Venous Gas Embolism during Hysteroscopic Endometrial Ablation: Report of 5 Cases and Review of the Literature.

STUDY OBJECTIVE: To highlight the circumstances, presentation, and treatment of venous gas embolism (VGE) and provide guidance and propose potential changes in surgical practice and perioperative monitoring to minimize the adverse consequences and sequalae of this potentially serious complication. DESIGN: A case series. SETTING: A university-affiliated teaching hospital. PATIENTS: Five women developed VGE during hysteroscopic endometrial ablation. INTERVENTIONS: From 1990 through 2014, the principle author (G.A.V.) performed 5249 primary and 458 repeat hysteroscopic endometrial ablations under general anesthesia using a monopolar 26F (9-mm) resectoscope connected to a peristaltic pump-driven active inflow and outflow irrigation and distension system (1.5% glycine) and an 8-mm monopolar loop electrode at a 120-W continuous (cut) and/or a 3- to 5-mm rollerball interrupted (coagulation) waveform or a combination of them. MEASUREMENTS AND MAIN RESULTS: Among 5707 procedures, we encountered 5 (0.09%, 1/1140) incidents of VGE during primary ablations. All patients exhibited the same symptoms of ventilatory and hemodynamic decompensation, beginning with a reduction in end-tidal carbon dioxide and arterial oxygen desaturation. All patients recovered after immediate cessation of the surgery and resuscitation including ventilatory support with 100% O2 and intravenous fluids. CONCLUSIONS: Although entrainment of some air/gas bubbles is common during hysteroscopy, life-threatening/fatal VGE is rare (1/1140 cases). Situational awareness and strict adherence to certain principles including understanding the conditions, prerequisites, and pathophysiology of VGE; attention to surgical principles and operative technique; close communication with the anesthesiologist; and early therapeutic intervention are of paramount importance to avoid this rare but potentially serious complication.

Fetal and perinatal exposure to drugs and chemicals: novel biomarkers of risk.

Pregnant women are almost always excluded from randomized controlled clinical trials, as the risks to the fetus posed by most new chemical entities or approved drugs cannot be sufficiently ruled out. Hence, a major scientific challenge in this field is to discover and validate alternative tools that will fill the knowledge gap created by the lack of participation in gold-standard randomized trials. This review focuses on novel tools that allow estimation of fetal risks after exposure to therapeutic agents, such as placental perfusion studies, biomarkers of fetal exposure, and novel epidemiological and pharmacogenetic tools, all of which have been tested successfully in recent years.

Drug Misuse in Adolescents Presenting to the Emergency Department.

OBJECTIVES: Drug misuse is a disturbing, common practice among youth. One in 4 American adolescents reports consuming prescription medications without a clinical indication. We sought to explore current trends of drug misuse in adolescents. METHODS: Using the 37 participating sites of the ToxIC (Toxicology Investigators Consortium) Case Registry, a cross-country surveillance tool, we conducted an observational cohort study of all adolescents (aged 13-18 years) who presented to emergency departments with drug misuse and required a bedside medical toxicology consultation between January 2010 and June 2013. RESULTS: Of 3043 poisonings, 202 (7%) involved drug misuse (139 [69%] were males). Illicit drugs (primarily synthetic cannabinoids and "bath salts") were encountered in 101 (50%), followed by prescription medications (56 [28%]) and over-the-counter (OTC) drugs (51 [25%]). Dextromethorphan was the most commonly misused legal medication (24 [12%]). Polypharmacy exposure was documented in 74 (37%). One hundred sixty-three adolescents (81%) were symptomatic; of these, 81% had central nervous system impairments: psychosis (38%), agitation (30%), coma (26%), myoclonus (11%), and seizures (10%); and 66 (41%) displayed a specific toxidrome, most commonly sedative-hypnotic. Benzodiazepines were the most frequently administered medications (46%). Antidotes were administered to 28% of adolescents, primarily naloxone, physostigmine, N-acetyl-cysteine, and flumazenil. No deaths were recorded. CONCLUSIONS: Adolescents presenting with drug misuse may be exposed to a wide range and combinations of therapeutics or illicit substances and frequently display central nervous system abnormalities, compromising the ability to obtain a reliable history. Frontline clinicians should maintain a high index of suspicion, as routine toxicology screenings fail to detect most contemporary misused legal and designer drugs.

False-positive meconium test results for fatty acid ethyl esters secondary to delayed sample collection.

