Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia.

Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.).

Prolonged Neuropsychiatric Symptoms in a Military Service Member Exposed to Mefloquine.

A 32-year-old male developed neuropsychiatric symptoms 2 weeks after starting mefloquine 250 mg/week for malaria prophylaxis. He continued to take the medication for the next 4 months. Initial symptoms included vivid dreams and anxiety, as well as balance problems. These symptoms persisted and progressed over the next 4 years to include vertigo, emotional lability, and poor short-term memory, which have greatly affected his personal and professional life. An extensive evaluation revealed objective evidence supporting a central vestibulopathy. These symptoms have been unresponsive to pharmacologic therapy and psychotherapy. A Naranjo assessment score of 6 was obtained for his initial symptoms, indicating a probable adverse drug reaction to mefloquine given the relationship between the clinical picture and drug exposure.

Safety and performance benefits of arginine supplements for military personnel: a systematic review.

CONTEXT: Dietary supplements are widely used by military personnel and civilians for promotion of health. OBJECTIVE: The objective of this evidence-based review was to examine whether supplementation with l-arginine, in combination with caffeine and/or creatine, is safe and whether it enhances athletic performance or improves recovery from exhaustion for military personnel. DATA SOURCES: Information from clinical trials and adverse event reports were collected from 17 databases and 5 adverse event report portals. STUDY SELECTION: Studies and reports were included if they evaluated the safety and the putative outcomes of enhanced performance or improved recovery from exhaustion associated with the intake of arginine alone or in combination with caffeine and/or creatine in healthy adults aged 19 to 50 years. DATA EXTRACTION: Information related to population, intervention, comparator, and outcomes was abstracted. Of the 2687 articles screened, 62 articles meeting the inclusion criteria were analyzed. Strength of evidence was assessed in terms of risk of bias, consistency, directness, and precision. RESULTS: Most studies had few participants and suggested risk of bias that could negatively affect the results. l-Arginine supplementation provided little enhancement of athletic performance or improvements in recovery. Short-term supplementation with arginine may result in adverse gastrointestinal and cardiovascular effects. No information about the effects of arginine on the performance of military personnel was available. CONCLUSIONS: The available information does not support the use of l-arginine, either alone or in combination with caffeine, creatine, or both, to enhance athletic performance or improve recovery from exhaustion. Given the information gaps, an evidence-based review to assess the safety or effectiveness of multi-ingredient dietary supplements was not feasible, and therefore the development of a computational model-based approach to predict the safety of multi-ingredient dietary supplements is recommended.

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.

Randomized, double-blind, placebo-controlled clinical trial of a two-day regimen of dihydroartemisinin-piperaquine for malaria prevention halted for concern over prolonged corrected QT interval.

Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia's formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. NCT01624337.).

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.

A review of pharmaceutical labeling for overdose treatment and toxicity data.

PURPOSE: Adverse drug reactions, including overdose are a major cause of morbidity and mortality, yet clinical toxicology data is limited at the time of drug approval. This study was conducted to determine the quality of clinical toxicology data available for newly approved pharmaceuticals and time to labeling revisions. METHODS: The labeling data of 100 new molecular entities (NMEs) approved between 2005 and 2011 was systematically reviewed. Initial approval data and subsequent labeling revisions were evaluated. The type and quality of clinical toxicology data present at the time of approval as well as the time to any labeling revisions was recorded. The presence of black box warnings and Risk Evaluation and Mitigation Strategies (REMS) was noted. RESULTS: Of the NMEs reviewed, 27 had agent-specific toxicology data at approval. General recommendations for overdose management were made in 45 cases. Eight pharmaceuticals had toxicology updates during the study period. The average time to labeling revision was 27.4 months. Expanded adverse effects from case reports comprised 7/8 of the updates, and animal data was added in one case. Over a third of the NMEs had a black box warning or REMS status, suggesting potential for significant human toxicity. CONCLUSIONS: Our study suggests there is a paucity of clinical toxicology data at the time of drug approval, with a notable lag time between initial approval and labeling revisions. This lack of toxicology data limits the ability of providers to optimally care for poisoned patients.

Safety of atomoxetine in combination with intravenous cocaine in cocaine-experienced participants.

OBJECTIVES: Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration. METHODS: In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions. RESULTS: Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P < 0.0001). Other VAS descriptors, Brief Substance Craving Scale, Profile of Moods State, and Brief Psychiatric Rating Scale showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. CONCLUSIONS: Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

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.