Poisoning in the United States: 2012 emergency medicine report of the National Poison Data System.

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.

Evidence-based evaluation of potential benefits and safety of beta-alanine supplementation for military personnel.

This Department of Defense-sponsored evidence-based review evaluates the safety and putative outcomes of enhancement of athletic performance or improved recovery from exhaustion in studies involving beta-alanine alone or in combination with other ingredients. Beta-alanine intervention studies and review articles were collected from 13 databases, and safety information was collected from adverse event reporting portals. Due to the lack of systematic studies involving military populations, all the available literature was assessed with a subgroup analysis of studies on athletes to determine if beta-alanine would be suitable for the military. Available literature provided only limited evidence concerning the benefits of beta-alanine use, and a majority of the studies were not designed to address safety. Overall, the strength of evidence in terms of the potential for risk of bias in the quality of the available literature, consistency, directness, and precision did not support the use of beta-alanine by military personnel. The strength of evidence for a causal relation between beta-alanine and paresthesia was moderate.

2013 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st Annual Report.

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.

2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report.

BACKGROUND: 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. 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 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. RESULTS: 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). 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 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.

Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: phase 1b study.

BACKGROUND: Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC. METHODS: Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study. RESULTS: Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (C(max)) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and C(max) values of AS and DHA were increased proportionally to the AS climbing multiple doses. DISCUSSION: The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia.

Assessment of the relative potency of fentanyl buccal tablet to intravenous morphine in healthy volunteers using a thermally induced hyperalgesia pain model.

This exploratory randomized, double-blind, placebo-controlled, 5-treatment, 5-period crossover study was conducted using a thermally induced hyperalgesia pain model in 51 healthy volunteers (33 evaluable) to characterize the relative potency of fentanyl buccal tablet (FBT) versus intravenous morphine. Relative potency was assessed using the sum of pain intensity differences over 60 minutes after the application of a 43°C, 46°C, and 49°C painful stimulus following thermally induced hyperalgesia. Relative potency was also assessed by pupil diameter and responses to subjective questionnaires. The relative potency of FBT was 46.2 times that of intravenous morphine (95% confidence interval [CI], 17.6-575.3) based on the 49°C stimulus. The relative potency of FBT based on opiate-induced miosis was 44.6 (95% CI, 29.7-77.0) at 60 minutes. These results are an initial relative potency assessment and should not be considered guidance for dose-equivalent switching between agents in clinical practice.

2011 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 29th Annual Report.

BACKGROUND: 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. 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 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 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). CONCLUSIONS: 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.

2010 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 28th Annual Report.

BACKGROUND: This is the 28th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). All US poison centers upload case data automatically with a median time interval of 19.0 [11.9, 40.6] (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 cases with medical outcomes of death were evaluated by a team of 33 medical and clinical toxicologist reviewers using an ordinal scale of 1 (Undoubtedly responsible) - 6 (Unknown) to determine Relative Contribution to Fatality (RCF) of the exposure to the death. RESULTS: In 2010, 3,952,772 closed encounters were logged by NPDS: 2,384,825, human exposures, 94,823 animal exposures, 1,466,253 information calls, 6537 human confirmed nonexposures, and 334 animal confirmed nonexposures. Total encounters showed a 7.7% decline from 2009 while health care facility calls increased by 2.7%. Human exposures with more serious outcomes (minor, moderate, major or death) increased 4.5% while those with less serious outcomes (all other medical outcome categories) decreased 5.9%. All information calls decreased 12.6% and health care facility (HCF) information calls decreased 13.6%, Drug ID calls decreased 10.9%, and human exposures decreased 3.8%. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.5%), cosmetics/personal care products (7.7%), household cleaning substances (7.3%), sedatives/hypnotics/ antipsychotics (6.0%), and foreign bodies/toys/miscellaneous (4.2%). Analgesic exposures as a class increased the most rapidly by 32.8% over the last decade. The top f ve most common exposures in children age 5 years or less were cosmetics/personal care products (13.2%), analgesics (9.4%), household cleaning substances (9.2%), foreign bodies/toys/miscellaneous (7.2%), and topical preparations (6.8%). THC homolog and designer amphetamine ("Bath Salts") exposures were identified as emerging public health threats. Drug identification requests comprised 64.3% of all information calls. NPDS documented 1730 human exposures resulting in death with 1146 human fatalities judged related with an RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory. CONCLUSIONS: 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.

