Enhanced Response to Drug-Induced QT Interval Lengthening in Patients with Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Patients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown. METHODS AND RESULTS: We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QTF) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QTFvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QTF interval exposure. Maximum QTF (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QTF from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different. CONCLUSIONS: HFpEF is associated with enhanced response to drug-induced QT interval lengthening.

Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts.

INTRODUCTION: Higher progesterone concentrations are protective against drug-induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP). METHODS AND RESULTS: Female New Zealand white rabbits (2.5-3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo-treated rabbits (3.8 [range, 2.8-5.1] vs 0.7 [0.4-1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22-72] vs 53 [34-62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT c interval and short-term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits. CONCLUSIONS: Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy, and trigeminy in isolated perfused AV node-ablated rabbit hearts.

Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration.

This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 µg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 µg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.).

Extracorporeal treatment for tricyclic antidepressant poisoning: recommendations from the EXTRIP Workgroup.

The Extracorporeal Treatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, the workgroup presents its results for tricyclic antidepressants (TCAs). After an extensive literature search, using a predefined methodology, the subgroup responsible for this poison reviewed the articles, extracted the data, summarized findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Blinded votes were compiled, returned, and discussed in person at a meeting. A second vote determined the final recommendations. Seventy-seven articles met inclusion criteria. Only case reports, case series, and one poor-quality observational study were identified yielding a very low quality of evidence for all recommendations. Data on 108 patients, including 12 fatalities, were abstracted. The workgroup concluded that TCAs are not dialyzable and made the following recommendation: ECTR is not recommended in severe TCA poisoning (1D). The workgroup considers that poisoned patients with TCAs are not likely to have a clinical benefit from extracorporeal removal and recommends it NOT to be used in TCA poisoning.

Guidelines for reporting case studies on extracorporeal treatments in poisonings: methodology.

A literature review performed by the EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup highlighted deficiencies in the existing literature, especially the reporting of case studies. Although general reporting guidelines exist for case studies, there are none in the specific field of extracorporeal treatments in toxicology. Our goal was to construct and propose a checklist that systematically outlines the minimum essential items to be reported in a case study of poisoned patients undergoing extracorporeal treatments. Through a modified two-round Delphi technique, panelists (mostly chosen from the EXTRIP workgroup) were asked to vote on the pertinence of a set of items to identify those considered minimally essential for reporting complete and accurate case reports. Furthermore, independent raters validated the clarity of each selected items between each round of voting. All case reports containing data on extracorporeal treatments in poisoning published in Medline in 2011 were reviewed during the external validation rounds. Twenty-one panelists (20 from the EXTRIP workgroup and an invited expert on pharmacology reporting guidelines) participated in the modified Delphi technique. This group included journal editors and experts in nephrology, clinical toxicology, critical care medicine, emergency medicine, and clinical pharmacology. Three independent raters participated in the validation rounds. Panelists voted on a total of 144 items in the first round and 137 items in the second round, with response rates of 96.3% and 98.3%, respectively. Twenty case reports were evaluated at each validation round and the independent raters' response rate was 99.6% and 98.8% per validation round. The final checklist consists of 114 items considered essential for case study reporting. This methodology of alternate voting and external validation rounds was useful in developing the first reporting guideline for case studies in the field of extracorporeal treatments in poisoning. We believe that this guideline will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports may provide early signals of effectiveness and/or harm, thereby improving healthcare decision-making.

Gentamicin pharmacokinetics and pharmacodynamics during short-daily hemodialysis.

