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The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures.We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4.The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose (Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower

This is the 38We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.In 2020, 3,316,738 closed encounters were logged by NPDS: 2,128,198 human exposures, 66,745 animal exposures, 1,116,568 information requests, and 5,160 human confirmed nonexposures. Total encounters showed a 28.9% increase from 2019, while health care facility (HCF) human exposure cases decreased by 10.6%. While all information requests increased by 218.0%, medication identification (Drug ID) requests decreased by 31.5%, and human exposure cases decreased by 0.928%. Medical Information requests showed a 32.6-fold increase, reflecting COVID-19 pandemic calls to PCs. Human exposures with less serious outcomes have decreased 1.90% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.59% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (10.3%), household cleaning substances (8.37%), cosmetics/personal care products (6.53%), antidepressants (5.30%), and sedatives/hypnotics/antipsychotics (4.92%). As a class, antidepressant exposures increased most rapidly, by 1,793 cases/year (5.84%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (11.8%), household cleaning substances (11.3%), analgesics (7.57%), foreign bodies/toys/miscellaneous (6.71%), and dietary supplements/herbals/homeopathic (6.44%). Drug identification requests comprised 2.89% of all information contacts. NPDS documented 4,488 human exposures resulting in death; 3,869 (86.2%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

Aims Early identification of patients likely to die after acetaminophen (APAP) poisoning remains challenging. We sought to compare the sensitivity and time to fulfilment (latency) of established prognostic criteria. Methods Three physician toxicologists independently classified every in-hospital death associated with APAP overdose from eight large Canadian cities over three decades using the Relative Contribution to Fatality scale from the American Association of Poison Control Centres. The sensitivity and latency were calculated for each of the following criteria: King's College Hospital (KCH), Model for End Stage Liver Disease (MELD) ≥33, lactate ≥3.5 mmol/L, phosphate ≥1.2 mmol/L 48+ hours post-ingestion, as well as combinations thereof. Results A total of 162 in-hospital deaths were classified with respect to APAP as follows: 26 Undoubtedly, 40 Probably, 27 Contributory, 14 Probably not, 25 Clearly not, and 30 Unknown. Cases from the first three classes (combined into n = 93 "APAP deaths") typically presented with supratherapeutic APAP concentrations, hepatotoxicity, acidaemia, coagulopathy and/or encephalopathy, and began antidotal treatment a median of 12 hours (IQR 3.4-30 h) from the end of ingestion. Among all patients deemed "APAP deaths", meeting either KCH or lactate criteria demonstrated the highest sensitivity (94%; 95% CI 86-98%), and the shortest latency from hospital arrival to criterion fulfilment (median 4.2 h; IQR 1.0-16 h). In comparison, the MELD criterion demonstrated a substantially lower sensitivity (55%; 43-66%) and longer latency (52 h; 4.4-∞ h, where "∞" denotes death prior to criterion becoming positive). Conclusions Meeting either KCH or serum lactate criteria identifies most patients who die from acetaminophen poisoning at or shortly after hospital presentation.

Objectives Our six goals are: 1) describe the relationship between the National Strategy for the COVID-19 Response and Pandemic Preparedness and the 55 US poison centers (PCs); 2) detail FDA emergency Use Authorization (EUA) COVID-19 vaccine-related regulatory procedures and associated acronyms; 3) list availability of specific vaccine clinical information to support PC staff COVID-19 vaccination and adverse event (AE) data collection; 4) describe required health care practitioner COVID-19 vaccine AE reporting to the Vaccine AE Reporting System (VAERS) and PC reporting options; 5) document public and health care professionals' use of PCs for COVID-19 vaccine information; and 6) propose strategy to maximize PCs contribution to the pandemic solution. Methods We reviewed 13-Feb-2020 through 15-Apr-2021 National Poison Data System (NPDS) COVID-19 records for changes over time. We examined NPDS cases and VAERS COVID-19 vaccine reports 1-Nov-2020 through 2-Apr-2021 for vaccine manufacturer, patient characteristics, state, and clinical effects. Results PCs reported 1,052,174 COVID-19 contacts; maximum (peak) contacts/day (12,163) on 16-Mar-2020. As of 5-Apr-2021 the US reported >167 million administrations of COVID-19 vaccines (Pfizer-BioNTech, Moderna or Janssen). US PCs reported 162,052 COVID-19 vaccine contacts. Most (61.1%) were medical information calls, 34.9% were drug information, and 2.58% were exposures. Over the same period VAERS reported 49,078 COVID-19 vaccine cases reporting 226,205 symptoms - headache most frequent, ranging from 20% to 40% across the 3 vaccines. Conclusions and recommendations Although differences exist between the intent and content of the 2 data sets, NPDS volume is compelling. The PC nationwide 800 number facilitates data collection and suggests comingling the 2 data streams has merit. PC professionals received tens of thousands of calls and can: 1) support fact-based vaccine information; 2) contribute vaccine AE follow-up information: 3) advocate for best-case coding and reporting, especially for vaccine adverse experiences.

Introduction: We described calls to U.S. poison centers (PCs) related to potential exposure to substances through breast milk. Materials and Methods: We analyzed National Poison Data Syste...

