Study objective To compare outcomes after acute acetaminophen poisoning in 2 large cohorts of patients treated with either the 20-hour intravenous or 72-hour oral acetylcysteine protocol. Methods We ...conducted a retrospective cohort study with historical control comparing patients treated with one of 2 acetylcysteine regimens. Data for the 20-hour group were obtained from a medical record review of patients on whom the 20-hour intravenous protocol was initiated in Canadian hospitals from 1980 to 2005. The 72-hour group consisted of a historical cohort of patients treated in US hospitals with the 72-hour oral protocol from 1976 to 1985. The primary outcome was hepatotoxicity (aminotransferase levels >1,000 IU/L). Results Of the 4,048 patients analyzed, 2,086 were in the 20-hour group and 1,962 were in the 72-hour group. The incidence of hepatotoxicity was 13.9% in the 20-hour group and 15.8% in the 72-hour group (–1.9% absolute difference; 95% confidence interval CI -4.2 to 0.3). The relative risk of hepatotoxicity was lower in the 20-hour group when acetylcysteine was initiated within 12 hours of ingestion. The relative risk was lower in the 72-hour group when acetylcysteine was initiated later than 18 hours after ingestion. There was no significant risk difference between groups when acetylcysteine treatment was started 12 to 18 hours after ingestion. One patient in the 20-hour group received a liver transplant and died because of acetaminophen toxicity compared with no liver transplants and 3 deaths in the 72-hour group. Anaphylactoid reactions to intravenous acetylcysteine were reported in 148 of 2,086 patients (7.1%; 95% CI 6.1% to 8.3%). This study is limited by comparison of 2 separate data sets from different countries and study years. Conclusion The risk of hepatotoxicity differed between the 20-hour and 72-hour protocols according to the time to initiation of acetylcysteine. It favored the 20-hour protocol for patients presenting early and favored the 72-hour protocol for patients presenting late after acute acetaminophen overdose.
Rapid delivery of potent opioid to the systemic circulation is an important feature for the effective treatment of acute and acute-on-chronic breakthrough pain. The delivery of different opioids by ...the pulmonary route has been inconsistent, usually resulting in low bioavailability of the drug. Staccato® Fentanyl for Inhalation is a handheld inhaler producing a single metered dose of aerosolized fentanyl during a single inspiration. The aerosol is of high purity (≥98%) at a particle size (1 to 3.5 microns) shown to be best for pulmonary absorption.
We conducted the study in healthy volunteers in 2 stages. In the crossover stage, 10 subjects received IV fentanyl 25 µg and inhaled fentanyl 25 µg on separate occasions. The dose escalation stage was a multidose, randomized, double-blind, placebo-controlled, single-period dose escalation study of inhaled fentanyl (50 to 300 µg). Serial blood sampling was performed over an 8-hour period after drug administration to determine the pharmacokinetic profile, and serial pupillometry was performed as a measure of pharmacodynamic effect.
In the crossover stage the pharmacokinetic profiles of the inhaled and IV fentanyl showed similar peak arterial concentrations and areas under the curve. The time to maximum concentration was slightly shorter for the inhaled than IV fentanyl, 20.5 and 31.5 seconds, respectively. In the dose escalation stage the administration of repeated doses resulted in predictable, dose-dependent serum concentrations.
This study has demonstrated that the pharmacokinetic profile of single doses of inhaled fentanyl is comparable to IV administration.
We described calls to U.S. poison centers (PCs) related to potential exposure to substances through breast milk.
We analyzed National Poison Data System calls between 2001 and 2017 with "Exposure ...through breast milk" or "Drug use during breastfeeding" as the coded scenario. Data handling and descriptive statistics were carried out using SAS JMP 12.01.
