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.

Can ophthalmic drops cause central nervous system depression and cardiogenic shock in infants?

Topical ocular medications have been widely prescribed and successfully used in children for the management of different ophthalmic disorders. We present 2 infants admitted to our pediatric intensive care unit who developed altered state of consciousness, hypotonia, hypothermia, bradycardia, and apnea after instillation of ophthalmic drops. The second infant also had hypotension and broncho-obstruction. Few days before admission, both infants were diagnosed with congenital glaucoma, and topical antiglaucoma treatment was initiated. Ophthalmic drops with brimonidine and brinzolamide were prescribed to both patients, whereas the second infant also received topical timolol. After elimination of other possible causes, the diagnosis of intoxication with topical antiglaucoma medications was established. After discontinuation of eye drops and vigorous symptomatic treatment, both infants recovered without sequels. Topically applied ophthalmic drops may cause life-threatening systemic adverse effects in infants, such as central nervous system depression and cardiogenic shock. Moreover, these 2 patients illustrate the importance of careful evaluation of all topical medications and their consideration as possible causes of the derangements in critically ill infants.

Fatality following a suicidal overdose with varenicline.

The smoking cessation agent varenicline acts as a partial agonist on α(4)ß(2) nicotinic acetylcholine receptors. Although debated, several reports have linked varenicline therapy to an increased risk of suicidal thoughts and/or suicide. In addition, several non-fatal overdose cases have been reported. In this report, we utilised a sample preparation procedure suitable for postmortem samples and gas chromatography coupled to mass spectrometry to analyse samples obtained from a suicidal case in which ingestion of an overdose of varenicline had occurred. Extremely high concentrations of varenicline (>250 ng/ml) were detected in the blood of the deceased, in addition to high concentrations in urine and vitreous humour. To the best of our knowledge, similar high concentrations have not been reported yet. Although, with respect to the mechanism of death in this case, confounding factors were concomitant ethanol consumption and, importantly, potentially fatal hypothermia, this is the first report of a fatality associated with the ingestion of an overdose of varenicline.

A retrospective poison center review of varenicline-exposed patients.

BACKGROUND: Varenicline was approved by the Food and Drug Administration (FDA) as a prescription smoking cessation aid in May 2006. Varenicline is both a partial nicotine agonist and an antagonist. Recent reports by the Institute of Safe Medication Practices identified safety problems associated with varenicline use, and the FDA recently issued a boxed warning. These safety concerns regarding varenicline use prompted this study. OBJECTIVE: To characterize varenicline-exposed patients as reported to a poison control system. METHODS: We performed a retrospective search of the California Poison Control System electronic database from August 2006 through August 2008, using the term varenicline or Chantix. Cases matching these results were reviewed. All ages were included. Excluded were patients with coingestants and unknown outcomes. Clinical parameters and medical outcomes were extracted from the database. RESULTS: Thirty-six cases met inclusion criteria and 17 cases were excluded, Ten cases involved nonpediatric patients; 9 cases involved patients less than 6 years old, which were defined as pediatric patients. The median duration of poison center follow-up for pediatric patients was 253 minutes; median duration of follow-up for nonpediatric patients with unintentional exposures was 28.5 minutes. The majority of exposures were unintentional and included all the pediatric patients and 6 nonpediatric patients who had unintentional medication errors. Gastrointestinal and neuropsychiatric adverse events were most frequently reported. The majority of these patients were managed at home. Among those evaluated at a healthcare facility, only 1 pediatric patient was admitted. Of the remaining patients, 1 nonpediatric patient reported a deliberate exposure and 3 nonpediatric patients experienced adverse effects at therapeutic doses. Median duration of follow-up for these patients was 308 minutes. CONCLUSIONS: Patients exposed to varenicline in our study had favorable outcomes. Gastrointestinal and neuropsychiatric effects were the most commonly reported adverse events. A dose-response relationship could not be determined and triage criteria to a healthcare facility remain undetermined.

Cardiorespiratory depression and hyperglycemia after unintentional ingestion of brimonidine in a neonate.

