A case series of patients with lamotrigine toxicity at one center from 2003 to 2012.

INTRODUCTION: Lamotrigine is a phenyltriazine compound that inhibits voltage-gated sodium channels, decreasing release of glutamate and aspartate, and inhibits serotonin, norepinephrine and dopamine reuptake. Reports of toxicity in the literature are limited to case reports and primarily involve coingestants. This case series is intended to report the clinical manifestations of lamotrigine toxicity. METHODS: This retrospective case series from 2003 to 2012 studies the effects of lamotrigine toxicity when not confounded by coingestants. Admission records at an inpatient toxicology center were reviewed for lamotrigine-only exposure based on history with supporting laboratory data when available. After identification, these charts were reviewed again to characterize vital signs, neurological examination findings, specific laboratory and electrocardiography parameters, and complications. RESULTS: Fifty-seven patients were identified with possible lamotrigine toxicity. Nine patients, including three toddlers, had lamotrigine-only ingestions. Three of these patients had seizures, four were hypertensive, five were tachycardic, and four experienced tachypnea. Mental status was altered in all nine (depressed (n = 4), agitated (n = 5) or both (n = 3)). Five patients were hyperreflexic and experienced intermittent myoclonus, and two had inducible clonus. On electrocardiogram, two patients experienced QRS prolongation (114-116 ms), and four had QTc prolongation (463-586 ms). No patient had life-threatening symptoms or signs. Serum levels of lamotrigine were available in seven patients, and averaged 35.4 mg/L (17-90 mg/L). The therapeutic range for sLTG is 3-14 mg/L. CONCLUSIONS: Lamotrigine toxicity manifested with minor-moderate neurologic and/or electrocardiographic effects. Toxicity reflects the known pharmacologic actions of lamotrigine: serotonin, norepinephrine and dopamine reuptake inhibition, and sodium channel blockade.

Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group.

BACKGROUND: Ethylene glycol poisoning causes metabolic acidosis and renal failure and may cause death. The standard treatment is inhibition of alcohol dehydrogenase with ethanol, given in intoxicating doses, and adjunctive hemodialysis. We studied the efficacy of fomepizole, a new inhibitor of alcohol dehydrogenase, in the treatment of ethylene glycol poisoning. METHODS: We administered intravenous fomepizole to 19 patients with ethylene glycol poisoning (plasma ethylene glycol concentration, > or =20 mg per deciliter [3.2 mmol per liter]). Patients who met specific criteria also underwent hemodialysis. Treatment was continued until plasma ethylene glycol concentrations were less than 20 mg per deciliter. Acid-base status, renal function, the kinetics of fomepizole, and ethylene glycol metabolism were assessed at predetermined intervals. RESULTS: Fifteen of the patients initially had acidosis (mean serum bicarbonate concentration, 12.9 mmol per liter). Acid-base status tended to normalize within hours after the initiation of treatment with fomepizole. One patient with extreme acidosis died. In nine patients, renal function decreased during therapy; at enrollment, all nine had high serum creatinine concentrations and markedly elevated plasma glycolate concentrations (> or =97.7 mg per deciliter [12.9 mmol per liter]). None of the 10 patients with normal serum creatinine concentrations at enrollment had renal injury during treatment; all 10 had plasma glycolate concentrations at or below 76.8 mg per deciliter (10.1 mmol per liter). Renal injury was independent of the initial plasma ethylene glycol concentration. The plasma concentration of glycolate and the urinary excretion of oxalate, the major metabolites of ethylene glycol, uniformly fell after the initiation of fomepizole therapy. Few adverse effects were attributable to fomepizole. CONCLUSIONS: In patients with ethylene glycol poisoning, fomepizole administered early in the course of intoxication prevents renal injury by inhibiting the formation of toxic metabolites.

Hemodialysis following butoxyethanol ingestion.

