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1.  A Randomized Controlled Trial of a Comprehensive Migraine Intervention Prior to Discharge From an Emergency Department 
Patients who use an emergency department (ED) for acute migraine headaches have higher migraine disability scores and lower socioeconomic status and are unlikely to have used a migraine-specific medication prior to presentation to the ED. The objective was to determine if a comprehensive migraine intervention, delivered just prior to ED discharge, could improve migraine impact scores 1 month after the ED visit.
This was a randomized controlled trial of a comprehensive migraine intervention versus typical care among patients who presented to an ED for management of acute migraine. At the time of discharge, for patients randomized to comprehensive care, the authors’ protocol reinforced their diagnosis, shared a migraine education presentation from the National Library of Medicine, provided them with six tablets of sumatriptan 100 mg and 14 tablets of naproxen 500 mg, and if they wished, provided them with an expedited free appointment to our institution's headache clinic. Patients randomized to typical care received the care their attending emergency physicians (EPs) felt was appropriate. The primary outcome was a between-group comparison of the Headache Impact Test (HIT-6) score, a validated headache assessment instrument, 1 month after ED discharge. Secondary outcomes included an assessment of satisfaction with headache care and frequency of use of migraine-specific medication within that 1-month period.
Over a 19-month period, 50 migraine patients were enrolled. One-month follow-up was successfully obtained in 92% of patients. Baseline characteristics were comparable. One-month HIT-6 scores in the two groups were nearly identical (59 vs. 56, 95% confidence interval [CI] for difference of 3 = –5 to 11), as was dissatisfaction with overall headache care (17% vs. 18%, 95% CI for difference of 1% = –22% to 24%). Patients randomized to the comprehensive intervention were more likely to be using triptans or migraine-specific therapy (43% vs. 0%, 95% CI for difference of 43% = 20 to 63%) 1 month later.
A comprehensive migraine intervention, when compared to typical care, did not improve HIT-6 scores (a validated measure of the effect of migraine on one's daily life) 1 month after ED discharge. Future work is needed to define a migraine intervention that is practical and useful in an ED, where many underserved patients, of necessity, present for care.
PMCID: PMC3473153  PMID: 22994458
2.  Risk of acute kidney injury associated with the use of fluoroquinolones 
Case reports indicate that the use of fluoroquinolones may lead to acute kidney injury. We studied the association between the use of oral fluoroquinolones and acute kidney injury, and we examined interaction with renin–angiotensin-system blockers.
We formed a nested cohort of men aged 40–85 enrolled in the United States IMS LifeLink Health Plan Claims Database between 2001 and 2011. We defined cases as men admitted to hospital for acute kidney injury, and controls were admitted to hospital with a different presenting diagnosis. Using risk-set sampling, we matched 10 controls to each case based on hospital admission, calendar time (within 6 wk), cohort entrance (within 6 wk) and age (within 5 yr). We used conditional logistic regression to assess the rate ratio (RR) for acute kidney injury with current, recent and past use of fluoroquinolones, adjusted by potential confounding variables. We repeated this analysis with amoxicillin and azithromycin as controls. We used a case-time–control design for our secondary analysis.
We identified 1292 cases and 12 651 matched controls. Current fluoroquinolone use had a 2.18-fold (95% confidence interval [CI] 1.74–2.73) higher adjusted RR of acute kidney injury compared with no use. There was no association between acute kidney injury and recent (adjusted RR 0.87, 95% CI 0.66–1.16) or past (RR 0.86, 95% CI 0.66–1.12) use. The absolute increase in acute kidney injury was 6.5 events per 10 000 person-years. We observed 1 additional case per 1529 patients given fluoroquinolones or per 3287 prescriptions dispensed. The dual use of fluoroquinolones and renin–angiotensin-system blockers had an RR of 4.46 (95% CI 2.84–6.99) for acute kidney injury. Our case-time–control analysis confirmed an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52–3.18). The use of amoxicillin or azithromycin was not associated with acute kidney injury.
We found a small, but significant, increased risk of acute kidney injury among men with the use of oral fluoroquinolones, as well as a significant interaction between the concomitant use of fluoroquinolones and renin–angiotensin-system blockers.
