance to evaluate residual standard deviation. Precision was defined as intrasubject QTcF variance. Two core lab approaches were compared: QTinno, fully automated, 5 replicates and HeartSignals, computer-assisted manual, 3 replicates. Core lab values were then compared to an automated commercial algorithm (VERITAS). Results: Twenty-three subjects provided 3450 ECGs potentially available for analysis. QTinno QTcF values were based upon 3419 ECGs, HeartSignals data on 2028 ECGs. Variance was similar between the QTinno and HeartSignals approaches (41.5 and 44 ms 2). After excluding VERITAS QTcF measurements that deviated by >40 ms on visual review, variance in a set of 1907 common ECGs was lowest for HeartSignal, followed by QTinno and VERITAS (43.8, 52.6, 89.4 ms 2) P = 0.02 HeartSignals versus QTinno, P < 0.0001 for both HeartSignals and QTinno versus VERITAS. Conclusions: A fully automated core lab approach using 5 replicates and a computer-assisted manual approach using 3 replicates were equally precise. When an identical number of ECGs were compared, the computer-assisted manual method was most precise, while the commercial algorithm was relatively imprecise. Although suitable for clinical assessment the standard commercial algorithm cannot be recommended for regulated safety research.

Blood, Sep 1, 2001

different concentrations. Consistent with our earlier report, incubation of Karpas 299 cells with... more different concentrations. Consistent with our earlier report, incubation of Karpas 299 cells with immobilized antibodies to CD30 was found to potently induce cell death, whereas in the same experiment the addition of these antibodies in their soluble form did not induce cell death and actually slightly enhanced viability (Figure 1). Also noteworthy is the fact that, in the earlier report by Gruss et al 4 in which the cytotoxic effects of M44 and M67 were originally described, plate-bound antibodies were used. In preliminary experiments using plate-bound HeFi-1, we have also observed a proapoptotic effect (data not shown). In summary, we suggest that apparently different experimental methods are the most likely explanation for the discrepancies between our report and that of Levi et al, in particular the use of immobilized antibody versus plate-bound antibody. The different effects of soluble and immobilized antibody are suggestive of an intriguing physiologic mechanism by which low levels of CD30 activation may induce cell-cycle arrest, activation of NF-B, and the concomitant induction of antiapoptotic genes, whereas a stronger CD30-activation signal may result in a transient and more limited activation of NF-B and ultimately cell death. The strength of the CD30 signal may be determined by numerous factors, including the density of CD30 receptors on the cell and the form of ligand (ie, membrane-bound or soluble). The threshold sensitivity of a given cell may also be determined by additional factors, such as the stability of intracellular signaling intermediates, particularly TRAF2. Thus, the apparent discrepancies between our data and those of Levi et al may reflect a novel physiologic function of CD30.

Clinical Pharmacology & Therapeutics, Aug 1, 1995

The plasma concentration-response relationship of the antihistamine chlorpheniramine is poorly ch... more The plasma concentration-response relationship of the antihistamine chlorpheniramine is poorly characterized. This study examined concurrently the concentrations of chlorpheniramine and presence of H1-receptor antagonist in plasma after administration of 8 mg chlorpheniramine in normal volunteers. Six extensive metabolizers and five poor metabolizers, as judged by CYP2D6 phenotype (dextromethorphan metabolic ratio), were enrolled in the study. More than 80% occupancy of H1-receptors by antagonist in plasma was observed for 12 hours after the dose in extensive metabolizers and greater than 60% from 12 to 30 hours in poor metabolizers, when plasma concentrations had fallen below those that should result in 50% occupancy of receptors. The results suggest that (+/-)-chlorpheniramine plasma concentrations do not predict H1-receptor antagonist in plasma. In addition, a role is suggested for CYP2D6 in formation of a potent active metabolite of chlorpheniramine.