BACKGROUND: Meconium analysis for fatty acid ethyl esters (FAEEs) is a validated method for identifying heavy prenatal ethanol (EtOH) exposure. This study investigated whether delayed sample collection can result in false-positive test results for FAEEs because of collection of samples potentially contaminated with postnatally produced stool. METHODS: Serial excretions were prospectively collected from neonates born to nondrinking mothers to capture the transition from meconium to postnatal stool. These were analyzed for FAEEs using headspace-solid phase microextraction and gas chromatography-mass spectrometry. Experiments involving incubation of samples with glucose or EtOH were performed to explore a potential mechanism of FAEE elevation. RESULTS: A total of 136 samples were collected from 30 neonates during their first few days of life (median of 4 samples/baby over a mean period of 68.5 hours postpartum). Although the first-collected meconium sample tested negative for FAEEs in all babies, later samples tested above the 2 nmol/g positive cutoff in 19 of 30 babies. Median time to appearance of FAEE-positive samples was 59.2 hours postpartum. In vitro experiments demonstrated that FAEE levels can be further increased in late samples (likely containing postnatal stool) after incubation with glucose, and that FAEEs are readily formed in meconium in the presence of EtOH. CONCLUSIONS: Collection of samples excreted later in the postpartum period can lead to false-positive test results for FAEEs, which could be because of contamination with dietary components of postnatally produced stool and EtOH-producing microorganisms. Clinically, it is critical to collect the earliest possible excretion for determination of FAEEs to ensure that the FAEE content is representative of in utero EtOH exposure.

Methadone: a review of drug-drug and pathophysiological interactions.

Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to α1-acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone's fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.

Acetaminophen in late pregnancy and potential for in utero closure of the ductus arteriosus-a pharmacokinetic evaluation and critical review of the literature.

Acetaminophen has become a novel treatment option for patent ductus arteriosus closure in premature infants. This raises concerns about whether acetaminophen should be avoided in late pregnancy, similar to nonsteroidal anti-inflammatory drugs, because of the risk of in utero ductus arteriosus closure. This article critically evaluated the literature reporting an association between acetaminophen use and in utero ductus arteriosus closure and provided a comparative pharmacokinetic analysis of fetal acetaminophen exposure in pregnancy vs drug levels in neonates, with the goal of making an expert recommendation regarding its safety. Here, 1 prospective cohort study and 12 case reports and series evaluating the risk of premature ductus arteriosus closure with prenatal acetaminophen use were reported and overall do not suggest causation. Pharmacokinetic studies showed that acetaminophen fetal transplacental exposures are well below the levels shown to close the ductus arteriosus in neonates. Short-term use of acetaminophen in the third trimester of pregnancy poses a negligible risk of premature ductus arteriosus closure and can still be considered safe in the third trimester of pregnancy at recommended doses.

The incidence of prenatal alcohol exposure in Montevideo Uruguay as determined by meconium analysis.

Prenatal alcohol exposure can lead to a wide range of deficits known as fetal alcohol spectrum disorder. Epidemiologic studies regarding alcohol consumption in pregnancy have concentrated on North America, but recent reports have suggested that consumption is significant in many parts of the world. In Uruguay, alcohol consumption has changed into more risky and dangerous patterns and thus has a theoretical risk of having a high rate of prenatal alcohol exposure. This study characterizes the incidence of prenatal alcohol exposure in Montevideo, Uruguay, using a novel biomarker, fatty acid ethyl esters, in meconium as well as a survey to mothers. Nine hundred five meconium samples were collected from Hospital Pereira Rossell and Hospital de Clínicas in Montevideo, Uruguay. A maternal questionnaire was also completed. Meconium was analyzed for fatty acid ethyl esters using liquid-liquid and solid phase extraction with gas chromatography-flame ionization detection. Meconium was also analyzed for other drugs of abuse using enzyme-linked immunosorbent assay. Forty-four percent of meconium samples were above the positive cutoff for fatty acid ethyl esters and represent those newborns with risky prenatal exposure during the final two trimesters of pregnancy. Infants with prenatal alcohol exposure were more likely to have prenatal exposure to tobacco (odds ratio, 1.56; 95% confidence interval, 1.11-2.20) or any illicit drug (odds ratio, 2.29; 95% confidence interval, 0.98-5.31). Ethyl linoleate was a significant predictor of infant birth weight along with prenatal tobacco exposure, maternal body mass index, and infant sex. This study highlights a 44% incidence of prenatal alcohol exposure.

