Biomedical subjects
Publications and source records attributed to G Koren.
Infant exposure to ketoconazole in human milk was calculated to be 0.4% on average (maximum 1.4%) of those expected from therapeutic doses given directly to infants. Potential risk of adverse reactions from this low exposure level seem to be outweighed by the benefits of breast-feeding.
OBJECTIVE: Our purpose was to quantitate the risk of perinatal thyroid dysfunction and other amiodarone-induced adverse effects among infants exposed in utero to amiodarone. STUDY DESIGN: A historic cohort study of gestational exposure to amiodarone was conducted by contacting Canadian cardiac electrophysiologists. RESULTS: Twelve cases were identified. Of six with first-trimester exposure, one child had congenital nystagmus with synchronous head titubation. There was one case each of transient neonatal hypothyroidism (9%) and hyperthyroidism (9%). A fourth child, exposed to amiodarone from 20 weeks' gestation, had developmental delay, hypotonia, hypertelorism, and micrognathia. Four small-for-gestational-age infants were also exposed to beta-blockers, which in addition to maternal cardiac disease, have been recognized to cause growth restriction. beta-Blockers may also have contributed to bradycardia in one of the three fetuses in whom this was observed. CONCLUSIONS: Gestational exposure to amiodarone may be complicated by perinatal hypothyroidism or hyperthyroidism and possibly neurologic abnormalities, intrauterine growth retardation or fetal bradycardia. Concomitant beta-blocker therapy should probably be avoided. Full neonatal thyroid function tests and developmental follow-up are recommended.
BACKGROUND: Pemoline is a central nervous system stimulant used in treating children with attention deficit-hyperactivity disorder. Hepatotoxicity has been commonly reported in association with pemoline; however, only two reports of cases of fatal liver failure have been published. OBJECTIVES: We report on a 14-year-old boy who received concomitant pemoline and methylphenidate in whom fulminant liver failure occurred and for whom liver transplantation failed. Other causes of fulminant liver failure were ruled out, and the liver biopsy was suggestive of drug toxicity. We estimated the probability that these three cases represent an increased risk of fulminant liver failure associated with pemoline. RESULTS: Based on the three known cases of fatal liver failure associated with pemoline use, we calculated that a child receiving pemoline has a relative risk of development of fulminant liver failure of 45.3 (95% confidence interval, 4.1 to 510). This highly significant association (p < 0.001) suggests causation. CONCLUSIONS: Because pemoline has been widely used in recent years, further studies are needed to better quantify this risk in children with attention deficit-hyperactivity disorder.
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OBJECTIVE: To determine if first-trimester exposure to sex hormones, and oral contraceptives (OCs) specifically, is associated with an increased risk of external fetal genital malformations. DATA SOURCES: MEDLINE and Science Citation Index data bases were searched for the years 1966-1992 for relevant English-language articles on first-trimester sex-hormone exposure and fetal genital changes. METHODS OF STUDY SELECTION: One hundred eighty-six articles were identified initially. Inclusion criteria were cohort or case-control studies, first-trimester sex-hormone exposure, and live infants or full-term stillborn infants with external genital malformations. Exclusion criteria were diethylstilbestrol exposure, spontaneous abortions, and teratogen exposure. DATA EXTRACTION AND SYNTHESIS: The Methods section of each study was reviewed independently by two authors and two outside reviewers, using the above criteria. Fourteen studies, seven cohort and seven case-control, involving 65,567 women, met the criteria for meta-analysis. Extracted data were entered into 2 x 2 tables. The overall summary odds ratio (OR) was 1.09 (95% confidence interval [CI] 0.90-1.32); subanalysis of OC exposure identified an OR of 0.98 (95% CI 0.24-3.94). CONCLUSION: There was no association between first-trimester exposure to sex hormones generally (or to OCs specifically) and external genital malformations. Thus, women exposed to sex hormones after conception may be assured there is no increased risk of fetal sexual malformation.
