Increase In QTc Interval Research Articles

The Additive Interactions Between Ondansetron and Droperidol for Preventing Postoperative Nausea and Vomiting

Prophylactic ondansetron or droperidol reduces the incidence of postoperative nausea and vomiting (PONV). Previous studies showed that the combination of these two drugs produced better antiemetic effect than either drug alone. We present a nonparametric method to determine the pharmacologic interaction between ondansetron and droperidol and compared the observed response of the drug combination with that predicted from additivity. This is calculated as the product of the individual drug response, normalized to that of the controls. Five minutes before induction of anesthesia, 400 patients scheduled for laparoscopic gynecologic surgery were randomly assigned to receive 1) saline IV; 2) ondansetron 4 mg IV; 3) droperidol 1.25 mg IV; or 4) a combination of droperiodol 1.25 mg and ondansetron 4 mg IV. A standardized anesthetic technique and postoperative analgesic regimen were used. Patients were reviewed regularly for 48 h. Changes in the heart rate adjusted QT (QTc) interval were measured from electrocardiograms recorded before and 5 min after study drug administration. In a subgroup of 160 patients, QTc intervals were measured again at 2-3 h after surgery. During the first 48 h after the surgery, the proportion of patients experiencing PONV was 68% (95% CI 58-77) in the control group. A single dose of ondansetron or droperidol decreased the incidence of PONV to 30% (95% CI 21-40) and 28% (95% CI 20-38), respectively. The predicted incidence of PONV after drug combination, 11.8% (7.1-11.9), was similar to that observed, 12.1% (6.4-20.2), P = 0.94. The corresponding predicted and observed treatment responses in the combination group were 88.2% and 87.9%, respectively. There was a modest and transient increase in QTc interval after administration of ondansetron, droperidol, or their combination. The changes were however similar among groups. We conclude that the interaction between ondansetron and droperiodol was additive. Both drugs acted independently of each other through their specific mechanisms of action. The incidence of QTc prolongation did not increase with the drug combination.

Cardiovascular Changes Associated With Venlafaxine in the Treatment of Late-Life Depression

Potential cardiovascular side effects from venlafaxine-XR must be considered when prescribing this medication, especially in geriatric patients, who often present with comorbid medical conditions. Participants age 60 and older with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of a major depressive episode without psychotic features were treated openly with venlafaxine-XR for 12 weeks during which venlafaxine-XR was titrated based on tolerability and response according to predefined guidelines. Sitting and standing blood pressures and heart rates were measured. A 12-lead electrocardiogram was obtained at baseline and at week 12. Sixty-two participants started treatment; 59 completed at least two weeks of the 12-week study. The mean final dose of venlafaxine-XR was 195.5 mg/day (standard deviation: 72.2). Twenty-four percent (95% confidence interval [CI]: 7.3%-40.7%) of initially normotensive participants and 54% (95% CI: 34.3%-74%) of those with preexisting hypertension experienced an increase in blood pressure. Twenty-nine percent (95% CI: 14.6%-43.4%) of participants developed orthostatic hypotension. Two participants experienced a clinically significant increase in QTc interval. One participant reported new-onset mild dizziness, whereas four participants reported new-onset tachycardia or palpitation. Overall, 17 unique participants (28.8%; 95% CI: 17.3%-40.4%) experienced a new-onset cardiovascular problem, potentially related to the study medication. Overall, venlafaxine-XR was well tolerated. However, similar to previous reports, venlafaxine-XR was associated with some undesirable cardiovascular effects in some of the participants. Systematic monitoring of cardiovascular parameters during treatment with venlafaxine-XR should be strongly recommended, especially in the elderly.

