New evidence for oxetorone toxicity.

CONTEXT: Oxetorone is a serotonin antagonist antimigraine drug but literature relating to its toxic properties is poor. The aim of this study is to describe the toxicological profile of oxetorone and to highlight any relationship between clinical and analytical findings. MATERIALS AND METHODS: This is a retrospective and observational study of cases exposure to oxetorone, reported to the Angers Poison and Toxicovigilance Centre between January 2002 and May 2016. Severity was assessed using the Poisoning Severity Score (PSS). Cases where data were incomplete, where oxetorone was deemed not accountable, where clinical signs were linked mainly to a co-ingested drug or where the plasma concentration of oxetorone was negative were all excluded. RESULTS: We included 43 cases of exposure, 31 of whom were suicide attempts. The assumed ingested dose (60-3600 mg) was correlated to severity (rs = 0.45, p = 0.01). Symptoms of moderate severity (PSS2 = drowsiness, hypertonia, myosis, convulsions, arterial hypotension, QRS widening, QTc prolongation) were observed following ingestion of more than 600 mg of oxetorone (median dose =1200 mg) and severe symptoms (PSS 3 = coma, convulsions, QTc prolongation, QRS widening, ventricular tachycardia, arterial hypotension, cardiogenic shock) were observed starting from 1800 mg (median dose =2700 mg). In four cases, a secondary worsening of symptoms 10-48 h following ingestion was observed. Plasma oxetorone was measured in four patients. Severe symptoms were observed in the event of a concentration over 0.3 mg/L and the highest measured serum oxetorone level was delayed by 20-48 h following the ingestion for two cases. CONCLUSIONS: Several clinical and paraclinical parameters strongly point towards membrane-stabilising properties of the molecule and the risk of a delayed occurrence of symptoms or a secondary worsening.

Review of the epidemiology and characteristics of intentional cyproheptadine overdose in Hong Kong.

OBJECTIVES: To identify the epidemiological characteristics and clinical outcome in patients who intentionally ingested cyproheptadine or cyproheptadine-containing sleeping pills, and to investigate any association between dose ingested and reported adverse effects. METHOD: A retrospective study was performed based on data from the Hong Kong Poison Information Centre from July 2005 to December 2009. Fifty-seven eligible patients were recruited. Patients' epidemiological data, type and dose of cyproheptadine or cyproheptadine-containing sleeping pills ingested, symptoms, clinical outcome, and length of stay in hospital were reviewed. RESULTS: The majority of patient with intentional overdose had no (42.1%) or mild (40.4%) sedative symptoms. Some 17% of patients developed anticholinergic symptoms, such as delirium, agitation, disorientation, and hallucination. The mean dose ingested was found to be significantly higher in patients who presented with delirium (188.6 mg) than those who were asymptomatic (49.8 mg) (p < 0.001). The time of symptom onset in all symptomatic patients was less than 6 h. CONCLUSIONS: The majority of patients with intentional cyproheptadine overdose had no or mild symptoms only. Patients who have ingested a significant amount of cyproheptadine are more prone to develop delirium. Patients who remain asymptomatic 6 h after exposure are unlikely to develop serious symptoms.

Dolasetron overdose resulting in prolonged QTc interval and severe hypotension: a case report and literature review.

Dolasetron (Anzemet) overdose is uncommon, and, to our knowledge, this is the only case report of an intentional overdose. Dolasetron (dolasetron mesylate) is a selective 5-hydroxytryptamine 3 antagonist derived from pseudopelletierine, and is used in the prevention and treatment of nausea and vomiting. Transient and asymptomatic ECG changes, including QRS widening and PR and QTc prolongation, have been reported in therapeutic doses. The case of a 21-year-old woman who presented after an intentional overdose of 10x200 mg dolasetron tablets resulting in prolongation of the QTc interval and severe hypotension is reported here. Management of hypotension included intravenous fluid resuscitation and norepinephrine infusion with invasive monitoring in a high dependency unit. Sodium cardiac channel block contributes to cardiotoxicity observed in dolasetron overdose. Sodium bicarbonate was used in an attempt to reduce cardiac sodium channel block, although we observed no apparent benefit. As dolasetron becomes more commonly used in the outpatient setting, both doctors and patients need to be aware of the dangers of dolasetron in toxic doses. The pharmacology and toxicology of dolasetron are discussed.

Teaching application of clinical pharmacology skills using unusual observations from clozapine overdoses.