BACKGROUND/AIMS: Gentamicin pharmacokinetics have not been described in patients undergoing short-daily hemodialysis (SDHD). The aim of this study is to describe gentamicin pharmacokinetics and dialytic clearance (Cl(dial)) in SDHD patients and simulate gentamicin exposure after six dosing regimens to help guide future dosing. METHODS: Six anuric patients undergoing SDHD were enrolled. Patients received intravenous infusion of 2 mg/kg gentamicin on day 1 after the first HD session followed by HD sessions on days 2, 3, and 4. Blood samples for determination of gentamicin concentrations were serially collected. Gentamicin pharmacokinetic parameters and Cl(dial) and interindividual variability terms (IIV) were estimated using NONMEM VII. Influence of patient weight on systemic clearance (Cl(s)) and central volume of distribution (V(c)) and influence of urea removal estimates on Cl(dial) were assessed. The model was used to simulate gentamicin concentrations after six dosing regimens including pre- and postdialysis as well as daily and every-other-day dosing. RESULTS: A two-compartment model with first-order elimination from central compartment described gentamicin pharmacokinetics. Population estimates for Cl(s) and Cl(dial) were 7.6 and 134 ml/min, respectively. Patient weight was statistically significantly associated with Cl(s) and V(c). Predialysis every-other-day regimens were as effective (C(max) ≥8 mg/l and AUC(48 h) ≥140 mg·h/l) and less toxic (C(min) <2 mg/l and AUC(48 h) <240 mg·h/l) than postdialysis regimens. CONCLUSIONS: Estimated gentamicin Cl(dial) is higher than previous estimates with thrice-weekly regimens. Predialysis every-other-day dosing may be recommended during SDHD.

Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis.

OBJECTIVE: To investigate daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis to develop dosing recommendations. DESIGN: Prospective, open-label pharmacokinetic study. SETTING: : Intensive care units located within a teaching medical center. PATIENTS: Eight adults with known/suspected Gram-positive infections receiving continuous venovenous hemodialysis and daptomycin. INTERVENTIONS: Daptomycin at 8 mg/kg intravenously over 30 mins. Serial blood and effluent samples were collected over the next 48 hrs. Daptomycin protein binding was determined by equilibrium dialysis. Daptomycin continuous venovenous hemodialysis transmembrane clearance was determined by dividing daptomycin effluent by serum concentrations and multiplying by mean effluent production rate for each subject. Equations describing a two-compartment, open-pharmacokinetic model were fitted to each subject's daptomycin concentration-time data and pharmacokinetic parameters were determined by standard methods. Serum concentration-time profiles were simulated for two daptomycin regimens (8 mg/kg every 48 hrs and 4 mg/kg every 24 hrs). MEASUREMENTS AND MAIN RESULTS: A total of 7.7 ± 0.6 mg/kg (mean ± sd) of daptomycin was administered, resulting in an observed peak concentration of 81.2 ± 19.0 µg/mL. Daptomycin steady-state volume of distribution (0.23 ± 0.14 L/kg) and free fraction (17.5% ± 5.0%) were increased in critically ill subjects receiving continuous venovenous hemodialysis compared with previous values reported in healthy volunteers. Daptomycin transmembrane clearance (6.3 ± 2.9 mL/min) accounted for more than half of total clearance (11.3 ± 4.7 mL/min). Simulations demonstrated 8 mg/kg daptomycin every 48 hrs would result in higher peak (88.8 ± 20.0 µg/mL vs. 53.0 ± 12.3 µg/mL) and lower trough concentrations (7.2 ± 5.2 µg/mL vs. 12.3 ± 5.1 µg/mL) than 4 mg/kg every 24 hrs. CONCLUSIONS: Daptomycin at 8 mg/kg every 48 hrs in critically ill patients receiving continuous venovenous hemodialysis resulted in good drug exposure, achieved high peak concentrations to maximize daptomycin's concentration-dependent activity, and resulted in trough concentration that would minimize the risk of myopathy. CLINICALTRIALS.GOV IDENTIFIER: NCT00663403.

The influence of progesterone alone and in combination with estradiol on ventricular action potential duration and triangulation in response to potassium channel inhibition.