Circulation, Feb 1, 1988

Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic ... more Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic effects are not well correlated. One explanation is the generation of active metabolites: while in most patients (extensive metabolizers; EMs) concentrations of the metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3MODE) are higher than those of encainide, a small subset (poor metabolizers; PMs) lack the ability to extensively biotransform encainide. Considerable data from studies in vitro and animal studies, as well as indirect evidence in patients, indicate that ODE and 3MODE produce the effects seen during long-term encainide therapy in EMs. We now report the initial direct evaluation of the pharmacologic actions of these metabolites of encainide in man. Nine patients with ventricular arrhythmias, seven of the EM phenotype and two of the PM phenotype, were studied. Chronic high-frequency ventricular arrhythmias were suppressed by encainide therapy in seven of nine; monitoring arrhythmia frequency during withdrawal of encainide allowed definition of plasma concentrations of encainide and metabolites associated with arrhythmia suppression. Intravenous infusions of both ODE and 3MODE suppressed chronic ventricular arrhythmias, while infusions ofplacebo had no effect. ODE clearance was a function of metabolizer phenotype, with higher clearance (mean 914 ml/min; range 554 to 1314) in EMs than in PMs (434, 298 ml/min); moreover, 3MODE was detected during ODE infusions in all seven EMs but in neither PM. 3MODE clearance was more uniform (mean 289 ml/min in EMs [range 180-410] vs 300 and 78 ml/min in the two PMs) and ODE was not detected in any subject during 3MODE infusion. Encainide itself was not detected after any infusion of ODE or 3MODE. During withdrawal of encainide therapy, ODE plasma concentration at the time of arrhythmia recurrence was 55 + 40 ng/ml (mean ± SD), while ODE by infusion was effective at a concentration of 37 + 15 ng/ml. Similarly, plasma concentration of 3MODE at the time of arrhythmia recurrence after withdrawal of chronic encainide was 116 ± 35 ng/ml and that during 3MODE infusion was 105 ± 50 ng/ml. While both compounds prolonged QRS duration, ODE was the more potent, increasing QRS by 9.2 ± 1.6% per 100 ng/ml vs 1.2 ± 0.5% per 100 ng/ml for 3MODE. On the other hand, 3MODE prolonged the corrected JT interval by 1.9 ± 0.6% per 100 ng/ml, while ODE shortened it by 2.7 ± 1.9% per 100 ng/ml. These data indicate that ODE and 3MODE are potent sodium channel-blockers that suppress arrhythmias at the low concentrations noted during long-term encainide therapy in EMs. The disposition of ODE was itself a function of metabolizer phenotype, while that of 3MODE was not strongly associated with metabolizer phenotype. These findings suggest that therapy with ODE would result in variable plasma concentrations, with particularly high values in PMs. 3MODE, however, appears to be a promising agent with different electrocardiographic characteristics than ODE and more uniform disposition, and it therefore merits further evaluation in man.

Clinical Pharmacology & Therapeutics, Jul 1, 1993

Immediate-versus controlled-release disopyrarnide: Importance of saturable 1 1 binding Objective:... more Immediate-versus controlled-release disopyrarnide: Importance of saturable 1 1 binding Objective: To examine the effects of saturable plasma binding on the pharmacokinetics of immediaterelease (IR) and controlled-release (CR) disopyramide. Backflround: Saturable binding causes a lack of correspondence between the pharmacokinetics of total and unbound plasma disopyramide. Levels of total drug may therefore be insensitive to important differences between formulations. Methods: Patients receiving long-term disopyramide underwent serial blood sampling during withdrawal of equivalent doses of IR and CR disopyramide, and during accumulation of I R disopyramide. Plasma disopyramide was measured by enzyme-multiplied immunoassay technique, protein binding by ultrafiltration, and a,-acid glycoprotein by radial immunodiffusion. Pharmacologic effect was assessed by use of high-speed ECGs. Values for plasma area under the concentration-time curve and elimination half-life were determined from the log-plasma concentration data; rate of plasma drug accumulation was determined by nonlinear modeling. Results: Saturable plasma binding was evident in all patients. Comparison of total to unbound drug showed that peak-to-trough ratios during steady state were smaller (1.45 versus 2.39; p < 0.001), elimination half-life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steadystate levels during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0.05). Comparison of IR and CR disopyramide showed that unbound drug levels for CR disopyramide revealed lower peak plasma concentrations (0.75 versus 0.96 pglml) and peak-to-trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in ECG intervals during usual dosing were observed only with IR disopyramide. Conclusimts: Because of saturable plasma binding, total plasma concentrations underestimate fluctuations in unbound disopyramide during usual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects. (CLIN P-COL THER 1993;54:16-22.

