Accidental apixaban intoxication in a 23-month-old child: a case report.

BACKGROUND: Direct oral anticoagulants, such as apixaban, are increasingly used in everyday practice in order to treat or prevent thromboembolic diseases. To date, there is no available data about apixaban pharmacokinetics in children, and no intoxication has previously been described. CASE PRESENTATION: A 23-month-old boy, with no medical history, was admitted to the emergency department 2 h after accidentally ingesting 40 mg apixaban and 0.75 mg digoxin. No adverse event was observed. Digoxin trough level was within therapeutic values. Apixaban blood concentration increased up to 1712 µg/L at H + 6 (1000-2750 µg/L using 2-5 mg/kg of apixaban in adults). The terminal half-life was 8.2 h (6-15 h in adults). The rapid elimination may explain the absence of bleeding despite high concentrations. CONCLUSIONS: Despite an important intake of apixaban and a real disturbance in routine coagulation assays, no clinical sign of bleeding was observed, perhaps due to wide therapeutic range of apixaban. It may also be explained by its rapid elimination. Considering the high Cmax and a possible enteroenteric recycling, the use of activated charcoal should be considered in such situations in order to prevent eventual bleeding.

Self-poisoning with 60 tablets of Apixaban, a pharmacokinetics case report.

A 67-year-old man was admitted to the emergency department about 5 h after deliberate self-poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 µg l-1 of Apixaban. The Cmax was observed 17 h after the intake (3654 µg l-1 ), about four times the classical Tmax value (median [range]: 4 h [2-4]). The Apixaban was then eliminated following a first order elimination with a calculated half-life of 10.8 h. The anti-Xa activity seems to be linearly related to concentration up to 4000 µg l-1 . This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake.

123I-FP-CIT SPECT and MRI Findings in a Patient With Parkinsonism After Fenpyroximate Intoxication.

Fenpyroximate is a widely used acaricide. Its main action is to inhibit the mitochondrial respiratory chain. Chronic exposure to fenpyroximate is associated with dopaminergic cell loss and parkinsonism; however, to date, there has not been a reported case of parkinsonism as a result of acute fenpyroximate intoxication. Here, we report a 58-year-old man who developed parkinsonism after deliberate fenpyroximate intoxication, but with normal presynaptic I-Ioflupane SPECT image.

An unusual case of insecticide poisoning presenting as acute kidney injury.

Poisoning due to insecticides such as organophosphorus and super vasmol presenting as acute kidney injury (AKI) is well-reported. Poisoning due to fipronil (phenylpyrazole) is known to present with mild neurological and dermatological complaints. However, fipronil poisoning presenting as AKI and hepatic dysfunction is not known. Herein, we are presenting a case of fipronil poisoning presenting with severe AKI.

The X factor: Lack of bleeding after an acute apixaban overdose.

We present an acute apixaban overdose without reported coingestants; it is the first such case report associated with multiple serum drug levels to assist in determining overdose kinetics. A 62 year old female presented to an emergency department (ED) 2 hours after ingesting sixty 5 mg tablets (5mg/kg) of her spouse's apixaban medication. She denied coingestants, and did not take her prescribed medications that day. Her vital signs were normal and she denied symptoms. Chemistry and hematology labs were unremarkable. Plasma apixaban concentrations were 2765.6 ng/ml at 14 hours post ingestion with a non-linear half life. There was no utilization of blood products or factor replacement. There was never any bleeding, and her hemoglobin did not decrease. This case demonstrates that a single ingestion of apixaban can occur without any complications occurring.

Anti-Xa activity in apixaban overdose: a case report.

INTRODUCTION: Apixaban is a novel oral anticoagulation agent that exerts its effect through direct factor Xa inhibition. We present a case of multi-drug overdose including apixaban with associated apixaban concentrations. CASE: A 53 year-old man presented to our metropolitan hospital following a deliberate self-poisoning with 200 mg apixaban, 35 mg ramipril, 105 mg bisoprolol, 280 mg atorvastatin, 6 mg colchicine, 37.4 mg magnesium, 4 × 500 mg paracetamol/9.5 mg codeine/5 mg phenylephrine and alcohol. He developed hypotension that was treated with noradrenaline. His initial and peak apixaban concentration was 1022.6 ng/ml and was associated with only minor bleeding from his femoral central line insertion site, which improved with local compression. Vitamin K 10 mg (at 9 h post-ingestion) and Prothrombinex-VF 2000 units (at 13 h post-ingestion) were also administered without any observed effect on coagulation studies. Apixaban elimination appeared to display first-order kinetics with an elimination half-life of 7.4 h. His plasma apixaban concentration was within the therapeutic dose range 10 h post-ingestion and he recovered uneventfully. CONCLUSION: A case of apixaban overdose with associated apixaban concentrations is presented. There was rapid resolution of anticoagulation with no demonstrable benefit of currently available clotting factor replacement.