INTRODUCTION: Females are at increased risk for torsades de pointes (TdP). Some evidence suggests that progesterone may protect against TdP, but few data exist regarding the effects of progesterone on cardiac repolarization. We determined the effects of progesterone alone and in combination with estradiol on ventricular action potential duration (APD) and triangulation in response to potassium channel inhibition. METHODS AND RESULTS: Female New Zealand white rabbits (n = 30) underwent ovariectomy and were implanted with 21-day sustained release pellets (each n = 6): progesterone; estradiol; progesterone; & estradiol combined; dihydrotestosterone (DHT); and placebo. After 20 days, hearts were excised, mounted, perfused with modified Krebs-Henseleit buffer, and paced at 150 bpm. After baseline measurements, hearts were perfused with quinidine 3 µmol/L. The degree of quinidine-associated prolongation of ventricular APD at 90% repolarization (APD(90) ) in the progesterone group was significantly less than that in the estradiol and the combined estradiol and progesterone groups, and not significantly different than in the DHT group. The degree of prolongation of action potential triangulation (APD(90) - APD(30) ) in hearts from progesterone-treated rabbits was significantly less than that in the estradiol group, and not significantly different from that in hearts from DHT-treated rabbits. There were no significant differences in quinidine effects on ventricular APD(90) or action potential triangulation between hearts exposed to estradiol alone or those exposed to both estradiol and progesterone. CONCLUSIONS: Progesterone protects against prolongation of APD(90) and triangulation associated with potassium channel inhibition. However, progesterone does not attenuate the effects of estradiol on prolongation of ventricular APD(90) associated with potassium channel inhibition.

Cefuroxime pharmacokinetics in pediatric cardiovascular surgery patients undergoing cardiopulmonary bypass.

OBJECTIVES: The objective of this study was to determine the pharmacokinetics of cefuroxime in children undergoing cardiopulmonary bypass (CPB) for cardiovascular surgery. DESIGN: A prospective study. SETTING: A tertiary pediatric teaching hospital. PARTICIPANTS: Infants and children undergoing CPB were enrolled in the study. INTERVENTION: An initial dose (mean, 24.2 ± 1.6 mg/kg) of cefuroxime was administered before surgical incision, and a second dose (mean, 14.4 ± 7.9 mg/kg) was administered in the CPB prime solution. Serial blood samples were obtained before, during, and after the CPB process. Samples were shipped on dry ice to the analytic laboratory and concentrations determined by a validated high-performance liquid chromatography method. A 2-compartment pharmacokinetic model was fitted to the data using maximum a priori-Bayesian estimation, with weight as a covariate. Monte Carlo simulations of a single-dose (25 mg/kg pre-CPB) approach and a 2-dose (25 mg/kg pre- and 12.5-mg/kg prime solution dose) approach were performed. MEASUREMENTS AND MAIN RESULTS: Fifteen subjects (9 males/6 females) were enrolled in the study, with median (range) age and weight of 11 (3-34) months and 9.5 (4.5-15.4) kg, respectively. The median (range) duration of CPB was 136 (71-243) minutes. Median and range cefuroxime pharmacokinetic parameters were as follows: maximum concentration (Cmax) dose, 1: 328 (150-512) µg/mL; systemic clearance, 0.050 (0.041-0.058) L/h/kg; steady-state volume of distribution, 0.213 (0.081-0.423) L/kg; volume of distribution in the central compartment, 0.081 (0.046-0.162) L/kg; and elimination half-life, 3.76 (1.03-6.81) hours. The median 8-hour post-dose-simulated cefuroxime concentrations were 26.5 and 16.0 mg/L for the 2-dose and single-dose regimens, respectively. CONCLUSION: Manufacturers recommend that pediatric doses of cefuroxime (25-50 mg/kg) can be used in infants and children undergoing CPB to maintain adequate serum concentrations for surgical-site infection prophylaxis. A second intraoperative dose, administered through the CPB circuit, provides no additional prophylactic advantage.

Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men.

