scholarly journals A Thorough QT Study To Evaluate the Effects of Therapeutic and Supratherapeutic Doses of Delafloxacin on Cardiac Repolarization

2015 ◽  
Vol 59 (6) ◽  
pp. 3469-3473 ◽  
Author(s):  
Jeffrey S. Litwin ◽  
Michael S. Benedict ◽  
Michael D. Thorn ◽  
Laura E. Lawrence ◽  
Sue K. Cammarata ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Vital Signs ◽  
Study Drug ◽  
Pharmacokinetic Profile ◽  
Positive Control ◽  
Qtc Interval ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Thorough Qt Study ◽  
Time Point

ABSTRACTA randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug.

scholarly journals Evaluation of the Effect of a Supratherapeutic Dose of Intravenous Ceftaroline Fosamil on the Corrected QT Interval

2013 ◽  
Vol 57 (4) ◽  
pp. 1777-1783 ◽  
Author(s):  
Todd A. Riccobene ◽  
Ludmyla Rekeda ◽  
Douglas Rank ◽  
Lily Llorens
Keyword(s):  
Qt Interval ◽  
Plasma Concentrations ◽  
Vital Signs ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Qtc Interval ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Ceftaroline Fosamil ◽  
Supratherapeutic Dose

ABSTRACTA randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed.

scholarly journals Evaluation of the Effect of Contezolid (MRX-I) on the Corrected QT Interval in a Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study in Healthy Chinese Volunteers

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Junzhen Wu ◽  
Guoying Cao ◽  
Hailan Wu ◽  
Yuancheng Chen ◽  
Beining Guo ◽  
...  
Keyword(s):  
Therapeutic Dose ◽  
Qt Interval ◽  
Qtc Interval ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Supratherapeutic Dose ◽  
Qt Interval Prolongation ◽  
Point Analysis ◽  
Complicated Skin ◽  
Time Point

ABSTRACT Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1,600 mg) dose, placebo, and oral moxifloxacin at 400 mg in four separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (ΔΔQTc) were <10 ms for the contezolid therapeutic dose at each time point. The upper bound of the 90% CI for ΔΔQTc was slightly more than 10 ms with the contezolid supratherapeutic dose at 3 and 4 h postdose, and the prolongation effect on the QT/QTc interval was less than that of the positive control, moxifloxacin, at 400 mg. At 3 and 4 h after the moxifloxacin dose, the moxifloxacin group met the assay sensitivity criteria outlined in ICH Guidance E14 by having a lower confidence bound of ≥5 ms. The results of a linear exposure-response model which were similar to that of a time point analysis demonstrated a slightly positive relationship between contezolid plasma levels and ΔQTcF interval with a slope of 0.227 ms per mg/liter (90% CI, 0.188 to 0.266). In summary, contezolid did not prolong the QT interval at a therapeutic dose and may have a slight effect on QT interval prolongation at a supratherapeutic dose.

scholarly journals 628. Pharmacokinetics, Safety and Tolerability of Co-administration of Nacubactam and β-lactams after Multiple Doses in Japanese Healthy Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S418-S418
Author(s):  
Hiroki Sato ◽  
Jun Morita ◽  
Tatsuo Miura ◽  
Masayo Sumiya ◽  
Risako Takaya ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Plasma Concentrations ◽  
Vital Signs ◽  
Study Drug ◽  
Concomitant Administration ◽  
Remarkable Change ◽  
Double Blind ◽  
Carbapenem Resistant ◽  
Laboratory Test Results ◽  
Dose Study