PMCID: PMC3708027  PMID: 23734036
3.  Antihypertensive Drug Class Interactions and Risk for Incident Diabetes: A Nested Case–Control Study 
We aimed to determine how single and combination antihypertensive therapy alters risk for diabetes mellitus (DM).Thiazide diuretics (TD), β blockers (BB), and renin–angiotensin system blockers (RASB) impact DM risk while calcium channel blockers (CCB) are neutral. DM risk associated with combinations is unclear.
Methods and Results
We enrolled nondiabetic patients from Kaiser Permanente Northwest with a fasting plasma glucose (FPG) <126 mg/dL between 1997 and 2010. DM cases were defined by a FPG ≥126 mg/dL, random plasma glucose ≥200 mg/dL, HbA1c ≥7.0%, or new DM prescription (index date). We used incidence density sampling to match 10 controls per case on the date of follow‐up glucose test (to reduce detection bias), in addition to age and date of cohort entry. Exposure to antihypertensive class was assessed during the 30 days prior to index date. Our cohort contained 134 967 patients and had 412 604 glucose tests eligible for matching. A total of 9097 DM cases were matched to 90 495 controls (median age 51 years). Exposure to TD (OR 1.54, 95% CI 1.41 to 1.68) or BB (OR 1.19, 95% CI 1.11 to 1.28) was associated with an increased DM risk, while CCB and RASB exposure was not. TD+BB combination resulted in the fully combined diabetogenic risk of both agents (OR 1.99, 95% CI 1.80 to 2.20; interaction OR 1.09, 95% CI 0.97 to 1.22). In contrast, combination of RASB with either TD or BB showed significant negative interactions, resulting in a smaller DM risk than TD or BB monotherapy.
Diabetogenic potential of combination therapy should be considered when prescribing antihypertensive therapy.
PMCID: PMC3698771  PMID: 23752710
β blockers; diabetes; diabetogenic; drug interactions; hypertension; RAS blockers; thiazide diuretics
4.  Intralipid Fat Emulsion Decreases Respiratory Failure in a Rat Model of Parathion Exposure 
Academic Emergency Medicine  2012;19(5):504-509.
Therapies exist for acute organophosphate (OP) exposure but mortality rates remain high (10% to 20%). Currently, treatment focuses on reversing the resultant cholinergic excess effects through the use of atropine. Intralipid fat emulsion (IFE) has been used to treat lipophilic drug ingestions and theoretically would be beneficial for some OP agents.
The hypothesis was that IFE would decrease the acute respiratory depressant effects following lethal OP exposure using a lipophilic OP agent (parathion).
The authors used a previously validated animal model of OP poisoning with detailed physiologic respiratory recordings. The model consisted of Wistar rats anesthetized but spontaneously breathing 100% oxygen. Airflow, respiratory rate, tidal volume, mean arterial pressure, and pulse rate were digitally recorded for 120 minutes following OP exposure or until respiratory failure. Three study groups included parathion alone (n = 6), parathion and IFE 5 minutes after poisoning (n = 6), and parathion and IFE 20 minutes after poisoning (n = 6). In all groups, parathion was given as a single oral dose of 54 mg/kg (4 times the rat oral 50% population lethal dose [LD50]). Three boluses of IFE (15 mg/kg/min) were given over 3 minutes, 20 minutes apart, starting either 5 or 20 minutes after poisoning. Timing of IFE was based on parathion kinetics. In one study group IFE was initiated 5 minutes after poisoning to coincide with initial absorption of parathion. In another study group IFE was given at 20 minutes to coincide with peak intravenous parathion concentration. Primary outcome was percent of animals with apnea. Secondary outcome was time to apnea.
Animals exposed to parathion alone demonstrated a steady decline in respiratory rate and tidal volume post-exposure, with apnea occurring a mean of 51.6 minutes after poisoning (95% CI = 35.8 min to 53.2 min). Animals treated with IFE 5 minutes post-exposuredemonstrated no difference in mean time to apnea (44.5 minutes vs. 51.6 minutes, p = 0.29), or number of animals with respiratory arrest (100% vs. 100%, p = 1.00). Animals treated with IFE 20 minutes post-exposure demonstrated a significantly prolonged mean time to apnea (95.3 minutes vs. 51.6 minutes, p = 0.002), but there was no difference in number of animals with respiratory arrest (100% vs. 66.7%, p = 0.45).
