Higher baseline heart rate variability in CCHS patients with progestin-associated recovery of hypercapnic ventilatory response.

After a fortuitous observation of two cases of chemosensitivity recovery in women with congenital central hypoventilation syndrome (CCHS) who took desogestrel, we aimed to evaluate the ventilatory response to hypercapnia of five CCHS patients with or without treatment consisting of desogestrel (DESO) or levonorgestrel (LEVO). Only two patients became responsive to hypercapnia under treatment, according to their basal vagal heart rate variability. These results suggest that heart rate variability may be promising tool to discriminate patients susceptible to become responsive to hypercapnia under DESO-LEVO treatment.Clinical Trials Identifier NCT01243697.

Baclofen destabilises breathing during sleep in healthy humans: A randomised, controlled, double-blind crossover trial.

AIMS: Periodic breathing is frequent in patients with severe heart failure. Apart from being an indicator of severity, periodic breathing has its own deleterious consequences (sleep-related oxygen desaturations, sleep fragmentation), which justifies attempts to correct it irrespective of the underlying disease. Animal models and human data suggest that baclofen can reconfigure respiratory central pattern generators. We hypothesised that baclofen, a GABAB agonist, may thus be able to correct periodic breathing in humans. METHODS: Healthy volunteers were exposed to hypoxia during sleep. Participants who developed periodic breathing (n = 14 [53 screened]) were randomly assigned to double-blind oral baclofen (progressively increased to 60 mg/d) or placebo. The primary outcome was the coefficient of variation (CoVar) of respiratory cycle total time considered as an indicator of breathing irregularity. Secondary outcomes included the CoVar of tidal volume, apnoea-hypopnoea index, sleep fragmentation index and ventilatory complexity (noise limit). RESULTS: The analysis was conducted in 9 subjects after exclusion of incomplete datasets. CoVar of respiratory cycle total time significantly increased with baclofen during non-rapid eye movement sleep (median with placebo 56.00% [37.63-78.95]; baclofen 85.42% [68.37-86.40], P = .020; significant difference during the N1-N2 phases of sleep but not during the N3 phase). CoVar of tidal volume significantly increased during N1-N2 sleep. The apnoea-hypopnoea index, sleep fragmentation index and ventilatory complexity were not significantly different between placebo and baclofen. CONCLUSION: Baclofen did not stabilise breathing in our model. On the contrary, it increased respiratory variability. Baclofen should probably not be used in patients with or at risk of periodic breathing.

Reduced Reverse Cholesterol Transport Efficacy in Healthy Men with Undesirable Postprandial Triglyceride Response.

Elevation of nonfasting triglyceride (TG) levels above 1.8 g/L (2 mmol/L) is associated with increased risk of cardiovascular diseases. Exacerbated postprandial hypertriglyceridemia (PP-HTG) and metabolic context both modulate the overall efficacy of the reverse cholesterol transport (RCT) pathway, but the specific contribution of exaggerated PP-HTG on RCT efficacy remains indeterminate. Healthy male volunteers (n = 78) exhibiting no clinical features of metabolic disorders underwent a postprandial exploration following consumption of a typical Western meal providing 1200 kcal. Subjects were stratified according to maximal nonfasting TG levels reached after ingestion of the test meal into subjects with a desirable PP-TG response (GLow, TG < 1.8 g/L, n = 47) and subjects with an undesirable PP-TG response (GHigh, TG > 1.8 g/L, n = 31). The impact of the degree of PP-TG response on major steps of RCT pathway, including cholesterol efflux from human macrophages, cholesteryl ester transfer protein (CETP) activity, and hepatic high-density lipoprotein (HDL)-cholesteryl ester (CE) selective uptake, was evaluated. Cholesterol efflux from human macrophages was not significantly affected by the degree of the PP-TG response. Postprandial increase in CETP-mediated CE transfer from HDL to triglyceride-rich lipoprotein particles, and more specifically to chylomicrons, was enhanced in GHigh vs GLow. The hepatic HDL-CE delivery was reduced in subjects from GHigh in comparison with those from GLow. Undesirable PP-TG response induces an overall reduction in RCT efficacy that contributes to the onset elevation of both fasting and nonfasting TG levels and to the development of cardiometabolic diseases.

Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia.