Massive drug overdoses provide a unique opportunity to observe human pharmacokinetic data not otherwise ethically available. They can also provide practical examples for teaching thoughtful application of the principles of clinical pharmacology. Following a case of clozapine overdose in which onset of toxicity was delayed by 72 hours, a probable explanation was found in an exploration of three cases with unusual concentration-time profiles and revealed unexpected implications for the management of clozapine overdoses. The authors systematically addressed the possible mechanisms proposed in the literature for an unusual plateau in concentrations observed in three clozapine overdoses. The effects that the most commonly suggested explanations (i.e., delayed absorption and saturated or impaired metabolism) would have on both clozapine and norclozapine concentrations were then modeled using the data available from those three cases to provide an objective illustration for comparison. This exercise was then used as a teaching seminar, leading students through the steps required to reach a logical explanation for the observed delayed toxicity and to consider the implications for therapy. Delayed absorption best predicted the sustained serum clozapine and norclozapine concentrations observed in three cases, and modeling suggests that much of the drug remains in the gut, available for absorption for days following an overdose. As a seminar, the exercise provides students with a practical example of the value of systematically ruling out possible explanations by considering what effects various pharmacokinetic alterations would have on observed data. Absorption following massive clozapine overdose appears fundamentally different from that with conventional dosing. This suggests a potential for delayed or prolonged toxicity, extending well beyond the time frame predicted by its half-life, unless aggressive and sustained efforts are applied to remove clozapine from the gut. Data from drug overdoses provide opportunities to explore unusual aspects of pharmacokinetics, better understand future overdoses of the same agent, and present excellent material for teaching. A seminar illustrating the role that thoughtful application of pharmacologic principles had in addressing this case is now used to introduce the clinical aspects of pharmacology to students at our institutions.

Successful use of cardiac allograft from serotonin antagonist intoxication.

BACKGROUND: Compromised organ donors are generally not accepted for heart transplantation (HT) despite the increasing number of critically ill patients on the waiting lists. By extending the donor criteria to include certain cases of intoxication, the organ shortage may be reduced. METHODS: The case of a successful orthotopic HT with an allograft from a donor poisoned by antidepressant overdose is presented. RESULTS: Early graft function was satisfactory with anteroseptal dyskinesis and an ejection fraction of 75% on echocardiography. The cardiac allograft recipient suffered some postoperative complications including gastrointestinal problems. The following period was up to now uneventful. Discharge from the intensive care unit was after 4 days. In-hospital stay was prolonged at 26 days. CONCLUSIONS: Because of limited myocardial toxicity, donor hearts from certain victims of antidepressant intoxication may be safely used for HT. Existing cardiac organ donor criteria must be reevaluated to maximise the available organ pool.

Akinetopsia from nefazodone toxicity.

PURPOSE: To investigate two cases of selective impairment of motion perception (akinetopsia) induced by toxicity from the antidepressant nefazodone, a new drug that blocks serotonin reuptake and antagonizes 5-HT2 receptors. METHODS: Case reports. RESULTS: A 47-year-old man receiving nefazodone (Serzone; Bristol-Meyers Squibb, New York, N.Y.) (100 mg twice daily), reported a bizarre derangement of motion perception. Moving objects were followed by a trail of multiple "freeze-frame" images, which dissipated promptly when motion ceased. A 48-year-old woman receiving nefazodone (400 mg daily at bedtime) reported a similar phenomenon, with visual trails following moving objects. In both patients, vision returned to normal after the dosage of nefazodone was reduced or eliminated. CONCLUSIONS: Nefazodone toxicity can result in akinetopsia, characterized by the inability to perceive motion in a normal, smooth fashion; persistence of multiple, strobelike images; and visual trails behind moving objects. In this rare syndrome, stationary elements are perceived normally, indicating that nefazodone causes selective impairment of pathways involved in motion processing in the visual system.

A cyproheptadine fatality.

A 28-year-old man was found dead by his girlfriend. No anatomic cause of death was identified at autopsy. The heart-blood ethanol concentration was 0.09 g/dL. Comprehensive testing for abused and therapeutic drugs in the blood and urine identified cyproheptadine, a serotonin and histamine antagonist. This was one of the medications prescribed for the girlfriend, who admitted that several tablets were missing from the vial. The heart blood contained 0.46 mg/L of cyproheptadine. A review of the literature indicated that only trace amounts of parent drug are identified in the blood following therapeutic use of cyproheptadine. Therefore, the medical examiner concluded that the cause of death in this case was ethanol and cyproheptadine intoxication.

Acute risperidone overdose.

Risperidone (Risperdal) is a recently released novel antipsychotic medication. It is different from the conventional neuroleptics, such as haloperidol, as it has both serotinergic and dopaminergic activity. It has a more tolerable side-effect profile compared with other antipsychotic medications. We review the literature regarding the side effects of risperidone use, describe a case of overdose with risperidone, and discuss the clinical sequelae and management of such an overdose.