The Rumack-Matthew nomogram stratifies patients into discrete risk zones following acetaminophen (APAP) overdose. Treatment decisions have traditionally been based on the initial risk zone. "Line-crossing" between zones occurs and is poorly understood. The study objective was to characterize line-crossing behavior in acute APAP overdose patients, especially moving from below to above the nomogram treatment threshold.The study was a secondary analysis of the Canadian Acetaminophen Overdose Study (CAOS) database, a large medical record review of patients hospitalized in eight large Canadian cities (1980-2005) following APAP poisoning. Population consisted of acute APAP overdose patients with at least two serum concentrations performed during hospitalization. Using ordinal logistic regression, we studied the effects of patient demographics, ingestion size/timing, APAP concentrations, time to N-acetylcysteine (NAC), and co-ingestants on a three-level dependent variable: patients whose risk increased two or more zones, those remaining in the same or adjacent zone, and those whose risk fell by two or more zones.Of the 3201 eligible hospitalizations with 7705 APAP concentrations, half (1679, 52.5%) crossed at least one zone (up or down) within 24 h of acute ingestion, including 190 (5.9%), who crossed at least two lines into a higher risk zone, and 516 (16.1%) at least two lines into a lower risk zone. Of the 1251 patients initially below the nomogram treatment line of 150 μg/mL, 131 (10.8%) patients crossed above this line. Being older, male, and co-ingesting opioids, antimuscarinics, or NSAIDs were independently associated with line-crossing.Patients commonly crossed nomogram risk zones, including from below to above the current treatment threshold. These findings support recommendations for serial APAP testing until the individual risk of hepatic injury is clearly established.

Introduction: This is the 35th Annual Report of the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS). As of 1 January 2017, 55 of the nation’s poison cente...

Introduction: This is the 37th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January, 2019, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 6.52 [6.12, 8.68] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.Results: In 2019, 2,573,180 closed encounters were logged by NPDS: 2,148,141 human exposures, 68,711 animal exposures, 351,163 information requests, 5,078 human confirmed nonexposures. Total encounters showed a 1.70% increase from 2018, while health care facility (HCF) human exposure cases remained nearly steady with a slight decrease of 0.495%. All information requests decreased by 4.58%, medication identification (Drug ID) requests decreased by 29.7%, and human exposure cases increased by 2.30%. Human exposures with less serious outcomes have decreased 2.08% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.61% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (11.0%), household cleaning substances (7.13%), cosmetics/personal care products (6.16%), antidepressants (5.32%), and sedatives/hypnotics/antipsychotics (5.21%). As a class, antidepressant exposures increased most rapidly, by 1,957 cases/year (3.90%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (11.4%), household cleaning substances (10.5%), analgesics (8.97%), foreign bodies/toys/miscellaneous (7.17%), and dietary supplements/herbals/homeopathic (5.06%). Drug identification requests comprised 13.4% of all information contacts. NPDS documented 2,619 human exposures resulting in death; 2,048 (78.2%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

Anaphylactoid reactions to intravenous (IV) N-acetylcysteine (NAC) are well-recognized adverse events during treatment for acetaminophen (APAP) poisoning. Uncertainty exists regarding their incidence, severity, risk factors, and management. We sought to determine the incidence, risk factors, and treatment of anaphylactoid reactions to IV NAC in a large, national cohort of patients admitted to hospital for acetaminophen overdose. This retrospective medical record review included all patients initiated on the 21-h IV NAC protocol for acetaminophen poisoning in 34 Canadian hospitals between February 1980 and November 2005. The primary outcome was any anaphylactoid reaction, defined as cutaneous (urticaria, pruritus, angioedema) or systemic (hypotension, respiratory symptoms). We examined the incidence, severity and timing of these reactions, and their association with patient and overdose characteristics using multivariable analysis. An anaphylactoid reaction was documented in 528 (8.2%) of 6455 treatment courses, of which 398 (75.4%) were cutaneous. Five hundred four (95.4%) reactions occurred during the first 5 h. Of 403 patients administered any medication for these reactions, 371 (92%) received an antihistamine. Being female (adjusted OR 1.24 [95%CI 1.08, 1.42]) and having taken a single, acute overdose (1.24 [95%CI 1.10, 1.39]) were each associated with more severe reactions, whereas higher serum APAP concentrations were associated with fewer reactions (0.79 [95%CI 0.68, 0.92]). Anaphylactoid reactions to the 21-h IV NAC protocol were uncommon and involved primarily cutaneous symptoms. While the protective effects of higher APAP concentrations are of interest in understanding the pathophysiology, none of the associations identified are strong enough to substantially alter the threshold for NAC initiation.

This is the 34th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January 2016, 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 9.50 [7.33, 14.6] (median [25%, 75%]) min, facilitating a near real-time national exposure and information database and surveillance system.We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.In 2016, 2,710,042 closed encounters were logged by NPDS: 2,159,032 human exposures, 54,019 animal exposures, 490,215 information cases, 6687 human confirmed non-exposures, and 89 animal confirmed non-exposures. US PCs also made 2,718,022 follow-up calls in 2016. Total encounters showed a 2.94% decline from 2015, while health care facility (HCF) human exposure cases increased by 3.63% from 2015. All information calls decreased by 12.5% but HCF information calls increased 0.454%, and while medication identification requests (Drug ID) decreased 29.6%, human exposure cases were essentially flat, decreasing by 0.431%. Human exposures with less serious outcomes have decreased 2.59% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.39% per year since 2000. The top five substance classes most frequently involved in all human exposures were analgesics (11.2%), household cleaning substances (7.54%), cosmetics/personal care products (7.20%), sedatives/hypnotics/antipsychotics (5.84%), and antidepressants (4.74%). As a class, sedative/hypnotics/antipsychotics exposures increased most rapidly, by 10.7% per year (2088 cases/year), over the last 15 years for cases showing more serious outcomes. The top five most common exposures in children age 5 years or less were cosmetics/personal care products (13.3%), household cleaning substances (11.1%), analgesics (9.21%), foreign bodies/toys/miscellaneous (6.48%), and topical preparations (5.07%). Drug identification requests comprised 28.1% of all information calls. NPDS documented 1977 human exposures resulting in death; 1492 (75.5%) of these were judged as related (RCF of 1 - undoubtedly responsible, 2 - probably responsible, or 3 - contributory).These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in cases involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource for collecting and monitoring US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g. foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the real-time surveillance of national and global public health.