Abstract Background Increase of carbapenem-resistant Enterobacterales (CRE) is a serious problem in the clinical setting and drugs which can treat patients with CRE are still limited. Nacubactam (OP0595) is a novel diazabicyclooctane-type β-lactamase inhibitor and being developed as a standalone drug to be co-administered with cefepime or aztreonam. Methods A randomized, double-blind multiple dose study of nacubactam in co-administration with cefepime (Cohort 1) or aztreonam (Cohort 2) in Japanese healthy subjects was performed to assess pharmacokinetics, safety, and tolerability of co-administrations of nacubactam and cefepime or aztreonam. In each cohort, 6 subjects received 2 g of nacubactam and 2 g of concomitant drug (cefepime or aztreonam) and 2 subjects received placebo (saline) intravenously over 60 minutes, three times daily every 8 hours for 7 days. Plasma samples were collected and concentrations of each drug were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and the evaluation of changes from baseline in safety laboratory test results, 12-lead electrocardiograms (ECGs), vital signs, and physical examinations. Results Profiles of Cmax, tmax, AUC0-8, AUC0-∞ and t1/2 for nacubactam, cefepime and aztreonam are summarized in Table 1. Summary of Ctrough for nacubactam, cefepime and aztreonam are summarized in Table 2. Plasma concentrations of nacubactam, cefepime and aztreonam reached the steady-state by Day 4, and the mean accumulation ratios of Cmax and AUC0-8 on Day 7 to those of Day 1 were in the range of 0.91 to 1.10. As for the safety, no serious adverse event was observed in this study. There was 1 TEAE (seborrhoeic dermatitis) leading to the discontinuation in 1 subject in nacubactam/cefepime group, but it was judged as “Not related to study drug”. Table 1. PK profiles of nacubactam and concomitant drugs on Day 1 and Day 7 Table 2. Summary of Ctrough of nacubactam and concomitant drugs Conclusion In conclusion, no remarkable change in pharmacokinetics was observed in each drug with multiple concomitant administration for 7 days and safety and tolerability of co-administrations of nacubactam and cefepime or aztreonam were confirmed. Based on these results, nacubactam is currently under further development. Disclosures All Authors: No reported disclosures

scholarly journals The effect of the glucosylceramide synthase inhibitor lucerastat on cardiac repolarization: results from a thorough QT study in healthy subjects

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Markus S. Mueller ◽  
Patricia N. Sidharta ◽  
Christine Voors-Pette ◽  
Borje Darpo ◽  
Hongqi Xue ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Plasma Concentrations ◽  
Published Data ◽  
Cardiac Repolarization ◽  
Qtc Interval ◽  
Glucosylceramide Synthase ◽  
Assay Sensitivity ◽  
Benefit Risk Assessment ◽  
Thorough Qt Study ◽  
Synthase Inhibitor

Abstract Background Fabry disease is a rare inherited glycosphingolipid storage disorder caused by deleterious mutations in the GLA gene coding for the lysosomal enzyme α-galactosidase A. The glucosylceramide synthase inhibitor lucerastat is an iminosugar with potential to provide oral substrate reduction therapy in Fabry disease, regardless of the patient´s underlying mutation. Since lucerastat exhibits systemic exposure and many patients with Fabry disease suffer from rhythm and conduction abnormalities its effects on cardiac repolarization were evaluated in a thorough QT study. Methods In Part A of this randomized, double-blind, placebo-controlled phase 1 study, single oral doses of 2000 and 4000 mg lucerastat were investigated to determine the supratherapeutic dose for Part B. The latter was a four-way crossover study to demonstrate that lucerastat at single oral therapeutic and supratherapeutic doses had no effect on the QTc interval > 10 ms using concentration-QTc modeling as primary analysis. The primary ECG endpoint was placebo-corrected change-from-baseline (ΔΔ) in Fridericia-corrected QTc (ΔΔQTcF). Open-label moxifloxacin served as positive control. Results The effect of lucerastat on ΔΔQTcF was predicted as 0.39 ms (90% confidence interval [CI] − 0.13 to 0.90) and 1.69 ms (90% CI 0.33–3.05) at lucerastat peak plasma concentration after dosing with 1000 mg (5.2 µg/mL) and 4000 mg (24.3 µg/mL), respectively. A QTcF effect > 10 ms was excluded up to lucerastat plasma concentrations of approximately 34.0 µg/mL. Lucerastat did not exert an effect on other ECG parameters. Across doses, absorption of lucerastat was rapid, its elimination half-life ranged from 8.0 to 10.0 h, and the pharmacokinetics (PK) of lucerastat were dose-proportional. Moxifloxacin PK were in line with published data and assay sensitivity was demonstrated by the moxifloxacin QTc response. Lucerastat was safe and well tolerated. Conclusions Lucerastat up to a dose of 4000 mg has no clinically relevant liability to prolong the QT interval or any clinically relevant effect on other ECG parameters. This will be an important factor in the overall benefit-risk assessment of lucerastat in the potential treatment of Fabry disease. Trial registration The study was registered with the ClinicalTrials.gov identifier NCT03832452 (February 6th, 2019, https://clinicaltrials.gov/ct2/show/NCT03832452) and the EudraCT number 2018-004546-42 (December 17th, 2018).