U.S. PCs received 76,416 information calls and 2,319 exposure calls related to breast milk. Exposure calls were from a residence in 76% (
= 1,758), from health care facilities (HCFs) in 15.5% (
= 360), and from a workplace in 0.6% (
= 15). A total of 466 exposures (20.1%) were subsequently managed at a HCF: 269 were evaluated and released (58%), 38 were admitted to intensive care unit (8.2%), and 53 were admitted to hospital floor (11%). Medical outcomes included 1 death (0.04%), 8 major effect (0.3%), 43 moderate effect (1.9%), 170 minor effect (7.3%), and 390 no effect (16.8%). Exposure calls that reported major effects involved opioids, benzodiazepines, ethanol, cyclobenzaprine, insulin, and amphetamines. Exposure calls most commonly involved antibiotics, antifungals, benzodiazepines, opioids, and selective serotonin reuptake inhibitors (SSRIs). A total of 1,192 exposures (51.4%) had reported signs/symptoms including drowsiness, agitation, rash, and vomiting/diarrhea. Information calls most commonly involved systemic antibiotics, SSRIs, antihistamines, corticosteroids, and benzodiazepines.
Substances common to both exposure and information calls included antibiotics, benzodiazepines, and SSRIs. Most cases of severe toxicity included potential exposures through breast milk to benzodiazepines and opioids. These data may help inform educational outreach, risk assessment, and bedside care for breastfeeding mothers.
This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT ...(QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710).
Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart+oral placebo, two doses of inhaled placebo+oral placebo, or two doses of inhaled placebo+oral moxifloxacin (400 mg; positive control), with ≥3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed.
Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE.
Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.
Context: The Centers for Disease Control (CDC) monitors influenza like illness (ILI) and the National Poison Data System (NPDS) warehouses call data uploaded by US poison centers regarding reported ...exposures to medication. Objective: We examined the relationship between calls to poison centers regarding reported exposures to medications commonly used to treat ILI and weekly reports of ILI. Materials and Methods: The CDC reports ILI, by age group, for each of 10 Health and Human Services (HHS) regions. We examined NPDS summary data from calls reported to poison centers regarding reported exposures to acetaminophen, cough/cold medications, and promethazine, for the same weeks, age groups, and HHS regions for influenza seasons 2000-2013. ILI and NPDS exposures were examined using graphical plots, descriptive statistics, stepwise regression analysis, and Geographic Information Systems (GIS). Results: About 5,101,841 influenza-like illness cases were reported to the CDC, and 2,122,940 calls regarding reported exposures to medications commonly used to treat ILI, were reported by poison centers to the NPDS over the 13 flu seasons. Analysis of stepwise models of the linear untransformed data involving 24 NPDS data groups and for 60 ILI measures, over the 13 influenza seasons, demonstrated that reported exposures to medications used to treat ILI correlated with reported cases of ILI with a median R
2
=
0.489 (min R
2
=
0.248, max R
2
=
0.717), with mean ± SD of R
2
=
0.494 ± 0.121. Median number of parameters used (degrees of freedom - 1) was 7. Conclusions: NPDS data regarding poison center calls for selected ILI medication exposures were highly correlated with CDC ILI data. Since NPDS data are available in real time, it provides complimentary ILI monitoring. This approach may provide public health value in predicting other illnesses which are not currently as thoroughly monitored.
Loxapine inhalation powder delivered by a hand-held device as a thermally generated aerosol (ADASUVE) was recently approved in the United States and European Union for use in the acute treatment of ...agitation in patients with bipolar disorder or schizophrenia. As smokers comprise a large subpopulation of these patients, and many antipsychotic drugs require dose adjustments for smokers, the objective of this study was to compare the pharmacokinetics of inhaled loxapine administered to smokers and nonsmokers.
Pharmacokinetics and sedation pharmacodynamics using a visual analog scale were studied in 35 male and female adult subjects (18 nonsmokers and 17 smokers) following a single dose of 10 mg of inhaled loxapine. Blood samples were drawn at predose, 30 seconds, 1, 2, 3, 10, 30, and 60 minutes, and 2, 6, 12, and 24 hours after dosing. Loxapine and 8-OH-loxapine were analyzed using reverse-phase liquid chromatography coupled with a tandem mass spectrometer. Pharmacokinetic parameters assessed included Cmax, Tmax, AUCinf, and T1/2 for loxapine and 8-OH-loxapine. Geometric mean ratios (GMRs) were determined for smokers to nonsmokers.
Loxapine Cmax was similar in smokers and nonsmokers with a GMR of 99.0%. The median loxapine Tmax was 1.88 and 1.01 minutes for nonsmokers and smokers, respectively. Loxapine AUCinf and AUClast values in nonsmokers were comparable with smokers (GMRs of 85.3% and 86.7%, respectively). A slight decrease in the observed mean terminal half-life values was observed for smokers (6.52 hours for smokers and 7.30 hours for nonsmokers).