Background Efficacy of inhaled loxapine 5 or 10 mg in treating agitation was shown using the Positive and Negative Syndrome Scale – Excited Component (PANSS-EC) in two Phase III randomised, double-blind, placebo-controlled trials in 344 agitated patients with schizophrenia and 314 patients with bipolar I disorder (Clinicaltrials.gov: NCT00628589, NCT00721955). Aims To examine the five individual items comprising the PANSS-EC and the percentage of patients achieving a clinical response (reduction of ≥40%) in PANSS-EC (Response-40) for these two studies. Method Response-40 was examined at the primary end-point (2 h) and over time. Results Response-40 and each PANSS-EC item score were statistically significant v. placebo at 2 h and at each assessment time point for both doses. Conclusions Inhaled loxapine produced rapid improvement in agitated patients with schizophrenia or bipolar I disorder, achieving Response-40 at the first assessment (10 min post dose). These results highlight the effectiveness of loxapine across all components of agitation as measured by the PANSS-EC. Declaration of interest S.Z. is a member of the speakers bureau for Grupo Ferrer. L.Z. has been a speaker and grant recipient for Teva Pharmaceuticals. J.V.C. and D.A.S. were employees of Alexza Pharmaceuticals during execution of the studies, and are currently paid consultants for and have received stock and/or stock options from Alexza Pharmaceuticals. P.P.Y. is a full-time employee and receives stock options from Teva Pharmaceuticals. Copyright and usage © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

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Introduction: This is the 36th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January, 2018, 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.72 [6.90, 12.0] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.Results: In 2018, 2,530,238 closed encounters were logged by NPDS: 2,099,751 human exposures, 57,017 animal exposures, 368,025 information requests, 5,346 human confirmed nonexposures, and 99 animal confirmed nonexposures. United States PCs also made 2,621,242 follow-up calls in 2018. Total encounters showed a 2.96% decline from 2017, while health care facility (HCF) human exposure cases remained nearly steady with a slight decrease of 0.261%. All information requests decreased by 15.5%, medication identification (Drug ID) requests decreased by 30.2%, and human exposure cases decreased by 0.729%. Human exposures with less serious outcomes have decreased 2.33% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.45% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (10.8%), household cleaning substances (7.28%), cosmetics/personal care products (6.53%), sedatives/hypnotics/antipsychotics (5.53%), and antidepressants (5.22%). For cases with more serious outcomes, sedative/hypnotics/antipsychotics exposures were the class that increased most rapidly, by 1,828 cases/year (9.21%/year) over the past 18 years. Over just the past 10 years (for cases with the most serious outcomes) antidepressant exposures increased most rapidly, by 1,887 cases/year (7.02%/year).The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (12.1%), household cleaning substances (10.7%), analgesics (9.04%), foreign bodies/toys/miscellaneous (6.87%), and topical preparations (4.69%). Drug identification requests comprised 18.2% of all information requests. NPDS documented 3,111 human exposures resulting in death; 2,582 (83.0%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information requests. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

This is the 33rd Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January 2015, 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 9.52 [7.40, 13.6] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.In 2015, 2,792,130 closed encounters were logged by NPDS: 2,168,371 human exposures, 55,516 animal exposures, 560,467 information calls, 7657 human confirmed nonexposures, and 119 animal confirmed nonexposures. US PCs also made 2,695,699 follow-up calls in 2015. Total encounters showed a 3.42% decline from 2014, while health care facility (HCF) human exposure cases increased by 5.09% from 2014. All information calls decreased by 15.5% but HCF information calls increased 2.67%, and while medication identification requests (Drug ID) decreased 31.7%, human exposures reported to US PCs were essentially flat, increasing by 0.149%. Human exposures with less serious outcomes have decreased 2.95% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.34% per year since 2000. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.1%), household cleaning substances (7.54%), cosmetics/personal care products (7.41%), sedatives/hypnotics/antipsychotics (5.83%), and antidepressants (4.58%). Sedative/Hypnotics/Antipsychotics exposures as a class increased the most rapidly (2597 calls (11.4%)/year) over the last 14 years for cases showing more serious outcomes. The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (13.6%), household cleaning substances (11.2%), analgesics (9.12%), foreign bodies/toys/miscellaneous (6.45%), and topical preparations (5.33%). Drug identification requests comprised 35.0% of all information calls. NPDS documented 1831 human exposures resulting in death with 1371 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in calls involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, viral, bacterial, venomous, chemical agent, or commercial product), the identification of events of public health significance, resilience, response and situational awareness tracking. NPDS is a model system for the real-time surveillance of national and global public health.

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.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.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).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.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.

BACKGROUND: Anaphylactoid reactions to intravenous (IV) N-acetylcysteine (NAC) are well-recognized adverse events during treatment for acetaminophen (APAP) poisoning. Uncertainty exists regarding their incidence, severity, risk factors, and management. We sought to determine the incidence, risk factors, and treatment of anaphylactoid reactions to IV NAC in a large, national cohort of patients admitted to hospital for acetaminophen overdose. METHODS: This retrospective medical record review included all patients initiated on the 21-h IV NAC protocol for acetaminophen poisoning in 34 Canadian hospitals between February 1980 and November 2005. The primary outcome was any anaphylactoid reaction, defined as cutaneous (urticaria, pruritus, angioedema) or systemic (hypotension, respiratory symptoms). We examined the incidence, severity and timing of these reactions, and their association with patient and overdose characteristics using multivariable analysis. RESULTS: An anaphylactoid reaction was documented in 528 (8.2%) of 6455 treatment courses, of which 398 (75.4%) were cutaneous. Five hundred four (95.4%) reactions occurred during the first 5 h. Of 403 patients administered any medication for these reactions, 371 (92%) received an antihistamine. Being female (adjusted OR 1.24 [95%CI 1.08, 1.42]) and having taken a single, acute overdose (1.24 [95%CI 1.10, 1.39]) were each associated with more severe reactions, whereas higher serum APAP concentrations were associated with fewer reactions (0.79 [95%CI 0.68, 0.92]). CONCLUSION: Anaphylactoid reactions to the 21-h IV NAC protocol were uncommon and involved primarily cutaneous symptoms. While the protective effects of higher APAP concentrations are of interest in understanding the pathophysiology, none of the associations identified are strong enough to substantially alter the threshold for NAC initiation.