scholarly journals Lack of an Effect of Standard and Supratherapeutic Doses of Linezolid on QTc Interval Prolongation

2011 ◽  
Vol 55 (9) ◽  
pp. 4302-4307 ◽  
Author(s):  
Bharat Damle ◽  
Robert R. LaBadie ◽  
Cheryl Cuozzo ◽  
Christine Alvey ◽  
Heng Wee Choo ◽  
...  
Keyword(s):  
Vital Signs ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Ventricular Rate ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Qtc Prolongation ◽  
Double Blind ◽  
Qtc Interval Prolongation ◽  
Clinically Significant

ABSTRACTA double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the populationTmax, the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted.

scholarly journals Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study of the Effects of Omadacycline on QT/QTc Intervals in Healthy Subjects

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Borje Darpo ◽  
Hongqi Xue ◽  
S. Ken Tanaka ◽  
Evan Tzanis
Keyword(s):  
The United States ◽  
Cardiac Conduction ◽  
Qtc Interval ◽  
Response Model ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Once Daily ◽  
Exposure Response ◽  
Thorough Qt Study ◽  
Positive Controls

ABSTRACT Omadacycline, an aminomethylcycline, is an antibiotic that is approved in the United States for once-daily intravenous (i.v.) and oral use for treatment of adults with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. In this thorough QT study, the effects of a therapeutic (100 mg i.v.) dose and a supratherapeutic (300 mg i.v.) dose of omadacycline on the electrocardiogram were studied, with placebo and moxifloxacin as negative and positive controls. Omadacycline at these doses had no effect on the QTc interval. The largest mean placebo-corrected change-from-baseline QTcS (ΔQTcS) were 1.7 ms (90% confidence interval [CI], 0.06 to 3.30) and 2.6 ms (90% CI, 0.55 to 4.67), observed at 20 min and 2 h after the start of the infusion of 100 mg and 300 mg, respectively. Assay sensitivity was demonstrated with moxifloxacin, which caused clear prolongation of QTcS, with the largest mean placebo-corrected ΔQTcS of 9.8 ms at 1.5 and 2 h. With a linear exposure-response model, the estimated slope of the concentration-change-from-baseline QTcF (ΔQTcF) relationship was very shallow: 0.0007 ms per ng/ml (90% CI, 0.0000 to 0.0014). The possibility of an effect on placebo-corrected ΔQTcS exceeding 10 ms can be excluded at omadacycline concentrations in plasma of up to ∼8 μg/ml. Omadacycline had no effect on cardiac conduction (PR and QRS intervals) but caused an increase in heart rate of 16.8 beats per min at 35 min after the 100-mg dose and 21.6 beats per min at 50 min after the 300-mg dose.

Evaluation Of The Effect Of Idelalisib On The QT/QTc Interval In Healthy Subjects

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5573-5573 ◽  
Author(s):  
Feng Jin ◽  
Michelle Robeson ◽  
Huafeng Zhou ◽  
Andie Nichols ◽  
Srini Ramanathan
Keyword(s):  
Dose Range ◽  
Plasma Concentrations ◽  
Qtc Interval ◽  
Employment Equity ◽  
Assay Sensitivity ◽  
Time Points ◽  
Thorough Qt Study ◽  
Equity Ownership ◽  
The Mean ◽  
Definition Of