2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 27th Annual Report.

BACKGROUND: 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. 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 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. RESULTS: 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. CONCLUSIONS: 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.

2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report.

BACKGROUND: 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. 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 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. RESULTS: 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). CONCLUSIONS: 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.

Pharmacokinetic profiles of artesunate after single intravenous doses at 0.5, 1, 2, 4, and 8 mg/kg in healthy volunteers: a phase I study.

The pharmacokinetics of good manufacturing process injection of artesunate (AS) were evaluated after single doses at 0.5, 1, 2, 4, and 8 mg/kg with a 2-minute infusion in 40 healthy subjects. Drug concentrations were analyzed by validated liquid chromatography and mass spectrometry system (LC-MS/MS) procedures. The drug was immediately converted to dihydroartemisinin (DHA), with elimination half-lives ranging 0.12-0.24 and 1.15-2.37 hours for AS and DHA, respectively. Pharmacokinetic model-dependent analysis is suitable for AS, whereas DHA fits both model-dependent and -independent methods. Although DHA concentration was superior to that of AS with a 1.12-1.87 ratio of area under the curve (AUC)(DHA/AS), peak concentration of AS was much higher than that of DHA, with a 2.80- to 4.51-fold ratio of peak concentration (C(max AS/DHA)). Therefore, AS effectiveness has been attributed not only to its rapid hydrolysis to DHA, but also to itself high initial C(max).

A randomized, double-blind, safety and tolerability study to assess the ophthalmic and renal effects of tafenoquine 200 mg weekly versus placebo for 6 months in healthy volunteers.

A randomized, double-blind, placebo-controlled study was conducted to assess the effect of tafenoquine, 200 mg weekly for 6 months on ophthalmic and renal safety. This trial was carried out after observations in previous clinical trials that tafenoquine may be associated with the development of corneal deposits and elevations in serum creatinine. In 120 healthy volunteers who received tafenoquine or placebo in a 2:1 randomization, there was no effect on night vision or other ophthalmic indices measured. Persons taking tafenoquine also showed no difference in mean change in glomerular filtration rate (GFR, mL/s/1.73 m(2)) after 6 months of dosing, with a treatment difference of -0.061 (95% confidence interval, -0.168, 0.045), and non-inferiority margin of -0.247 mL/s/1.73 m(2). Tafenoquine was well tolerated over the course of the study. The results of this study showed no clinically significant effects of tafenoquine on ophthalmic or renal function, and support its continued development as an antimalarial drug.

2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report.

BACKGROUND: 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. 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. 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. RESULTS: 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. CONCLUSIONS: 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.

2006 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS).

BACKGROUND: The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org ) maintains the National Poison Data System (NPDS). Today, 60 of the nation's 61 US poison centers upload case data automatically. Most upload every 1- 60 minutes (median 11 minutes) to NPDS creating a real-time national exposure 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. Fatalities were reviewed by a team of 27 medical and clinical toxicologists and assigned to 1 of 6 categories according to Relative Contribution to Fatality (RCF). RESULTS: Over 4 million calls were captured by NPDS in 2006: 2,403,539 human exposure calls, 1,488,993 information requests, and 128,353 nonhuman exposure calls Substances involved most frequently in all human exposures were analgesics. The most common exposures in children less than age 6 were cosmetics/personal care products. NPDS documented 1,229 human fatalities. CONCLUSIONS: Poisoning continues to be a significant cause of morbidity and mortality in the US. NPDS represents a valuable national resource to collect and monitor US 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.

Prevalence of abnormal liver-associated enzymes in cocaine experienced adults versus healthy volunteers during phase 1 clinical trials.

The frequency and nature of elevation of liver-associated enzymes (LAE) are important safety endpoints in Phase 1 clinical trials of new anti-cocaine agents, yet very little information is available on the prevalence of abnormal LAE in cocaine experienced adults. The aim of this retrospective study was to investigate the alterations of liver-associated enzymes (LAE) aspartate- (AST) and alanine transaminase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and bilirubin in healthy "normal" (HN) and cocaine experienced (actively using cocaine preadmission (CE)) adults participating in long term inpatient clinical trials. We examined LAE values collected from 3 inpatient Phase 1 trials of anti-cocaine agents. Analysis of variance (ANOVA) was applied to determine the significance of various factors on LAE alterations. Gender, baseline BMI, treatment did not demonstrate significant group differences in LAE levels. CE study volunteers were found to have significantly higher AST and ALT values than HN volunteers (P<0.05) during their respective inpatient stays. 94.1% of the 17 subjects with abnormal LAE were CE, and 37.5% of these CE received placebo. In conclusion, despite normal baseline values, most subjects demonstrated an increase in the ALT level even on placebo. For CE subjects, differences (Delta ALT and Delta AST) between baseline and the maximum observed values were significantly higher than that observed for HN subjects. The potential to obscure important signals for hepatotoxicity during Phase 1 research may be higher in the CE study population.

