[A case of myasthenia-like symptoms induced by cibenzoline overdosage].

The present patient was an 87-year-old man who had been taking cibenzoline for tachyarrhythmia. Five years after initiation of administration, he was referred to our hospital for ptosis that worsened from midday, as well as weakness of the facial and limb muscles. He tested negative for anti-acetylcholine receptor antibody but positive in the edrophonium test, suggesting that he had myasthenia gravis. He was admitted to our hospital 3 years later due to worsening symptoms of ptosis and muscle weakness. He had hypoglycemia, cardiac conduction defect, and renal dysfunction. In addition, blood concentration of cibenzoline was markedly high (1,850 ng/ml). We terminated the administration of cibenzoline, after which the patient's neurologic symptoms improved. Our findings suggest that cibenzoline toxicity must be considered in differentiating myasthenia gravis when a patient also presents with renal dysfunction.

Field evidence of bird poisonings by imidacloprid-treated seeds: a review of incidents reported by the French SAGIR network from 1995 to 2014.

The large-scale use of neonicotinoid insecticides has raised growing concerns about their potential adverse effects on farmland birds, and more generally on biodiversity. Imidacloprid, the first neonicotinoid commercialized, has been identified as posing a risk for seed-eating birds when it is used as seed treatment of some crops since the consumption of a few dressed seeds could cause mortality. But evidence of direct effects in the field is lacking. Here, we reviewed the 103 wildlife mortality incidents reported by the French SAGIR Network from 1995 to 2014, for which toxicological analyses detected imidacloprid residues. One hundred and one incidents totalling at least 734 dead animals were consistent with an agricultural use as seed treatment. Grey partridges (Perdix perdix) and "pigeons" (Columba palumbus, Columba livia and Columba oenas) were the main species found. More than 70% of incidents occurred during autumn cereal sowings. Furthermore, since there is no biomarker for diagnosing neonicotinoid poisonings, we developed a diagnostic approach to estimate the degree of certainty that these mortalities were due to imidacloprid poisoning. By this way, the probability that mortality was due to poisoning by imidacloprid-treated seeds was ranked as at least "likely" in 70% of incidents. As a result, this work provides clear evidence to risk managers that lethal effects due to the consumption by birds of imidacloprid-treated seeds regularly occur in the field. This in turn raises the question of the effectiveness of the two main factors (seed burying and imidacloprid-treated seeds avoidance) that are supposed to make the risk to birds negligible. Risk factors and the relevance of mitigation measures are discussed.

Gene-environment interaction of genome-wide association study-identified susceptibility loci and meat-cooking mutagens in the etiology of renal cell carcinoma.

BACKGROUND: Meat-cooking mutagens may be associated with renal cell carcinoma (RCC) risk. In the current study, the authors examined associations between meat-cooking mutagens, genetic susceptibility variants, and risk of RCC. METHODS: The authors used 659 newly diagnosed RCC cases and 699 healthy controls to investigate the association between dietary intake of meat-cooking mutagens and RCC. They examined whether associations varied by risk factors for RCC and genetic susceptibility variants previously identified from genome-wide association studies. Odds ratios and 95% confidence intervals were estimated using tertiles of intake of dietary polycyclic aromatic hydrocarbons/heterocyclic amines. RESULTS: Dietary intake of the mutagenic compounds 2-amino-3,8-dimethylimidazo-(4,5-f) quinoxaline (MeIQx) and 2-amino-1 methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) were found to be significantly associated with an increased risk of RCC (odds ratios across tertiles: 1.00 [referent], 1.28 [95% confidence interval, 0.94-1.74], and 1.95 [95% confidence interval, 1.43-2.66] [P for trend <.001], respectively; and 1.00 [referent], 1.41 [95% confidence interval, 1.04-1.90], and 1.54 [95% confidence interval, 1.14-2.07] [P for trend =.02], respectively). The authors observed evidence of interactions between PhIP and RCC susceptibility variants in 2 genes: inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) (rs718314; multiplicative P for interaction = .03 and additive P for interaction =.002) and endothelial PAS domain-containing protein 1 (EPAS1) (rs7579899; additive P for interaction =.06). CONCLUSIONS: The intake of meat may increase the risk of RCC through mechanisms related to the cooking compounds MeIQx and PhIP. These associations may be modified by genetic susceptibility to RCC. Further research is necessary to understand the biological mechanisms underlying these interactions.