An Observational Study of the Factor Xa Inhibitors Rivaroxaban and Apixaban as Reported to Eight Poison Centers.

STUDY OBJECTIVE: Rivaroxaban and apixaban are part of a new group of oral anticoagulants targeting factor Xa and approved by the Food and Drug Administration in 2011 and 2012. These oral anticoagulants are administered at fixed daily doses, without the need for laboratory-guided adjustments. There are limited data available on supratherapeutic doses or overdose of the oral Xa inhibitors. This study characterizes the clinical effect in patients exposed to rivaroxaban and apixaban. METHODS: A retrospective study collected data from 8 regional poison centers covering 9 states. Cases were initially identified by a search of the poison centers' databases for case mentions involving a human exposure to Xarelto, rivaroxaban, Eliquis, or apixaban. Inclusion criteria included single-substance exposure. Exclusion criteria were animal exposure, polysubstance exposure, or information call. Data for the study were collected by individual chart review, including case narratives, and compiled into a single data set. RESULTS: There were 223 patients: 124 (56%) were female patients, mean age was 60 years, and 20 were children younger than 12 years (9%). One hundred ninety-eight patients ingested rivaroxaban (89%) and 25 ingested apixaban (11%). Dose was reported in 182 rivaroxaban patients, with a mean dose of 64.5 mg (range 15 to 1,200 mg), and in 21 apixaban patients, with a mean dose of 9.6 mg (range 2.5 to 20 mg). For rivaroxaban, prothrombin time was measured in 49 patients (25%) and elevated in 7; partial thromboplastin time, measured in 49 (25%) and elevated in 5; and international normalized ratio, measured in 61 (31%) and elevated in 13. For apixaban, prothrombin time was measured in 6 patients (24%) and elevated in none; partial thromboplastin time, measure in 6 (24%) and elevated in none; and international normalized ratio, measured in 5 patients (20%) and elevated in none. Bleeding was reported in 15 patients (7%): 11 rivaroxaban and 4 apixaban. The site of bleeding was gastrointestinal (8), oral (2), nose (1), bruising (1), urine (1), and subdural (1). The subdural bleeding occurred after fall and head injury. All cases with bleeding involved long-term ingestions. Coagulation test results were normal in most patients with bleeding: prothrombin time 5 of 6 (83%), partial thromboplastin time 5 of 6 (83%), and international normalized ratio 5 of 9 (55%). Blood products were used in 7 rivaroxaban patients (1 suicide) and 3 apixaban patients. No bleeding or altered coagulation test results occurred in children, which all involved a one-time ingestion. All 12 suicide attempts involved rivaroxaban: altered coagulation test results occurred for 5 patients (42%), no bleeding occurred in any suicide attempt patient, 1 patient was treated with fresh frozen plasma (international normalized ratio 12.47), and dose by patient history did not predict risk of altered coagulation or bleeding. Two rivaroxaban patients experienced elevation of hepatic transaminase levels greater than 1,000 U/L. CONCLUSION: Bleeding after Xa inhibitor ingestion as a single agent is uncommon. Prothrombin time, partial thromboplastin time, or international normalized ratio may be elevated in a minority of cases but appears unreliable to measure risk of bleeding. Massive acute ingestion in suicide attempt may result in significant anticoagulation. Single exploratory ingestion by children was not associated with toxicity.

A case of suspected brain death within 24 hours after ingestion of tolfenpyrad and an organophosphorus insecticide.

A 55-year-old man attempted suicide by ingesting tolfenpyrad, emulsion formulation insecticide, and organophosphorus pesticide emulsion, each three gulps. He was found lying on the floor and his family called an ambulance an hour later from ingesting. On arrival at our hospital, his Glasgow Coma Scale score was 14 (E3V5M6), his vital signs were stable, and he was able to converse. Activated charcoal and laxatives were injected through a gastric tube, and continuous administration of pralidoxime iodide was started. After hospitalization, he complained of nausea and his consciousness level decreased immediately. Endotracheal intubation was performed, and mechanical ventilation management was started Subsequently, he experienced bradycardia leading to transient cardiopulmonary arrest. Return of spontaneous circulation was achieved after one cycle of cardiopulmonary resuscitation. While blood pressure was stabilized with continuous catecholamine administration, blood gas analysis revealed severe lactic acidosis, which gradually aggravated. Electroencephalography performed 16.5 hours after the suicide attempt showed flat waves, and he wa's suspected brain dead. He died about 37 hours after the suicide attempt.

Acute fatal poisoning with Tolfenpyrad.