We have previously reported that transdermal testosterone attenuates drug-induced QT interval lengthening in older men. However, it is unknown whether this is due to modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis of a prospective, randomized, double-blind, placebo-controlled three-way crossover study, we determined if transdermal testosterone and oral progesterone attenuate drug-induced lengthening of early and late ventricular repolarization, represented by the electrocardiographic measurements J-Tpeak c and Tpeak -Tend , respectively, as well as Tpeak -Tend /QT, a measure of transmural dispersion of repolarization. Male volunteers ≥ 65 years of age (n = 14) were randomized to receive transdermal testosterone 100 mg, oral progesterone 400 mg, or matching transdermal/oral placebo daily for 7 days. On the morning following the seventh day, subjects received intravenous ibutilide 0.003 mg/kg, after which electrocardiograms were performed serially. One subject was excluded due to difficulty in T-wave interpretation. Pre-ibutilide J-Tpeak c was lower during the testosterone phase than during progesterone and placebo (216 ± 23 vs. 227 ± 28 vs. 227 ± 21 ms, P = 0.002). Maximum post-ibutilide J-Tpeak c was also lower during the testosterone phase (233 ± 22 vs. 246 ± 29 vs. 248 ± 23 ms, P < 0.0001). Pre-ibutilide Tpeak -Tend was not significantly different during the three phases, but maximum post-ibutilide Tpeak -Tend was lower during the testosterone phase (80 ± 12 vs. 89 ± 18 vs. 86 ± 15 ms, P = 0.002). Maximum Tpeak -Tend /QT was also lower during the testosterone phase (0.199 ± 0.023 vs. 0.216 ± 0.035 vs. 0.209 ± 0.031, P = 0.005). Progesterone exerted minimal effect on drug-induced lengthening of J-Tpeak c, and no effect on Tpeak -Tend or Tpeak -Tend /QT. Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men.

Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulations and steady-state pharmacokinetic data from hospitalized patients.

BACKGROUND: Prolonging the infusion of a beta-lactam antibiotic enhances the time in which unbound drug concentrations remain above the minimum inhibitory concentration (fT>MIC). OBJECTIVE: To compare the pharmacodynamics of several dosing regimens of piperacillin/tazobactam administered by intermittent and prolonged infusion using pharmacokinetic data from hospitalized patients. METHODS: Steady-state pharmacokinetic data were obtained from 13 patients who received piperacillin/tazobactam 4.5 g every 8 hours, infused over 4 hours. Monte Carlo simulations (10,000 pts.) were performed to calculate pharmacodynamic exposures at 50% fT>MIC for 4 intermittent-infusion regimens (3.375 g every 4 and 6 h, 4.5 g every 6 and 8 h) and 4 prolonged-infusion regimens (2.25 g, 3.375 g, 4.5 g, and 6.75 g every 8 h [4-h infusion]) of piperacillin/tazobactam using pharmacokinetic data for piperacillin. Cumulative fraction of response (CFR) was calculated using MIC data for 6 gram-negative pathogens (Meropenem Yearly Susceptibility Test Information Collection, 2004-2007), and probability of target attainment (PTA) was calculated at MICs ranging from 1 microg/mL to 64 microg/mL. RESULTS: The CFR for 3.375 g every 4 hours (intermittent infusion) and 3.375-4.5 g every 8 hours (prolonged infusion) greater than or equal to 90.3% for Escherichia coli, Serratia marcescens, and Citrobacter spp. Increasing the prolonged-infusion dose to 6.75 g improved the CFR to greater than 90% for Enterobacter spp. For every regimen evaluated, the CFR was less than 90% for Klebsiella pneumoniae and Pseudomonas aeruginosa. At an MIC of 16 microg/mL, PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every 4 h) and 3 prolonged-infusion regimens (> or = 3.375 g every 8 h), but no regimen achieved a PTA greater than 90% at an MIC of 64 microg/mL. CONCLUSIONS: At doses greater than or equal to 3.375 g every 8 hours, 4-hour infusions of piperacillin/tazobactam achieved excellent target attainment with lower daily doses compared with standard regimens at MICs less than or equal to 16 microg/mL.

Steady-state pharmacokinetics and pharmacodynamics of meropenem in hospitalized patients.