BACKGROUND: Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown. OBJECTIVE: The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia. METHODS: Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg. Blood samples were drawn to determine ropivacaine concentrations, and sensory blockade was assessed using pinprick testing. Ropivacaine plasma concentrations and sensory block level were analyzed using a nonlinear mixed-effects modeling approach with Monolix 4.2.2. Uncertainty of parameters was estimated by bootstrapping. RESULTS: Overall, 216 plasma ropivacaine values and 407 sensory block-related data were available for pharmacokinetic-pharmacodynamic (PK-PD) model evaluation. A two-compartment open model connected to a spinal compartment was selected to describe the PKs of ropivacaine. Sensory block modeling was performed using a sigmoid E max model assuming an equilibration delay between the amount in the depot or spinal compartment and at the effect site. Using multiple linear regression analysis, we were able to demonstrate the importance of dose, age and weight as major predictors of sensory block-level kinetics. CONCLUSIONS: This first population PK-PD model for ropivacaine in spinal anesthesia confirms the relationship between plasma ropivacaine concentrations and effect. We also clarify the relationship between the spread of sensory block level and dose, age and, for the first time, weight. STUDY REGISTRATION: This study was approved by the Reims University Hospital Ethics Committee (protocol: PHRC-2005; registered at Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM: D60890). This was an open, prospective, monocentric study conducted in the University Hospital of Reims (France).

GENomE wide analysis of sotalol-induced IKr inhibition during ventricular REPOLarization, "GENEREPOL study": Lack of common variants with large effect sizes.

Many drugs used for non-cardiovascular and cardiovascular purposes, such as sotalol, have the side effect of prolonging cardiac repolarization, which can trigger life-threatening cardiac arrhythmias by inhibiting the potassium-channel IKr (KCNH2). On the electrocardiogram (ECG), IKr inhibition induces an increase in QTc and Tpeak-Tend (TpTe) interval and a decrease of T wave maximal amplitude (TAmp). These changes vary markedly between subjects, suggesting the existence of predisposing genetic factors. 990 healthy individuals, prospectively challenged with an oral 80mg sotalol dose, were monitored for changes in ventricular repolarization on ECG between baseline and 3 hours post dosing. QTc and TpTe increased by 5.5±3.5% and 15±19.6%, respectively, and TAmp decreased by 13.2±15.5%. A principal-component analysis derived from the latter ECG changes was performed. A random subsample of 489 individuals were subjected to a genome-wide-association analysis where 8,306,856 imputed single nucleotide polymorphisms (SNPs) were tested for association with QTc, TpTe and TAmp modulations, as well their derived principal-components, to search for common genetic variants associated with sotalol-induced IKr inhibition. None of the studied SNPs reached the statistical threshold for genome-wide significance. This study supports the lack of common variants with larger effect sizes than one would expect based on previous ECG genome-wide-association studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00773201.

Effect of Intralipid® on the Dose of Ropivacaine or Levobupivacaine Tolerated by Volunteers: A Clinical and Pharmacokinetic Study.

BACKGROUND: Rapid intravenous administration of lipid emulsion has become the standard treatment of severe local anesthetic systemic toxicity. This experiment in volunteers aimed at determining the effect of Intralipid® administration on the time to neurologic symptoms. METHODS: Ropivacaine or levobupivacaine was infused intravenously in 16 volunteers (8 mg/min up to 120 mg) with 120 ml Intralipid® 20% (Fresenius, Paris France) or placebo infused at T + 2 min). Each subject received all four treatments in a crossover manner. The infusion was stopped after the intended dose had been administered or on occurrence of incipient neurologic signs of toxicity. The primary outcome was time-to-event. In addition, blood ropivacaine and levobupivacaine concentrations were measured. RESULTS: The dose infused was not different whether volunteers received placebo (81.7 ± 22.3 vs. 80.8 ± 31.7 mg, ropivacaine vs. levobupivacaine) or Intralipid® (75.7 ± 29.1 vs. 69.4 ± 26.2 mg, ropivacaine vs. levobupivacaine), P = 0.755, Intralipid® versus placebo groups. Plasma concentrations were best modeled with an additional volume of distribution associated with Intralipid®. Simulations suggested that decreased peak concentrations would be seen if Intralipid® was given during a period of increasing concentrations after extravascular administration. CONCLUSIONS: At modestly toxic doses of ropivacaine or levobupivacaine, we were unable to find any effect of the infusion of Intralipid® on the time to early signs of neurologic toxicity in volunteers. Peak concentration was decreased by 26 to 30% in the subjects receiving Intralipid®. Simulations showed that Intralipid® might prevent the rapid increase of local anesthetic concentration after extravascular administration.

Nefopam, a non-opioid analgesic, does not alleviate experimental work/effort dyspnoea in healthy humans: A randomised controlled trial.