Polymorphism of the ADRB2 gene and response to inhaled beta- agonists in children with asthma: a meta-analysis.

BACKGROUND: About 9% of children have asthma, corresponding to almost 6.8 million children in the USA and 1.1 million in the UK. Asthma exacerbations are the leading cause of pediatric emergency room visits and impose a large burden on the individual, family, and society. There is mounting evidence that therapeutic failure of inhaled beta-agonists is associated with polymorphisms of the beta(2)-adrenergic receptor gene (ADRB2); specifically, mutations leading to amino acid changes at positions 16 and 27, which alter down-regulation of the beta(2)-adrenergic receptor (beta(2)AR), induce resistance to the smooth-muscle relaxing effect of beta(2)-adrenergic agonists. METHODS: We conducted a meta-analysis to examine the association between ADRB2 polymorphisms and the response to inhaled beta(2)-adrenergic agonists in children with asthma. We included all published studies until November 2008, in which asthmatic children underwent testing for acute bronchodilator response, defined as > or = 15% improvement in forced expiratory volume in 1 second (FEV(1)) and single nucleotide polymorphism (SNP) genotyping for positions 16 and/or 27 of the beta(2)AR. Individual and summary odds ratios were calculated using a random effects model. RESULTS: We identified three case-control or family-based studies involving 960 asthmatic children (692 children with negative beta(2)-bronchodilator response, defined as < 15% improvement in FEV(1) and 268 children with positive bronchodilator response). We found a significant association between favorable therapeutic response to inhaled beta(2)-adrenergic agonists in asthmatic children and the Arg/Arg phenotype at position 16 of the beta(2)AR [OR = 1.77; 95% CI (1.01; 3.1); p = 0.029], compared with the Arg/Gly or Gly/Gly phenotypes. The beneficial effect of Arg at position 16 of the beta(2)AR was most pronounced in African-American asthmatic children [OR = 3.54; 95% CI (1.37, 9.13)]. There was no association between clinical response to beta(2)-agonists and polymorphism at amino acid position 27 of the beta(2)AR (OR = 1.04; 95% CI [0.76,1.42]). CONCLUSIONS: Failure of bronchodilator response to inhaled beta-agonists in asthmatic children is associated with the Gly allele (Arg/Gly and Gly/Gly genotypes) at position 16 of the beta(2)-adrenergic receptor. Genetic typing for beta(2)AR polymorphism may help identify children with drug-resistant asthma.

Repetition of intentional drug overdose: a population-based study.

CONTEXT: Intentional overdose is a leading method of self-harm and suicide, and repeat attempts strongly predict eventual death by suicide. OBJECTIVES: To determine the risk of recurrence after a first intentional overdose. Secondary objectives included characterization of the temporal course and potential predictors of repeat overdose, a strong risk factor for death from suicide. DESIGN: Population-based cohort study. SETTING: Ontario, Canada, from 1 April 2002 to 31 March 2013. PARTICIPANTS: All Ontario residents presenting to an emergency department after a first intentional overdose. MAIN OUTCOME MEASURES: The incidence and timing of recurrent overdose. RESULTS: We followed 81,675 patients discharged from hospital after a first intentional overdose. Overall, 13,903 (17.0%) returned with a repeat overdose after a median interval of 288 (inter-quartile range: 62 to 834) days. Of these, 4493 (5.5%) had multiple repeat episodes. Factors associated with repeat self-poisoning included psychiatric care in the preceding year (adjusted hazard ratio [aHR] 1.55; 95% confidence interval [CI] 1.50 to 1.61), alcohol dependence (aHR 1.41; 95% CI 1.35 to 1.46) and documented depression (aHR 1.39; 95% CI 1.34 to 1.44). Female sex, rural residence, lower socioeconomic status, ingestion of psychoactive drugs and younger age were also weakly associated with repeat overdose. DISCUSSION: Hospital presentation for repetition of intentional overdose is common, with recurrent episodes often far removed from the first. While several factors predict overdose repetition, none is particularly strong. CONCLUSION: Secondary prevention initiatives should be implemented for all individuals who present to the emergency department and survive intentional overdose.

Acute Poisoning During Pregnancy: Observations from the Toxicology Investigators Consortium.