All animals exposed to 4x LD50 of oral parathion demonstrate apnea and respiratory arrest. IFE given immediately after oral parathion does not prolong time to apnea. IFE given 20 minutes after oral exposure to parathion decreases the acute effects of the OP, and prolongs the time to apnea.
PMCID: PMC3356925  PMID: 22594353
5.  Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis 
There is an increased risk of venous thromboembolism among women taking oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown.
We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organizations in the United States. Women aged 18–46 years taking combined oral contraceptives and who had a claim for PCOS (n = 43 506) were matched, based on a propensity score, to control women (n = 43 506) taking oral contraceptives. Venous thromboembolism was defined using administrative coding and use of anticoagulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS.
The incidence of venous thromboembolism among women with PCOS was 23.7/10 000 person-years, while that for matched controls was 10.9/10 000 person-years. Women with PCOS taking combined oral contraceptives had an RR for venous thromboembolism of 2.14 (95% confidence interval [CI] 1.41–3.24) compared with other contraceptive users. The incidence of venous thromboembolism was 6.3/10 000 person-years among women with PCOS not taking oral contraceptives; the incidence was 4.1/10 000 person-years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10–2.19).
We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking combined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous thromboembolism when prescribing contraceptive therapy to women with PCOS.
PMCID: PMC3563911  PMID: 23209115
6.  Towards Improvements in the Estimation of the Coalescent: Implications for the Most Effective Use of Y Chromosome Short Tandem Repeat Mutation Rates 
PLoS ONE  2012;7(10):e48638.
Over the past two decades, many short tandem repeat (STR) microsatellite loci on the human Y chromosome have been identified together with mutation rate estimates for the individual loci. These have been used to estimate the coalescent age, or the time to the most recent common ancestor (TMRCA) expressed in generations, in conjunction with the average square difference measure (ASD), an unbiased point estimator of TMRCA based upon the average within-locus allele variance between haplotypes. The ASD estimator, in turn, depends on accurate mutation rate estimates to be able to produce good approximations of the coalescent age of a sample. Here, a comparison is made between three published sets of per locus mutation rate estimates as they are applied to the calculation of the coalescent age for real and simulated population samples. A novel evaluation method is developed for estimating the degree of conformity of any Y chromosome STR locus of interest to the strict stepwise mutation model and specific recommendations are made regarding the suitability of thirty-two commonly used Y-STR loci for the purpose of estimating the coalescent. The use of the geometric mean for averaging ASD and across loci is shown to improve the consistency of the resulting estimates, with decreased sensitivity to outliers and to the number of STR loci compared or the particular set of mutation rates selected.
PMCID: PMC3485328  PMID: 23119076
7.  The association between drospirenone and hyperkalemia: a comparative-safety study 
Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia.
A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone
The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy.
A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.
PMCID: PMC3265420  PMID: 22208934
8.  Timing and Frequency of Physostigmine Redosing for Antimuscarinic Toxicity 
Journal of Medical Toxicology  2010;6(4):386-392.
We sought to determine how frequently antimuscarinic-poisoned patients receiving physostigmine receive multiple doses of physostigmine, the length of time between physostigmine doses, and what impact multiple doses of physostigmine have on the disposition and total length of hospital stay. We performed a retrospective chart review of patients given physostigmine for likely antimuscarinic toxicity. A total of 45 patients met inclusion criteria. We abstracted patient demographics, vital signs, physical exam findings, electrocardiograms, the timing and dose of physostigmine, the implicated antimuscarinic agents, and disposition from the hospital. We counted the number of patients who required multiple physostigmine doses and calculated the time to repeat dosing. Fourteen of the 45 patients (31%) given physostigmine for antimuscarinic toxicity received multiple doses: nine patients (20%) received two doses, three patients (6.6%) received three doses, and two patients (4.4%) received four doses. Less than 5.5 h elapsed between sequential physostigmine doses, and less than 6.5 h elapsed between the first and last dose. Forty-five percent of patients receiving one dose of physostigmine were discharged from the emergency department (ED) and 36% of patients receiving more than one dose of physostigmine were discharged from the ED. Whether admitted or discharged, there was no statistically significant difference in the length of hospital stay between patients receiving one or multiple doses of physostigmine. Repeated physostigmine administration is not frequently needed in medication-induced antimuscarinic toxicity. Patients are not likely to require further physostigmine redosing more than 6.5 h from their first dose.