Objective 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). Methods 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 (ΔΔQTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔQTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazettcorrected QT duration and QTcI outliers Pharmacokinetics and adverse events (AEs) were also assessed. Results Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔQTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔQTcI 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. Conclusions Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.

This randomized, double‐blind, placebo‐controlled, parallel‐group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty‐two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median Tmax was 2 minutes, and concentrations declined to about half Cmax approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single‐dose study showed a slope (90%CI) of log AUCinf versus log dose of 0.818 (0.762–0.875) across the 8 doses (n = 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well‐tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials.gov identifier: NCT00555412

Deaths from drug overdose have become the leading cause of injury death in the United States, where the poison center system is available to provide real-time advice and collect data about a variety of poisonings. In 2012, emergency medical providers were confronted with new poisonings, such as bath salts (substituted cathinones) and Spice (synthetic cannabinoid drugs), as well as continued trends in established poisonings such as from prescription opioids. This article addresses current trends in opioid poisonings; new substances implicated in poisoning cases, including unit-dose laundry detergents, bath salts, Spice, and energy drinks; and the role of poison centers in public health emergencies such as the Fukushima radiation incident.

Background: This is the 31st Annual Report of the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS). As of January 1, 2013, 57 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 8.08 [7.10, 11.63] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system. Methodology: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center (PC) cases with medical outcomes of death were evaluated by a team of 38 medical and clinical toxicologist reviewers using an ordinal scale of 1–6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death. Results: In 2013, 3,060,122 closed encounters were logged by NPDS: 2,188,013 human exposures, 59,496 animal exposures, 806,347 information calls, 6,116 human-confirmed nonexposures, and 150 animal-confirmed nonexposures. Total encounters showed a 9.3% decline from 2012, while health care facility human exposure calls were essentially flat, decreasing by 0.1%.All information calls decreased 21.4% and health care facility (HCF) information calls decreased 8.5%, medication identification requests (drug ID) decreased 26.8%, and human exposures reported to US PCs decreased 3.8%. Human exposures with less serious outcomes have decreased 3.7% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.7% per year since 2000. The top five substance classes most frequently involved in all human exposures were analgesics (11.5%), cosmetics/personal care products (7.7%), household cleaning substances (7.6%), sedatives/hypnotics/antipsychotics (5.9%), and antidepressants (4.2%). Sedative/hypnotics/antipsychotics exposures as a class increased most rapidly (2,559 calls/year) over the last 13 years for cases showing more serious outcomes. The top five most common exposures in children of 5 years or less were cosmetics/personal care products (13.8%), household cleaning substances (10.4%), analgesics (9.8%), foreign bodies/toys/miscellaneous (6.9%), and topical preparations (6.1%). Drug identification requests comprised 50.7% of all information calls. NPDS documented 2,477 human exposures resulting in death with 2,113 human fatalities judged related (RCF of 1, undoubtedly responsible; 2, probably responsible; or 3, contributory). Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage the more severe exposures, despite a decrease in calls involving less severe exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the United States. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response and situational awareness tracking. NPDS is a model system for the nation and global public health.

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.

The authors sought to determine the relative morbidity and mortality associated with drugs used to treat depression and to examine specific clinical effects associated with serious outcomes.The National Poison Data System, which receives exposure reports from regional poison centers serving the United States, Puerto Rico, and the District of Columbia, was queried for single drug exposures in individuals 12 years and older during the period 2000-2014. Medications included were antidepressants, atypical antipsychotics, anticonvulsants, lithium, and other medications used in the treatment of depression. The main outcomes were the morbidity index (the number of serious outcomes per 1,000 exposures) and the mortality index (the number of fatal outcomes per 10,000 exposures).During this 15-year period, there were 962,222 single substance exposures to the 48 medications studied. Serious outcomes rose 2.26-fold and in linear fashion over the 15 years. While tricyclic and monoamine oxidase inhibitor medications were associated with high morbidity and mortality, several newer agents also appeared hazardous. Lithium, quetiapine, olanzapine, bupropion, and carbamazepine were associated with high morbidity indices. Lithium, venlafaxine, bupropion, quetiapine, olanzapine, ziprasidone, valproic acid, carbamazepine, and citalopram were associated with higher mortality indices.Serious outcomes after overdose or nonintentional exposures to medications used to treat depression have risen dramatically over the past 15 years. The present data suggest that the morbidity and mortality risks vary substantially among these medications. These differences become important when selecting treatments for patients with depression, especially those at increased risk for suicide.

Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of inhaled zaleplon were assessed in healthy volunteers. Forty participants received 0.5, 1, 2, or 4 mg zaleplon or placebo as a thermally generated aerosol in a randomized, double-blind, parallel-group, dose escalation study. Blood was collected up to 24 hours after dosing, and sedation was assessed up to 8 hours. Following inhalation, the observed median time to maximum plasma concentrations (25%, 75%) was 1.89 (1.45, 3.08) minutes and the mean (SD) elimination half-life was 1.24 (0.24) hours. The equilibration half-life for sedation (t(1/2) k(e0) ) was 1.16 (0.62, 2.17) minutes. The zaleplon AUC was dose proportional across doses, with a slope (90% confidence interval) of log-AUC versus log-dose of 0.92 (0.82, 1.02). No clinically significant changes were noted in laboratory values, vital signs, or spirometry. The most common adverse events were dizziness, somnolence, euphoria, headache, and visual disturbance. Zaleplon inhalation represents a safe, well-tolerated means of rapidly achieving effective plasma concentrations.

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.We examined the relationship between calls to poison centers regarding reported exposures to medications commonly used to treat ILI and weekly reports of ILI.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).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.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.

Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, Spyker DA, Kehne JH, Cassella JV. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord 2012: 14: 31–40. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder. Methods: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N = 314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests. Results: For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo). Conclusions: Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

This is the 32nd Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January 2014, 56 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.82 [7.02, 11.17] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death.In 2014, 2,890,909 closed encounters were logged by NPDS: 2,165,142 human exposures, 56,265 animal exposures, 663,305 information calls, 6,085 human confirmed nonexposures, and 112 animal confirmed nonexposures. US poison centers (PCs) also made 2,617,346 follow-up calls in 2014. Total encounters showed a 5.5% decline from 2013, while health care facility human exposure cases increased by 3.3% from 2013. All information calls decreased by 17.7% and health care facility (HCF) information calls were essentially flat, decreasing by 0.04%, medication identification requests (Drug ID) decreased 29.8%, and human exposures reported to US PCs decreased 1.1%. Human exposures with less serious outcomes have decreased 3.40% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.29% per year since 2000. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.3%), cosmetics/personal care products (7.7%), household cleaning substances (7.7%), sedatives/hypnotics/antipsychotics (5.9%), and antidepressants (4.4%). Sedative/Hypnotics/Antipsychotics exposures as a class increased the most rapidly (2,368 calls (12.2%)/year) over the last 13 years for cases showing more serious outcomes. The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (14.0%), household cleaning substances (11.0%), analgesics (9.3%), foreign bodies/toys/miscellaneous (6.7%), and topical preparations (5.8%). Drug identification requests comprised 43.3% of all information calls. NPDS documented 1,835 human exposures resulting in death with 1,408 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in calls involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, viral, bacterial, venomous, chemical agent, or commercial product), the identification of events of public health significance, resilience, response and situational awareness tracking. NPDS is a model system for the real-time surveillance of national and global public health.[Box: see text].

Pharmacodynamic effects and safety of single‐dose inhaled loxapine administered via the Staccato® system and intramuscular (IM) lorazepam in combination versus each agent alone were compared in a randomized, double‐blind, crossover study in healthy volunteers. Subjects received: inhaled loxapine 10 mg + IM lorazepam 1 mg; inhaled loxapine 10 mg + IM placebo; IM lorazepam 1 mg + Staccato placebo in random order, each separated by a 3‐day washout. Primary endpoints were maximum effect (minimum value) and area under the curve (AUC) from baseline to 2 h post treatment for respirations/min and pulse oximetry. Least‐squares means (90% confidence interval [CI]) for concomitant treatment versus each agent alone were derived and equivalence (no difference) confirmed if the 90% CI was within 0.8–1.25. Blood pressure (BP), heart rate (HR), sedation (100‐mm visual analog scale), and adverse events (AEs) were recorded. All 18 subjects (mean age, 20.4 years; 61% male) completed the study. There was no difference between inhaled loxapine + IM lorazepam and either agent alone on respiration or pulse oximetery during the 12‐h postdose period, confirmed by 90% CIs for AUC and C min ratios. BP and HR were no different for inhaled loxapine + IM lorazepam and each agent alone over a 12‐h postdose period. Although the central nervous system sedative effects were observed for each treatment in healthy volunteers, the effect was greater following concomitant lorazepam 1 mg IM + inhaled loxapine 10 mg administration. There were no deaths, serious AEs, premature discontinuations due to AEs, or treatment‐related AEs.

BackgroundThere is a need for a rapid-acting, non-injection, acute treatment for agitation.AimsTo evaluate inhaled loxapine for acute treatment of agitation in schizophrenia.MethodThis phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov number NCT00628589) enrolled 344 individuals who received one, two or three doses of inhaled loxapine (5 or 10 mg) or a placebo. Lorazepam rescue was permitted after dose two. The primary efficacy end-point was change from baseline in Positive and Negative Syndrome Scale–Excited Component (PANSS–EC) 2 h after dose one. The key secondary end-point was Clinical Global Impression–Improvement scale (CGI–I) score 2 h after dose one.ResultsInhaled loxapine (5 and 10 mg) significantly reduced agitation compared with placebo as assessed by primary and key secondary end-points. Reduced PANSS–EC score was evident 10 min after dose one with both 5 and 10mg doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications.ConclusionsInhaled loxapine provided a rapid, well-tolerated acute treatment for agitation in people with schizophrenia.

Amlodipine is a long-acting calcium channel blocker capable of producing hypotension and dysrhythmia in overdose. The toxic doses of amlodipine in children are unclear.The purposes of this study were to describe amlodipine poisoning in children and to determine whether a dose-response relationship could be detected in this population using standardized call data from United States (US) poison centers.1251 amlodipine-only ingestions in children6 years of age were reviewed. Cases with doses coded as "Exact" or "Estimated" and with dose, age, and medical outcome were analyzed (n = 678). Ingestions reported as a "taste or lick" (n = 53) were included as a dose of 1/10 of the dosage form involved. A clinically important response was defined as bradycardia, hypotension, dysrhythmia, conduction disturbance, or hyperglycemia. The risk of such responses was examined over four dosage intervals (2.5 mg, 2.5-5 mg, 5.1-10 mg, and10 mg).The median estimated dose ingested was 5 mg (range 0.25-200 mg). Clinically important responses developed in 27 patients (3.98%), and the prevalence of such response significantly increased from 0% for the lowest to 11.1% for the highest dose interval (p = 0.001). The smallest dose to produce a clinically important response was 2.5 mg (0.15 mg/kg). Children who ingested10 mg were 4.4 times more likely to develop clinically important responses than those ingestingor = 5 mg.Hypotension may occur in children with amlodipine doses as low as 2.5 mg. The National Poison Data System might provide useful insights regarding dose-response.