Acute poisonings during pregnancy pose a particular challenge to health care providers because of the potential for an immediate life threat or possible life-long implications for both the mother and fetus, including teratogenicity of the poison or its antidote. We describe recent consequential exposures among pregnant women in the USA. We identified all poisoning cases involving pregnant women that were catalogued by the medical toxicology services across the 37 sites of the Toxicology Investigators Consortium (ToxIC) Registry of the American College of Medical Toxicology between January 2010 and December 2012. Of 17,529 exposure cases reported in the ToxIC Registry, 103 (0.6 %) involved pregnant women, 80 % of whom were symptomatic and about a quarter displayed a specific toxidrome. The majority of cases (n = 53; 51.5 %) involved intentional exposures, most commonly to pharmaceutical agents, followed by unintentional pharmaceutical exposures (10 %) and withdrawal syndromes (9 %). Non-opioid analgesics were the most common class of agents encountered (31 %), followed by sedative-hypnotics/muscle relaxants (18 %), opioids (17 %), anti-convulsants (10 %), and anti-depressants (10 %). Over a third of cases involved exposure to multiple substances, and 32 % involved exposure to more than one drug class. The most commonly administered antidotes were N-acetylcysteine (23 %), sodium bicarbonate (10 %), flumazenil (4 %), and physostigmine (4 %). About half of acute poisoning cases among pregnant women presenting for emergency care involved intentional exposures, mostly with over-the-counter analgesics and psychoactive medications. Clinicians should be cognizant of the unique circumstances, maternal and fetal risks, and management principles of the acutely poisoned pregnant woman.

Long-term outcomes following self-poisoning in adolescents: a population-based cohort study.

BACKGROUND: Suicide is the third most common cause of death among adolescents worldwide, and poisoning is the leading method of attempted suicide. Unlike more violent methods, survival after self-poisoning is common, providing an opportunity for secondary prevention. We determined the risk and time course of completed suicide after adolescent self-poisoning, and explored potential risk factors. METHODS: We did a population-based cohort study using multiple linked health-care databases in Ontario, Canada, from Jan 1, 2001, to Dec 31, 2012. We identified all adolescents aged 10-19 years presenting to hospital after a first self-poisoning episode. Each was matched with 50 population-based reference individuals with no such history, matching on age, sex, and year of cohort entry. The primary outcome was the risk of suicide after a first self-poisoning episode. Secondary analyses explored factors associated with suicide and self-poisoning repetition. FINDINGS: We identified 20,471 adolescents discharged from hospital after a first self-poisoning episode and 1,023,487 matched reference individuals. Over a median follow-up of 7·2 years (IQR 4·2-9·7), 248 (1%) adolescents discharged after self-poisoning died, 126 (51%) of whom died by suicide. The risk of suicide at 1 year after self-poisoning was greatly increased relative to reference individuals (hazard ratio [HR] 32·1, 95% CI 23·6-43·6), corresponding to a suicide rate of 89·6 (95% CI 75·2-106·7) per 100,000 person-years over the course of follow-up. The median time from hospital discharge to suicide was 3·0 years (IQR 1·1-5·3). Factors associated with suicide included recurrent self-poisoning (adjusted HR 3·5, 95% CI 2·4-5·0), male sex (2·5, 1·8-3·6) and psychiatric care in the preceding year (1·7, 1·1-2·5). Adolescents admitted to hospital for self-poisoning were also more likely to die from accidents (5·2, 4·1-6·6) and from all causes (3·9, 2·8-5·4) during follow-up. INTERPRETATION: Self-poisoning in adolescence is a strong predictor of suicide and premature death in the ensuing decade, and identifies a high-risk group for targeted secondary prevention. Suicide risk is increased for many years after the index hospital admission, emphasising the importance of sustained prevention efforts. FUNDING: The Canadian Drug Safety and Effectiveness Research Network, Ontario Ministry of Health and Long-Term Care, Paediatric Consultants Partnership.

Risk of Suicide Following Deliberate Self-poisoning.