Insular involvement in brain infarction increases risk for cardiac arrhythmia and death

Brain injuries may induce cardiac dysrhythmias and sudden cardiac death. We analyzed 12-lead electrocardiograms of 493 consecutive patients with brain infarction (BI) proved by an magnetic resonance imaging and 493 control subjects matched for age, sex, and center. Insular involvement (insula (+/-)) was assessed by two independent readings of the magnetic resonance imaging scans. Cases were followed for 5 years. Acute BI was independently associated with heart rate (< or = 64 beats/min), abnormal repolarization, atrial fibrillation, and ventricular and supraventricular ectopic beats. Lower heart rate in BI patients was due to an interaction with smoking (p for interaction = 0.004). Insula(+) group was significantly associated with abnormal repolarization with no interaction with infarct side. Atrial fibrillation by history was also more frequent in the insula(+) than in the insula(-) group (p = 0.07). After adjustment for age, sex, cardiovascular history, and handicap at admission, right insula(+) BI was significantly associated with 2-year all-cause death (hazard ratio, 2.11; 95% confidence interval, 1.27-3.52) and with vascular death (hazard ratio, 2.00; 95% confidence interval, 1.00-3.93). In multivariate analysis including age, sex, cardiovascular history, handicap at admission, and lesion side, increased QTc interval and left bundle branch block were independent predictors of all-cause and vascular mortality at 2 years in right insula(+) patients. These findings support the notion that right insular involvement may lead to electrocardiographic abnormalities with potential prognostic implications. This could be important for optimal care in patients with right insular infarct.

Effect of Buprenorphine and Antiretroviral Agents on the QT Interval in Opioid-Dependent Patients

Cardiac arrhythmias have been linked to treatment with methadone and levacetylmethadol. HIV-positive patients often have conditions that place them at risk for QT interval prolongation including HIV-associated dilated cardiomyopathy, coronary artery disease as a consequence of highly active antiretroviral (ARV) therapy-associated metabolic syndrome, and uncorrected electrolyte abnormalities. As of February 14, 2006, no cases of adverse events related to QT interval prolongation have been reported in patients receiving buprenorphine, an opioid partial agonist and the newest drug approved for the treatment of opioid dependence. To evaluate the effects of buprenorphine/naloxone alone and in combination with 1 of 5 ARV agents (efavirenz, nelfinavir, delavirdine, ritonavir, lopinavir/ritonavir) on the QT interval. This study was prospective, open-label, and within-subject in design, with subjects serving as their own controls. In 50 HIV-negative, opioid-dependent subjects, electrocardiogram recordings were obtained at baseline, after receiving buprenorphine/naloxone for 2 weeks, and then following buprenorphine/naloxone plus ARV administration for 5-15 days at steady-state. QTc interval measurements were compared using mixed-model, repeated-measures ANOVA. Recent cocaine use and gender were considered covariates. Buprenorphine/naloxone alone and often in the presence of evidence for recent use of cocaine did not significantly alter the QT interval (p = 0.612). Buprenorphine/naloxone in combination with ARVs caused a statistically, but not clinically, significant increase (p = 0.005) in the QT interval. Subjects receiving buprenorphine/naloxone in combination with either delavirdine or ritonavir had the greatest increase in QTc intervals. Prolonged QT intervals were not observed in opioid-dependent subjects receiving buprenorphine/naloxone alone. QT interval increases were observed with buprenorphine/naloxone in combination with either delavirdine or ritonavir, which inhibit CYP3A4.

Safety and tolerability of high-dose formoterol (via Aerolizer ®) and salbutamol in patients with chronic obstructive pulmonary disease