STUDY OBJECTIVE: To evaluate the steady-state pharmacokinetics and pharmacodynamics of meropenem 500 mg every 6, 8, and 12 hours, based on renal function, in hospitalized patients. DESIGN: Prospective, open-label, steady-state pharmacokinetic study. SETTING: One tertiary care medical center and one community hospital. PATIENTS: Twenty adult patients (12 men, 8 women) with suspected or documented bacterial infections requiring antimicrobial therapy. INTERVENTION: Patients received 30-minute infusions of meropenem 500 mg every 6 hours (group 1), every 8 hours (group 2), or every 12 hours (group 3) based on estimated creatinine clearances greater than 60, 40-60, or 10-39 ml/minute, respectively. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected after 2 or more days of therapy. Meropenem concentrations were determined by high-performance liquid chromatography, and pharmacokinetic data were analyzed by noncompartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for a percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC) of 40% by using pharmacokinetic data for each group and MIC data for seven gram-negative pathogens from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC, 2004-2005) database. Maximum and minimum serum concentrations (mean +/- SD) were 29.2+/-9.8 and 2.4+/-1.1 microg/ml, 33.2+/-8.5 and 3.8+/-2.7 microg/ml, and 33.5+/-4.7 and 4.9+/-1.6 microg/ml for groups 1, 2, and 3, respectively. The half-life values were 2.5+/-0.9, 3.4+/-1.3, and 6.1+/-1.4 hours, and the values for volume of distribution at steady state were 29.3+/-8.7, 23.8+/-8.1, and 28.7+/-8.6 L for groups 1, 2, and 3, respectively. For all three groups, the CFR was greater than 90% for the enteric pathogens and Pseudomonas aeruginosa and 82.4-85.2% for Acinetobacter species. CONCLUSION: Pharmacodynamic analyses suggest that regimens of meropenem 500 mg every 6, 8, or 12 hours, adjusted for renal function, are acceptable for treatment of infections caused by enteric gram-negative pathogens and P. aeruginosa. However, more aggressive dosing or alternative dosing strategies may be necessary for Acinetobacter species.

Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction.

STUDY OBJECTIVE: To assess whether the increased risk of ibutilide-induced torsade de pointes in patients with heart failure may be due to increased ibutilide exposure, we sought to determine if the pharmacokinetics of ibutilide are altered in patients with heart failure due to left ventricular systolic dysfunction. DESIGN: Multicenter, prospective pharmacokinetic study. SETTING: Four academic medical centers in the United States. PATIENTS: Sixteen adult patients with atrial fibrillation or atrial flutter requiring conversion to normal sinus rhythm: six patients who had New York Heart Association (NYHA) class II or III heart failure due to left ventricular dysfunction (mean +/- SD left ventricular ejection fraction [LVEF] 30 +/- 9%); 10 patients who did not have left ventricular dysfunction (mean +/- SD LVEF 54 +/- 5% in six of these 10 patients) served as controls. INTERVENTION: All patients received a single dose of ibutilide 1.0 mg administered intravenously over 10 minutes. Blood samples were obtained through an indwelling catheter in the contralateral arm before ibutilide administration, at the end of the infusion, and at 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 48 hours after the infusion. MEASUREMENTS AND MAIN RESULTS: Serum ibutilide concentrations were determined by using high-performance liquid chromatography and mass spectrometry. No significant differences were noted between the heart failure and normal left ventricular function groups in the following parameters: maximum serum ibutilide concentration (median [interquartile range] 3.8 [2.3-5.7] vs 5.8 [3.1-14.4] microg/L, p=0.31), area under the serum concentration-time curve from time zero extrapolated to infinity (mean +/- SD 11.0 +/- 9.4 vs 13.2 +/- 10.6 microg*hr/L, p=0.88), steady-state volume of distribution (1380 +/- 334 vs 1390 +/- 964 L, p=0.99), systemic clearance (129 +/- 60 vs 125 +/- 81 L/hr, p=0.92), or half-life (12.5 +/- 10.7 vs 12.4 +/- 8.6 hrs, p=0.99). CONCLUSION: The pharmacokinetics of ibutilide do not appear to be altered in patients with NYHA class II or III heart failure due to left ventricular systolic dysfunction. Therefore, the increased risk of ibutilide-induced torsade de pointes in patients with heart failure does not appear to be due to increased ibutilide exposure.

Biostatistics primer: part 2.

Biostatistics is the application of statistics to biologic data. This article is the second part of a 2-part series on the application of statistics in nutrition science. The first article, published in the December 2007 issue, reviewed descriptive statistics. Inferential statistics, to be discussed in this article, can be used to make predictions based on a sample obtained from a population or some large body of information. It is these inferences that are used to test specific research hypotheses. This article focuses on inferential statistics and their application in the nutrition and biomedical literature. Additionally, this review will outline some of the most commonly used statistical tests found in the biomedical literature.

