Risk assessment of isolated aripiprazole exposures and toxicities: a retrospective study.

STUDY OBJECTIVE: To characterize the clinical effects of acute isolated aripiprazole poisonings and to assess the toxic dose of this drug. METHODS: All isolated acute aripiprazole exposures reported to a poison control system from January 2002 through September 2006 were retrospectively reviewed. Patients with incomplete information or those lost to follow-up were excluded. RESULTS: A total of 286 cases were identified. Mean age was 18.9 years (SD 15.7), with a range of 6 months-70 years. Seventy-seven patients (27%) were or=18 years. Doses were known in 255 patients (89%). Symptoms occurred in 158 patients (55%): somnolence 89 (56%), tachycardia 32 (20%, heart rate 102-186), nausea/vomiting 29 (18%), dystonic reactions 21 (13%), tremor 9 (6%), agitation 3 (2%), dizziness 3 (2%), paresthesia 2 (1%), headache 2 (1%), dysphagia 1 (<1%), syncope 1 (<1%), minor facial swelling 1 (<1%), and hypotension 1 (<1%). None of the patients required intubation, and there were no deaths or EKG abnormalities. Median dose for symptomatic and asymptomatic groups were 25 and 15 mg, respectively, for or=18 (p = 0.25). In comparison of drug groups (Group 1, or=91 mg), symptoms were more likely to occur in Group 2 versus Group 1 (OR 2.29, 95% CI 0.79-6.61) in patients or=18 years. CONCLUSIONS: Acute aripiprazole poisonings most commonly result in sedation, sinus tachycardia, nausea/vomiting, or dystonic reactions. Symptoms are more likely with doses above 90 mg, although pediatric patients can be affected at a lower dose.

Review of prehospital sodium bicarbonate use for cyclic antidepressant overdose.

OBJECTIVE: To describe the clinical presentation of patients with cyclic antidepressant (CA) and use of sodium bicarbonate (NaHCO(3)) in the treatment of this overdose in the prehospital setting. METHODS: A three year retrospective observational review of records was performed using the San Diego County Quality Assurance Network database for prehospital providers. All adult patients who were treated with NaHCO(3) by paramedics for a CA overdose were included. Demographic data, presenting cardiovascular and neurological symptoms, paramedic treatments, and any changes in status were reviewed. RESULTS: Twenty one patients were treated by paramedics with NaHCO(3) for CA overdose. Seventeen patients (80%) presented with mental status changes, including 11 presenting with a GCS<8. Seven of the 21 (33%) presented with a cardiac arrhythmia expected to possibly respond to NaHCO(3) treatment. Seven of the 21 (33%) were hypotensive, and five (24%) patients had reported seizure activity. Only 2 of the 21 patients (10%) treated with NaHCO(3) had recorded improvements after administration of the drug, while the other 19 remained stable without any deterioration. Sixteen of 21 patients (76%) were given NaHCO(3) for indications on standing order, while five patients were treated outside the standing order indications by base physician order with none of the five patients having any change in status ater treatment. CONCLUSIONS: After prehospital NaHCO(3) use in patients with CA overdose, there were no complications reported, two patients improved in status and the others remained unchanged. Base hospital physician orders of NaHCO(3) for indications beyond the standing orders were not associated with changes in patient status.

Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens.

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.

A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States.

BACKGROUND: Current therapy for crotaline snakebite includes antivenin (Crotalidae) polyvalent, an antivenom with numerous adverse effects. We compared the efficacy and safety of 2 dosing regimens with a new antivenom, Crotalinae polyvalent immune Fab (Fab AV). METHODS: A single dose of Fab AV alone (as-needed [PRN] group) was compared with an initial dose plus repeated treatments during 18 hours (scheduled group) in a multicenter randomized trial. The study included patients with minimal or moderate envenomation by a crotaline snake within the preceding 6 hours, aged 10 years or older, in whom worsening of the envenomation syndrome was observed before Fab AV treatment. After treatment with Fab AV to achieve initial control, patients were randomized to the scheduled or PRN treatment group. Scheduled group patients received additional doses of Fab AV every 6 hours for 3 doses. The PRN group received no planned additional doses of antivenom. RESULTS: The mean severity score of the 31 patients decreased from 4.35 to 2.39 points (P<.001); there was no difference between scheduled and PRN groups. No patient in the scheduled group received unplanned Fab AV doses, but 8 of 16 patients in the PRN group received unplanned doses (P =.002). Acute reactions occurred in 6 patients (19%), and serum sickness occurred in 6 (23%) of 26 patients who returned for follow-up. CONCLUSIONS: In the first randomized trial of antivenom in the United States, Fab AV effectively terminated venom effects. Since the unplanned use of Fab AV in the PRN group was common, the treatment regimen may require more than 1 initial dose.