CASE REPORT: This case report describes a 19-year-old male who ingested a product containing butoxyethanol, propylene glycol, and monoethanolamine. Neurotoxicity, acidosis, and butoxyacetic acid persisted after hemodialysis. Hemodialysis was used to treat the acidosis, but the half-life of butoxyacetic acid did not appear to have been significantly altered. Fomepizole, a recently approved alcohol dehydrogenase inhibitor for ethylene glycol intoxication, was not available at the time of this case. Residual neurological deficits persisted after recovery from this severe intoxication by a glycol ether.

Alterations in tau phosphorylation in rat and human neocortical brain slices following hypoxia and glucose deprivation.

Tau is a microtubule-associated protein which is regulated by phosphorylation. Highly phosphorylated tau does not bind microtubules and is the main component of the paired helical filaments seen in Alzheimer's and related neurodegenerative diseases. Recent reports suggested that patterns of tau phosphorylation changed following ischemia and/or reperfusion in vivo. We used an in vitro model employing rat and human neocortical slices to investigate changes in tau phosphorylation which accompany oxygen and glucose deprivation. Western blotting with polyclonal and phosphorylation-sensitive Tau-1 monoclonal antisera was used to monitor changes in tau which accompanied conditions of oxygen and glucose deprivation and reestablishment of these nutrients. In vitro hypoglycemia/hypoxia caused tau to undergo significant dephosphorylation in both rat and human neocortical slices after 30 and 60 min of deprivation. This dephosphorylation was confirmed using immunoprecipitation experiments after radiolabeling tau and other proteins with 32Pi. Okadaic acid, a phosphatase inhibitor, was able to prevent tau dephosphorylation in both control and ischemic slices. Lubeluzole, a benzothiazole derivative with in vivo neuroprotective activity, did not significantly alter patterns of tau phosphorylation. Restoration of oxygen and glucose following varied periods of in vitro hypoxia/hypoglycemia (15-60 min) led to an apparent recovery in phosphorylated tau. These data suggest that tau undergoes a rapid, but reversible dephosphorylation following brief periods of in vitro hypoxia/hypoglycemia in brain slices and that changes in tau phosphorylation help determine the extent of recovery following oxygen and glucose deprivation.

Thrombocytopenia following timber rattlesnake envenomation.

STUDY OBJECTIVE: To better characterize timer rattlesnake venom--induced thrombocytopenia and coagulopathy and the response to therapy with Antivenin (Crotalidae) Polyvalent. METHODS: We conducted a retrospective multicenter review of timber rattlesnake envenomation. RESULTS: We reviewed 18 cases at two institutions. Restoration of normal prothrombin time and partial thromboplastin time was achieved in all cases with antivenom therapy. In contrast, complete reversal of thrombocytopenia was not achieved, despite antivenom therapy. CONCLUSION: Antivenom (Crotalidae) Polyvalent was less effective in reversing thrombocytopenia than coagulopathy after timber rattlesnake envenomation, suggesting that a component of timber rattlesnake venom persists in the blood despite antivenom therapy. Persistent thrombocytopenia may be due to a venom factor that the antivenom does not neutralize or to inadequate dosing of antivenom. Prompt reversal of thrombocytopenia following treatment of timber rattlesnake envenomation with this antivenom appears unlikely.

Pulmonary toxicity following exposure to an aerosolized leather protector.

BACKGROUND: An aerosol spray for leather protection was reformulated to remove trichloroethane. The new formulation contained isobutane, n-heptane, ethyl acetate and fluoroaliphatics. RETROSPECTIVE REVIEW: Thirty-nine patients reported symptoms to the regional poison center. Respiratory symptoms developed within hours of exposure. Most symptoms resolved within two days. Abnormal pulmonary function tests, including obstructive disease or diminished diffusing capacity, were demonstrated in three of the four tested patients. CONCLUSIONS: The mechanism for the pulmonary toxicity has not been determined.

Attending supervision of nonemergency medicine residents in a university hospital ED.