To evaluate the safety and tolerability of high-dose formoterol and salbutamol in patients with chronic obstructive pulmonary disease (COPD). In this two-way crossover, double-blind, double-dummy study, 17 adults with mild-to-moderate COPD were randomized to receive either formoterol 24 microg (2 x 12 microg via Aerolizer), or salbutamol 600 microg (6 x 100 microg via metered-dose inhaler), and the appropriate double-dummy q.i.d. at 4-h intervals for 3 consecutive days (total daily dose: 96 and 2400 microg, respectively). After a 4-7-day washout period, patients were switched to the other treatment. Treatment with high-dose formoterol and salbutamol was equally well tolerated, with no reports of serious adverse events. Both agents were associated with decreased plasma potassium (mean minimum values: 3.4 and 3.3 mmol/l for formoterol and salbutamol, respectively; P=0.914), increased serum glucose (mean maximum values: 9.0 and 8.7 mmol/l, respectively; P=0.373), and small increases in mean QTc interval (mean maximum 439 ms with both treatments; P=0.813). No clinically relevant between-treatment differences in adverse events or laboratory values occurred. Both drugs improved lung function (mean maximum forced expiratory volume in 1s [FEV(1)] 2.6 l with both treatments; P=0.624), with the improvement being significantly greater with formoterol than with salbutamol on all 3 days of treatment (mean area under the curve [AUC](0-24 h) of FEV(1) formoterol vs. salbutamol on days 1-3, all P<0.05). High-dose formoterol via Aerolizer (up to 96 microg/day) has a comparable tolerability profile to that of salbutamol in patients with mild-to-moderate COPD.

The effects of thioridazine on the QTc interval - cardiovascular safety in a South African setting

Background. Thioridazine has long been used as a first-line antipsychotic in South Africa without any apparent problems. Recently the American Food and Drug Administration (FDA) and Novartis have warned of potentially lethal arrhythmias that may result from the use of thioridazine. Abnormal QT-interval prolongation on the electrocardiogram (ECG) seems to be the most reliable indicator of risk of arrhythmias, such as torsade de pointes and ventricular fibrillation.Objective. The purpose of this study was to determine whether these warnings are of clinical relevance in a setting where there are already a limited number of antipsychotics available.Method. Thirty hospitalised subjects who required switching from a high-potency to a low-potency antipsychotic were included. All subjects were commenced on thioridazine 300 mg per day and had an ECG 1 week after initiation and 48 hours after each dose adjustment. QTc was determined using Bazett’s formula.Results. Thioridazine induced a significant increase (p = 0.0001) in QTc interval from baseline values of 400.6 (± 27.3) milliseconds to 429.1 (± 44.2) milliseconds. The QTc interval increased to above 450 milliseconds in 7 subjects (23%) and thioridazine was discontinued in 2 subjects because of a QTc interval greater or equal to 500 milliseconds.Conclusion. Thioridazine caused a significant, although asymptomatic, increase in QTc interval in almost one-quarter of subjects who received the medication as second-line treatment. Thioridazine should no longer be used as a first-line treatment and if used it should be accompanied by regular ECG monitoring.

The pharmacodynamic effect on cardiac repolarization of combination single dose ZD6474 and ondansetron in healthy subjects

3197 Background: ZD6474, a selective inhibitor of VEGFR-2 and EGFR tyrosine kinase activity, is being evaluated in combination with certain chemotherapy agents as part of an ongoing Phase II program. Ondansetron (OND), a 5-HT3 antagonist known to prolong the QTc interval, is widely used for chemotherapy-induced emesis. Because of their likely concomitant use, this Phase I study investigated the potential for a pharmacodynamic interaction between ZD6474 and OND. Methods: Healthy male volunteers were recruited to this randomized, double-blind, 2-part study. In Phase A, subjects received OND (32 mg) or placebo via 15 min i.v. infusion, followed by the alternate regimen after 24 h washout. In Phase B, subjects received two single doses of ZD6474 (700 mg p.o.) at least 5 weeks apart, once in combination with OND and once with placebo (given 6 h after the ZD6474 dose). Pharmacokinetic (PK) sampling and continuous ECG monitoring were performed over 12 h (Phase A) or 24 h (Phase B). Results: Twenty-eight volunteers were enrolled (mean age 28 yrs, range 21–42). In Phase A, OND increased the QTc interval from baseline compared with placebo by a maximum of 12.45 ms on average (90% CI = 7.1–17.8 ms), at 30 min post-infusion. In Phase B, the average increase in QTc interval from baseline was 11.44 ms following ZD6474 + placebo, and 22.28 ms following ZD6474 + OND (both at 15 min post-infusion). The maximum additional effect of OND on QTc interval was therefore 10.84 ms, on average (90% CI = 4.4–17.3 ms), which is slightly less than additive compared with OND alone (Phase A). These changes were not considered to be of clinical concern in this study. Overall, no PK interaction between OND and ZD6474 was seen. Four patients were discontinued from the study: one in Phase A due to non-drug-related vomiting, and three in Phase B due to QTc prolongation as per protocol (>30 ms increase from baseline). No serious adverse events were reported. Conclusions: Because ZD6474/OND co-administration did not result in greater than additive effects on QTc prolongation, significant adverse cardiovascular effects would be unlikely with their concomitant use. ZD6474, both alone and in combination with OND, was well tolerated in healthy male volunteers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca

A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

Racemic fluoxetine consists of R- and S-fluoxetine, which are metabolized to R- and S-norfluoxetine, respectively. This study was designed to compare brain levels achieved with R-fluoxetine to those achieved with racemic fluoxetine in healthy subjects using fluorine-19 (19-F) magnetic resonance spectroscopy (MRS). In all, 13 healthy volunteers received study drug for 5 weeks using a dosing schedule designed to achieve steady state for 20 mg/day racemic fluoxetine, 80 mg/day R-fluoxetine, or 120 mg/day R-fluoxetine. The resulting brain drug levels were measured using 19-F MRS. At 5 weeks, the racemate, 80 and 120 mg/day R-fluoxetine groups had mean brain levels of 25.5, 34.9, and 41.4 microM, respectively. In the serum, R-norfluoxetine, which is thought to be an inactive metabolite, accounted for 17, 71, and 63% of the fluoxetine/norfluoxetine concentration, respectively. When the relative proportion of active to total species in serum are taken into account, the data suggest that doses of R-fluoxetine greater than 120 mg/day would be needed to achieve brain levels of active drug comparable to 20 mg/day of racemate. The 120 mg/day R-fluoxetine group experienced a mean increase in QTc interval of 44 ms, with one individual having an increase of 89 ms, which suggests that higher doses may not be tolerable. While these data support the use of MRS to aid in defining the therapeutic dose range for drug development, they also highlight the need for additional studies with concurrent animal models to establish the validity of using serum drug/metabolite ratios to interpret MRS determined brain drug levels.

Méfloquine versus halofantrine dans le traitement de l'accès simple à Plasmodium falciparum de l'enfant voyageur

Aim of the study. To evaluate mefloquine versus halofantrine in children suffering from acute uncomplicated falciparum malaria. Material and methods. Prospective non randomized study in hospitalized children during one year. Acute falciparum malaria was defined by fever and a positive thin and/or thick smear. Malaria was presumed to have been contracted in Comoros archipelago and/or Madagascar 6 months previously. Patients were excluded, when quinine had to be used, according to World Health Organization's severity criteria. Results. Forty-nine children were included: 29 were treated with halofantrine and 20 with mefloquine. Patients features in the two groups of treatment were identical, with exception for the mean time between first clinical signs and diagnosis (shorter in mefloquine group). Fever's and hospitalization's duration under treatment were similar. An increase in QTc interval was frequently observed in patients treated with halofantrine (56 versus 0%), although patients with mefloquine experienced vomiting (45 versus 0%). Relapses seemed to be more frequent with halofantrine (14 versus 0%). Discussion. Halofantrine and mefloquine are efficient for falciparum malaria treatment in our pediatric series, despite a high rate of adverse events. Mefloquine's tolerance may probably be improved with changes in regimen and dose. Relapses are more frequent with a single first treatment of halofantrine, than with mefloquine. Unfortunately, features of a second halofantrine treatment are not defined.