IMPORTANCE: Suicide is the tenth leading cause of death in the United States, and its rate has risen by 16% in the past decade. Deliberate self-poisoning is the leading method of attempted suicide. Unlike more violent methods, which are almost universally fatal, survival following self-poisoning is common, providing an opportunity for secondary prevention. However, the long-term risk of suicide following a first episode of self-poisoning is unknown. OBJECTIVE: To determine the risk of suicide and mortality from other causes following a first self-poisoning episode. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study using multiple linked health care databases. We identified all individuals with a first self-poisoning episode in Ontario, Canada, from April 1, 2002, through December 31, 2010, and followed up all surviving participants until December 31, 2011, or death, whichever occurred first. For each individual with a deliberate self-poisoning episode, we randomly selected 1 control from the same population with no such history, matched for age (within 3 months), sex, and calendar year. MAIN OUTCOMES AND MEASURES: The primary analysis examined the risk of suicide following discharge after self-poisoning. The secondary analyses explored factors associated with suicide and examined the risk of death caused by accidents or any other cause. RESULTS: We identified 65 784 patients (18 482 [28.1%] younger than 20 years) who were discharged after a first self-poisoning episode. During a median follow-up of 5.3 years (interquartile range, 3.1-7.6 years), 4176 died, including 976 (23.4%) by suicide. The risk of suicide following self-poisoning was markedly increased relative to controls (hazard ratio, 41.96; 95% CI, 27.75-63.44), corresponding to a suicide rate of 278 vs 7 per 100 000 person-years, respectively. The median time from hospital discharge to completed suicide was 585 days (interquartile range, 147-1301 days). Older age, male sex, multiple intervening self-poisoning episodes, higher socioeconomic status, depression, and recent psychiatric care were strongly associated with suicide. Patients with a self-poisoning episode were also more likely to die because of accidents (hazard ratio, 10.45; 95% CI, 8.10-13.47) and all causes combined (hazard ratio, 5.55; 95% CI, 5.12-6.02). CONCLUSIONS AND RELEVANCE: A first self-poisoning episode is a strong predictor of subsequent suicide and premature death. Most suicides occur long after the index poisoning, emphasizing the importance of longitudinal, sustained secondary prevention initiatives.

Current use of domperidone and co-prescribing of medications that increase its arrhythmogenic potential among older adults: a population-based cohort study in Ontario, Canada.

BACKGROUND AND OBJECTIVES: Domperidone is commonly used to treat nausea and gastrointestinal disorders. Recent data suggests that it may increase the risk of sudden cardiac death, particularly in older people. Little is known about how it is used in contemporary practice. This study sought to characterize the population of older adults newly dispensed domperidone, describe dosages of domperidone used, and determine the frequency of co-prescribing domperidone with medications that may increase the arrhythmogenic potential of domperidone. METHODS: This is a retrospective cohort study using administrative health database information from Ontario, Canada. Prescription medication records were obtained from the Ontario Drug Benefit Claims Database. Diagnostic codes were obtained from the Ontario Health Insurance Plan Database, the Canadian Institute for Health Information Discharge Abstract Database, and the same-day surgery database. Patients who received a new prescription for domperidone between April 1, 2003 and March 31, 2010 were included. RESULTS: A total of 122,233 patients met inclusion criteria; 85 % were between 66 and 84 years old and 63 % were female. The mean estimated daily domperidone dose was 35 mg, and the estimated daily dose was <40 mg for 62 % of users. Strong or moderately strong cytochrome P-450 (CYP) 3A4 inhibitors were co-prescribed for 4.3 and 10.7 % of users, while medications with a known risk or possible risk for torsades de pointes (TdP) were co-prescribed to 18.3 and 18.8 % of users. CONCLUSIONS: Older domperidone users were commonly co-prescribed drugs with the potential to increase the risk for TdP. These combinations should be avoided, as iatrogenic QT prolongation is a modifiable risk factor for TdP.

Toxico-surveillance of infant and toddler poisonings in the United States.

Infant and toddler poisonings are important to capture and may be challenging to manage. We aim to describe the Toxicology Investigators Consortium (ToxIC) Case Registry as a tool for toxico-surveillance of this problem in the United States. Using the ToxIC Case Registry database of the American College of Medical Toxicology, we identified infant and toddler poisonings over a 15-month period between April 1, 2010 and June 30, 2011 reported to the 31 Registry sites. Of 6,810 poisoning cases reported to the ToxIC registry, 248 (3.6 %) involved children younger than 2 years (51 % males). Fifty-four percent were hospital inpatients, 42 % were in the Emergency Department and 4 % were outpatients. Sixty-three percent were symptomatic. The most common ingested compounds were highly toxic-cardiac drugs (16 %), psychotropics (15 %), recreational drugs, alcohols, and controlled narcotic drugs (13 %), analgesics (9 %), and cleaning compounds (7 %). Fourteen percent of cases involved multiple agents. The ToxIC registry is a potentially useful toxico-surveillance tool to identify and trend clinically significant poisonings in young children, and potentially other populations. These data could be used to target specific preventive interventions.