Multi-drug intoxication fatality involving atorvastatin: A case report.

Mixed antihypertensive drug intoxication poses a significant risk for patient mortality. In tandem to antihypertensives, hypolipidemic medicines (especially statins) are often prescribed. Among their well-known adverse effects belongs rhabdomyolysis. We report a case of fatal multi-drug overdose in a 65-year-old female alcoholic. The patient was unconscious at admission. Empty blister packs indicated the abuse of 250 tablets of urapidil, 42 tablets of verapamil/trandolapril, 50 tablets of moxonidin, 80 tablets of atorvastatin and 80 tablets of diacerein. Standard measures (gastric lavage, activated charcoal, mechanical ventilation, massive doses of vasopressors, volume expansion, diuretics and alkalinization) failed to provide sufficient drug elimination and hemodynamic support and the sufferer deceased on the fourth day. Dramatic elevations of serum myoglobin (34,020 µg/L) and creatine kinase (219 µkat/L) were accompanied by rise in cardiac troponin I and creatinine. Gas chromatography revealed ethanol 1.17 g/kg (blood) and 2.81 g/kg (urine). Thin layer chromatography and gas chromatography of gastric content and urine verified verapamil, moxonidin and urapidil fragment (diacerein method was unavailable). Atorvastatin and trandolapril concentrations (LC-MS(n)) equaled 277.7 µg/L and 57.5 µg/L, resp. (serum) and 8.15 µg/L and 602.3 µg/L, resp. (urine). Histology confirmed precipitates of myoglobin with acute necrosis of proximal renal tubules in association with striated muscle rhabdomyolysis and myocardial dystrophy. Cardiogenic-distributive shock in conjunction with acute renal failure due to the combined self-poisoning with vasoactive agents and atorvastatin were determined to be this decedent's immediate cause of death. The manner of death was assigned to be suicidal.

Worker illness related to newly marketed pesticides--Douglas County, Washington, 2014.

On April 10, 2014 the Washington State Department of Agriculture (WSDA) was notified by a local newspaper of a suspected pesticide poisoning incident in Douglas County involving pesticides not previously reported in the published literature to be associated with human illness. On that same day, WSDA notified the Washington State Department of Health, which investigated this incident by conducting a site visit, reviewing medical and applicator records, and interviewing affected farmworkers, pesticide applicators, and the farmworkers' employer. In addition, on April 11, WSDA collected swab, foliage, and clothing samples and tested them for residues of pyridaben, novaluron, and triflumizole. In this incident, all 20 farmworkers working in a cherry orchard became ill from off-target drift of a pesticide mixture that was being applied to a neighboring pear orchard. Sixteen sought medical treatment for neurologic, gastrointestinal, ocular, and respiratory symptoms. This event highlights the need for greater efforts to prevent off-target drift exposures and promote awareness about the toxicity of some recently marketed pesticides. Incidents such as this could be prevented if farm managers planning pesticide applications notify their neighbors of their plans.