Investigation of the effects of physiological and vasodilation‐induced autonomic activation on the QTc Interval in healthy male subjects

Drug-induced prolongation of the QTc interval is an important marker for potential proarrhythmic action. Prolongation of the QTc interval results from alteration of the ionic currents that regulate cardiac repolarisation. Such effects may result from direct drug action or alternatively they could also occur indirectly by drug-induced modulation of autonomic tone, which is known to regulate cardiac repolarization. This study examined the effects of physiological and drug-induced autonomic activation on heart rate, QT and QTc intervals. We studied 29 healthy male subjects aged 18-30 years. Electrocardiographs were recorded before and during autonomic activation induced by mental activation, standing, exercise and glyceryl trinitrate (GTN) (0.5 mg sublingual)-induced vasodilation in the presence and absence of beta-blockade (atenolol 100 mg daily for 4 days). QT intervals were measured manually by electronic callipers and corrected using the Fridericia formula. Heart rates were significantly increased during mental arithmetic, standing, exercise and GTN and this effect was significantly attenuated by atenolol, except for mental activation. QTc intervals were significantly reduced on standing and exercise and this was significantly attenuated by atenolol during exercise. In contrast, GTN increased QTc intervals (Delta = 5.7 ms, confidence interval +/- 3.2 ms, P < 0.005) and this was not attenuated by atenolol. Alteration in QTc intervals may result from physiological manoeuvres and vasodilation, interventions known to induce autonomic activation. We suggest that QTc prolongation due to GTN is indirectly mediated and unlikely to carry any proarrhythmic effect. Understanding whether drug-induced QTc prolongation is directly or indirectly mediated may be important to determine any potential proarrhythmic risk.

Safety and tolerability of high-dose formoterol (Aerolizer) and salbutamol (pMDI) in patients with mild/moderate, persistent asthma

This double-blind, double-dummy, crossover study evaluated the tolerability of high-dose formoterol and salbutamol. Sixteen adults with mild/moderate persistent asthma (FEV 1≥70% predicted) were randomized to receive either formoterol 36 μg three times daily (TID) at 5-h intervals via Aerolizer ® (total daily dose 108 μg), or salbutamol 600 μg TID via pressurized metered-dose inhaler (total daily dose 1800 μg) for 3 consecutive days. After a 3–7-day washout period patients received the other treatment. FEV 1 was measured 15 min pre-dose and 2 h post-dose. Both formoterol and salbutamol were associated with decreased plasma potassium (mean of minimum values: 3.4 and 3.6 mmol/L, respectively; P<0.001), increased serum glucose (mean of maximum values: 8.3 and 7.9 mmol/L, respectively; P=0.021), and small increases in mean QTc interval (mean of maximum values: 428.8 and 417.4 ms, respectively; P<0.001). However, none of these effects was clinically significant. Both treatments increased FEV 1 to a mean maximum of 4.6 L ( P=0.613), but the mean FEV 1 AUC 0–72 h for formoterol was significantly greater than for salbutamol (302.2 L h, vs. 277.4 L h; P<0.001). No patients discontinued due to treatment-related adverse events. High-dose formoterol via Aerolizer ® did not produce any clinically significant systemic effects in patients with mild/moderate asthma.

Predicting Cardiac Arrhythmias and Sudden Death in Diabetic Users of Proarrhythmic Drugs

In diabetic patients, the corrected QT (QTc) interval is relatively long (1). In accordance with the concept of “reduced repolarization reserve” (2), a subsequent increase in QTc interval by proarrhythmic drugs may lead to cardiac arrhythmias and sudden death. Recently, it was shown that patients with diabetes are at increased risk of drug-induced arrhythmias (3). We developed a decision tool to predict the risk of serious ventricular arrhythmias and sudden death among diabetic users of nonantiarrhythmic proarrhythmic drugs. A cohort study among 61,280 diabetic patients using nonantiarrhythmic proarrhythmic medication (amitriptyline, astemizole, chloroquine, chlorpromazine, cisapride, clarithromycin, clomipramine, cotrimoxazole, diphenhydramine/dimenhydrinate, domperidone, doxepine, droperidol, erythromycin, grepafloxacin, halofantrine, haloperidol, indapamide, ketanserin, lidoflazine, mianserine, pentamidine, pimozide, probucol, promethazine, protriptyline, sulfamethoxazole, sultopride, tacrolimus, terfenadine, terodiline, thioridazine, trimethoprim, and zimeldine) (4) in the General Practice Research Database (1987–2001) was performed. This database contains computerized medical records of ∼650 general practices, including ∼6.5% of the population of England and Wales. Diabetic patients were followed from the 1st day of prescription of any nonantiarrhythmic proarrhythmic drug. Follow-up was censored when the duration of (one of) the prescription(s) had elapsed, when the study outcome occurred, in case of death, upon exit from the study population, or at the end of the study period, whichever of these events came first. The combined study outcome included ventricular tachycardia, ventricular fibrillation and flutter, cardiac arrest, and sudden death. …