This is the 26th Annual Report of the American Association of Poison Control Centers (AAPCC; http://www. aapcc.org ) National Poison Data System (NPDS). During 2008, 60 of the nation's 61 US poison centers uploaded case data automatically. The median upload time was 24 [7.2, 112] (median [25%, 75%]) minutes creating a real-time national exposure and information database and surveillance system.We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of 28 medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to determine Relative Contribution to Fatality (RCF) from the exposure to the death.In 2008, 4,333,012 calls were captured by NPDS: 2,491,049 closed human exposure cases, 130,495 animal exposures, 1,703,762 information calls, 7,336 human confirmed nonexposures, and 370 animal confirmed nonexposures. The top five substances most frequently involved in all human exposures were analgesics (13.3%), cosmetics/personal care products (9.0%), household cleaning substances (8.6%), sedatives/hypnotics/antipsychotics (6.6%), and foreign bodies/toys/miscellaneous (5.2%). The top five most common exposures in children age 5 or less were cosmetics/personal care products (13.5%), analgesics (9.7%), household cleaning substances (9.7%), foreign bodies/toys/miscellaneous (7.5%), and topical preparations (6.9%). Drug identification requests comprised 66.8% of all information calls. NPDS documented 1,756 human exposures resulting in death with 1,315 human fatalities deemed related with an RCF of at least contributory (1, 2, or 3).Poisoning continues to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national resource to collect and monitor US poisoning exposure cases and information calls. NPDS continues its mission as one of the few real-time national surveillance systems in existence, providing a model public health surveillance system for all types of exposures, public health event identification, resilience response and situational awareness tracking.

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.

A thermally generated aerosol (TGA) system can effect reliable delivery of excipient-free drug to alveoli, resulting in rapid systemic drug absorption. We developed a pharmacokinetic model of prochlorperazine, administered by inhalation and as a rapid intravenous infusion, and we determined absolute TGA bioavailability in eight healthy volunteers in this institutional review board-approved, two-period crossover study. After the drug was administered as either a 5-s intravenous infusion or a TGA single-breath inhalation, blood was collected at various times for up to 24 h. Plasma prochlorperazine concentrations were measured using liquid chromatography-tandem mass spectrometry. Inhalation and rapid intravenous administration produced similar plasma prochlorperazine concentration profiles. Intravenous and inhalation pharmacokinetics were well characterized by a simultaneous two-compartment model with multiple absorption delays. Prochlorperazine pharmacokinetic parameters were similar to those reported for single intravenous doses. The geometric mean bioavailability after TGA delivery was 1.10. The administration of prochlorperazine by inhalation resulted in pharmacokinetics similar to that seen after intravenous administration, in terms of speed, extent, and consistency of absorption.

This report is the 25th Annual Report of the American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) National Poison Data System (NPDS). During 2007, 60 of the nation's 61 U.S. Poison Centers upload case data automatically. The median upload time is 14 [5.3, 55] (median [25%, 75%]) min creating a real-time national exposure database and surveillance system.We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Fatalities were reviewed by a team of 29 medical and clinical toxicologists and assigned to 1 of 6 categories according to Relative Contribution to Fatality.Over 4.2 million calls were captured by NPDS in 2007: 2,482,041 human exposure calls, 1,602,489 information requests, and 131,744 nonhuman exposure calls. Substances involved most frequently in all human exposures were analgesics (12.5% of all exposures). The most common exposures in children less than age 6 were cosmetics/personal care products (10.7% of pediatric exposures). Drug identification requests comprised 66.8% of all information calls. NPDS documented 1,597 human fatalities.Poisoning continues to be a significant cause of morbidity and mortality in the United States NPDS represents a valuable national resource to collect and monitor U.S. poisoning exposure cases. It offers one of the few real-time surveillance systems in existence, provides useful data, and is a model for public health surveillance.

The minimum recommended treatment duration for i.v. N-acetylcysteine (NAC) after an acute, single acetaminophen (APAP) overdose is 21 h. Some have questioned whether shorter courses may be sufficient in carefully selected cases.We sought to describe the incidence of hepatotoxicity in a cohort of acute APAP overdose patients who received21 h of i.v. NAC for any reason.We performed a secondary analysis of a large multicenter retrospective cohort of patients hospitalized for APAP poisoning. We selected patients with a potentially toxic serum APAP concentration measured between 4 and 24 h post ingestion, in whom i.v. NAC was initiated but discontinued before completing the full 21-h course. We further characterized outcomes in these patients as a function of two novel risk-prediction tools, the psi (ψ) parameter and APAP × aminotransferase (AT) product. The ψ parameter is an estimate of the cellular burden of injury based on the area under the concentration-time curve before treatment, and calculated with respect to the APAP concentration and time to initiation of NAC.Fifty-nine patients met inclusion criteria. Intravenous NAC was initiated a median of 11.3 h post ingestion and administered for a median of 11.0 h. Hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]1,000 IU/L) occurred in one patient (1.7%; 95% confidence interval 0.04-9.1), and eight additional patients developed hepatic injury (AST or ALT100 IU/L). No fatalities occurred. A multiplication product of APAP and AT (APAP × AT) that falls below 10,000 μmol/L/IU-L, or pretreatment ψ5 mmol/L-h suggested a low risk of hepatic injury.In this retrospective analysis of patients treated with21 h of i.v. NAC for acute APAP overdose, the incidence of hepatotoxicity and coagulopathy was low, despite delays to NAC treatment.

A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.