Abstract Abstract 5573 Background Idelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110δ catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. IDELA displayed no significant inhibition of hERG channel activity for in vitro studies (IC50 ≥ 50 μM). ECG assessments in clinical studies indicated no evidence of QT interval prolongation or relationships between IDELA concentrations and QT or PR interval parameters over a dose range of 17 mg to 400 mg. A Phase 1, thorough QT study was performed in accordance with ICH E14 requirements for clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential of non-antiarrhythmic drugs. This study evaluated the effect of therapeutic and supratherapeutic doses of IDELA on QTc interval in healthy subjects, relative to matched placebo and active control. Methods A total of 48 subjects were enrolled in the study and randomized to one of two cohorts, each with a 4 x 4 Williams square design, to receive IDELA single dose at 150 (therapeutic dose) or 400 mg (supratherapeutic dose), placebo, or moxifloxacin at 400 mg (positive control) with 10 days of washout between each treatment. Multiple 12-lead time-matched ECGs were collected in triplicate at various time points over 24hours after each treatment and ECGs collected were obtained digitally using a Mortara H12+ Holter monitor. Time matched blood samples were collected and levels of IDELA and GS-563117 were measured using LC/MS/MS. Parametric analyses of covariance (ANCOVA) using a mixed-effects model were used to assess the change of QTc from predose baseline and proportionality of IDELA PK. A linear mixed effects model was used to quantify the relationship between IDELA plasma concentration and the DDQTc (time-matched, baseline-adjusted, placebo corrected QTc). Safety assessments were performed throughout the study. Results A total of 48 subjects were enrolled into this study. The majority of subjects were Black or African-American (58.3%) or White (33.3%), with even distribution of female (47.9%) and male (52.1%), and with a mean age of 33 years (range, 20 to 45 years).  Study treatments were generally well tolerated.  The majority of AEs were reported as Grade 1 (mild) in severity. There were no clinically relevant changes in any hematology or chemistry parameter for any treatment (including IDELA 150 and 400 mg, placebo, and moxifloxacin). The majority of treatment-emergent laboratory abnormalities were Grade 1. Idelalisib was generally well-tolerated at therapeutic (150 mg) and supratherapeutic (400 mg) doses. Plasma exposures IDELA and its major circulating metabolite GS-563117 were slightly less than dose-proportional between the 400 mg vs 150 mg (over a 2.7-fold dose range, IDELA and GS-563117 Cmax increased ∼1.7- and ∼1.8-fold respectively; corresponding values for AUCinfincreased ∼2.3 and 2.4-fold, respectively). Following moxifloxacin treatment, the lower bound of the 2-sided 90% CI for the mean difference in QTcF between moxifloxacin and placebo was greater than 5 msec at 2 time points (3 and 4 hours) after dosing, thereby establishing assay sensitivity. Following IDELA treatment, the upper bounds of the 2-sided 90% CIs for the mean difference in QTcF between therapeutic or supratherapeutic doses of IDELA and placebo were below 10 msec at all time points after dosing, meeting the definition of a “negative” thorough QT study. Results from the analyses of secondary endpoints QTcB, QTcN, and QTcI were consistent with those from the primary QTcF analysis. There were no relevant relationships between time-matched, baseline-adjusted, placebo-corrected QTcF and IDELA or GS-563117 plasma concentrations. Conclusion In a study with demonstrated assay sensitivity, IDELA 150 mg and 400 mg administration did not affect QTc interval in healthy adults, and met the definition of a negative thorough QT study as defined by ICH guidance. There were no relevant relationships between time-matched, baseline-adjusted, placebocorrected QTcF and IDELA or GS-563117 plasma concentrations. Single oral doses of IDELA 150 mg and 400 mg were well tolerated. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Nichols:Gilead Sciences: Employment. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

scholarly journals Droperidol and Ondansetron-induced QT Interval Prolongation

2008 ◽  
Vol 109 (2) ◽  
pp. 206-212 ◽  
Author(s):  
Beny Charbit ◽  
Jean Claude Alvarez ◽  
Eric Dasque ◽  
Emuri Abe ◽  
Jean Louis Démolis ◽  
...  
Keyword(s):  
Qt Interval ◽  
Plasma Concentrations ◽  
Postoperative Nausea And Vomiting ◽  
Pharmacokinetic Interaction ◽  
Controlled Study ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Double Blind ◽  
Qt Interval Prolongation ◽  
Controlled Conditions

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.

Electrocardiographic and Hemodynamic Effects of Panax Ginseng

2002 ◽  
Vol 36 (5) ◽  
pp. 758-763 ◽  
Author(s):  
Michael F Caron ◽  
Audrea L Hotsko ◽  
Stacy Robertson ◽  
Lilia Mandybur ◽  
Jeffrey Kluger ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diastolic Blood Pressure ◽  
Panax Ginseng ◽  
Study Drug ◽  
Healthy Adults ◽  
Controlled Study ◽  
Qtc Interval ◽  
Double Blind ◽  
Ginseng Extract ◽  
Days Of Therapy