BACKGROUND: Dyspnoea is a distressing and debilitating symptom with a major impact on quality of life. Alleviation of dyspnoea therefore constitutes a major clinical challenge. When causative physiological disorders cannot be corrected ("persistent dyspnoea"), nonspecific treatment must be considered. Morphine alleviates dyspnoea but has numerous side-effects including ventilatory depression, which justifies looking for alternatives. Certain forms of dyspnoea involve C-fibres, and can be attenuated by C-fibres blockade. We hypothesised that nefopam, a non-sedative benzoxazocine analgesic known to block the transient receptor potential vanilloid subtype 1 abundantly present on C-fibres, would attenuate dyspnoea. METHODS: We conducted a randomised, double-blind, placebo-controlled crossover study of nefopam in healthy subjects submitted to experimental work/effort dyspnoea by inspiratory threshold loading (15 healthy male volunteers; age 23-41). We studied a perceptual outcome (dyspnoea visual analogue scale -D-VAS-) and a neurophysiological outcome (effect of nefopam on dyspnoea-pain counter-irritation as assessed by laser-evoked potentials; an effect of nefopam on dyspnoea was hypothetised to reduce the ability of dyspnoea to inhibit pain). Somaesthetic evoked potentials (SEPs) were studied as a control. RESULTS: A statistically significant decrease in LEP amplitude was observed in response to loading with nefopam (F = 19.1; p < 0.001) and placebo (F = 5.73 and p < 0.001), with no significant difference between nefopam and placebo and no change in SEP characteristics. CONCLUSIONS: In this study, nefopam did not exhibit any effects on dyspnoea.

Infection duration and inflammatory imbalance are associated with atherosclerotic risk in HIV-infected never-smokers independent of antiretroviral therapy.

OBJECTIVES: To determine whether the reported increased atherosclerotic risk among HIV-infected individuals is related to antiretroviral therapy (ART) or HIV infection, whether this risk persists in never-smokers, and whether inflammatory profiles are associated with higher risk. DESIGN: Matched cross-sectional study. METHODS: A total of 100 HIV-infected patients (50 ART-treated >4 years, 50 ART-naive but HIV-infected >2 years) and 50 HIV-negative controls were recruited in age-matched never-smoking male triads (mean age 40.2 years). Carotid intima-media maximal thickness (c-IMT) was measured across 12 sites. Pro-inflammatory [highly sensitive C-reactive protein (hs-CRP), resistin, interleukin-6, interleukin-18, insulin, serum amyloid A, D-dimer) and anti-inflammatory (total and high molecular weight adiponectin, interleukin-27, interleukin-10) markers were dichotomized into high/low scores (based on median values). c-IMT was compared across HIV/treatment groups or inflammatory profiles using linear regression models adjusted for age, diabetes, hypertension, and, for HIV-infected patients, nadir CD4 cell counts. RESULTS: Although adjusted c-IMT initially tended to be thicker in ART-exposed patients (P=0.2), in post-hoc analyses stratifying by median HIV duration we observed significantly higher adjusted c-IMT in patients with longer (>7.9 years: 0.760±0.008 mm) versus shorter prevalent duration of known HIV infection (<7.9 years: 0.731±0.008 mm, P=0.02), which remained significant after additionally adjusting for ART (P=0.04). Individuals with low anti-inflammatory profile (median score) had thicker c-IMT (0.754±0.006mm versus 0.722±0.006 mm, P<0.001), with anti-inflammatory markers declining as prevalent duration of HIV infection increased (P for linear trend <0.001). CONCLUSION: Known HIV duration is related to thicker c-IMT, irrespective of ART, in these carefully selected age-matched never-smoking HIV-treated and ART-naive male individuals. Higher levels of anti-inflammatory markers appeared protective for atherosclerosis.

Effect of contrasted sodium diets on the pharmacokinetics and pharmacodynamic effects of renin-angiotensin system blockers.

Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained <1% and 21% of the variance of the AUC0-24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia.

OBJECTIVE: Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility. DESIGN: Case/control study. METHODS: Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28 ± 3 days), were included. LH pulse patterns over 6 h were determined in patients and controls. RESULTS: No differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels. CONCLUSIONS: LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.

Human plasma quantification of droperidol and ondansetron used in preventing postoperative nausea and vomiting with a LC/ESI/MS/MS method.