Objective: The toxic and lethal doses of clonidine in children are unclear. This study was designed to determine whether data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) could be utilized to determine a dose-response relationship for pediatric clonidine exposure. Methods: 3458 single-substance clonidine exposures in children

This is the 30(th) Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of July 1, 2012, 57 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.58 [6.30, 11.22] (median [25%, 75%]) min, creating a near real-time national exposure and information database and surveillance system.We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of 34 medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death.In 2012, 3,373,025 closed encounters were logged by NPDS: 2,275,141 human exposures, 66,440 animal exposures, 1,025,547 information calls, 5,679 human confirmed nonexposures, and 218 animal confirmed nonexposures. Total encounters showed a 6.9% decline from 2011, while healthcare facility (HCF) exposure calls increased by 1.2%. All information calls decreased by 14.8% and HCF information calls decreased by 1.7%, medication identification requests (Drug ID) decreased by 22.0%, and human exposures reported to US PCs decreased by 2.5%. Human exposures with less serious outcomes have decreased by 3.7% per year since 2008, while those with more serious outcomes (moderate, major, or death) have increased by 4.6% per year since 2000. The top five substance classes most frequently involved in all human exposures were analgesics (11.6%), cosmetics/personal care products (7.9%), household cleaning substances (7.2%), sedatives/hypnotics/antipsychotics (6.1%), and foreign bodies/toys/miscellaneous (4.1%). Analgesic exposures as a class increased the most rapidly (8,780 calls/year) over the last 12 years. The top five most common exposures in children aged 5 years or less were cosmetics/ personal care products (13.9%), analgesics (9.9%), household cleaning substances (9.7%), foreign bodies/toys/ miscellaneous (7.0%), and topical preparations (6.3%). Drug identification requests comprised 54.4% of all information calls. NPDS documented 2,937 human exposures resulting in death with 2,576 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).These data support the continued value of PC expertise and need for specialized medical toxicology information to manage the more severe exposures, despite a decrease in calls involving less severe exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response, and situational awareness tracking. NPDS is a model system for the nation and global public health.

The objective of this study was to establish effects of inhaled loxapine on the QTc interval in this randomized, placebo-controlled, double-blind crossover study. Forty-eight healthy volunteers received a single inhaled placebo or 10 mg loxapine. Plasma concentrations of loxapine increased with a median Tmax of 1 minute and a mean Cmax of 312 ng/mL. After an initial rapid distribution phase, plasma concentrations of loxapine declined with a terminal half-life of 8 hours. Exposure to the active metabolite 7-OH-loxapine was 15% of the parent compound based on mean AUCinf and its terminal half-life was 12 hours. Inhaled loxapine did not increase QT intervals, as demonstrated by the upper bound of the 1-sided 95% CIs placed on the point estimate of the placebo-subtracted change of QTcI (ΔΔQTcI) being less than 10 milliseconds at all 11 post-dose times. The maximum ΔΔQTcI occurred at 1 hour post-dose (LSmean 5.42 milliseconds, upper confidence bound 7.75 milliseconds). The study outcome was validated by the demonstrated assay sensitivity using the positive control moxifloxacin maximum ΔΔQTcI occurred at 3 hour post-dose (LSmean 8.36 milliseconds, lower confidence bound 5.82 milliseconds). The analyses of QTc outliers, and the lack of emergent diagnostic findings for QTcI, QTcB, and QTcF; and simple mean placebo-subtracted changes of QTcI and QTcF supported the primary QT analysis conclusion that this is a negative finding and there is no apparent QT prolongation associated with the therapeutic dose of inhaled loxapine.

Monitoring of poison control center data has provided an important public health surveillance tool. Previous work has identified the population with the greatest risk of poisoning as children of6 years. It follows that the size of the population at highest risk should be an important driver/factor of poison center volume. Therefore, one would expect population changes to be reflected in corresponding National Poison Data system (NPDS) call volume changes. We examined this relationship.This was a retrospective comparison of young children's poison exposures reported to NPDS with changes in US population as reported by the US Census Bureau and by live birth counts in the United States. We examined the relation of population and live birth counts to NPDS exposures in children of 0-5 years and for the total (children of 0-5 years).There was a statistically significant relation between exposures and population for the three of the seven age groups (1-3 years old) and between exposures and live birth counts for the five of the seven age groups (1-4 years old and total (0-5)). The highest correlation was seen with the age groups of 2-year olds (r = 0.815; slope, 4.7373; 95% CI, 2.36-7.11) and 1-year olds (r = 0.785; slope, 4.878; 95% CI, 2.163-7.592). Live birth count was more closely related than population for all but the 1-year-old age groups.Our study reports a number of interesting findings including 1) live birth counts and population are closely associated with each other, 2) poison exposures in NPDS were more strongly associated with live birth counts than with population, 3) the population at greatest risk is the 1- and 2-year-old age groups and the strongest associations between exposures and population and exposures and live birth counts occurred in these two age groups, and 4) changes occurring in the live birth counts, both positive and negative, were reflected in annual changes reported in NPDS human exposures in children6 years. These results mean that population changes underlie 37%-66% of the changes in poison exposures and suggests that the population at risk should be considered in monitoring poisoning injuries in the future.These results provide a quantitative assessment of the age-based risk rates and changes over time for NPDS exposure in children who are 0-5 years old. With the decrease in live births noted over the last 4 years (2008, 2009, 2010, and estimated 2011), US poison centers may expect a similar decline in human exposures in children of 0-5 years. Our analysis adds additional support to the validity of this data set as a public health surveillance tool.

This is the 29th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 July 2011, 57 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 8.43 [6.29, 13.7] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of 38 medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death.In 2011, 3,624,063 closed encounters were logged by NPDS: 2,334,004 human exposures, 80,266 animal exposures, 1,203,282 information calls, 6,243 human confirmed nonexposures, and 268 animal confirmed nonexposures. Total encounters showed an 8.3% decline from 2010, while health care facility exposure calls increased by 4.8%. Human exposures with less serious outcomes decreased by 3.4% while those with more serious outcomes (moderate, major or death) increased by 6.8%. All information calls decreased by 17.9% and health care facility (HCF) information calls decreased by 2.9%, Medication identification requests (Drug ID) decreased by 24.1%, and human exposures reported to US poison centers decreased by 2.2%. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.7%), cosmetics/personal care products (8.0%), household cleaning substances (7.0%), sedatives/hypnotics/antipsychotics (6.1%), and foreign bodies/toys/miscellaneous (4.1%). Analgesic exposures as a class increased most rapidly (10,134 calls/year) over the last 11 years. The top 5 most common exposures in children aged 5 years or less were cosmetics/personal care products (14.0%), analgesics (9.9%), household cleaning substances (9.2%), foreign bodies/toys/miscellaneous (6.9%), and topical preparations (6.6%). Drug identification requests comprised 59.5% of all information calls. NPDS documented 2,765 human exposures resulting in death with 1,995 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).These data support the continued value of poison center expertise and need for specialized medical toxicology information to manage the more severe exposures, despite a decrease in calls involving less severe exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response and situational awareness tracking. NPDS is a model system for the nation and global public health.

