John C. Pezzullo

QTc interval prolongation associated with intravenous methadone

&NA; Numerous medications prolong the rate‐corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether‐a‐go‐go‐related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (±standard error) per patient in QTc intervals on and off methadone was 41.7 (±7.8) ms, p<0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (±6.1) ms, p=0.15. The approximately linear relationship between QTc measurements and log‐dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration‐dependent manner with IC50 values of 20±2 &mgr;M and 4.4±0.3 mM, respectively. Chlorobutanol potentiates methadones ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.

Effect of Arsenic Trioxide on QT Interval in Patients With Advanced Malignancies

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

Association of Human Milk Feedings With a Reduction in Retinopathy of Prematurity Among Very Low Birthweight Infants

INTRODUCTION: With the increased survival of very low birthweight (VLBW) infants, weighing less than 1500 g at birth, the incidence of retinopathy of prematurity (ROP), a significant cause of blindness among children in the United States, is also increasing. Preterm infants with a positive diagnosis of ROP during the perinatal period are at increased risk for ocular abnormalities and for deficits in visual function during later periods of development. Human milk has many antioxidant constituents including inositol, vitamin E, and beta-carotene that may protect against the development of ROP.OBJECTIVE: The objective of this study was to examine the effect of human milk feedings on the incidence of ROP among VLBW infants.STUDY DESIGN: Observational cohort study.PARTICIPANTS: We identified 283 VLBW infants admitted to the Georgetown University Medical Center Neonatal Intensive Care Unit (NICU) from January 1992 through September 1993. All infants surviving to receive enteral feeding and ophthalmologic examinations for ROP (n=174) were included in the analysis.METHODS: Type of feeding (human milk versus exclusive formula), presence of ROP, and potential confounding variables were abstracted retrospectively from medical records. ROP was present if any stage of ROP was diagnosed at any age during the initial NICU hospitalization; each case was counted once based on the worse severity of ROP in either eye. Multiple logistic regression was used to control for confounders.MAIN OUTCOME MEASURE: ROP.RESULTS: Major predictors of ROP were similar in both feeding groups including gestational age, days on mechanical ventilation, and total number of days on supplemental oxygen. The incidence of ROP differed significantly by type of feeding (human milk −41.0% vs. formula −63.5%, p=0.005). Human milk feeding independently correlated with a reduced odds of ROP (OR: 0.42, 95% CI: 0.19 to 0.93) (p=0.03), controlling for gestational age, duration of supplemental oxygen therapy, 5-minute Apgar score, and race. Human milk feeding independently correlated with a reduced odds of ROP (OR: 0.46, 95% CI: 0.18 to 0.91) (p=0.03), controlling for birthweight, duration of supplemental oxygen therapy, 5-minute Apgar score, and race.CONCLUSION: Human milk feeding among VLBW infants was associated with a lower incidence of ROP compared to exclusively formula-fed VLBW infants after adjusting for confounding variables.

Health care and indemnity costs across the natural history of disability in occupational low back pain.

Study Design. The administrative database maintained by the National Council on Compensation Insurance (United States) was used to compare health care use and indemnity costs within the natural history of work‐related low back pain disability. Objectives. To determine the relative costs of health care services and indemnity at different phases of work disability. Summary of Background Data. Existing studies have compared total costs along the work disability continuum. This study replicates and extends these earlier studies by providing detailed evaluations of costs by service categories along this continuum. Methods. Total health care and indemnity costs accrued along the disability curve were examined. Based on the number of days workers were absent from work and receiving indemnity payments (disability days), detailed mean health care costs by type of medial service were computed and compared across four time intervals for the sample. Results. Health care costs were disproportionately distributed along the disability curve, with 20% of claimants disabled 4 months or more, accounting for 60% of health care costs. The most costly service category was diagnostic procedures (25% of total medical costs), with surgical costs (21%) and physical therapy (20%) representing the next two most costly categories. Mental health and chiropractic care represented a small percentage of overall costs (0.4% and 2.9%, respectively). Conclusions. These data provide policy‐makers, program development, and health care industry groups with cost information from which to establish benchmarks for future decisions that facilitate the allocation of resources for more cost‐effective management and prevention of work disability.

Chronic Nicotine Differentially Regulates α6- and β3-Containing Nicotinic Cholinergic Receptors in Rat Brain

We investigated the effects of chronic nicotine on α6- and β3-containing nicotinic acetylcholine receptors (nAChRs) in two rat brain regions using three methodological approaches: radioligand binding, immunoprecipitation, and nicotine-stimulated synaptosomal release of dopamine. Nicotine was administered by osmotic minipumps for 2 weeks. Quantitative autoradiography with [125I]α-conotoxin MII to selectively label α6* nAChRs showed a 28% decrease in binding in the striatum but no change in the superior colliculus. Immunoprecipitation of nAChRs labeled by [3H]epibatidine in these two regions showed that chronic nicotine increased α4- and β2-containing nAChRs by 39 to 67%. In contrast, chronic nicotine caused a 39% decrease in α6-containing nAChRs in striatum but no change in superior colliculus. No changes in β3-containing nAChRs were seen in either region after chronic nicotine. The decreased expression of α6-containing nAChRs persisted for at least 3 days, recovering to baseline by 7 days after removal of the pumps. There was a small but significant decrease in total nicotine-stimulated dopamine release in striatal synaptosomes after nicotine exposure. However, the component of dopamine release that was resistant to α-conotoxin MII blockade was unaffected, whereas dopamine release that was sensitive to blockade by α-conotoxin MII was decreased by 56%. These findings indicate that the α6* nAChR is regulated differently from other nAChR subtypes, and they suggest that the inclusion of a β3 subunit with α6 may serve to inhibit nicotine-induced down-regulation of these receptors.

Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis.

Background  TZP‐101 is a synthetic, selective ghrelin agonist in development for gastroparesis.

Meta-analysis of antiarrhythmic therapy in the prevention of postoperative atrial fibrillation and the effect on hospital length of stay, costs, cerebrovascular accidents, and mortality in patients undergoing cardiac surgery.

T have been 13 randomized controlled trials of prophylactic antiarrhythmic therapy in patients undergoing cardiac surgery that have assessed its effects on hospital length of stay.1–13 These have shown consistent and marked decreases in the incidence of atrial fibrillation (AF), but the effects on hospital stay have been less concordant. Correlation of a decreased incidence of this arrhythmia with a reduction in hospital length of stay, costs, morbidity, or mortality would help determine how much continuing effort should be placed on its prevention. To determine whether this decreased incidence translates into clinically important outcomes, we conducted a meta-analysis of various antiarrhythmic therapies and their effects on the length of hospitalization, costs, stroke, and mortality. • • • We conducted a review of reports (in English) in the MEDLINE database, using the keywords “antiarrhythmics” and “postoperative atrial fibrillation” between January 1977 and March 2001. Published reviews, computerized literature search, and analysis of references identified potentially eligible studies. Only published data were included in this analysis. Unpublished studies and results reported in abstracts were excluded. Studies were included if they met the following criteria: (1) randomized comparison of an intervention to placebo; (2) evaluation of pacing modality or drug administration excluding calcium channel blockers, digoxin, and magnesium; (3) reported hospital length of stay; (4) AF identified as the arrhythmia. Thirteen randomized trials met the criteria and are included in this analysis. Forty trials were excluded because they did not include data on hospital length of stay, 14 because they did not include a placebo group, 7 because they evaluated atrial flutter or supraventricular arrhythmias as a group, and 4 because they were retrospective studies. Data were also extracted on 3 additional outcomes when available (costs, stroke, and death). Six studies had data on costs, 5 had data on the incidence of stroke, and 9 had data on mortality. All trial analyses were double-blinded and performed on an intention-to-treat basis. In the study by Dorge et al,8 the 2 different dosing regimens of amiodarone were considered as a single treatment group when evaluated for outcomes in the meta-analysis. In cases where different pacing modalities resulted in no significantly different effect on the incidence of atrial fibrillation, the results for outcomes were averaged before statistical analysis.3 In trials of different pacing modalities that showed superiority of 1 treatment group in decreasing the incidence of atrial fibrillation, only this group was included in the analysis of outcomes.10,11 The trials by Guanieri et al5 and Fan et al9 did not have SDs for the cost analysis; therefore, we approximated the SD to be 70% to 75% of the total cost, based on an evaluation of other studies in this meta-analysis that included data on SDs. Our primary outcomes for analysis were the effects on duration of hospitalization, defined as the number of days from surgery to hospital discharge, as well as hospital costs. The clinically important outcomes of the incidence of stroke and mortality were also assessed. For quantitative outcomes, the difference in the outcomes between the patient and the intervention groups was computed along with 95% confidence intervals. These were checked for consistency with an analysis of variance. By taking a weighted average of the differences, the results from the separate studies were combined, the weight being inversely proportional to the square of the width of the confidence interval. The values were combined using a method described by Fleiss.14 For dichotomous outcome variables, odds ratios and confidence intervals were computed, and these were combined on the basis of the weighted logarithms of the odds ratio, as described in the aforementioned source.14 In the 13 studies, a total of 1,783 patients were enrolled and included in the meta-analysis. Of these patients, 1,038 were assigned to the antiarrhythmic group and 745 were assigned to the control group. One thousand five hundred and sixty-nine patients underwent isolated coronary artery bypass grafting, 87 underwent only valvular surgery, 117 underwent both coronary artery bypass grafting and valvular surgery, and 10 underwent other types of cardiac surgery. The incidence of AF varied from 8% to 37% in the treatment groups and 29% to 53% in the control groups, From the Department of Cardiology, Veterans Affairs Medical Center; and Georgetown University Medical Center, Washington, DC. Dr. Singh’s address is: Department of Cardiology, Veterans Affairs Medical Center, 50 Irving Street, NW, Room 1E301, Washington, DC 20422. E-mail: singh@va.med.gov. Manuscript received September 24, 2002; revised manuscript received and accepted January 22, 2003.

Premature Ovarian Failure in Women with Epilepsy

Summary:  Purpose: Women with epilepsy (WWE) have an increased risk for several reproductive endocrine disorders that may affect their fertility. The incidence of premature ovarian failure (POF) in women with epilepsy has not been systematically studied. This study examined the incidence of POF in women with epilepsy.

Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study

Background  Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP‐101, is in clinical development for treatment of gastroparesis. This double‐blind, randomized, placebo‐controlled study evaluated the safety and efficacy of multiple TZP‐101 doses in patients with moderate to severe symptomatic diabetic gastroparesis.

A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis

Objective  To compare the efficacy of S‐adenosyl‐l‐methionine and ursodeoxycholic acid in improving serum biochemical abnormalities in gestational cholestasis.