There have been a limited number of studies assessing the impact of attending physician supervision of residents in the emergency department (ED). The objective of this study is to describe the changes in patient care when attending emergency physicians (AEPs) supervise nonemergency medicine residents in a university hospital ED. This was a prospective study including 1,000 patients, 32 second- and third-year nonemergency medicine residents and eight AEPs. The AEPs classified changes in care for each case as major, minor, or none, according to a 40-item data sheet list. There were 153 major changes and 353 minor changes by the AEP. The most common major changes were ordering laboratory or x-ray tests that showed a clinically significant abnormality, and eliciting important physical exam findings. Potentially limb- or life-threatening errors were averted by the AEP in 17 patients. Supervision of nonemergency medicine residents in the ED resulted in frequent and clinically important changes in patient care.

Reversal of toxicity using avidin-based hemoperfusion: a model system in rats using biotinylated melittin.

The high-affinity interaction between avidin and biotin (Kd = 10(-15)M) can be exploited to develop specific protocols for retrieval of biotinylated drugs and toxicants from biological fluids. Melittin, the main toxic component of bee venom, was biotinylated and used as a model toxicant to determine whether avidin-based extracorporeal hemoperfusion could remove biotinylated melittin and thus alter the severity of the toxic response in rats. Melittin was biotinylated using N-hydroxysuccinimide-long-chain biotin. Biotinylated melittin produced 100% lethality in rats by 120 min following four sequential intravenous injections of 1.7 mg/kg biotinylated melittin (0, 5, 20, and 35 min). An avidin hemoperfusion column was constructed (10 mg avidin/1 ml gel) and connected via the femoral vasculature to rats intoxicated with biotinylated melittin. Controls rats were hemoperfused using avidin columns blocked with d-biotin. None of the 6 rats hemoperfused using the biotin-blocked avidin column control survived, whereas 5 of 9 of the experimental rats survived to 120 min. The difference between the two survival rates was statistically significant (p < 0.0048). Thus, avidin-based hemoperfusion improved survival following biotinylated melittin toxicity and strengthens the concept that avidin-based hemoperfusion can reverse the toxicity of biotinylated toxicants.

Cimetidine as adjunctive treatment for acetaminophen overdose.

The aim of this study was to determine if cimetidine in addition to N-acetylcysteine and standard supportive care provide additional hepatoprotection following acute acetaminophen poisoning. It was designed as a prospective study with alternate month treatment protocol, and the work was carried out at a regional certified poison information centre. For a 2-year period, consultations received by the Rocky Mountain Poison Center involving acute acetaminophen overdose patients with a serum level above the nomogram line, but who would not receive N-acetylcystine therapy until at least 8 h postingestion, were prospectively evaluated for adjunctive treatment with cimetidine. All patients received standard supportive therapy and N-acetylcysteine treatment. During odd numbered months, cimetidine 300 mg was administered intravenously every 6 h for the duration of N-acetylcysteine therapy. Forty-one cimetidine treated patients were compared to 66 patients in the control group. The peak measured AST levels (+/- s.e.) were 1259+/-330 and 1301+/-451 for the control and cimetidine treatment groups, respectively (P = 0.94). Fourteen of 64 patients (21%) in the control group and 8/41 patients (20%) in the cimetidine group developed an AST > 1000 IUL-1. There were no statistical differences between the cimetidine-treated and control groups when classified by AST < 100 IUL-1, 100-1000 IUL-1, or > 1000 IUL-1. The addition of cimetidine therapy to standard N-acetylcysteine treatment did not provide additional hepatoprotection in acutely acetaminophen poisoned patients when treatment was started later than 8 h post overdose.(ABSTRACT TRUNCATED AT 250 WORDS)

Chinese herbal medicine induced acute renal failure.

A patient with acute interstitial nephritis secondary to ingestion of a Chinese herbal medicine adulterated with mefenamic acid is presented. Following hemodialysis and cessation of the medication the patient's renal function returned to normal.