PMCID: PMC3550455  PMID: 20405266
Physostigmine; Antimuscarinic; Anticholinergic; Toxicity
9.  Non-muscarinic Therapeutic Targets for Acute Organophosphorus Poisoning 
Journal of Medical Toxicology  2010;6(4):408-412.
Organophosphorus (OP) pesticides are a broad class of acetylcholinesterase inhibitors that are responsible for tremendous morbidity and mortality worldwide, contributing to an estimated 300,000 deaths annually. Current pharmacotherapy for acute OP poisoning includes the use of atropine, an oxime, and benzodiazepines. However, even with such therapy, the mortality from these agents is as high as 40%. It is increasingly recognized that not all OPs are the same. Significant differences exist in their toxicity, lipophilicity, and response to oxime therapy. Other non-muscarinic effects of OP pesticides exist, such as acute and chronic neuromuscular junction failure and central respiratory failure. In part because most of the mortality from these chemicals takes place in the developing world, little National Institutes of Health (NIH) research has been directed towards these agents. However, the similar mechanism of action of OP pesticides and the military nerve agents, along with increasing concerns about chemical terrorism has lead to the formation of the NIH Countermeasures Against Chemical Threats (CounterACT) Program. As part of the CounterACT Program, the NIH has recently designated six OP pesticides as “threat agents”. This concept paper describes some of the knowledge gaps related to non-muscarinic effects of OP pesticides and highlights needed areas of further research. Leveraging the current NIH interest in these chemicals to medical necessities in the developing world offers the possibility of delivering new therapeutics where they are needed on a daily basis.
PMCID: PMC3550473  PMID: 20532844
Organophosphorus; Nicotinic; Muscarinic; Poisoning
10.  Pharmacokinetics of OpdA, an organophosphorus hydrolase, in the African Green Monkey 
Biochemical pharmacology  2010;80(7):1075-1079.
Organophosphorus (OP) pesticides are a broad class of acetylcholinesterase inhibitors that are responsible for tremendous morbidity and mortality worldwide, contributing to an estimated 300,000 deaths annually. Current pharmacotherapy for acute OP poisoning includes the use of atropine, an oxime, and benzodiazepines. However, even with such therapy, the mortality from these agents are as high as 40%.
Enzymatic hydrolysis of OPs is an attractive new potential therapy for acute OP poisoning. A number of bacterial OP hydrolases have been isolated. A promising OP hydrolase is an enzyme isolated from Agrobacterium radiobacter, named OpdA. OpdA has been shown to decrease lethality in rodent models of parathion and dichlorvos poisoning. However, pharmacokinetic data have not been obtained. In this study, we examined the pharmacokinetics of OpdA in an African Green Monkey model.
At a dose of 1.2 mg/kg the half-life of OpdA was approximately 40 minutes, with a mean residence time of 57 minutes. As expected, the half-life did not change with the dose of OpdA given: at doses of 0.15 and 0.45 mg/kg, the half-life of OpdA was 43.1 and 38.9 minutes, respectively. In animals subjected to 5 daily doses of OpdA, the residual activity that was measured 24 hours after each OpdA dose increased 5-fold for the 0.45 mg/kg dose and 11-fold for the 1.2 mg/kg dose.
OpdA exhibits pharmacokinetics favorable for the further development as a therapy for acute OP poisoning, particularly for hydrophilic OP pesticides. Future work to increase the half-life of OpdA may be beneficial.
PMCID: PMC2923271  PMID: 20599794
organophosphorus; pesticide; hydrolysis; monkey
11.  Liver Aminotransferases Are Elevated with Rhabdomyolysis in the Absence of Significant Liver Injury 
Journal of Medical Toxicology  2010;6(3):294-300.