The efficacy and safety of PDE5 inhibitors

Inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cyclic guanosine monophosphate, which allows erectile function to occur by relaxation of penile smooth muscle. Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) in a range of doses are available. PDE5 therapy, compared with placebo, significantly improves scores on the International Index of Erectile Function and has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. Sildenafil and vardenafil show some interaction with food intake. Time to onset of action is usually 30-120 minutes, but there are reports of shorter times to onset of action. The duration of action of sildenafil and vardenafil is about 4 hours, whereas that of tadalafil is about 36 hours. The overall safety of the treatments is good, even in patients with a history of cardiovascular disease. However, there is a risk of hypotension if nitrates are given concurrently. Increased QTc intervals have been reported, the longest with vardenafil, shortest with tadalafil, and intermediate with sildenafil. Priapism and prolonged erection are rare adverse events. Common side-effects include headache, facial flushing, nasal congestion, and dyspepsia. There may be interactions with other medications metabolized in a similar way, such as erythromycin and HIV protease inhibitors.

Drugs, QT Interval Prolongation and ICH E14

Regulatory concerns on the ability of an ever-increasing number of non-cardiovascular drugs to prolong the corrected QT (QTc) interval and induce potentially fatal ventricular tachyarrhythmias have culminated in initiatives to harmonise internationally the regulatory guidance on strategies by which to evaluate new drugs for this liability. The International Conference on Harmonisation (ICH) has released consensus texts for clinical (ICH topic E14) and non-clinical (ICH topic S7B) strategies as regulatory drafts for wider consultation. Draft ICH E14 calls for a clinical 'thorough QT/QTc study' (typically in healthy volunteers) for new drugs with systemic bioavailability, regardless of the non-clinical data. This indifference to non-clinical data has sparked off a major debate, even among the regulators. The 'thorough QT/QTc study' is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarisation, as detected by QT/QTc prolongation, and proposes the use of a positive control to validate the study. The guideline recommends exploration of the effect of concentrations that are higher than those achieved following the anticipated therapeutic doses and, consequently, a negative 'thorough QT/QTc study', even in the presence of non-clinical data of concern, will almost always allow standard collection of on-therapy ECGs. The proposed threshold of a 5 ms increase in mean placebo-corrected QTc interval for designating a study as positive for an effect, with all its implications for subsequent development of the drug and its regulatory assessment and labelling, has also generated a controversy. This paper provides an overview commentary on some contentious or ambiguous aspects of draft ICH E14 with a view to stimulating a debate and inviting scientifically supported comments from stakeholders in order to ensure that the application of the ICH E14 strategy, when finalised and adopted, does not result in either restriction in the use (or even rejection) of a potentially beneficial drug or approval of an otherwise hazardous drug without the restrictions required to promote its safe use.