Acute pain in infants is not assessed or managed optimally. The objectives of the study were (a) to adapt a behavioral pain assessment measure (Children's Hospital of Eastern Ontario Pain Scale, CHEOPS) for use with infants, and (b) to establish the reliability and validity of the measure in a study of infants undergoing immunization. Ninety-six healthy 4- to 6-month-old infants were randomized to receive either the local anesthetic cream Eutectic Mixture of Local Anesthetics (EMLA) (N = 49), or a placebo (N = 47) prior to immunization. The infant's behavioral response was videotaped immediately before and following the immunization. Postprocedural pain scores were assessed from the videotape and were significantly lower in infants who received EMLA (P = 0.01). Pain scores were also significantly correlated with visual analogue scale (VAS) scores assessed during vaccination. Five independent raters also independently rated ten infants to determine interrater reliability. Agreement between raters' scores was high (intraclass correlation coefficient, 0.95). Results from this study suggest that this measure has beginning construct and concurrent validity and interrater reliability when used in a research study. Further testing of the measure in the clinical setting is required.
The safety of lidocaine-prilocaine cream (EMLA) was evaluated in an open trial in 30 preterm neonates (mean gestational age, 32.8 weeks; birth weight, 1911 gm); 0.5 gm was applied to the heel for 1 hour. Mean baseline and follow-up (4, 8, or 12 hours after EMLA application) methemoglobin levels were not different, ranging from 1.15% to 1.45%, and from 1.13% to 1.49%, respectively.
Interactions between drugs and the kidney are necessary for renal drug elimination, metabolism, and occasionally for therapeutic effect. These interactions may result also in renal toxicity. Understanding the kidney's role in drug-handling helps the clinician to be aware of potential drug interactions and toxicity. Drug disposition, elimination, and toxicity may differ with development and are to be considered when prescribing drugs for children. Nephrotoxicity associated with drugs, although common, is usually reversible with discontinuation of the drug; however, when drug therapy with a well-known nephrotoxic drug (e.g., cisplatin) is necessary, pharmacologic modulators may play a role in limiting the associated nephrotoxicity.
Pediatric patients with leukemia, other malignancies, and rheumatological disease receive methotrexate chronically. Because of the documented correlation between methotrexate levels of compliance and clinical outcome, it is conceivable to verify appropriate systemic exposure to the drug. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is ethically limited. Our study shows poor correlation between serum total/free methotrexate concentrations and saliva levels, precluding the clinical use of this test.
During the past decade, new evidence has been collected regarding the fetal risks of environmental tobacco smoke. Throughout gestation, the unborn baby is exposed to increasing concentrations of nicotine through maternal blood and gastrointestinal and skin absorption of the nicotine in the amniotic fluid. Recent research shows measurable concentrations of cotinine in the hair of infants born to passively smoking mothers. This exposure has been recently associated with effects on fetal growth.
Asymptomatic bacteriuria is common during pregnancy and may adversely affect both the mother and her fetus. Nitrofurantoin (NF) has been long recognized as an effective agent in both nonpregnant and pregnant women suffering from urinary tract infections. This meta-analysis was conducted in order to evaluate the safety of NF ingested during early pregnancy. Of twenty-two studies, only four met the inclusion criteria and their analysis could not demonstrate any significant correlation between NF ingestion and fetal malformation. The pooled odds ratio was 1.29 with 95% confidence interval 0.25-6.57. Although the number and quality of the studies included are limited, we thought it important to present the existing data. More extensive controlled studies are urgently needed in order to increase the significance of our study.