The authors present a fatal case of poisoning with Tolfenpyrad (TFP), a pesticide first approved in Japan in 2002. A man in his fifties was found dead in the supine position at his son's home and the small towel with a smell of naphthalene was found nearby. Forensic autopsy was unremarkable, except for a very small amount of light pink fluid in the stomach, with naphthalene odour. The toxicological analyses revealed the presence of TFP and its major metabolite PTCA (4-[4-[(4-chloro-3-ethyl-1-methylpyrazol-5-yl)carbonylaminomethyl]phenoxy]benzoic acid), together with naphthalene and methyl naphthalenes in the post-mortem sample, with liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) respectively. The plasma concentrations of each substance were quantified as 1.97 µg/ml (TFP), 2.88 µg/ml (PTCA), 1.70 µg/ml (naphthalene), 0.67 µg/ml (1-methyl naphthalene) and 1.44 µg/ml (2-methyl naphthalene). According to these results together with autopsy findings, the cause of his death was determined to be acute Tolfenpyrad poisoning. This is the first case report of fatal poisoning attributable to an intake of TFP product.

A case of near-fatal fenpyroximate intoxication: the role of percutaneous cardiopulmonary support and therapeutic hypothermia.

INTRODUCTION: Fenpyroximate is a potent inhibitor of the mitochondrial proton-translocating NADH-quinone oxidoreductase (complex I). Although it is widely used as an acaricide, data on the acute toxicity of fenpyroximate in humans are very limited. CASE DETAIL: A 44-year-old woman was brought to our hospital with a reduced level of consciousness, hypotension, and severe lactic acidosis after deliberate ingestion of 5% fenpyroximate solution. The acidosis progressively deteriorated despite maximal supportive treatment, and cardiac arrest refractory to standard cardiopulmonary resuscitation developed. The patient was successfully resuscitated with percutaneous cardiopulmonary support, therapeutic hypothermia, and intravenous acetylcysteine. Blood gases of simultaneously obtained arterial and central venous blood revealed decreased arteriovenous oxygen difference. DISCUSSION: The present case, along with previous cases of fatal complex I inhibitor poisoning, indicates that impaired oxygen utilization at the tissue level is the major mechanism underlying the fatality of this condition. Percutaneous cardiopulmonary support may help restore vital organ perfusion by increasing oxygen delivery even in the presence of decreased oxygen consumption, thereby allowing additional time for recovery and drug metabolism. Therapeutic hypothermia also may be beneficial in treating severe complex I inhibitor poisoning, since hypothermia itself attenuates oxidative processes and decreases the metabolic rate.

Analysis of tolfenpyrad and its metabolites in plasma in a tolfenpyrad poisoning case.

Tolfenpyrad (TFP) is a pesticide that was first approved in 2002 in Japan under the trade name of Hachi-hachi. Analyses of TFP and its major metabolite, 4-[4-[(4-chloro-3-ethyl-1-methylpyrazol-5-yl)carbonylaminomethyl]phenoxy]benzoic acid (PTCA), in plasma obtained from a cadaver suspected to have died of TFP poisoning, were conducted by liquid chromatography-mass spectrometry. The existence of TFP and PTCA was confirmed by scan mode and quantitative analysis was performed by selected ion monitoring mode. Calibration curves showed good linearity over the range of 0.1-4 and 0.25-4 µg/mL, and concentrations were estimated to be 1.97 ± 0.02 and 2.88 ± 0.04 µg/mL for TFP and PTCA, respectively. The plasma extract was further examined to find other metabolites using quadrupole time-of-flight MS, and the results revealed three more metabolites, which were suggested to be hydroxy-TFP, dehydro-TFP and hydroxy-PTCA. Plausible metabolic pathways of TFP in humans are: (i) oxidation of the methyl group on the benzene ring, and (ii) hydroxylation followed by dehydration at the ethyl group on the pyrazole ring.

Acute illnesses associated with exposure to fipronil--surveillance data from 11 states in the United States, 2001-2007.

INTRODUCTION: Fipronil is a broad-spectrum phenylpyrazole insecticide widely used to control residential pests and is also commonly used for flea and tick treatment on pets. It is a relatively new insecticide and few human toxicity data exist on fipronil. OBJECTIVE: This paper describes the magnitude and characteristics of acute illnesses associated with fipronil exposure. METHODS: Illness cases associated with exposure to fipronil-containing products from 2001 to 2007 were identified from the Sentinel Event Notification System for Occupational Risks (SENSOR)-Pesticides Program and the California Department of Pesticide Regulation. RESULTS: A total of 103 cases were identified in 11 states. Annual case counts increased from 5 in 2001 to 30 in 2007. Of the cases, 55% were female, the median age was 37 years, and 11% were <15 years old. The majority (76%) had exposure in a private residence, 37% involved the use of pet-care products, and 26% had work-related exposures. Most cases (89%) had mild, temporary health effects. Neurological symptoms (50%) such as headache, dizziness, and paresthesia were the most common, followed by ocular (44%), gastrointestinal (28%), respiratory (27%), and dermal (21%) symptoms/signs. Exposures usually occurred from inadvertent spray/splash/spill of products or inadequate ventilation of the treated area before re-entry. CONCLUSIONS: Our findings indicate that exposure to fipronil can pose a risk for mild, temporary health effects in various body systems. Precautionary actions should be reinforced to prevent fipronil exposure to product users.