Biostatistics primer: part I.

Biostatistics is the application of statistics to biologic data. The field of statistics can be broken down into 2 fundamental parts: descriptive and inferential. Descriptive statistics are commonly used to categorize, display, and summarize data. Inferential statistics can be used to make predictions based on a sample obtained from a population or some large body of information. It is these inferences that are used to test specific research hypotheses. This 2-part review will outline important features of descriptive and inferential statistics as they apply to commonly conducted research studies in the biomedical literature. Part 1 in this issue will discuss fundamental topics of statistics and data analysis. Additionally, some of the most commonly used statistical tests found in the biomedical literature will be reviewed in Part 2 in the February 2008 issue.

Gatifloxacin pharmacokinetics in healthy men and women.

The sex-based pharmacokinetics of gatifloxacin were investigated. Healthy subjects (6 men, 6 women) received a single oral dose of gatifloxacin 400 mg. Blood and urine samples were collected, and gatifloxacin concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were estimated by fitting appropriate models to the serum concentration-time data using ADAPT II. Linear regression analysis was used to determine the influence of sex and weight on the oral clearance (CL(s)/F) and apparent steady-state volume of distribution (V(ss)/F) of gatifloxacin. Women had a significantly smaller V(ss)/F compared to men (93.5 +/- 21.3 L vs 128.8 +/- 16.2 L, P = .009); however, there was no significant difference when normalized for total body weight (TBW) or lean body weight (LBW). Neither CL(s)/F nor peak serum concentration (C(max)) was significantly different between sexes, although C(max) was 25% higher in women (P = .06). Regression analyses revealed that TBW (R(2) = .63) and LBW (R(2) = .65) were strong predictors of V(ss)/F. Given the smaller V(ss)/F, women may have slightly higher maximum concentrations, but these differences are unlikely to have clinical significance.

Educational Background and Academic Rank of Faculty Members within US Schools of Pharmacy.

Objective. To characterize the educational background and academic rank of faculty members in US schools of pharmacy, estimate the extent to which they are employed by institutions where they received previous training, and determine whether differences in degree origin and rank exist between faculty members in established (≤1995) vs newer programs. Methods. A cross-sectional study was conducted using the American Association of Colleges of Pharmacy (AACP) faculty database and demographic information from the public domain. Results. Among 5516 faculty members, 50.3% held two or more types of degrees. Established schools had a higher median number of faculty members and a higher mean faculty rank than did newer schools. Conclusion. The difference in mean faculty rank highlights the shortage of experienced faculty members in newer schools. Future research efforts should investigate educational attainment in correlation to other faculty and school characteristics and prospectively track and report trends related to pharmacy faculty members composition.

Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

OBJECTIVES: We tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. BACKGROUND: Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. METHODS: In this prospective, double-blind, crossover study, 19 healthy female volunteers (21-40 years) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 minutes, after which QT intervals were recorded and blood samples collected for 12 hours. Prior to the treatment phases, subjects underwent ECG monitoring for 12 hours to calculate individualized heart rate-corrected QT intervals (QTcI). RESULTS: Fifteen subjects completed all study phases. Maximum serum ibutilide concentrations in the progesterone and placebo phases were similar (1247±770 vs 1172±709 pg/mL, p=0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2±11.0 vs 1.2±1.0 ng/mL, p<0.0001), while serum estradiol concentrations in the two phases were similar (89.3±62.8 vs 71.8±31.7 pg/mL, p=0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412±15 vs 419±14 ms, p=0.04). Maximum ibutilide-associated QTcI (443±17 vs 458±19 ms, p=0.003), maximum percent increase in QTcI from pretreatment value (7.5±2.4 vs 9.3±3.4%, p=0.02) and area under the effect (QTcI) curve during the first hour post-ibutilide (497±13 vs 510±16 ms-hr, p=0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. CONCLUSIONS: Oral progesterone administration attenuates drug-induced QTcI lengthening.