General Hospital Psychiatry, Mar 1, 2012

Background: Anorexia nervosa (AN) carries the highest mortality of any psychiatric disorder large... more Background: Anorexia nervosa (AN) carries the highest mortality of any psychiatric disorder largely attributable to sudden cardiac death and suicide. Controversy exists regarding the underlying mechanism of cardiac risk, whether QT prolongation is a consistent feature of the disorder and whether repolarization varies by disease severity. Some of the uncertainty may relate to a lack of standardized electrocardiography (ECG). To date, studies have not utilized centrally adjudicated digital ECG, and most have relied on the Bazett formula for rate-correction, which is suboptimal at the extremes of heart rate often observed in AN. Methods: We evaluated a hospitalized cohort of medically compromised, very-low-body mass index (BMI) AN patients. The QT interval was measured with high-precision calipers by a single, blinded electrophysiologist and rate corrected (QTc) using the Fridericia formula. Anatomically corrected left ventricular (LV) mass and resting energy expenditure (REE) were calculated as proxies for disease severity. Proportions exceeding categorical thresholds for QTc prolongation and correlations between admission QTc and disease severity were performed. Results: Among 19 patients, mean BMI was 12.3 kg/m 2 , and 95% were female. The majority (68%) of patients were receiving QTprolonging drugs. Four patients (21%) had QTc prolongation. Two of these patients (10.5%) exceeded the 500 ms threshold for marked QTcprolongation, though each had concomitant factors contributing to delayed repolarization. The QTc interval was not significantly correlated with LV mass, LV mass index, BMI or REE. Conclusions: Although delayed cardiac repolarization was observed among a medically compromised cohort of patients with anorexia nervosa, the QTc interval was not a reliable correlate of disease severity despite digital ECG adjudication and optimal rate correction.

Clinical Pharmacology & Therapeutics, May 1, 2002

British Journal of Clinical Pharmacology, Mar 1, 2001

Aims 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time ... more Aims 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)-and (x)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults. Methods Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained. Results Mean accumulation half-times (days) for halofantrine were: 7.0t4.8 [(+)halofantrine] and 7.3t4.8 [(x)-halofantrine]. Mean steady-state concentrations were: 97.6t52.0 ng ml x1 [(+)-halofantrine] and 48.5t20.8 [(x)-halofantrine]. Steadystate oral clearance was: 139t73 l h x1 [(+)-halofantrine] and 265t135 l h x1 [(x)-halofantrine]. Peak plasma concentrations of both (+)-and (x)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4±8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)-and (x)-halofantrine concentration. The ®ve subjects who received placebo had no demonstrable change in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.

Clinical Pharmacology & Therapeutics, Feb 1, 1999

Clinical Pharmacology & Therapeutics (1999) 65, 150–150; doi:

European Heart Journal Supplements, Sep 1, 2001

In 1996 the Committee for Proprietary Medicinal Products published their 'Points to consider' whi... more In 1996 the Committee for Proprietary Medicinal Products published their 'Points to consider' which have been used as unofficial guidelines by drug companies developing new pharmacologic compounds. Recommendaitons endorsed by the CPMP regarding hand measurement of the QT interval, QT dispersion, the Bazett QT interval correction for heart rate and the use of signal values for QTc changes compared to baseline are discussed in this paper.

Gastroenterology, Apr 1, 2000

Adverse cardiac events have been reported in patients receiving cisapride. We conducted an indepe... more Adverse cardiac events have been reported in patients receiving cisapride. We conducted an independent case review of all spontaneous adverse event reports of serious ventricular arrhythmias (SVAs) and QT prolongation (t QT) and of clinical events possibly due to SVAs in patients treated with the prokinetic agent, classifying cases by confidence in diagnosis (dx) and presence of cofactors. We assigned confidence in dx conservatively (erring on side of dx of LQTS), and decisions were made solely by us, without company involvement. Of 471 cases reported worldwide from December 1990 through March 1999, 327 (69%) cases of LQTS or t QT were identified; in 83 (18%) no LQTS or t QT was identified and in 61 (13%) there were insufficient data to assess LQTS. In most of the 327 LQTS or t QTcases, we had high (122,51% ofLQTS cases) or medium (77, 32%) confidence in LQTS dx; 86 (26%) had only t QT. Recognized cofactors were present in 222 (68%) t QT or LQTS cases. The percentage of LQTS cases with cofactors rose with confidence level (P<.OOI): Recognized cofactors were present in 100 (82%) cases with high confidence LQTS and 54 (70%) with medium confidence, versus 14 (33%) with low confidence. The most common recognized cofactors in t QT or LQTS were coadministration of medications that increase cisapride levels by inhibiting cytochrome P450 3A4 (97 cases, 44%), electrolyte disturbances (69, 31%), and concomitant QT prolonging drugs (54, 24%). Of cases in which cytochrome P450 3A4 inhibitors were coadministered, clarithromycin, erythromycin, or fluconazole, or a combination of these drugs, was administered in 79 (81%). Other medical conditions cited as contraindications in labeling (eg, heart failure) were uncommon sole cofactors (45,14%). Of 34 (14%) LQTS cases without cofactors, 9 (4%) were designated high-confidence. Most patients with high confidence dx LQTS and no cofactors or other labeled conditions had complex medical histories. We conclude that in the vast majority of cases of LQTS in patients receiving cisapride, recognizable and often preventable cofactors are present and that LQTS risk diminishes when this drug is used appropriately. Additional data and analysis from this ongoing study will be presented. GASTROENTEROLOGY Vol. 118, No.4