PURPOSE: Brimonidine is a third-generation selective alpha-2 adrenergic agonist that lowers intraocular pressure by decreasing aqueous humor production and increasing uveoscleral flow. Its safety profile for children <2 years of age remains unknown. METHODS: We describe a case of ingestion of a single drop of brimonidine 0.2% in a newborn, resulting in sedation, cardiorespiratory depression, and hyperglycemia within minutes. CONCLUSIONS: This report adds to the existing evidence that brimonidine can have serious adverse side effects and should therefore be used with extreme caution in infants <2 years of age. Additionally,safety procedures like double-checking should also include vitamins or oral supplements to improve medication safety in the neonatal intensive care unit.

Brimonidine tartrate poisoning in children: frequency, trends, and use of naloxone as an antidote.

BACKGROUND: Brimonidine tartrate, a centrally acting selective alpha-2 adrenergic agonist with a toxicity that is often compared with that of clonidine, is used as eye drops to lower intraocular pressure in glaucoma. We investigated characteristics of childhood exposures to brimonidine-containing products. METHODS: All brimonidine exposures in children 0 to 5 years of age between 1997 and 2005 were retrieved from the American Association of Poison Control Centers' Toxic Exposure Surveillance System database and the US Food and Drug Administration's Medwatch Adverse Events Reporting System. The design of the study was retrospective, and the main outcome measures were frequency of exposures over time, reason, symptoms/signs of toxicity, dose, management site, treatment, and outcome. RESULTS: There were 413 brimonidine reports in the Toxic Exposure Surveillance System and 340 in the Adverse Events Reporting System during the 9 years under study, of which 185 Toxic Exposure Surveillance System reports involved children < or =5 years of age versus 15 cases in the Adverse Events Reporting System. There were no deaths. The peak age of poisoning in the Toxic Exposure Surveillance System pediatric cases was 2 years of age, and circumstances were unintentional poisoning in 176 cases, usually by ingestion (84.3%). Common symptoms in 176 children included drowsiness (40.9%), ataxia (4.5%), pallor (4.5%), irritability (4.0%), hypotension (4.0%), bradycardia (4.0%), miosis (3.4%), and respiratory depression (3.4%). Of the 176 unintentional pediatric poisonings, 73 children were observed at home and 103 were seen at a health care facility; 28 were hospitalized and 11 received naloxone. Of the 15 pediatric cases in the Adverse Events Reporting System data set, all were hospitalized, and 13 had ocular exposures only. CONCLUSIONS: All children < or =5 years of age with confirmed brimonidine ingestions should be medically evaluated and monitored for an extended period. Indications for the use of naloxone in brimonidine poisoning remain uncertain.

Unintentional ingestion of brimonidine antiglaucoma drops: a case report and review of the literature.

A previously healthy, 1-year 7-month-old boy was brought to the emergency department after having unintentionally ingested topical brimonidine antiglaucoma drops. He was pale and lethargic and had brief periods of apnea and bradycardia. Activated charcoal was administered, and supportive measures were initiated, achieving complete resolution of the symptoms 4 hours after admission. Brimonidine poisoning is very rare, and a high index of suspicion is necessary to identify its signs and symptoms in the pediatric emergency department. To our knowledge, only 1 case of brimonidine poisoning after oral ingestion of this topical drug has been previously reported in the literature.

Adrenoceptor agonist poisoning after accidental oral ingestion of brimonidine eye drops.

OBJECTIVE: Brimonidine tartrate is a relatively selective alpha(2) adrenic agonist that lowers elevated intraocular pressure. A 2-yr-old boy presented with severe cardiorespiratory symptoms of systemic alpha(2) adrenergic intoxication after accidentally ingesting 2 mL of brimonidine ophthalmic solution (0.2%) orally. At 20 mins after ingestion, he became acutely pale and lethargic, with shallow infrequent respirations. The symptoms resolved completely within the next 10 hrs. METHODS: The pharmacokinetics of brimonidine in plasma and urine were analyzed using gas chromatography and mass spectrometry. RESULTS: Maximum plasma concentrations were 40 ng/mL 5 hrs after ingestion. The plasma elimination half-life value was 2.7 hrs. Elimination via urine was calculated as having a terminal half-life value of 3.2 hrs. CONCLUSIONS: This case illustrates the ability of brimonidine to gain rapid access to the central nervous system. This first passage is followed by a redistribution phase with rising plasma concentrations. Children who accidentally ingest brimonidine orally should be admitted to a pediatric intensive care unit.

Clinical effects of brimonidine ophthalmic drops ingestion in 52 dogs.