Intoxicación por imidazólicos en pediatría: experiencia del centro de información y asesoramiento toxicológico en niños y adolescentes / Imidazole poisoning in children: experience and poison information center consulting in children and adolescents

Introducción: los derivados imidazólicos del tipo de la nafazolina son utilizados como vasoconstrictores locales, descongestivos nasales y oftálmicos. Su utilización en niños puede ocasionar una intoxicación aguda potencialmente grave. Conocer la epidemiología de esta enfermedad, los aspectos toxicológicos y la forma de presentación clínica puede contribuir a disminuir su incidencia. Objetivos: comunicar la experiencia del Centro de Información y Asesoramiento Toxicológico (CIAT) en menores de 15 años expuestos a imidazólicos y presentar tres casos clínicos de intoxicación por nafazolina asistidos en el Servicio de Emergencia Pediátrica del Hospital Británico (HB).Material y métodos: estudio retrospectivo de las consultas telefónicas por exposición a derivados imidazólicos realizadas al CIAT desde el 1° de enero del 2010 al 31 de diciembre del 2012. Revisión de historias clínicas de tres niños intoxicados por nafazolina asistidos en el 2013 en el HB.Resultados: el CIAT registró 27 casos, edad promedio 2 años y 10 meses. El agente más frecuente fue nafazolina (n=23). La vía intranasal administrado por un familiar, sin indicación médica, y la vía oral por ingesta accidental fueron las circunstancias de exposición más frecuentes. Los tres niños asistidos en el HB se presentaron como pacientes graves. Depresión neuropsíquica, hipotermia, bradicardia, frialdad periférica e hipertensión arterial transitoria o hipotensión, fueron los síntomas predominantes.Conclusiones: el uso de imidazólicos genera riesgo de intoxicación aguda, los niños pequeños son los más afectados, a pesar de la forma típica de presentación clínica puede confundirse con otras patologías. El pediatra es fundamental en la prevención, desaconsejando formalmente su uso.

Introduction: naphazoline type imidazole derivatives are used as local vaso constrictors, nasal and ophthalmic decongestants. Potentially severe acute poisoning in children use is described. Know about the disease epidemiology, toxicological aspects and clinical presentation can contribute to reduce their incidence.Objectives: communicate the experience of the Montevideo Poison Control Center (PCC) in children under 15 years exposed to imidazole derivatives, and present 3 clinical cases of children intoxicated by naphazoline assisted in the pediatric emergency room of the British Hospital (BH). Material and methods: retrospective study of phone consultations by exposure to imidazole derivatives at Montevideo PCC from January 1st of 2010 to December 31st of 2012. Medical records review of 3 poisoned children by naphazoline assisted in 2013 in the BH.Results: Montevideo PCC registered 27 cases, with average age of 2 years and 10 months. Naphazoline was the most frequent agent involved (n = 23). Intranasal route administered by a family member without medical indication, and non-intentional ingestion were the most frequent circumstances of exposure. The three children assisted in the BH emergency department were serious ill patients. Depression of consciousness, altered mental status, peripheral hypoperfusion, hypothermia, bradycardia and transient hypertension or hypotension, were the predominant symptoms. Conclusions: use of imidazolic derivatives generates great risk of acute intoxication. Young children are the most affected despite the typical form of clinical presentation can be confused with other severe diseases. The pediatrician has a critical role in preventing formally and discouraging its use.

Xylometazoline poisoning: A 40-fold nasal overdose caused by a compounding error in 3 children.

The imidazoline derivative xylometazoline, an alpha-2-adrenergic agonist, is used as non-prescription nasal preparation due to its vasoconstrictive and decongestive properties. Especially in children, an overdose can quickly cause severe central nervous system depression and cardiovascular adverse effects. In three 3-year-old boys (triplets) a xylometazoline intoxication was diagnosed by toxicological analysis. On admission to an emergency unit all three children were still unresponsive. One triplet showed respiration of 15-20 breaths/min and required oxygen support (3L/min) via face mask; his electrocardiogram revealed sinus bradycardia of 64 beats/min with supraventricular extrasystoles. However, no interventions were necessary except fluid management via intravenous lines. Eleven hours after the event, two of the triplets were awake but still not fully oriented. The third triplet woke up 20h after instillation of nose drops. Intoxication was caused by a compounding error in a pharmacy resulting in a concentration 40 times above the adequate dosage for children. In general, physicians, pharmacists and the public should be educated about the toxicity of over-the-counter preparations.

Significance of the imidazoline receptors in toxicology.