An analytical method based upon liquid chromatography coupled to ion trap mass spectrometry (MS) detection with electrospray ionization interface has been developed for the simultaneous identification and quantification of droperidol and ondansetron in human plasma. The two drugs were isolated from 0.5 mL of plasma using a basic liquid-liquid extraction with diethyl ether/heptane (90/10, v/v) and tropisetron and haloperidol as internal standards, with satisfactory extraction recoveries. They were separated on a 5-µm C(18) Highpurity column (150 mm×2.1 mm I.D.) maintained at 30°C. The elution was achieved isocratically with a mobile phase of 2 mM HCOONH(4) pH 3.8 buffer/acetonitrile (60/40, v/v) at a flow rate of 200 µL/min. Data were collected either in full-scan MS mode at m/z 100-450 or in full-scan MS-MS mode, selecting the [M+H] (+) ion at m/z=294.0 for ondansetron, m/z=285.2 for tropisetron, m/z=380.0 for droperidol and m/z=376.0 for haloperidol. The most intense daughter ion of ondansetron (m/z=212.0) and droperidol (m/z=194.0) were used for quantification. Retention times for tropisetron, ondansetron, droperidol and haloperidol were 2.50, 2.61, 3.10 and 4.68 min, respectively. Calibration curves were linear for both compounds in the 0.50-500 ng/mL range. The limits of detection and quantification were 0.10 ng/mL and 0.50 ng/mL, respectively. The intra- and inter-assay precisions were lower than 6.4% and intra- and inter-assay recoveries were in the 97.6-101.9% range for the three 3, 30 and 300 ng/mL concentrations. This method allows simultaneous and rapid measurement of droperidol and ondansetron, which are frequently co-administrated for the prevention of postoperative nausea and vomiting.

Impact of age and gender interaction on circulating endothelial progenitor cells in healthy subjects.

OBJECTIVE: To assess the level of circulating endothelial progenitor cells (CEPC) in cycling women compared with men and menopausal women. DESIGN: Controlled clinical study. SETTING: Healthy, nonsmoking volunteers. PATIENT(S): Twelve women, aged 18-40 years, with regular menstrual cycles, 12 menopausal women, and two groups of 12 age-matched men were recruited. Women did not receive any hormone therapy. INTERVENTION(S): Collection of 20 mL of peripheral blood. MAIN OUTCOME MEASURE(S): The number of CEPC, defined as (Lin-/7AAD-/CD34+/CD133+/KDR+) cells per 10(6) mononuclear cells (MNC), was measured by flow cytometry. RESULT(S): The number of CEPC was significantly higher in cycling women than in age-matched men and menopausal women (26.5 per 10(6) MNC vs. 10.5 per 10(6) MNC vs. 10 per 10(6) MNC, respectively). The number of CEPC was similar in menopausal women, age-matched, and young men. CONCLUSION(S): The number of CEPC is influenced by an age-gender interaction. This phenomenon may explain in part the better vascular repair and relative cardiovascular protection in younger women as compared with age-matched men.

Droperidol and ondansetron in vitro electrophysiological drug interaction study.

Droperidol and ondansetron are potent anti-emetic agents which are often administered together. Although both drugs prolong QT interval in man by inhibition of Human Ether-a-go-go Related Gene-coded potassium channels, only droperidol was tested using more integrated experimental models. Therefore, we studied the effects of both compounds and their combination on action potentials (AP) of rabbit Purkinje fibers using conventional intracellular glass microelectrode. Purkinje fibers, driven at 1 Hz, were exposed to increasing concentrations (from 0.001 to 10 microm) of droperidol (n = 7) or ondansetron (n = 8) at 30 min intervals at 36.5 degrees C. Other fibers were exposed to a constant droperidol concentration (0.1 microm) alone (n = 7) or together with the same increasing concentrations of ondansetron (n = 6). Droperidol increased AP duration measured at 90% repolarization (APD90) in a concentration-dependent manner from 4.4 +/- 0.8% (mean +/- SEM) after 1 nm to a maximum of 158 +/- 72% after 1 microm. Ondansetron significantly increased APD90 by 5.3 +/- 2.1% at 100 nm up to 76 +/- 14% after 10 microm. Early after-depolarization occurred in 6/7 fibers exposed to droperidol and 1/8 fibers exposed to ondansetron. When given together, pure additive effects were observed. The concentrations that increased APD90 by 50% were 0.25 +/- 0.25 microm droperidol, 3.8 +/- 2.4 microm ondansetron and 1.5 +/- 0.8 microm ondansetron when given together with droperidol. Both ondansetron and droperidol prolong AP duration in Purkinje fibers, droperidol being 10 times more potent than ondansetron. Combination of ondansetron and droperidol exhibits an additive effect on AP duration. However, within clinically relevant concentrations, ondansetron does not further increase the AP prolongation caused by droperidol alone.

Effects of testosterone on ventricular repolarization in hypogonadic men.