A case of withdrawal from the GHB precursors gamma-butyrolactone and 1,4-butanediol.

We describe a case of withdrawal from the gamma hydroxybutyric acid (GHB) precursors gamma butyrolactone and 1,4-butanediol. Symptoms included visual hallucinations, tachycardia, tremor, nystagmus, and diaphoresis. Administration of benzodiazepines and phenobarbital successfully treated the withdrawal symptoms. As predicted from the metabolism of gamma butyrolactone and 1,4-butanediol to GHB, the symptoms were nearly identical to those reported from GHB withdrawal. Because GHB is now illegal in the United States, individuals have begun abusing the legal and easier to acquire GHB precursors. More frequent cases of both abuse and withdrawal from these GHB precursors can be expected.

Treatment of acetaminophen ingestion with a superactivated charcoal-cola mixture.

STUDY OBJECTIVE: We evaluate the adsorptive capacity of a superactivated charcoal-cola mixture to acetaminophen compared with superactivated charcoal alone. METHODS: This was a triple-arm, prospective, unblinded study of 8 healthy adult human volunteers who ingested 80 mg/kg of acetaminophen. In the control arm of the study, participants ingested acetaminophen alone. In the next arm, acetaminophen was followed by 1 g/kg of superactivated charcoal mixed with water. In the final arm, acetaminophen was followed by 1 g/kg of superactivated charcoal mixed with caffeine-free diet cola. Serum acetaminophen concentrations over 6 hours for each arm were analyzed for area under the time-concentration curve (AUC), peak concentrations, and time to peak concentrations. RESULTS: AUCs were 298.5+/-82.5 mg-h/L (control), 77.1+/-85.2 mg-h/L (superactivated charcoal), and 81.3 +/- 71.8 mg-h/L (superactivated charcoal-cola). Comparison of AUCs by analysis of variance revealed mean square of 128,315.1 between treatments, and residual mean square of 6,405.0, yielding an F ratio of 20.03 (P <.0001). Student-Newman-Keuls pairwise multiple comparison procedure revealed a statistically significant difference in AUC for control versus superactivated charcoal (P <.05) and for control versus superactivated charcoal-cola (P <.05), but not for superactivated charcoal versus superactivated charcoal-cola (P >.05). Time-concentration curves for the 3 study arms were illustrated graphically. CONCLUSION: Combining superactivated charcoal with cola does not limit the adsorptive capacity of superactivated charcoal.

5-Year analysis of mushroom exposures in California.

OBJECTIVE: To evaluate outcomes following toxic mushroom ingestions. DESIGN: Retrospective data analysis. METHODS: We analyzed American Association of Poison Control Center data for California from 1993 through 1997. RESULTS: A total of 6,317 exposures occurred during the study period. Most (n = 6,229 [99.7%]) were acute exposures, and the rest (0.3%) were chronic; 87.6% (n = 5,536) were unintentional. Most (n = 4,235 [67.0%]) were in children younger than 6 years, and of these, only 6.0% experienced any clinical effects. The most common symptoms in patients aged 6 years and older were vomiting in 588 patients (28.2%), nausea in 307 patients (14.7%), diarrhea in 263 patients (12.6%), and abdominal pain in 221 patients (10.6%). No effects were seen in 3,131 (49.6% of all patients). Major effects were seen in only 17 patients (0.3%). Only 61 patients (1.0%) were admitted to a critical care unit. Death occurred in a 32-year-old adult who ate foraged mushrooms. Of all patients, 1,375 (21.8%) received no therapy or were observed only. CONCLUSIONS: Most mushroom exposures were acute and unintentional and occurred in children younger than 6 years. Major toxic reactions or death was uncommon.

Retrospective analysis of ingestions of iron containing products in the united states: are there differences between chewable vitamins and adult preparations?