OBJECTIVE: To determine whether Panax ginseng ingestion can acutely or chronically alter electrocardiographic parameters: PR, QRS, QT, QTc, and RR intervals, and QT and QTc interval dispersion. Effects of P. ginseng on blood pressure and heart rate also were evaluated. METHODS: This is a prospective, randomized, double-blind, placebo-controlled study of healthy adults at the University of Connecticut. Thirty subjects were randomly allocated to receive 28 days of therapy with either P. ginseng extract 200 mg or placebo. Baseline 12-lead electrocardiograms (ECGs) were obtained. Subsequent ECGs were performed following study drug ingestion at 50 minutes, 2 hours, and 5 hours on days 1 and 28. Blood pressure readings were taken with each ECG. RESULTS: P. ginseng ingestion increased the QTc interval by 0.015 seconds on day 1 at 2 hours compared with the placebo group (p = 0.03). It also reduced diastolic blood pressure from 75 ± 5 mm Hg at baseline to 70 ± 6 mm Hg at the same time point (p = 0.02). The observed effects are not believed to be clinically significant. No other statistically significant changes were found in electrocardiographic or hemodynamic variables on days 1 or 28. CONCLUSIONS: P. ginseng, at doses of 200 mg of the extract daily, increases the QTc interval and decreases diastolic blood pressure 2 hours after ingestion in healthy adults on the first day of therapy.

34Efficacy and safety of various doses of the new dual endothelin receptor antagonist aprocitentan in the treatment of hypertension

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Danaietash ◽  
P Verweij ◽  
B Flamion ◽  
J Menard ◽  
M Bellet
Keyword(s):  
Dose Response ◽  
Study Drug ◽  
Positive Control ◽  
Digital Ulcers ◽  
Maximal Effect ◽  
Endothelin Receptor ◽  
Double Blind ◽  
Phase 2 Trial ◽  
Parallel Group ◽  
Treatment Of Hypertension

Abstract Background Endothelin Receptor Antagonists (ERAs) have been investigated for the treatment of a variety of cardiovascular conditions because of their potent vasodilating properties. However, until now, ERAs have only been registered for the treatment of pulmonary arterial hypertension and scleroderma-induced digital ulcers. This class of drugs may also be useful in the treatment of difficult to control hypertension with a medical need. Purpose To investigate the efficacy and safety of various doses of the new dual ERA, aprocitentan, in the treatment of hypertension in order to determine the most appropriate dose(s) for further clinical development using an unattended, automated office BP (AOBP) device (BpTRU). This Phase 2 trial was registered at ClinicalTrials.gov [NCT02603809]. Methods Eligible patients with hypertension (mean sitting systolic/diastolic BP 149.7/97.6 mmHg) received aprocitentan 5, 10, 25 or 50 mg, matching placebo or lisinopril 20 mg as a positive control, once daily for 8 weeks using a randomised, double-blind, parallel-group study design. AOBP was assessed at baseline and weeks 2, 4, 8, and 10 (withdrawal) by recording multiple BP readings with the patient resting quietly. Additionally, 24 h ambulatory BP monitoring was performed at baseline and week 8. Results A total of 490 eligible patients were randomised to the double-blind phase with 430 subjects successfully completing 8 weeks of treatment. Decreases in sitting systolic/diastolic AOBP, from baseline to week 8 were 10.3/6.3, 15.0/9.9, 18.5/12.0 and 15.1/10.0 mmHg for aprocitentan 5, 10, 25, and 50 mg, respectively vs. 7.7/4.9 mmHg for placebo and 12.8/8.4 mmHg for lisinopril. No changes in heart rate or body weight were observed for any dose of aprocitentan. Modelling the dose-response suggested that the maximal effect of aprocitentan is achieved at a dose of approximately 25 mg and that 70% of this effect is already observed at a dose of 10 mg. Aprocitentan treatment was associated with decreases in haemoglobin, haematocrit, and albumin which exhibited a monotonic dose-response relationship, in line with its known vasodilating effects. Estimated increases in plasma volume were 3.0%, 5.1%, 6.9%, and 9.5% for aprocitentan 5, 10, 25, and 50 mg, respectively, vs. 1.6% for lisinopril and a decrease of 0.3% for placebo. All these values are below the accepted pathophysiological threshold of 10%. The overall incidence of adverse events observed in the aprocitentan groups (ranging from 22.0% to 40.2%) was similar to that seen in the placebo group (36.6%). Overall, the most common events were hypertension, headache, and nasopharyngitis. Conclusions These findings support the use of aprocitentan at doses between 10 and 25 mg for further investigation as a potential treatment for hypertension. Acknowledgement/Funding Actelion conducted study. Drug discovery & early clinical pipeline demerged during Johnson & Johnson acquisition. Idorsia supported abstract.

Sign in / Sign up

Export Citation Format

Share Document