Cases of pediatric ingestion of celecoxib reported to Texas poison control centers in 2000-2007.

Little data exist regarding pediatric celecoxib ingestions. This study described the pattern of pediatric celecoxib ingestions reported to poison control centers. Cases were isolated celecoxib ingestions by patients aged 0-5 years during 2000-2007 reported to Texas poison control centers. The distribution of cases was described with respect to demographic and clinical factors. Of the 177 total patients, dose ingested in milligrams was reported for 92 patients. Mean reported dose was 305.5 mg (range 10-2300 mg). Of those 92 cases, distribution by management site was 89.1% on site, 6.5% already at/en route to healthcare facility and 4.3% referred to healthcare facility. Final medical outcome was no effect for 95.7% cases and minor effect for 4.3% cases. Specific clinical effects reported (in only one case each) were rash, abdominal pain, vomiting, agitation/irritability, and drowsiness. All of the pediatric celecoxib ingestions reported to Texas poison control centers resulted in no or minor effect.

Acute pesticide poisoning associated with pyraclostrobin fungicide--Iowa, 2007.

Pyraclostrobin is an agricultural pesticide product used to kill fungi (e.g., blights, mildews, molds, and rusts). Hazards to humans from pyraclostrobin exposure include eye injury and skin irritation. In July 2007, the Iowa Department of Public Health (IDPH) received reports of five events involving pyraclostrobin that sickened 33 persons, including 27 migrant workers who were exposed in a single incident during aerial application (i.e., crop dusting). This report describes those five events and provides recommendations for preventing additional illnesses associated with exposure to pyraclostrobin.

[An experimental study on acute poisoning by fipronil in mice and its pharmaceutical therapy].

OBJECTIVE: To investigate the toxicity of fipronil in mice and the therapeutic effects of diazepam and phenobarbital sodium. METHODS: Mice were administered by gastric tube with fipronil at six doses and their behavioral changes, pathological changes in their major viscera under light and electron microscopy and deaths were observed after acute poisoning. Distribution and quantity of nerve cells positive in glutamic acid (Glu) or gamma-aminobutyric acid (gamma-GABA) in the brain of mice were detected by immunohistochemical methods and micro-image analysis. The time of death time and survival rate were observed and compared between the varied groups of mice injected intraperitoneally with diazepam and phenobarbital sodium, respectively, 0.5 h after poisoning by fipronil at dose of 90 mg/kg. RESULTS: All the mice acutely poisoned by fipronil at varied doses showed some exciting symptoms in the central nervous system (CNS), including convulsion. Nuclear membrane space slightly expanded, neuroglia cells vacuolized and nerve fiber demyelinated under electron microscopy. The number and area of cells positive in Glu in the cerebral cortex of mice acutely poisoned by fipronil increased significantly, as compared to those in control mice. There was no significant difference in the number and area of cells positive in gamma-GABA in the hippocampal CA(1) region between poisoned and normal control groups. Survival rate of mice treated with diazepam or phenobarbital sodium was 58 percent. CONCLUSION: Mice with acute poisoning by fipronil appeared exciting symptoms in CNS, leading to damage in its nerve cells. Immunohistochemical techniques showed the damage could be related with the over-expression of glutamate transmitter in CNS. Early use of diazepam or phenobarbital sodium in treatment for acutely poisoned mice by fipronil could get better therapeutic efficacy.

Celecoxib exposures reported to Texas poison control centers from 1999 to 2004.

Concerns have been raised about the safety of celecoxib. This study described the pattern of exposures involving only celecoxib (isolated exposures) reported to Texas poison control centers from 1999 to 2004. The mean dose was 701 mg. The patient age distribution was < or = 5 years (48%), 6-19 years (8%), and > or = 20 years (44%). In 78% of cases, exposure was unintentional. Of the exposures, 74% were managed outside of health care facilities. The final medical outcome was classified as no effect for 82% of the cases, and minor effects for 12% of the cases. Adverse clinical effects were listed for 5% of the patients, the most frequently reported being rash (3%), drowsiness (3%), pruritus (2%), and vomiting (2%). The most frequently listed treatment was decontamination by dilution (43%) or food (32%). The majority of isolated celecoxib exposures could be managed outside of health care facilities, and the outcome was generally favorable.