Ziprasidone: First Year Experience in a Hospital Setting

The antipsychotic drug ziprasidone, FDA-approved and introduced in the United States in February 2001 for the treatment of schizophrenia, appears to have similar efficacy but better tolerability than older antipsychotics and requires further evaluation under clinical conditions. We analyzed medical records of McLean Hospital inpatients treated with ziprasidone between March 2001 and February 2002, gathering data on DSM-IV diagnoses, presenting symptoms, dosing, concomitant psychotropic medications, clinical changes, adverse effects, and electrocardiographic (ECG) findings. Ziprasidone was given to 151 inpatients (3.4% of admissions; 108 women, 43 men), aged 37.5 +/- 11.4 years, who presented with depression (n = 79), psychosis (n = 46), mania (n = 18), bipolar mixed-states (n = 4), or other conditions (n = 4). Daily doses averaged 49.8 +/- 34.1 mg initially and 83.2 +/- 46.3 mg at discharge; the greatest dose increases during hospitalization (by a mean of 61%) were in patients with schizoaffective disorder (n = 46; 30% of cases). In 41 cases (27%), ziprasidone was the only antipsychotic at discharge; in 61 (40%) it was used with other antipsychotics. Ziprasidone was discontinued during hospitalization in 49 cases (32.5%), due to lack of efficacy (n = 26; 17.2%), adverse effects (n = 13, 8.6%), or reasons not stated (n = 10, 6.6%). Of 70 patients for whom ECG data were obtained during treatment with ziprasidone, 8 (11%) had QTc intervals > 450 msec during treatment, but none of the 39 patients with ECGs both before and during ziprasidone treatment showed clinically meaningful increases in QTc intervals. Ziprasidone was discontinued in 4 patients (2.6%) due to concern about QTc intervals, but in no case was the QTc interval > or = 500 msec or associated with clinical cardiac toxicity. Improvements in CGI and GAF scores from admission to discharge were similar across diagnoses and unrelated to length of stay or ziprasidone dose. Ziprasidone was well tolerated by hospitalized patients with various major psychiatric disorders and may be of value in conditions other than schizophrenia.

Pediatric Case Report of Quetiapine Overdose and QTc Prolongation

Consideration of the risk of QTc interval prolongation associated with atypical antipsychotic administration is mounting, as this can lead to sudden cardiac death. This is a case report of a 14-year-old boy with a history of major depressive disorder with psychotic features, post-traumatic stress disorder, oppositional defiant disorder, and polysubstance abuse who ingested 1900 mg of quetiapine. One and one half hours after ingestion, the QTc interval lengthened from 453 msec to 618 msec on the printout (manual calculation was 444 msec to 500 msec, respectively). On the baseline EKG, the QTc interval was 411 msec (manual calculation of 416 msec). This report presents an association between higher doses of quetiapine, resulting in higher serum levels and QTc interval prolongation. Also, this report demonstrates the importance of manually calculating the QTc interval to ensure accuracy of the measurement. A review of the literature revealed two case reports and a study where quetiapine was associated with an increase in QTc interval. Further studies are necessary to understand the relationship between higher doses of quetiapine, resulting in higher serum levels, and the propensity for QTc interval prolongation to ensure safe clinical use of this medication.

Effects of head-up tilt after stellate ganglion block on QT interval and QT dispersion

Background and objectives The aim of this study is to examine the effects of head-up tilt (70°) 30 minutes after right or left stellate ganglion block (SGB) on RR interval, QT interval, the rate-corrected QT (QTc) interval, QT dispersion (QTD), and the rate-corrected QT dispersion (QTcD) using computerized measurement. Methods Ten healthy volunteers underwent both right and left SGBs using 7 mL 1% mepivacaine with a 7-day interval between the two blocks. A 12-lead electrocardiogram was monitored to measure parameters before SGB; 30 minutes after SGB (before head-up tilt); and immediately, 5, 10, and 15 minutes after head-up tilt. Results Right SGB induced significant increases in QT interval, QTc interval, QTD, and QTcD from 30 minutes after the block through 15 minutes after head-up tilt. There were significant increases of QT interval, QTc interval, and QTcD between before and immediately after head-up tilt in right SGB. Left SGB induced significant decreases of QT interval and QTc interval from 30 minutes after SGB through 15 minutes after head-up tilt. Left SGB also induced a significant decrease of QTD from immediately after through 10 minutes after head-up tilt. Conclusions Significant increases of QT interval, QTc interval, and QTcD, which are associated with an increased risk of ventricular arrhythmias and cardiac events, occur immediately after head-up tilt in right SGB. However, head-up tilt does not induce increases of QT interval, QTc interval, QTD, and QTcD in left SGB.

