[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.

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.

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.

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.

Cibenzoline intoxication necessitating implantation of a biventricular assist system in a patient with severe cardiomyopathy.

A 46-year-old man was admitted to our hospital in cardiogenic shock. A BVS-5000s biventricular assist system (BVAS) was implanted after establishment of extracorporeal membrane oxygenation. At admission, the patient's serum cibenzoline level was extremely high, 6336 ng/ml. As the cibenzoline level dropped, his cardiac function recovered gradually. The patient was weaned from the right ventricular assist system after pulmonary vein isolation ablation for atrial tachycardia on postoperative day 17, and from left ventricular assist system on day 33. There is the first report of a patient with severe cardiomyopathy induced by cibenzoline intoxication that necessitated implantation of a BVAS. This case illustrates the importance of checking cibenzoline levels regularly in patients receiving long-term therapy with this drug so as to avoid the possibility of severe drug-induced heart failure.

Tóxicos al alcance de los niños / Household hazardous

Existen productos frecuentes de uso doméstico y plantas ornamentales en nuestros jardines con gran poder toxigénico que son importantes de conocer.

Exposiçäo aguda a derivados imidazolínicos em crianças / Acute exposure to imidazoline derivatives in children

OBJETIVOS: Estudar a exposiçäo aguda a derivados imidazolínicos em crianças com idade inferior a 15 anos, atendidas no período de janeiro de 1994 a dezembro de 1999. MÉTODOS: Neste estudo retrospectivo foram avaliadas 72 crianças com idades entre dois meses e 13 anos, mediana de dois anos (25 por cento a 75 por cento; um a três anos), expostas a nafazolina (n = 48), fenoxazolina (n = 18), oximetazolina (n = 5) e tetrizolina (n = 1); por via oral (n = 46), nasal (n = 24) ou desconhecida (n = 2). RESULTADOS: No total, 57 crianças desenvolveram manifestações clínicas: sonolência (n = 34), sudorese (n = 20), palidez (n = 17), hipotermia (n = 16), bradicardia (n = 13), extremidades frias (n = 9), agitaçäo (n = 7), taquicardia (n = 6), vômitos (n = 34), respiraçäo irregular e apnéia (n = 5), miose/midríase (n = 4), sendo a nafazolina (n = 47), a fenoxazolina (n = 5) e a oximetazolina (n = 4) os princípios ativos mais envolvidos. O início das manifestações clínicas foi rápido, iniciando-se, em 32/57 crianças, até duas horas após a exposiçäo. Somente medidas de suporte foram empregadas, com uma criança necessitando de ventilaçäo mecânica após exposiçäo à nafazolina. Na maioria dos pacientes, o quadro clínico remitiu até 24 horas após a exposiçäo (n = 39/57). Näo houve evoluçäo letal. Pacientes expostos à nafazolina (n = 47/48) apresentaram maior freqüência de manifestações clínicas de intoxicaçäo em comparaçäo com aqueles expostos à fenoxazolina (n = 5/18) (p < 0,001). Comparando-se a freqüência de pacientes que desenvolveram manifestações clínicas de acordo com a via de exposiçäo (oral, n = 34/46; nasal, n = 21/24), näo foi encontrada uma diferença estatisticamente significante (p = 0,31). CONCLUSÕES: Na maioria dos casos de exposiçäo a derivados imidazolínicos, principalmente à nafazolina e em crianças com menos de três anos de idade, ocorreu, independentemente da via (oral ou nasal), o aparecimento precoce de manifestações clínicas de intoxicaçäo, destacando-se as depressöes neurológica, cardiovascular e respiratória, que regrediram até 24 horas após a exposiçäo

Toxicology of newer pesticides for use in dogs and cats.

The past 10 years have witnessed the development of several new insecticides that have been specifically designed to exploit physiologic differences between insects and mammals. This has resulted in products that seem to have a wide margin of safety when used in dogs and cats. Compared with the more acutely toxic organophosphorous, carbamate, and heavy metal insecticides as well as with the environmental problems of bioaccumulation associated with some of the organochlorine insecticides, these newer insecticides such as fipronil, imidacloprid, selamectin, lufenuron, and nitenpyram seem to alleviate these known problems while still providing satisfactory insecticidal activity.

[Absence of clinical and biological manifestations after massive absorption of nitulamide]. / Absence de manifestation clinique et biologique après absorption massive de nitulamide.

Nitulamide (ANANDRON (R] is an antiandrogen used as an adjuvant therapy in the treatment of advanced prostatic cancer. The effects of ingestion of high doses of nitulamide has not been so far reported. A 79 years old man was admitted 2 hours after the ingestion of 13 g of nitulamide (170 mg/kg or 43 times the therapeutic dose), in a suicide attempt. He was receiving nitulamide 300 mg/day for two weeks. On admission, he underwent immediately gastric lavage, followed by administration of oral activated charcoal and received an intravenous infusion of glucose in balanced salt solution. During the first 12 hours, the patient presented with moderate vomiting and diarrhoea. There was no change in the following parameters: blood cell count, plasma electrolytes, serum transaminases and serum bilirubin, arterial blood gases, plasma cortisol value, as compared to the pre-treatment values. Chest X ray was unchanged. Plasma concentrations were measured 2 hours, 3 hours, 12 hours, 24 hours, 48 hours and 72 hours after ingestion. The initial level reached 6 times the normal therapeutic range, then fell to 3.5 times at the 72th hour. The patient recovered rapidly and was discharged on the 4th day. Biologic parameters were controlled on 4th, 9th, 30th day and remained unchanged. Treatment was started again on the 30th day with nitulamide 150 mg/day. We did not notice any side effect previously described in daily administration of nitulamide: anemia, rise in serum transaminases, interstitial pneumopathy.

Intravenous naphazoline intoxication.

Nine pale perspiring drug addicts with drowsiness, nausea, headache, normal blood pressure and marked sinus bradycardia with premature ventricular beats were seen at the Casualty Department soon after alleged i.v. cocaine administration. Eight were treated with atropine, as the bradycardia suggested intoxication with a parasympathomimetic compound. Seven were discharged in good condition after a few hours' observation. One patient developed a blood pressure of 150/120 mmHg after atropine. Subsequently, a hemiparesis was found and an intracerebral haematoma was evaluated at surgery. Another patient was admitted forthwith to the CCU. He did not receive any medication and recovered within two days. Urinalysis of these two patients disclosed contents of naphazoline, a powerful alpha-adrenergic agent. Samples of the alleged cocaine contained 97% naphazoline HCl. A conscious rabbit was injected with naphazoline and thereafter with atropine. I.v. naphazoline doubled mean arterial pressure (MAP) and reduced heart rate (HR) from 167 to 30 beats/min. Atropine doubled HR, but caused a marked rise in MAP, too, stressing the adverse effects of atropine in these cases. When confronted with patients after alleged cocaine abuse, the role of substitute drugs, especially alpha-adrenergic compounds, should be considered as this should influence the therapeutic approach.