Brimonidine is an ophthalmic solution of 0.2% brimonidine tartrate used to lower intraocular pressure in human glaucoma patients. A retrospective study was conducted of brimonidine ophthalmic solution ingestion in 52 dogs reported to the ASPCA Animal Poison Control Center between January 1998 and December 2000. Eighty percent of the dogs were < 1-y of age. Approximate ingested dosages ranged from 0.18-5.55 mg/kg. Incidence of clinical signs were bradycardia (67%), depression (46%), ataxia (27%), hypotension (25%), pallor (23%), weakness (17%), change in mucous membrane color (17%), hypothermia (13%), vomiting or retching (13%.). Shock, weak pulses, and poor capillary refill time were also reported. Treatment involved early decontamination, supportive care, andyohimbine and atipamezole as specific alpha-2 antagonists that could be helpful in reversing the effects of brimonidine. Due to the possibility of severe cardiovascular effects developing, the ingestion of brimonidine ophthalmic solution in dogs should be considered dangerous.

Ophthalmic drops causing coma in an infant.

A 1-month-old infant with Peters anomaly had recurrent episodes of unresponsiveness, hypotension, hypotonia, hypothermia, and bradycardia. An extensive medical evaluation determined these episodes to be caused by brimonidine, an anti-glaucoma agent. There is the potential for serious toxic effects from the systemic absorption of topically applied ophthalmic agents in children.

[Pathomorphologic course study in fattening pigs after olaquindox poisoning]. / Pathomorphologische Verlaufsuntersuchungen nach Olaquindoxintoxikation bei Mastschweinen.

In an investigation over five months the adrenal toxic effect of the quinoxaline derivate olaquindox in pigs of different ages (10 and 16 weeks) after accidental feeding of a 15-fold overdosage of olaquindox is demonstrated. The substance induced clinical and hematological changes comparable with Addison's disease. A reduced gain of body weight was observed, predominant hematological findings were a hyperkalemia and a hyponatremia, which reversed to normal values after 17 weeks in the younger group and after 14 weeks in the older group. Whereas five weeks after the first intake of the feed, degenerative changes of the zona arcuata were most prominent, a destructive fibrosis and a reduction of the adrenal cortex were more marked 12 and 13 weeks later. Due to the loss of aldosterone the electrolyte imbalances led to degenerative changes in the skeletal muscles and in the myocardium. Pigs of younger age were more affected than elder ones. Subcapsular cells with basophilic nuclei resembling normal cells of the zona arcuata appear 18 to 22 weeks after the first overdosage of olaquindox and are suggestive in combination with normal electrolyte values of a regeneration of the zona arcuata.

[Clinical and hematological changes after olaquindox poisoning in fattening pigs]. / Klinische und hämatologische Veränderungen nach Olaquindoxvergiftung bei Mastschweinen.

A pig grower ration containing olaquindox at a concentration of 778 mg/kg was accidentally fed to 10 respectively 16 weeks old weaner pigs. The subsequent intoxication was characterized by poor growth and long-term disturbances of renal function and electrolyte metabolism. A deficiency of aldosterone, produced by a selective degeneration of the arcuate zone of the adrenal cortex, is probably the cause of the hyponatremia, hyperkalemia and hemoconcentration observed. Simultaneously plasma levels of urea and creatinine were elevated five- to eightfold. Due to hyperkalemia episodes with collapse, paralysis and severe electrocardiographic changes occurred several times. Two pigs died in the course of such attacks. Individuals, which transiently showed distinct clinical symptoms of intoxication, did not show any signs of disease 15 or 18 weeks later. Therefore it may be assumed, that the lesions of the adrenals, heart and skeletal muscle caused by olaquindox intoxication are reversible in some cases.

Accidental carbadox overdosage in pigs in an Irish weaner-producing herd.

A weaner ration containing carbadox at concentrations of 331 to 363 mg/kg was accidentally fed to suckling and weaned pigs in an 84 sow herd. Discarded ration was fed to 36 sows. One hundred and sixty five weaner pigs died in a 10 week period with clinical signs including refusal to eat, ill thrift, the passing of hard pelleted faeces, posterior paresis and death in seven to nine days. The surviving weaners did not thrive and some males showed poor testicular development. Sows and suckling pigs that consumed the ration also failed to thrive as did the progeny of affected sows. The main pathological finding was obliteration of the zona glomerulosa of the adrenal cortex. Increased potassium and decreased sodium concentrations in serum were the most notable and consistent biochemical findings.