No Significant QTc Interval Changes with High-Dose Ziprasidone: A Case Series

This study examined the effects of high-dose ziprasidone on the electrocardiograms (ECGs) of adult inpatients. This was done in an effort to assess the incremental risk of QTc interval prolongation when using ziprasidone in doses above the maximum dose of 160 mg/day approved by the Food and Drug Administration. We retrospectively examined pre- and post-treatment QTc intervals in 15 subjects at the James A. Haley Veterans Affairs Medical Center who had received high doses of ziprasidone, ranging from 240 to 320 mg/day, due to intractable psychotic symptoms. Pure baseline ECGs were not always attainable, since the majority of the subjects were taking concomitant medications at the time that ziprasidone was initiated. Analysis yielded an average increase of 3.4 msec from pre- to post-treatment, with a maximum post-treatment interval of 452 msec and no cases having a pre- to post- treatment QTc interval increase > 20 msec. These findings are statistically insignificant and do not approach the 500 msec threshold of concern. This study suggests that high-dose ziprasidone does not have a significant incremental effect on QTc interval prolongation in certain subsets of patients. However, it does not rule out the possibility that ziprasidone could have deleterious effects in higher risk populations or that ziprasidone could have rare, idiosyncratic cardiogenic effects. Limitations of the study are identified and recommendations for future research are presented.

Evaluation of PR, RR, QT Intervals and QT Dispersion Following Stellate Ganglion Block in Chronic Shoulder–Hand Pain Patients

Right stellate ganglion block (SGB) can increase QT interval, rate-corrected QT interval (QTc), QT dispersion (QTD), rate-corrected QTD (QTcD), and RR interval while left SGB can decrease these intervals in healthy volunteers. No such studies have been conducted in patients with chronic pain, hence this study was designed to investigate the effects of left and right SGB on these variables in chronic shoulder-hand pain patients. In this study, 28 patients with chronic shoulder-hand pain of at least 6 months duration were given right or left SGB depending on the shoulder affected. A 12-lead electrocardiogram (ECG) was recorded before the block, 30 minutes and 60 minutes after the block. PR interval, RR interval, QT interval were recorded in all 12 leads while QTc, QTD, and QTcD were calculated. Right SGB was performed in 21 patients. A significant decrease (P < 0.05) in PR interval and a significant increase (P < 0.05) in RR interval, QT interval, and QTc interval were observed. QTD showed a significant increase (P < 0.05) only at 30 minutes after right SGB. Left SGB was performed in seven patients. A significant decrease (P < 0.05) in QT interval was observed throughout the study period, while QTc showed a significant decrease (P < 0.05) only at 60 minutes after the block. We conclude that right SGB induces significant increase of QT interval, RR interval, QTc interval, QTD, and a significant decrease of PR interval while left SGB produces a significant decrease in QT and QTc intervals in patients with chronic shoulder-hand pain.

Effect of acute hyperinsulinemia on ventricular repolarization in uncomplicated obesity

Background: Acute hyperinsulinemia has been shown to increase QTc interval in lean subjects, but data on obese subjects are still unclear. Aim of this study was to evaluate the effect of acute hyperinsulinemia on QTc interval and QTc dispersion in uncomplicated obesity. Methods: We calculated QTc duration and QTc dispersion in 30 uncomplicated obese subjects (mean age 32.2±7, BMI 36.7±9.4 kg/m 2) by measurements of 12-lead ECG recording during a euglycemic hyperinsulinemic clamp. Results: Insulin infusion during the clamp did not significantly modify QTc interval and QTc dispersion in uncomplicated obese subjects (401.5±29.2 vs. 413.7±30.5; 35.4±10.5 vs. 38.7±14.5, respectively). Conclusions: Acute hyperinsulinemia seems to no significantly affect ventricular repolarization in uncomplicated obesity. Insulin resistance and the absence of diabetes and hypertension could explain, at least in part, this finding.