High performance liquid chromatographic measurement of iothalamate in human serum and urine for evaluation of glomerular filtration rate.

A simple and sensitive HPLC-UV assay was developed for the measurement of iothalamate (IOT) in human serum and urine. Chromatographic separation was achieved using an embedded-carbamate-group bonded RP18 column and mobile phase consisting of 50 mM monobasic sodium phosphate and methanol (90:10, v/v) without the addition of ion-pair reagents. The assay demonstrated a high analytical reliability within the IOT concentration range of 1-150 microg/ml in serum and 25-1500 microg/ml in urine. The relative standard deviations (RSDs) for intra- and inter-day analysis were less than 5.1% in all cases. This method has been used for the evaluation of glomerular filtration rate (GFR) in subjects participating in a phase I clinical trial of a novel antimalarial medicine. The average baseline GFR was 100.41+/-19.99 ml/min/1.73 m(2) in 119 healthy volunteers. The assay may also allow the simultaneous measurements of p-aminohippuric acid (PAH), N-acetyl PAH (aPAH), and IOT with some modification. PAH, IOT, aPAH, and beta-hydroxyethyl-theophylline internal standard peaks appeared approximately at 2.5, 3.7, 5.9, and 11.8 min, respectively, in an isocratic run.

Pyridostigmine, diethyltoluamide, permethrin, and stress: a double-blind, randomized, placebo-controlled trial to assess safety.

OBJECTIVE: To determine whether short-term human exposure to pyridostigmine bromide, diethyltoluamide, and permethrin, at rest or under stress, adversely affects short-term physical or neurocognitive performance. PARTICIPANTS AND METHODS: A multicenter, prospective, double-blind, placebo-controlled crossover trial exposing 64 volunteers to permethrin-impregnated uniforms, diethyltoluamide-containing skin cream, oral pyridostigmine, and corresponding placebos was performed. Each participant had 4 separate sessions, ensuring exposure to all treatments and placebos under both stress and rest conditions in random order. Outcomes Included physical performance (handgrip strength and duration, stair climbing, and pull-ups [males] or push-ups [females]), neurocognitive performance (computerized tests), and self-reported adverse effects. RESULTS: Permethrin was undetectable in the serum of all participants; pyridostigmine levels were higher Immediately after stress (41.6 ng/mL; 95% confidence Interval, 35.1-48.1 ng/mL) than rest (23.0 ng/mL; 95% confidence Interval, 19.2-26.9 ng/mL), whereas diethyltoluamide levels did not significantly differ by stress condition. Heart rate and systolic blood pressure increased significantly with stress compared with rest but did not vary with treatment vs placebo. Physical and neurocognitive outcome measures and self-reported adverse effects did not significantly differ by exposure group. CONCLUSION: Combined, correct use of pyridostigmine, diethyltoluamide, and permethrin is well tolerated and without evidence of short-term physical or neurocognitive impairment.

Rapid determination of N,N-diethyl-m-toluamide and permethrin in human plasma by gas chromatography-mass spectrometry and pyridostigmine bromide by high-performance liquid chromatography.