Iron is the one of the leading causes of pediatric poisoning deaths in the United States. Most cases of serious iron overdose reported in the medical literature have resulted from adult formulations of iron. To begin evaluating the possibility that differences in toxicity exist between iron preparations, we performed a retrospective evaluation of all exposures to pediatric and adult iron products reported to the American Association of Poison Control Centers' (AAPCC) Toxic Exposure Surveillance System (TESS) from 1983 to 1998. We attempted to determine the incidence of fatal iron poisoning for each group. A total of 195,780 ingestions of children's vitamins containing iron were reported to the TESS between 1983 and 1998 with no resulting fatalities. During the same twelve-year study period, 147,079 exposures to adult forms of iron were reported with 60 fatalities (p < 0.0001). A prospective study is required to assess whether differences may exist in the toxicity of these two iron preparations.

Synthesis of 2-fluoro-6-O-propargyl-11,12-carbamate ketolides. A novel class of antibiotics.

A novel class of 2-fluoro-6-O-propargyl-11,12-carbamate ketolide derivatives of erythromycin has been synthesized for antibacterial SAR studies. Replacement of the C2-hydrogen by a fluorine atom allows the synthesis of 6-O-propargylic ketones and electron-deficient 6-O-propargylic aromatic derivatives by preventing intramolecular C2-enolate Michael cyclization.

Coma and respiratory depression following the ingestion of GHB and its precursors: three cases.

Gamma hydroxybutyrate (GHB) is a product of the metabolism of both gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD). Gamma hydroxybutyrate (GHB) is an illegal agent that causes central nervous system depression. Chemical precursors of GHB, such as GBL and 1,4-BD, have been available for purchase from many health food stores and Internet websites for mood-enhancement, sleep-induction, and stimulation of growth hormone release. We report three cases of ingestion of products containing GHB and chemical precursors of GHB. All three patients had severe presentations followed by full recoveries. Some products containing GBL were withdrawn from the market after the FDA issued a warning regarding these products. Products containing 1,4-butanediol remain on the market today.

Falsely elevated digoxin level of 45.9 ng/mL due to interference from human antimouse antibody.

CASE REPORT: We report the case of a 77-year-old man who was admitted to the intensive care unit with a serum digoxin level of 45.9 ng/mL. The patient was hemodynamically stable throughout his hospital course and did not require antidigoxin antibody fragments. The elevated digoxin level was determined by subsequent testing to be falsely elevated by interference from human antimouse antibodies in his serum. A repeat digoxin measurement using an assay not affected by human antimouse antibodies indicated a level of 1.3 ng/mL. Newer digoxin assays are not affected by human antimouse antibody interference, but clinicians should be aware of possible human antimouse antibody interference with older digoxin assays and in other tests utilizing mouse monoclonal antibody reagents.

Synthesis and antibacterial activity of novel 6-O-substituted erythromycin A derivatives.

A series of novel 6-O-substituted erythromycin A derivatives has been synthesized. Good in vitro antibacterial activity has been demonstrated for analogues incorporating a variety of structural features. The methodology disclosed is expected to find application in the design of future macrolide antibiotics that target the prevalent bacterial resistance problem.

Pantomography vs mandibular series for the detection of mandibular fractures.

OBJECTIVE: The two primary radiographic techniques used for the evaluation of mandible injury are a pantomographic series (PS) and the standard four-view mandibular series (MS). Despite a tenuous foundation, there is apparent bias in favor of PS compared with MS. Many emergency departments do not have ready access to the specialized equipment necessary to perform a pantomographic study. The hypothesis of this study was that a high-quality standard MS is as sensitive and specific as a PS in the detection of mandibular fractures. METHODS: This was a prospective, blinded study of 54 patients presenting with acute mandibular injury comparing MS and PS. The study design used two board-certified emergency physicians and a single staff radiologist who read a series of MS and PS films in a randomized fashion without access to clinical information or identifying patient data. The absolute number of fractures present was determined by a neuroradiologist with access to both MS and PS simultaneously as well as pertinent clinical information. RESULTS: Thirty patients had 47 mandibular fractures. The sensitivity for fracture detection for each physician was 0.85, 0.77, and 0.89 with MS and 0.79, 0.74, and 0.83 with PS (p > or = 0.51, p > or = 1.00, and p > or = 0.51, respectively, McNemar's binomial test). The specificity for fracture detection for each physician was 0.88, 0.92, and 0.96 for MS and 0.96, 1.00, and 0.92 for PS (p > 0.625, p > 0.50, and p = 1.00, respectively, McNemar's binomial test). CONCLUSIONS: A standard mandibular series is as sensitive and specific as pantomography in the detection of mandibular fractures.