In a crossover design, control of blood pressure by extended release felodipine was compared with control by prolonged action nifedipine in 21 children with renal hypertension. Compliance with once daily felodipine was higher than with nifedipine, at 95.6 (SEM 2.7)% v 78.9 (6.0)% (p = 0.02). Mean diastolic blood pressure was lower during the day with felodipine than with nifedipine, at 77.6 (2.4) v 84.4 (2.8) mm Hg (p = 0.05). Similarly, blood pressure load (the percentage of the day during which the child had blood pressure exceeding the upper limits of normal for age) was lower for felodipine than for nifedipine: 43.5 (5.5)% v 61.3 (6.3)%. There was an opposite trend during the night, though this did not reach statistical significance. These data suggest that once a day felodipine is effective in children with hypertension. This may be because of improved compliance.
OBJECTIVE: To determine the effect of misoprostol, a synthetic prostaglandin E1 analogue, on the gastrointestinal tract (GIT) symptoms associated with non-steroidal anti-inflammatory drug (NSAID) administration and on the haemoglobin value, in children. METHODS: Retrospective chart review of children attending the paediatric rheumatology clinic at a tertiary referral hospital over a three year period, who were receiving NSAIDs and were prescribed misoprostol for treatment of GIT symptoms or anaemia. RESULTS: Twenty five children (mean age 12.0 (SD 2.8) (range 7-17) years were prescribed misoprostol (mean dose 308.4 (76.5) micrograms/m2/day; 9.8 (2.5) micrograms/kg/day) while NSAID therapy was continued. Of the 22 (88%) patients with GIT complaints, 18 (82%) had complete resolution of symptoms and two (9%) had some improvement. Four patients (18%) had a recurrence of symptoms after initial resolution while still receiving misoprostol. Misoprostol therapy was associated with a statistically significant increase in haemoglobin concentration (mean value before misoprostol 115 (18) g/l; after misoprostol 126 (15) g/l (p = 0.02)). The only adverse effect reported was self limited diarrhoea in one child. CONCLUSION: Misoprostol appeared to be effective in the treatment of GIT symptoms in children receiving NSAIDs and to result in significant increase in the haemoglobin concentration. Further prospective studies are needed to evaluate the role of misoprostol therapy for NSAID associated GIT complaints in the paediatric population.
The skin and liver may be targets for cytotoxicity induced by oxidative drug metabolites. We used human epidermoid A431 cells and human hepatoblastoma Hep G2 cells as the experimental model. The aim of the study was to investigate and evaluate the effect of silymarin on acetaminophen (APAP)-induced toxicity under controlled conditions. Silymarin is known to be a potent antioxidant that diminishes toxicity induced by a variety of other hepatotoxins (e.g. Amanita phaloides, algae's toxins, carbon tetrachloride). Glutathione (GSH) depletion was enhanced by adding to the medium buthionine sulfoximine [L-buthionine-(S,R)-sulfoximine, BSO]. Cells were incubated with high-concentration 5-20 mM APAP or alpha-(minimum essential medium for 2-24 h to evaluate the drug's ability to reduce cytoviability. Viability was then quantitated by metabolism of the tetrazolium dyes (MTT) and neutral red (NR). Cytoviability was 100% for controls. For Hep G2 treated for 24 h with 20 mM, APAP viability was 56.0% by MTT and 62.5% by NR. BSO-treated cells showed an enhanced cytotoxicity, determined by both assays. Administration of 0.5 mM silymarin reduced cytotoxicity significantly. In A431 cells, treatment with 20 mM APAP reduced viability by 57% (MTT) and 69% (NR) versus control (100%). BSO further decreased viability. Since incubation with silymarin showed significant protection against APAP toxicity, it can be considered a cytoprotective agent in this in vitro model of drug toxicity. GSH concentrations in both cell lines decrease significantly after exposure to 20 mM APAP, or 0.5 mM versus control (p < 0.05), and increased (p < 0.001) if incubated with APAP and silymarin. The protective effect could be through mitochondrial membrane stabilization and/or an increase in available GSH.