Sedation profiles and visual analog scale scores at each time point were similar for nonsmokers and smokers. It was concluded that inhaled loxapine does not require dosage adjustment based on smoking behavior.
Loxapine, a first-generation antipsychotic, delivered with a novel inhalation delivery device developed for the acute treatment of agitation in patients with schizophrenia or bipolar disorder was ...evaluated in subjects with asthma or chronic obstructive pulmonary disease (COPD).
Separate randomized, double-blind, parallel-arm, placebo-controlled trials compared two administrations of inhaled loxapine (10 mg) 10 hr apart with placebo in 52 subjects with asthma and in 53 subjects with COPD. A thermally-generated drug aerosol of loxapine was delivered to the deep lung for rapid systemic absorption. Controller medications were continued throughout the study, but quick-relief bronchodilators were withheld from 6-8 hr before through 34 hr after dose 1, unless indicated as rescue.
All airway adverse events (AEs) were of mild or moderate severity. Symptomatic bronchospasm occurred in 53.8% of subjects with asthma after inhaled loxapine and 11.5% after placebo; and in 19.2% of COPD subjects after inhaled loxapine and 11.1% after placebo. Subjects required inhaled albuterol as follows: asthma: 53.8% after inhaled loxapine and 11.5% after placebo; and COPD: 23.1% after inhaled loxapine and 14.8% after placebo. Respiratory signs/symptoms requiring treatment responded to rescue bronchodilator forced expiratory volume in 1 sec (FEV(1)) return to within 10% of baseline within 1 hr in 11 of 15 events in asthma subjects and four of seven events in COPD subjects, the remainder by the last spirometry.
In subjects with either asthma or COPD, FEV(1) decline and bronchospasm can occur following inhaled loxapine, but more frequently in asthmatic subjects. Most subjects with bronchospasm responded to rescue bronchodilator within 1 hr. No treatment-related serious AE occurred. Although inhaled loxapine is contraindicated in patients with active airways disease per the current approved US labeling, these studies demonstrated that rescue bronchodilator mitigated the symptomatic bronchospasms that may occur in case of inadvertent use.
Context: The interpretation of acetaminophen concentrations obtained prior to 4 hours after an acute, single overdose remains unclear. Patient care decisions in the Emergency Department could be ...accelerated if such concentrations could reliably exclude the need for treatment.
Objective: To determine the agreement between a serum acetaminophen concentration obtained less than 4 hours after an acute ingestion and the subsequent 4 + hour concentration, and the predictive accuracy of early concentrations for identifying patients with potentially toxic exposures.
Methods: A secondary analysis of patients admitted for acetaminophen poisoning at one of the 34 hospitals in eight Canadian cities from 1980 to 2005. We examined serum acetaminophen concentrations obtained less than 4 hours post-ingestion, and again 4 or more hours post-ingestion. For the diagnostic accuracy analysis, we specified a cutpoint of 100 μg/mL (662 μmol/L) obtained between 2 and 4 hours and a subsequent 4 to 20 hour acetaminophen concentration above the nomogram treatment line of 150 μg/mL (993 μmol/L).
Results: Of 2454 patients identified, 879 (36%) had a subsequent acetaminophen concentration above the nomogram treatment line. The 2-4 hour concentration demonstrated a sensitivity of 0.96 95% CI; 0.94, 0.97 and a negative likelihood ratio of 0.070 0.048, 0.10. Coingested opioids reduced this sensitivity to 0.91 0.83, 0.95, and antimuscarinics to 0.86 0.72, 0.94. Only very low to undetectable acetaminophen concentrations prior to 4 hours reliably excluded a subsequent concentration over the treatment line.
Conclusions: Applying an acetaminophen concentration cutpoint of 100 μg/mL (662 μmol/L) at 2-4 hours after an acute ingestion as a threshold for repeat testing and/or treatment would occasionally miss potentially toxic exposures. Absorption of acetaminophen is only slightly delayed by coingested opioids or antimuscarinics. Our analysis validates the practice of not retesting when the first post-ingestion acetaminophen concentration is below the lower limit of quantification.
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