INTRODUCTION: The alpha-2 adrenergic (AA-2) receptor agonists and imidazolines are common exposures in the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS). Although the interaction between the AA-2 receptor and imidazoline receptors has been extensively studied, it largely remains unknown to health-care professionals. This review describes these interactions and mechanisms by which agonists affect physiologic responses binding to these receptors. METHODS: Papers published in English from 1960 to 2013 were retrieved from PubMed. A total of 323 original articles were identified and 173 were included. Background. The toxicity associated with clonidine (e.g., bradycardia, miosis, and hypotension) is largely assumed to be secondary to the functional overlap of the AA-2 receptors and the mu receptors. However, the effects at the AA-2 receptor could not fully account for these symptoms. Subsequently, clonidine was found to produce its pharmacologic effect in the central nervous system (CNS) by interaction not only with the AA-2 receptor but also on selective imidazoline receptors. IMIDAZOLINE RECEPTORS: Since their discovery, three distinct classes of imidazoline receptors, also known as imidazoline binding sites or imidazoline/guanidinium receptive sites, have been characterized. Imidazoline-1 (I-1) receptors are involved in the hypotensive activity of clonidine and related compounds supporting the idea that the I-1 receptors are upstream from the AA-2 receptor and work in tandem for its effect on blood pressure. Additionally, stimulation of N-type Calcium-2 channels, G-protein inwardly rectifying potassium channel, adenosine receptors, phosphatidyl-choline-specific phospholipase C, and nicotinic receptors have been implicated to be involved. Previous studies have shown that I-1 receptors may also be involved in other physiologic responses beyond cardiac function. Imidazoline-2 (I-2) receptors interact with monoamine oxidase A and monoamine oxidase B leading to research that has focused on the effect of I-2 receptors and depression and the suggestion of a possible antidepressant action of the imidazolines. I-2 receptor ligands may have substantial antinociceptive activity and work synergistically with opioids in acute pain. Imidazoline-3 (I-3) receptors are located on the pancreatic ß-cells and modulate glucose homeostasis. IMIDAZOLINE LIGANDS: Four endogenous compounds have been found to bind and include clonidine-displacing substance, agmatine, harmane, and imidazole acetic acid. Significant interest in developing new agents with higher selectivity and affinity for I-1 receptors has resulted. Toxicology. Alpha-2 adrenoceptor and imidazoline receptor agonists such as clonidine and tetrahydrozoline are common ingestions reported to poison control centers. The most common toxic effects of clonidine are similar to those of the over-the-counter imidazolines and include CNS depression, bradycardia, hypotension, respiratory depression, miosis, hypothermia, and hypertension (early and transient). Based on their structure and subsequent studies, imidazoline receptors seem to be the primary binding site for these chemicals. Case reports typically illustrate rapid onset of action with serious side effects following ingestion of relatively small amounts. These agents have been reportedly used in drug-assisted sexual assaults. CONCLUSION: Much of the toxicity associated with drugs such as clonidine, guanfacine, and tetrahydrozoline are due to their binding to imidazoline receptors. Knowledge of the imidazoline receptors may lead to new therapeutic agents and inform management of patients with imidazoline overdose.

Neonicotinoid insecticide exposures reported to six poison centers in Texas.

Neonicotinoids are a relatively newer class of insecticide. Used primarily in agriculture, neonicotinoids are also used for flea control in domestic animals. Information on human exposures to neonicotinoids is limited. Neonicotinoid exposures reported to Texas poison centers during 2000-2012 were identified and the distribution by selected factors examined. Of 1,142 total exposures, most products contained imidacloprid (77%) or dinotefuran (17%). The exposures were seasonal with half reported during May-August. The most common routes of exposure were ingestion (51%), dermal (44%), and ocular (11%). The distribution by patient age was 5 years or less (28%), 6-19 years (9%), 20 years or more (61%), and unknown (2%); and 64% of the patients were female. Of all, 97% of the exposures were unintentional and 97% occurred at the patient's own residence. The management site was on-site (92%), already at/en route to a health care facility (6%), and referred to a health care facility (2%). The medical outcomes included no effect (22%), minor effect (11%), moderate effect (1%), not followed judged nontoxic (14%), not followed minimal effects (46%), unable to follow potentially toxic (1%), and unrelated effect (4%). The most commonly reported adverse clinical effects were ocular irritation (6%), dermal irritation (5%), nausea (3%), vomiting (2%), oral irritation (2%), erythema (2%), and red eye (2%). The most frequently reported treatments were dilution/wash (85%) and food (6%). In summary, these data suggest that the majority of neonicotinoid exposures reported to the poison centers may be managed outside of health care facilities with few clinical effects expected.