Chlordane is a potent neurotoxin and animal carcinogen, yet the frequency and severity of injury due to exposure from inhalation or contact in the home has not been widely documented. Neuropsychological dysfunction and emotional distress were observed in 10 individuals exposed to chlordane pesticide after their homes were treated for termites. Cognitive deficits ranged from mild to moderate on tasks requiring speeded processing, problem solving, and delayed memory. Somatization, hysterical features, and depression dominated the clinical picture. Current results implicate the hazards associated with chlordane treatment of residential homes and the continued need for further studies.

The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder.A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests.For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo).Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of inhaled zaleplon were assessed in healthy volunteers. Forty participants received 0.5, 1, 2, or 4 mg zaleplon or placebo as a thermally generated aerosol in a randomized, double-blind, parallel-group, dose escalation study. Blood was collected up to 24 hours after dosing, and sedation was assessed up to 8 hours. Following inhalation, the observed median time to maximum plasma concentrations (25%, 75%) was 1.89 (1.45, 3.08) minutes and the mean (SD) elimination half-life was 1.24 (0.24) hours. The equilibration half-life for sedation (t(1/2) k(e0) ) was 1.16 (0.62, 2.17) minutes. The zaleplon AUC was dose proportional across doses, with a slope (90% confidence interval) of log-AUC versus log-dose of 0.92 (0.82, 1.02). No clinically significant changes were noted in laboratory values, vital signs, or spirometry. The most common adverse events were dizziness, somnolence, euphoria, headache, and visual disturbance. Zaleplon inhalation represents a safe, well-tolerated means of rapidly achieving effective plasma concentrations.

This is the 27th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 July 2009, 60 of the nation's 60 US poison centers (PCs) uploaded case data automatically. The upload time was 19.9 [9.7, 58.7] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of 29 medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to determine Relative Contribution to Fatality (RCF) of the exposure to the death.In 2009, 4,280,391 calls were captured by NPDS: 2,479,355 closed human exposures, 116,408 animal exposures, 1,677,403 information calls, 6,882 human confirmed nonexposures, and 343 animal confirmed nonexposures. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.7%), cosmetics/personal care products (7.7%), household cleaning substances (7.4%), sedatives/hypnotics/antipsychotics (5.8%), and foreign bodies/toys/miscellaneous (4.3%). Analgesic exposures as a class increased the most rapidly (12,494 calls per year) over the last decade. The top 5 most common exposures in children age 5 or less were cosmetics/personal care products (13.0%), analgesics (9.7%), household cleaning substances (9.3%), foreign bodies/toys/miscellaneous (7.0%), and topical preparations (6.8%). Drug identification requests comprised 63.0% of all information calls. NPDS documented 1,544 human exposures resulting in death with 1,158 human fatalities judged related with an RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory.Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response and situational awareness tracking. NPDS is a model system for the nation and global public health.

The objective of this study was to assess the efficacy and safety of inhaled loxapine in the treatment of agitation in patients with psychotic disorders.In this randomized, double-blind, placebo-controlled study, 129 agitated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) were randomized to receive in a clinical or hospital setting a single inhalation of 5 or 10 mg of loxapine or placebo administered using the Staccato loxapine for inhalation device. The inhalation device delivered thermally generated drug aerosol to the deep lung for rapid absorption. The primary efficacy measure was change on the Positive and Negative Syndrome Scale-excited component (PANSS-EC) 2 hours following treatment. Secondary outcomes included the Clinical Global Impressions-Improvement scale (CGI-I), Behavioral Activity Rating Scale (BARS), and time to first rescue medication. The study was conducted between September 2006 and January 2007.Differences were statistically significant (P.05) between placebo and both 5-mg and 10-mg doses on the CGI-I and the CGI-I responder analyses at 2 hours and in time to first rescue medication, and they were statistically significant (P.05) between placebo and 10-mg loxapine on the PANSS-EC 20 minutes after administration continuing through 2 hours and in change from baseline BARS. Three serious adverse events occurred at least 6 days after treatment, but none were judged related to study treatment. The most common adverse events were sedation and dysgeusia (22% and 17%, respectively, in the 10-mg group, and 14% and 9%, respectively, in the placebo group).Inhaled loxapine was generally safe and well tolerated and produced rapid improvement in agitated patients with psychotic disorders. Statistically significant differences in efficacy were found for the 10-mg dose compared with placebo, with results suggesting 5 mg may be effective. The delivery of loxapine by inhalation may provide a rapid, well-tolerated option for treating acute psychotic agitation that allows patients to avoid the aversive effects and loss of autonomy often associated with use of intramuscular medications. Further investigation of this new loxapine formulation is warranted.ClinicalTrials.gov identifier: NCT00369577.

The objective of this randomized, double-blind, placebo-controlled, dose escalation study was to determine the pharmacokinetic characteristics, safety, and tolerability of single doses of inhaled loxapine aerosol in healthy volunteers. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Fifty participants were randomized to receive 0.625, 1.25, 2.5, 5.0, or 10 mg of loxapine aerosol or placebo. Following inhalation, the t(max) median (25%, 75%) was 2 (1, 3) minutes. The loxapine AUC(infinity) was dose proportional across all doses with slope (90% confidence interval) of log AUC(infinity) versus log dose = 0.909 (0.832, 0.987). No clinically meaningful changes were noted in hematology results, blood chemistry, vital signs, or respiratory function. The most common adverse events were dizziness, somnolence, and bad taste. The inhalation of Staccato loxapine represents a safe, well-tolerated means for rapidly achieving therapeutic plasma concentrations of loxapine.