EMLA (eutectic mixture of lidocaine and prilocaine) cream is currently not recommended for use in infants < 1 month of age because of the potential risk of methemoglobinemia as a result of the o-toluidine metabolite of prilocaine. We studied bioavailability and changes in methemoglobin levels following topical penile exposure to 1 g of EMLA cream for 1 hour in piglets. Lidocaine, prilocaine, and o-toluidine concentrations were measured simultaneously using a high-performance liquid chromatography method. The systemic bioavailability of EMLA was low: 4.0 +/- (SD) 4.7% for lidocaine (range 0-13.6; n = 8) and 7.2 +/- 5.7% for prilocaine (range 0-14.5; n = 8). The ratio between exposure to o-toluidine with EMLA versus intravenous administration (i.e., AUCEMLA/AUCIV; see text) was also low: 4.2 +/- 9.3% (range 0-28.6; n = 9). The mean maximum methemoglobin value after intravenous administration was 1.23 +/- 0.64% (range 0.5-3.0; n = 12) and after penile application 0.99 +/- 0.36% (range 0.5-2.0; n = 12). The methemoglobin value was elevated significantly above baseline after intravenous administration (p = 0.03), but not after penile application of EMLA. These findings suggest that penile administration of 1 g of EMLA may be safe for neonatal circumcision, but further study is required.
Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
We describe six children with acute decreases in heart rate temporally related to amphotericin B administration. All patients had achieved their maximal dose within 3 to 4 days. Heart-rate drops occurred as early as day 3 but could be delayed up to day 7 after start of therapy. The mean heart rate dropped from 104 +/- 8/min (range 96 to 114) to 62 +/- 8/min (range 48 to 72) (P = 0.0001). A slower heart rate than baseline was noted during the entire duration of drug administration, from 60 minutes of starting the infusion to 220 minutes (mean 120 +/- 40) after discontinuation of the infusion. This reaction was noted in six of 90 (6.7%) patients who had amphotericin. These six children were compared with six age-matched children who received the drug but in whom such changes in heart rate did not develop. The method of administration of amphotericin B was similar in both patients and controls, starting with 0.25 mg/kg/day and increasing by 0.25 mg/kg/day up to 1 mg/kg/day. Children with heart-rate drop received amphotericin for 4.6 +/- 1.8 days, significantly shorter than their controls (12.6 +/- 6.9 days) (P = 0.02), suggesting that this adverse effect has led to early discontinuation of amphotericin therapy. Physicians and nurses caring for children receiving amphotericin B should be aware of this potential adverse effect, which can be serious in a patient with an underlying heart condition or in a patient who is already on heart-rate-lowering drugs.
PURPOSE: An unusually high incidence of anaphylactoid reactions was observed during a phase I/II trial of high-dose intravenous cyclosporine (CsA) therapy to attenuate tumor multidrug resistance (MDR). Five of 21 children experienced severe anaphylactoid reactions shortly after initiation of the first or second CsA infusion. We hypothesized that improper dissolution of the vehicle Cremophor EL may have been a cause for these anaphylactoid reactions. METHODS: All nurses who had administered intravenous CsA were interviewed regarding their technique of preparing the infusion and the occurrence of an anaphylactoid reaction. The responses were statistically analyzed. The effect of various mixing techniques on the distribution of Cremophor EL in the infusion was experimentally evaluated. Different mixing techniques were used to assess their effect on the distribution of Cremophor EL in the solution. RESULTS: Analysis of the preparation techniques of the CsA infusion showed significant correlation between suboptimal mixing of CsA by nurses and the occurrence of anaphylactoid reactions (P = .02). Experimental simulation showed that suboptimal mixing results in an uneven distribution of Cremophor EL, which subsequently sinks to the bottom of the vial. CONCLUSION: Improper mixing of high-dose CsA infusions causes nonsolubilized Cremophor EL to sink to the outflow area of the bottle. An initial bolus infusion of highly concentrated Cremophor EL may produce an anaphylactoid-like response. This mechanism of toxicity is important to recognize, because it is easily preventable by proper preparation of the infusion, thus reducing the incidence of potentially life-threatening anaphylactoid reactions.