Rhabdomyolysis is an uncommon finding in the emergency department. However, the clinical implications of rhabdomyolysis are important, with a significant minority of patients developing acute renal failure and multiorgan failure. When present, the cause of elevated aminotransferases in the setting of rhabdomyolysis is often unclear. We sought to determine the incidence of abnormal aminotransferases (defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >40 U/L) in the setting of rhabdomyolysis and how the aminotransferases decrease relative to the creatine phosphokinase (CPK) concentration as rhabdomyolysis resolves. A retrospective chart review of 215 cases of rhabdomyolysis with CPK of ≥1,000 U/L was performed. The incidence of an abnormal AST in the setting of rhabdomyolysis was 93.1% (95% confidence interval, 88.7% to 95.8%). An abnormal ALT was much less common and found in 75.0% (95% confidence interval, 68.7% to 80.2%) of patients with a CPK of ≥1,000 U/L (p < 0.0001). In only one instance was the ALT > 40 U/L while the AST was <40 U/L. Furthermore, AST concentrations (and not ALT) fall in parallel with CPK during the first 6 days of hospitalization for patients with rhabdomyolysis. Aminotransferase abnormalities, particularly AST, are common in the setting of rhabdomyolysis. AST concentrations decrease in parallel to CPK, suggesting skeletal muscle may be a significant source of AST elevation in these patients.
PMCID: PMC3550495  PMID: 20407858
Aspartate aminotransferase; Alanine aminotransferase; Rhabdomyolysis
12.  Kinetics and efficacy of an organophosphorus hydrolase in a rodent model of methyl-parathion poisoning 
Organophosphorus (OP) pesticides exert a tremendous health burden, particularly in the developing world. Limited resources, the severity of intentional OP ingestions, and a paucity of beneficial therapies all contribute to the morbidity and mortality of this broad class of chemicals. A novel theoretical treatment for OP poisoning is the use of an enzyme to degrade the parent OP in the circulation after poisoning. The aims of this study were to determine the pharmacokinetics and efficacy of an OP hydrolase (OpdA) in a rodent model of severe methyl-parathion poisoning.
Two animal models were used. First, Wistar rats were administered two different doses of the hydrolase (0.15 mg/kg and 1.5 mg/kg), and the ex vivo hydrolytic activity of plasma was determined by a fluorometric method. Second, an oral methyl-parathion animal poisoning model was developed to mimic severe human poisoning, and the efficacy of post-poisoning OpdA (as measured by survival to 4 hours and 24 hours) was determined.
The half-life of OpdA in the Wistar rat was dependent upon the dose administered, and ranged between 45.0 and 57.9 minutes. The poisoning model of three times the lethal dose to 50% of the population (3×LD50) of methyl-parathion resulted in 88% lethality at 4 and 24 hours. Using a single dose of 0.15 mg/kg OpdA 10 minutes after poisoning resulted in 100% survival at 4 hours (p = 0.001 vs. placebo), but 0% at 24 hours post-poisoning (p = NS vs. placebo).
The OP hydrolase OpdA exhibits pharmacokinetics suitable for repeated dosing and increases short-term survival after severe methyl-parathion poisoning.
PMCID: PMC2911639  PMID: 20653588
organophosphate; pesticide; hydrolase
13.  Research Concepts, Collaboration, and JMT 
PMCID: PMC3550438
14.  Are post-treatment low-density lipoprotein subclass pattern analyses potentially misleading? 
Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL particle number (approximated by apolipoprotein B), and LDL particle size. This was a multicenter, double-blind, randomized, parallel-group study of hypercholesterolemic, high atherosclerotic coronary heart disease risk patients. After stabilization of atorvastatin 40 mg, 579 patients with LDL-C >70 mg/dL were randomized to 6 weeks of ezetimibe + atorvastatin 40 mg or atorvastatin 80 mg. Efficacy parameters included changes from baseline in LDL-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein subclasses (Vertical Auto Profile II) and pattern for the overall population, as well as patient subgroups with baseline triglyceride levels <150 mg/dL or ≥150 mg/dL.
Both treatments significantly reduced LDL-C (and the cholesterol content of most LDL subfractions [LDL1-4]) apolipoprotein B, non-HDL-C levels, but did not reduce the proportion of smaller, more dense LDL particles; in fact, the proportion of Pattern B was numerically increased. Results were generally similar in patients with triglyceride levels <150 or ≥150 mg/dL.
When assessing the effects of escalating cholesterol-lowering therapy, effects upon Pattern B alone to assess coronary heart disease risk may be misleading when interpreted without considerations of other lipid effects, such as reductions in LDL-C, atherogenic lipoprotein particle concentration, and non-HDL-C levels.
Trial Registration
(Registered at Clinical trial # NCT00276484)
PMCID: PMC3012666  PMID: 21118495
15.  Reply to the letter to the editor by Bretholz et al 
Toxicology  2008;257(3):173.