American Journal of Cardiology, 1990

OfpdiMtSWith vMtrkulartisupravenbicub arrhythmias. Un-fikeotber~bhckers,sotaMalso~classIII ~ythnk... more OfpdiMtSWith vMtrkulartisupravenbicub arrhythmias. Un-fikeotber~bhckers,sotaMalso~classIII ~ythnkactian,evHencedbyprdoneationof the myouudial action potential duatlan. This addi-tionalacthpmbabtyaccountsfortlKfgreaterantianlmythnkeffkacyofsotalodcmnparedwitbother /3 blockers. kmgathm of ratecocrected QT (QTc) (a measure of dassIIIacth)andttwdegreeofj+recept~blodcade (assessed by the redutii of the maximal exerciseinducedhecvtrate), 11 of 17patiemtshadan aMytbmk~. Eightofthesellre-had-tamqedve to camventbn8l j9receptormtagodsts. The plasma txnmntration associated wnfl signmad QTC p#tAongation (2.55 pg/ml)warfomdtobemuchgreaterthanthatas-soc&tedwith90%inmaximalslowingof beart rate (0.9 &ml). As with other @-receptor antagonists, the activHles of sotabl's 2 stereoisomers differ,withtlbel-bomcK having far more @bckhg activity. However, both isomers have equal dau Ill antlaMlytluniiactivHy.wheniMeasbBgdoses0f thedkomerofsotalol(SOto4OOmgevery12 hours) were evahated in patients wltb clue& ventrkdar a&ytlmnias, arrbytbmii trequency was ruppnnred>9O%h3patientsand9O%inlpatient. with 900 n&day, QTc was ptdonged by 12.3 f 7% (p <O.Ol) and the &crease in heart rate at rest by 19.3 f 8.4% (p <0.09) and during peak exercise by 12.3 f 7% (p <trzed wftbp4acebo.Onehterpratrtion sIowtngofthehaclrtrateco&lbetbatd-sotaklber

Journal of Cardiovascular Pharmacology and Therapeutics, Jun 1, 2002

Adverse cardiac events, typically long QT syndrome, have been reported in patients treated with t... more Adverse cardiac events, typically long QT syndrome, have been reported in patients treated with the gastrointestinal prokinetic agent cisapride. To analyze cases of cisapride-associated long QT syndrome and ascertain the degree of confidence in the diagnosis of long QT syndrome and the presence of risk factors. Review of all cases reported to the manufacturer, health authorities, or in the medical literature as of October 1999. Before review, specific definitions and a classification scheme were agreed upon. Each case was classified by confidence in the long QT syndrome diagnosis and the presence of recognized risk factors (cofactors) or other medical conditions that were listed as contraindications in the June 1998 United States labeling (labeled conditions). Of 574 cases reviewed, 391 cases of long QT syndrome or isolated QT prolongation were confirmed. Most of these were classified as long QT syndrome with high (145, 37%) or medium (92, 23.5%) confidence in the diagnosis. Recognized cofactors were present in 262 (67%) cases. The proportion of cases with recognized cofactors rose with confidence in the diagnosis (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) from 42.2% in the low-confidence group to 68.5% and 82.1% in the medium- and high-confidence groups, respectively. Conversely, the proportion of cases with other labeled conditions decreased with confidence in the diagnosis, from 33.3% for low confidence to 13% and 8.3% for medium and high confidence, respectively. Analysis of cases and prescribing data showed reporting rates decreased in studied months in 1999 compared with the average study period. In most cases with high or medium confidence in the diagnosis of cisapride-associated long QT syndrome, recognized cofactors for long QT syndrome were present. The risk of cisapride-related long QT syndrome may be minimized by avoiding cofactors.

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Clinical Pharmacology & Therapeutics, May 27, 2002

Cardiology Clinics, May 1, 1997

Vasodepressor syncope is a common medical problem that can be diagnosed through an accurate histo... more Vasodepressor syncope is a common medical problem that can be diagnosed through an accurate history and upright tilt testing. In most cases, patients experience a striking decrease in syncopal episodes following a tilt test, and long-term therapy is not necessary. In the rare patient who experiences no prodrome and continues to experience injury-causing syncope, empiric therapy with drugs or dual-chamber pacing has to be considered despite the lack of controlled trials establishing the efficacy of such therapies.