A case report of venlafaxine toxicity.

Venlafaxine hydrochloride is a novel bicyclic antidepressant which inhibits the reuptake of serotonin, norepinephrine and, to a lesser extent, dopamine. A 41-year-old female ingested 4.5 g venlafaxine, 500 mg diphenhydramine, 50 mg thiothixene and subsequently experienced severe central nervous system depression requiring intubation. She also developed elevated systolic and diastolic blood pressures and sinus tachycardia. The patient was decontaminated with gastric lavage and activated charcoal. She regained consciousness within a few hours and was extubated nine hours after ingestion. This case demonstrates that severe central nervous system depression may follow venlafaxine overdose.

Enhanced elimination of biotinylated antibodies by avidin-based hemoperfusion in rats.

We designed a hemoperfusion system using immobilized avidin for selective removal of biotinylated therapeutic antibodies from rats. Two prototype therapeutic antibodies, ovine antidigoxin Fab fragment and murine monoclonal 8A1 against Escherichia coli J5 lipopolysaccharide endotoxin, were biotinylated using biotin-long-chain-N-hydroxysuccinimide ester. Biotinylated antibodies were administered i.v. to anesthetized rats which were instrumented for measurement of cardiovascular parameters and connected to avidin-hemoperfusion devices. By using several different protocols of antibody administration and hemoperfusion, we found that the half-lives and areas under the time vs. concentration curves of biotinylated antibodies were reduced significantly after passage over immobilized avidin. Avidin hemoperfusion was not associated with adverse changes in blood pressure, heart rate or excess hemolysis. These data suggest that avidin hemoperfusion affords a means for selective removal of biotinylated ligands from serum, and that other therapeutic and potentially toxic compounds could be removed in this manner.

Comparison of topical magnesium and calcium treatment for dermal hydrofluoric acid burns.

STUDY OBJECTIVE: To compare topical preparations of magnesium and calcium in the treatment of dermal hydrofluoric acid burns. DESIGN: A randomized, blinded, controlled animal model study. SETTING: Animal care facility. TYPE OF PARTICIPANTS: New Zealand rabbits. INTERVENTIONS: Each rabbit was burned with hydrofluoric acid at four sites along the thoracolumbar spine. Equimolar amounts of calcium gluconate, magnesium gluconate, and a magnesium hydroxide antacid were added into a lubricating jelly. The jelly alone was a control preparation. After a water rinse, the burns were massaged with the gels for 1 minute five times; at 4 and 20 minutes and at 1, 4, and 24 hours. Each rabbit served as its own control by receiving all four treatments. MEASUREMENTS AND MAIN RESULTS: Burn diameter and burn surface area diminished over time, but there were no statistically significantly differences among the treatments. Burn ranking and burn rating of severity also did not demonstrate differences. The histologic analysis of the burns, however, demonstrated that calcium gluconate-treated burns were less severe and more superficial than the control and magnesium gluconate-treated burns; the magnesium hydroxide antacid-treated burns were not statistically different compared to the calcium gluconate-treated burns. CONCLUSION: Topical calcium gluconate is an efficacious treatment for dermal hydrofluoric acid burns. Further research is needed to determine the role of magnesium-containing antacids in the treatment of hydrofluoric acid burns.

Respiratory failure following adenosine administration.

Adenosine is frequently administered to convert the rhythm of patients with paroxysmal supraventricular tachycardia to sinus rhythm. Adverse reactions are common after its administration, but these have been short-lived because adenosine has a half-life of less than 10 seconds. This report describes a 54-year-old male patient with chronic obstructive pulmonary disease who presented with paroxysmal supraventricular tachycardia at 200 beats/min. A 12-mg bolus injection of adenosine aggravated mild bronchospasm and produced respiratory failure. The patient subsequently required ventilatory support for 9 days. The presence of bronchoconstriction should be considered as a possible contraindication to the administration of intravenous adenosine.