Prospective evaluation of mild to moderate pediatric acetaminophen exposures.

STUDY OBJECTIVE: To determine whether pediatric patients with acute, mild to moderate acetaminophen exposures, treated with home monitoring alone, develop systemic signs of hepatic injury. METHODS: A prospective, observational study of calls to a regional poison center over a 25-month period was performed. Patients were eligible for the study if they were younger than 7 years and had an acute maximum possible acetaminophen exposure of up to 200 mg/kg. Exclusion criteria included previous decontamination measures, possibility of ingestion of an extended-release preparation, health or medication issues that could increase susceptibility to hepatotoxicity, current symptoms of hepatotoxicity, and indeterminable ingestions. Study protocol included reviewing the signs and symptoms of early and late acetaminophen toxicity, a 4- to 6-hour follow-up call, and a 72-hour follow-up call. Outcome measures were defined as a verbal report by the patient's parent or guardian of the presence or absence of signs or symptoms of hepatotoxicity. RESULTS: A total of 1,039 patients were enrolled in the study, including 519 girls and 520 boys, with exposures ranging from 20 to 200 mg/kg. Eighteen patients were lost to follow-up; data were incomplete for 2 patients. At 72-hour follow-up, the remaining 1,019 patients were all doing well, without signs or symptoms of hepatotoxicity. CONCLUSION: On the basis of these data, pediatric patients with acute acetaminophen exposures of up to 200 mg/kg, treated with home monitoring alone, do not develop signs or symptoms of hepatic injury.

Posttranslational modification and plasma membrane localization of the Drosophila melanogaster presenilin.

Mutations in two genes, presenilin 1 (PS1) and presenilin 2, are linked to early onset cases of familial Alzheimer's disease. The presenilins are thought to contribute to the pathogenesis of Alzheimer's disease by directly or indirectly affecting the proteolytic processing of the amyloid precursor protein. They have also been implicated in the proteolytic processing of Notch. In PS1-deficient mammalian cells, the proteolytic release of the Notch intracellular domain is reduced. Likewise, loss-of-function mutations in Drosophila presenilin (Psn) prevent the production of the intracellular Notch signaling fragment and lead to phenotypes resembling Notch mutants. Here we characterize the Drosophila Psn protein and demonstrate that it undergoes a proteolytic cleavage. We describe Psn expression at different developmental stages of the fly and show Psn localization near both apical and basal plasma membranes. Furthermore, we demonstrate that portions of the Psn protein span the plasma membrane in S2 cells.

Retirement plan technology delivers big benefits to small business.

Retirement plan technology has made it possible for small businesses to be "competitive" in the benefits they offer employees. Small firms that have upgraded their plans have found they are able to offer programs that are less expensive for them and richer for their employees. Integration and Web-based technology have also facilitated employees' retirement planning.

Comparison of the toxicities of two iron formulations in a swine model.

OBJECTIVE: To describe the histopathologic and pharmacokinetic differences of acute iron poisoning between chewable multivitamins with iron and solid iron tablets in a swine model. METHODS: This was a prospective, randomized, unblinded toxicity study of iron poisoning of two iron formulations in male Yorkshire pigs. Eight swine were randomized to receive 60 mg/kg of iron in either solid iron tablets or chewable multivitamins with iron. Serum iron, arterial blood gases, and episodes of vomiting were recorded over a ten-hour period. Routine histologic evaluations of the esophagus, stomach, small intestine, large intestine, and liver were performed immediately after the study period. Pharmacokinetic analyses of area under the concentration-time curve (AUC), time to peak concentration, and peak serum iron concentration were performed. RESULTS: There was no significant difference between the serum iron levels except at three and four hours. There was a significant higher AUC in the chewable group compared with the solid group. Pathologic evaluation identified severe esophageal inflammation and focal erosion in the solid iron tablet group in two of the four animals, compared with no focal erosions and minimal esophageal inflammation in the chewable group. No significant change was identified in the liver, small intestine, or large intestine in either group. CONCLUSIONS: These results demonstrate increased local gastrointestinal toxicity following a large ingestion of solid iron tablets in a swine model, compared with chewable multivitamins with iron. Higher serum iron levels were identified in the animals that received chewable multivitamins with iron.