QT-interval duration is shorter in men than in women. Estrogens do not significantly influence the duration of repolarization. The effect of testosterone has not been studied directly in humans. The aim of this study was to assess the effects of testosterone on corrected QT duration in hypogonadic men. Eleven hypogonadic men were enrolled in this prospective interventional study. Digital electrocardiograms were recorded for each participant at 3 levels of testosterone, high, medium, and low, after a single intramuscular administration of testosterone. Heart rate-independent assessment of QT-interval duration was used. QT(1,000) (QT at 60 beats/min) was determined for each subject. Total blood testosterone and the ratio of testosterone to sex hormone-binding globulin were assessed at each visit. The median values of QT(1,000) were 352 ms (interquartile range 340 to 363), 357 ms (interquartile range 349 to 367), and 363 ms (interquartile range 357 to 384) at high, medium, and low testosterone concentrations, respectively (p <0.013 for the 3 comparisons). A maximal mean difference of 13.6 +/- 2.8 ms (p = 0.0007) was observed between high and low levels of testosterone. A negative linear relation was found between QT(1,000) and testosterone concentration (p = 0.0001) or the ratio of testosterone to sex hormone-binding globulin (p = 0.004). In conclusion, the difference in QT-interval duration between men and women might be explained by differences in testosterone levels, and testosterone shortens ventricular repolarization.

Relationship between HIV protease inhibitors and QTc interval duration in HIV-infected patients: a cross-sectional study.

AIMS: QTc interval prolongation and torsades de pointes have been reported in HIV-infected patients. Protease inhibitors (PIs) are suspected to contribute to this adverse reaction. However, many factors can prolong QTc interval. We examined factors influencing QTc duration in HIV-infected patients. METHODS: Unselected HIV-infected patients (n = 978) were enrolled in this prospective, single-centre cross-sectional study. Variables related to infection and treatments were collected. A digital electrocardiographic record was recorded in each patient and QT interval duration was measured and corrected using both Bazett's (QTcB) and Fridericia's (QTcF) formula. Results were analysed with a multivariable linear model. RESULTS: After excluding arrhythmias and complete bundle branch blocks, QT interval was measured in 956 patients. The mean (SD) QTcB was 418 ms (23) and QTcF was 405 ms (20). QTc was found prolonged (>450 ms in women and >440 ms in men) in 129 [13.5%; 95% confidence interval (CI) 11.5, 15.8] and 38 (4%; 95% CI 2.9, 5.4) patients using Bazett and Fridericia corrections, respectively. On multivariable analysis, incomplete bundle branch block, ventricular hypertrophy, signs of ischaemic cardiopathy, female gender, White ethnic origin and age were significantly associated with QTc prolongation. The only HIV variable independently associated with QTc prolongation was the duration of infection (P = 0.023). After adjustment, anti-HIV treatment, in particular PI (P = 0.99), was not associated with QTc prolongation. CONCLUSIONS: Although PIs block in vitro hERG current, they are not independently associated with QTc interval prolongation. Prolonged QTc interval in HIV-infected patients is primarily associated with factors commonly known to prolong QT and with the duration of HIV infection.

Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study.

BACKGROUND: Droperidol and ondansetron have previously been found to prolong the QT interval in the treatment of postoperative nausea and vomiting. However, this adverse effect has never been confirmed and compared with both drugs under controlled conditions. The objective was to study the effects of droperidol and ondansetron alone or in combination on QT interval duration in healthy subjects. METHODS: Sixteen healthy volunteers, eight males and eight females, were enrolled in this prospective, double-blind, randomized, placebo-controlled study. Subjects received 1 mg droperidol, 4 mg ondansetron, 1 mg droperidol plus 4 mg ondansetron, or a placebo, intravenously in a crossover design. Fridericia-corrected QT interval (QTcF) and plasma concentrations were measured repeatedly during 10 h at each study period. The primary endpoint was the maximal placebo time-matched and baseline-subtracted QTcF prolongation (DeltaDeltaQTcF). RESULTS: Compared with placebo, both droperidol and ondansetron significantly prolonged the QTcF interval. DeltaDeltaQTcF prolongation was 25 +/- 8 ms after droperidol, significantly greater than the 17 +/- 10-ms prolongation with ondansetron (P = 0.014). The combination of droperidol and ondansetron significantly increased the mean maximal DeltaDeltaQTcF by 28 +/- 10 ms. The combination induced greater QTcF prolongation compared with ondansetron alone (P = 0.001), but not with droperidol alone (P = 0.33). There was no significant pharmacokinetic interaction between droperidol and ondansetron. CONCLUSIONS: Under controlled conditions, both droperidol and ondansetron either alone or in combination induced significant marked QTc interval prolongation. However, the combination of both drugs did not significantly increase QTc prolongation compared with that induced by droperidol alone.