PMCID: PMC2646812  PMID: 20160842
16.  Journal impact factors,h indices, and citation analyses in toxicology 
Journal of Medical Toxicology  2008;4(4):261-274.
Overall, toxicology journals have low impact factors compared to other scientific journals. As academic promotion boards increasingly use semiquantitative methods of determining academic productivity (such as the impact factor andh index of the journals in which a person has published), it could be expected that the toxicology journals in which many people in the fields of medical and clinical toxicology publish will see decreased submissions, as authors attempt to get their work published in journals with higher impact factors.
PMCID: PMC3550115  PMID: 19031379
Impact factor; h indices; citation analyses; toxicology
17.  Self-plagiarism, recycling fraud, and the intent to mislead 
Journal of Medical Toxicology  2008;4(2):69-70.
PMCID: PMC3550132  PMID: 18570164
18.  OpdA, a bacterial organophosphorus hydrolase, prevents lethality in rats after poisoning with highly toxic organophosphorus pesticides 
Toxicology  2008;247(2-3):88-92.
Organophosphorus (OP) pesticides poison more than 3,000,000 people every year in the developing world, mostly through intentional self-poisoning. Advances in medical therapy for OP poisoning have lagged, and current treatment is not highly effective with mortality of up to 40% in even the most advanced Western medical facilities. Administration of a broadly active bacterial OP hydrolase to patients in order to hydrolyze OPs in circulation might allow current therapies to be more effective. The objective of this work was to evaluate the efficacy of a new recombinant bacterial OP hydrolase (OpdA), cloned from Agrobacterium radiobacter, in rat models of two chemically distinct but highly toxic and rapidly acting OP pesticides: dichlorvos and parathion. Without OpdA treatment, median time to death in rats poisoned with 3 × LD50 of dichlorvos or parathion was 6 minutes and 25.5 minutes, respectively. Administration of a single dose of OpdA immediately after dichlorvos resulted in 100% survival at 24 hours, with no additional antidotal therapy. After parathion poisoning, OpdA alone caused only a delay to death. However, an additional two doses of OpdA resulted in 62.5% survival at 24 hours after parathion poisoning. In combination with pralidoxime therapy, a single dose of OpdA increased survival to 75% after parathion poisoning. Our results demonstrate that OpdA is able to improve survival after poisoning by two chemically distinct and highly toxic OP pesticides.
PMCID: PMC2408951  PMID: 18378376
Organophosphorus (OP); hydrolase; acetylcholinesterase (AChE); pralidoxime (2-PAM)
19.  Antiemetic use in acetaminophen poisoning: How does the route of N-acetylcysteine administration affect utilization? 
Journal of Medical Toxicology  2007;3(4):152-156.
We sought to compare antiemetic use after acetaminophen poisoning in patients treated with oral or intravenous (IV) N-acetylcysteine (NAC).
Our retrospective chart review identified 20 orally treated patients and 17 IV-treated patients. For both groups, we calculated the total number of antiemetic doses given, their associated cost, and also determined parameters that correlated with antiemetic use.
IV-treated patients received fewer total antiemetic doses than those receiving oral NAC (1.1 ± 0.2 vs. 2.8 ± 0.7; P = 0.04). Antiemetic cost correlated with doses received for both groups; however, because the regression lines differed (P = 0.02), antiemetic therapy cost was less in IV-treated patients. In addition, serum acetaminophen concentration correlated with total antiemetic doses in oral NAC patients (P < 0.002) but not with IV treatment patients (P = 0.78).
Intravenous NAC reduced antiemetic utilization, and it costs less than oral therapy. Furthermore, antiemetic use appeared to be determined by a combination of acetaminophen concentration and NAC administration route.
PMCID: PMC3550020  PMID: 18072168
acetaminophen; antiemetics; n-acetylcysteine; overdose
20.  House officer procedure documentation using a personal digital assistant: a longitudinal study 
Personal Digital Assistants (PDAs) have been integrated into daily practice for many emergency physicians and house officers. Few objective data exist that quantify the effect of PDAs on documentation. The objective of this study was to determine whether use of a PDA would improve emergency medicine house officer documentation of procedures and patient resuscitations.