Detection of imidacloprid in biological fluids in a case of fatal insecticide intoxication.

Here, we describe a high-performance liquid chromatography/photodiode array detector method for the detection of imidacloprid in biological fluids in a case of suicide by ingestion of liquor mixed with Admire® Flowable insecticide (containing 20% imidacloprid). A plastic bottle containing a cloudy liquid (concentration of ethanol in the liquid was 150 mg/ml and that of imidacloprid was 50 mg/ml) was found near the decedent. The biological fluids collected at autopsy were prepared by deproteinization with acetonitrile. Zolpidem was used as an internal standard. The concentrations of imidacloprid in femoral blood and cerebrospinal fluid were 105 and 58.5 µg/ml, respectively. Ethanol was also detected in the samples, with concentrations of 1.0 mg/ml in femoral blood and 1.4 mg/ml in cerebrospinal fluid.

[Acute poisoning with sertindole--a case report]. / Ostre zatrucie sertindolem--opis przypadku.

The paper presents a case of acute, accidental sertindole poisoning. Intoxication had a stormy clinical course with symptoms of cardiovascular, respiratory and nervous system. A relatively small dose of ingested preparation and severe overdose course may indicate a low therapeutic drug index.

A case of acute prochloraz-manganese complex intoxication treated with extracorporeal elimination.

BACKGROUND/AIM: We treated a patient with critical manganese intoxication with vigorous extracorporeal elimination. In this article, we describe the clinical characteristics and treatment modalities of the patient. PATIENT: A 65-year-old man was brought to the emergency room (ER) 5.5 h after ingesting prochloraz-manganese complex. He experienced circulatory collapse and went into a coma without self-breathing on arrival at the ER. Mechanical ventilation was initiated and hemoperfusion, hemodialysis and continuous venovenous hemodiafiltration were performed with the help of norepinephrine. MEASUREMENT AND RESULT: The manganese levels on the first, second and fourth hospital days were 34.1, 23.6 and 12.5 µg/l, respectively. He recuperated from the shock state within 7 hospital days. After 4 critical weeks, the patient regained full consciousness. CONCLUSION: Rigorous extracorporeal elimination by hemoperfusion, hemodialysis and continuous venovenous hemodiafiltration was an effective treatment modality for patients with acute manganese intoxication.

One drop can be beneficial, one swig can be deadly: tetrahydrozoline intoxication.

Tetrahydrozoline is a commonly used imidazoline derivative with serious side effects and toxicity, particularly in small children. A one-year-old boy was admitted to the emergency department (ED) after he accidentally ingested about half a bottle of nasal decongestant solution containing tetrahydrozoline. He was unconscious, hypothermic and bradycardic on presentation. His respiration was irregular and superficial, and blood pressure was borderline hypotensive. His skin was pale and cold. Atropine was administered twice for symptomatic bradycardia, and the child was transferred to the pediatric intensive care unit (PICU). During the 12th hour of observation, vital signs returned to normal and there was no need for mechanical ventilation. Although suitable room temperature with passive warming was applied, hypothermia continued for approximately 24 hours. The patient was discharged on the second day of admission. There were no complaints one week later, and the physical examination was normal. We report a case of accidental tetrahydrozoline intoxication with life-threatening events accompanying hypothermia in a small infant.