Folic acid transport to the human fetus is decreased in pregnancies with chronic alcohol exposure.

BACKGROUND: During pregnancy, the demand for folic acid increases since the fetus requires this nutrient for its rapid growth and cell proliferation. The placenta concentrates folic acid into the fetal circulation; as a result the fetal levels are 2 to 4 times higher than the maternal level. Animal and in vitro studies have suggested that alcohol may impair transport of folic acid across the placenta by decreasing expression of transport proteins. We aim to determine if folate transfer to the fetus is altered in human pregnancies with chronic alcohol consumption. METHODOLOGY/PRINCIPAL FINDINGS: Serum folate was measured in maternal blood and umbilical cord blood at the time of delivery in pregnancies with chronic and heavy alcohol exposure (n = 23) and in non-drinking controls (n = 24). In the alcohol-exposed pairs, the fetal:maternal serum folate ratio was ≤ 1.0 in over half (n = 14), whereas all but one of the controls were >1.0. Mean folate in cord samples was lower in the alcohol-exposed group than in the controls (33.15 ± 19.89 vs 45.91 ± 20.73, p = 0.04). CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that chronic and heavy alcohol use in pregnancy impairs folate transport to the fetus. Altered folate concentrations within the placenta and in the fetus may in part contribute to the deficits observed in the fetal alcohol spectrum disorders.

Pharmacokinetic and pharmacogenetic determinants and considerations in chemotherapy selection and dosing in infants.

INTRODUCTION: There is a lack of high-quality data regarding optimal chemotherapy dosage regimens among infants. Dosing regimens for chemotherapy during the first year of life are commonly based on empiric recommendations extrapolated from older children; however, balancing efficacy and toxicity is critical as severe adverse drug reactions may lead to treatment failure or reduced adherence to needed medications. AREAS COVERED: This review describes pharmacokinetic and pharmacogenetic considerations when administering chemotherapeutic agents to infants. Examples of commonly used agents are provided with practical recommendations for dosing adjustments. EXPERT OPINION: Optimal chemotherapy for children and infants in particular has lagged behind the remarkable progress in cancer treatment and it is clear that far more basic and clinical research are needed with respect to the mechanistic basis of age-dependent differences in pharmacokinetic parameters. More recent studies which have combined pharmacokinetic data with clinical toxicity and outcome data have resulted in a number of more evidence-based guidelines at least for the initial chemotherapy dosing; however, at present, the dosing of chemotherapy drugs in neonates and infants remains largely empiric.

Use of clarithromycin and adverse cardiovascular events among older patients receiving donepezil: a population-based, nested case-control study.

BACKGROUND: Donepezil is a commonly used drug in older people that due to its procholinergic effects can provoke bradycardia and neurocardiogenic syncope. Donepezil is metabolized by the cytochrome P450 isozyme 3A4 (CYP3A4). Clarithromycin is a potent inhibitor of CYP3A4, and patients taking both of these drugs may be at increased risk of cardiac adverse events. OBJECTIVE: The aim of this study was to evaluate the association between recent use of clarithromycin and adverse cardiovascular events in elderly patients receiving donepezil. METHODS: A population-based, nested case-control study using provincial healthcare databases was conducted. The base cohort was made up of persons 66 years of age or older who were prescribed donepezil and also were prescribed clarithromycin, erythromycin, azithromycin, cefuroxime, moxifloxacin or levofloxacin. Cases were those members of the base cohort hospitalized for bradycardia, syncope or complete atrioventricular block. For each case patient, five controls were matched according to age, sex and residence (community or long-term care). RESULTS: Between July 2002 and March 2010, 17,712 patients continuously receiving donepezil were prescribed one of the antibacterials. In 1400 person-years of follow-up, 59 cases were identified. As compared with azithromycin, there was no statistically significant association between use of clarithromycin in donepezil users and subsequent adverse cardiovascular events (odds ratio 0.67; 95% CI 0.28, 1.63). There was no significant risk associated with exposure to either cefuroxime or respiratory quinolones. CONCLUSIONS: The use of clarithromycin in elderly donepezil users did not significantly increase the risk of adverse cardiovascular outcomes. However, our study cannot rule out a possible small increase in risk. Although antibacterials can be beneficial, care should be taken in selecting antibacterials for use in older people receiving donepezil.