A rapid and highly sensitive gas chromatography-mass spectrometry (GC-MS) method for simultaneous determination of N,N-diethyl-m-toluamide (DEET) and permethrin with (2)H(10)-phenanthrene (98 atom %) as an internal standard and a separate external standard high-performance liquid chromatography (HPLC) method for pyridostigmine bromide (PB) determination in human plasma were developed and validated. The GC-MS method for DEET and permethrin quantification utilizes a one-step extraction with tert-butylmethylether. The HPLC method for PB quantification involves a solid-phase extraction and UV detection. The range of the analytical method for DEET and permethrin was 1 ng/mL to 100 ng/mL and for PB was 5 ng/mL to 100 ng/mL. Recovery from plasma proved to be more than 80%. The intraday precision ranged from 1.3% to 8% for DEET, from 2.1% to 11.4% for permethrin, and from 3.0% to 4.8% for PB. The interday precision was 3% for DEET, ranged from 5% to 9% for permethrin, and from 5% to 9% for PB. The accuracy for the limit of quantification was 92% +/- 8% relative standard deviation (RSD) for DEET, 112% +/- 11% RSD for permethrin, and 109% +/- 5% RSD for PB. All 3 compounds were stable in human plasma at -80 degrees C for at least 12 months and after 2 freeze-thaw cycles with RSD values ranging from 7.1% (DEET, 80 ng/mL) to 8.1% (DEET, 8 ng/mL), from 2.3% (permethrin, 80 ng/mL) to 11.6 % (permethrin, 8 ng/mL), and from 0.2% (PB, 80 ng/mL) to 3.6% (PB, 8 ng/mL). Both methods were successfully applied to pharmacokinetic/ pharmacodynamic studies of combined exposure of DEET (skin application), permethrin (treated uniforms), and PB (30 mg orally three times/day for four doses) in healthy volunteers (n = 81).

The combined use of ibutilide as an active control with intensive electrocardiographic sampling and signal averaging as a sensitive method to assess the effects of tadalafil on the human QT interval.

OBJECTIVES: This study was designed to evaluate effects of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction (ED), on the QT interval. BACKGROUND: Cardiovascular disease is common in men with ED. Men with cardiovascular disease and ED may have decreased cardiac repolarization reserve. METHODS: Effects of tadalafil (100 mg by mouth), ibutilide (0.002 mg/kg intravenously), and placebo on the QT interval in healthy men were compared (placebo and tadalafil [n = 90], with a subset [n = 61] receiving all treatments; mean age 30 years, range 18 to 53 years). Electrocardiographic sampling was done for two days before treatment and on treatment days. The QT was corrected for RR interval with five correction methods, including an individual correction (QTcI). Plasma concentrations of tadalafil were measured to evaluate concentration-QT effect relationships. RESULTS: At the time corresponding to maximum plasma concentration of tadalafil, the mean difference in the change in QTcI between tadalafil and placebo was 2.8 ms; tadalafil was equivalent to placebo (a priori, upper limit of 90% confidence interval < 10 ms [actual = 4.4 ms]; post hoc, upper limit of 95% confidence interval < 5 ms [actual = 4.8]). The active control, ibutilide, significantly increased QTcI by 6.9 and 8.9 ms compared with tadalafil and placebo, respectively. Similar statistical results were obtained with four additional QT correction methods. No subject had a QTcI > or = 450 ms or an increase in QTcI > or = 30 ms with any treatment. CONCLUSIONS: Based on the a priori statistical test of equivalence, placebo and high-dose tadalafil produced equivalent effects on the QT interval. This study reliably discerned 5- to 10-ms changes in corrected QT in the ibutilide active control group.

Metabolism by N-acetyltransferase 1 in vitro and in healthy volunteers: a prototype for targeted inhibition.

Inhibition of drug metabolism is generally avoided but can be useful in limited circumstances, such as reducing the formation of toxic metabolites. Acetylation is a major pathway for drug elimination that can also convert substrates into toxic species, including carcinogens. Sulfamethoxazole, a widely used antibiotic, is metabolized via arylamine N-acetyltransferase 1. p-Aminosalicylate, used for antitubercular treatment, is also metabolized by N-acetyltransferase 1 and could potentially inhibit sulfamethoxazole metabolism. Human hepatocytes from 4 donors were incubated in vitro with sulfamethoxazole and paminosalicylate at clinically achievable concentrations. p-Aminosalicylate competitively reduced the acetylation of sulfamethoxazole in vitro by 61% to 83% at 200 microM. Four healthy volunteers were studied following doses of 500 mg sulfamethoxazole either alone or during administration of paminosalicylate (4 g ter in die). Plasma concentrations of paminosalicylate exceeded 100 microM. With each subject as his or her own control, p-aminosalicylate reduced by 5-fold the ratio of plasma concentrations of acetylsulfamethoxazole relative to parent drug (P < .001). Metabolic drug-drug interaction studies in vitro successfully predicted inhibition of acetylation via N-acetyltransferase 1 in vivo. Although no specific toxic species was investigated in this work, the potential was demonstrated for improving the therapeutic index of drugs that have toxic metabolites.