Twelve first-year Emergency Medicine (EM) residents were provided a Palm V (Palm, Inc., Santa Clara, California, USA) PDA. A customizable patient procedure and encounter program was constructed and loaded into each PDA. Residents were instructed to enter information on patients who had any of 20 procedures performed, were deemed clinically unstable, or on whom follow-up was obtained. These data were downloaded to the residency coordinator's desktop computer on a weekly basis for 36 months. The mean number of procedures and encounters performed per resident over a three year period were then compared with those of 12 historical controls from a previous residency class that had recorded the same information using a handwritten card system for 36 months. Means of both groups were compared a two-tailed Student's t test with a Bonferroni correction for multiple comparisons. One hundred randomly selected entries from both the PDA and handwritten groups were reviewed for completeness. Another group of 11 residents who had used both handwritten and PDA procedure logs for one year each were asked to complete a questionnaire regarding their satisfaction with the PDA system.
Mean documentation of three procedures significantly increased in the PDA vs handwritten groups: conscious sedation 24.0 vs 0.03 (p = 0.001); thoracentesis 3.0 vs 0.0 (p = 0.001); and ED ultrasound 24.5 vs. 0.0 (p = 0.001). In the handwritten cohort, only the number of cardioversions/defibrillations (26.5 vs 11.5) was statistically increased (p = 0.001). Of the PDA entries, 100% were entered completely, compared to only 91% of the handwritten group, including 4% that were illegible. 10 of 11 questioned residents preferred the PDA procedure log to a handwritten log (mean ± SD Likert-scale score of 1.6 ± 0.9).
Overall use of a PDA did not significantly change EM resident procedure or patient resuscitation documentation when used over a three-year period. Statistically significant differences between the handwritten and PDA groups likely represent alterations in the standard of ED care over time. Residents overwhelmingly preferred the PDA procedure log to a handwritten log and more entries are complete using the PDA. These favorable comparisons and the numerous other uses of PDAs may make them an attractive alternative for resident documentation.
PMCID: PMC1373615  PMID: 16438709
21.  Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology  
Objective To characterize risk of hypotension requiring admission to hospital in middle aged and older men treated with tamsulosin for benign prostatic hyperplasia.
Design Population based retrospective cohort study (between patient methodology) and self controlled case series (within patient methodology).
Setting Healthcare claims data from the IMS Lifelink database in the United States.
Participants Men aged 40-85 years with private US healthcare insurance entering the cohort at their first dispensing for tamsulosin or for a 5α reductase inhibitor (5ARI) between January 2001 and June 2011after a minimum of six months’ enrolment.
Main outcomes measures Hypotension requiring admission to hospital. Cox proportional hazards models estimated rate ratios at time varying intervals during follow-up: weeks 1-4, 5-8, and 9-12 after tamsulosin initiation; weeks 1-4, 5-8, and 9-12 after restarting tamsulosin (after a four week gap); and maintenance tamsulosin treatment (remaining exposed person time). Covariates included age, calendar year, demographics, antihypertensive use, healthcare use, and a Charlson comorbidity score. A self controlled case series, having implicit control for time invariant covariates, was additionally conducted.
Results Among 383 567 new users of study drugs (tamsulosin 297 596; 5ARI 85 971), 2562 admissions to hospital for severe hypotension were identified. The incidence for hypotension was higher for tamsulosin (42.4 events per 10 000 person years) than for 5ARIs (31.3 events per 10 000 person years) or all accrued person time (29.1 events per 10 000 person years). After tamsulosin initiation, the cohort analysis identified an increased rate of hypotension during weeks 1-4 (rate ratio 2.12 (95% confidence interval 1.29 to 3.04)) and 5-8 (1.51 (1.04 to 2.18)), and no significant increase at weeks 9-12. The rate ratio for hypotension also increased at weeks 1-4 (1.84 (1.46 to 2.33)) and 5-8 (1.85 (1.45 to 2.36)) after restarting tamsulosin, as did maintenance tamsulosin treatment (1.19 (1.07 to 1.32)). The self controlled case series gave similar results as the cohort analysis.
Conclusions We observed a temporal association between tamsulosin use for benign prostatic hyperplasia and severe hypotension during the first eight weeks after initiating treatment and the first eight weeks after restarting treatment. This association suggests that physicians should focus on improving counseling strategies to warn patients regarding the “first dose phenomenon” with tamsulosin.
PMCID: PMC3817852  PMID: 24192967

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