Doreen Matsui

Iron-chelation therapy with oral deferiprone in patients with thalassemia major

BACKGROUND To determine whether the orally active iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyridin-4-one) is efficacious in the treatment of iron overload in patients with thalassemia major, we conducted a prospective trial of deferiprone in 21 patients unable or unwilling to use standard chelation therapy with parenteral deferoxamine. METHODS Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens or magnetic-susceptibility measurements. Detailed clinical and laboratory studies were used to monitor safety and compliance. RESULTS The patients received deferiprone therapy for a mean (+/-SE) of 3.1 +/- 0.3 years. Ten patients in whom previous chelation therapy with deferoxamine had been ineffective had initial hepatic iron concentrations of at least 80 mumol per gram of liver, wet weight -- values associated with complications of iron overload. Hepatic iron concentrations decreased in all 10 patients, from 125.3 +/- 11.5 to 60.3 +/- 9.6 mumol per gram (P < 0.005), with values that were less than 80 mumol per gram in 8 of the 10 patients (P < 0.005). In all 11 patients in whom deferoxamine therapy had previously been effective, deferiprone maintained hepatic iron concentrations below 80 mumol of iron per gram. CONCLUSIONS Oral deferiprone induces sustained decreases in body iron to concentrations compatible with the avoidance of complications from iron overload. The risk of agranulocytosis associated with deferiprone may restrict its administration to patients who are unable or unwilling to use deferoxamine.

A Multicentre Prospective Controlled Study to Determine the Safety of Trazodone and Nefazodone Use during Pregnancy

Objectives: Trazodone and nefazodone are phenylpiperazine antidepressants. Currently, there are no adequate, well-controlled studies on the fetal safety of these drugs. Our primary objective was to determine whether the use of trazodone or nefazodone during pregnancy is associated with an increased risk for major malformations. Secondary outcomes of interest included rates of spontaneous and therapeutic abortions, rates of premature labour, and birth weight. Methods: Pregnant women from 5 centres who had been exposed to these drugs (n = 147) were enrolled in the study during their first trimester. We compared the women with 2 groups of women who took either other antidepressant drugs (n = 147) or nonteratogenic drugs (n = 147). All the women were followed up after delivery to ascertain pregnancy outcome and the health of the baby Results: We have completed 147 follow-ups. There were 121 (82.4%) live births, 20 (13.6%) spontaneous abortions, and 6 (4%) therapeutic abortions. Of the live births, there were 2 (1.6%) major malformations. In all cases, drug exposure occurred during the first trimester, with 52 (35%) of the women using these drugs throughout pregnancy. The mean gestational age at birth was 38 weeks (SD 4.2), and the mean birth weight was 3306.34 g (SD 655). We found no statistically significant differences among the 3 groups in any of the endpoints of interest that we examined. Of the sample, 58 women were exposed to trazodone, and 89 were exposed to nefazodone. Conclusion: Our results suggest that these drugs do not increase the rates of major malformations above the baseline rate of 1% to 3%.

Is maternal use of selective serotonin reuptake inhibitors in the third trimester of pregnancy harmful to neonates

1Physicians were advised to taper the dosage of antidepressants in pregnant women during the last trimester so that the fetus receives no drug for at least 7–10 days before delivery. A month later, Health Canada followed suit; the Canadian advisory 2 similarly suggested that “Physicians may consider slowly decreasing the dose of these medications in the third trimester.” These advisories were based on “reports reveal[ing] that some newborns whose mothers took these medications during pregnancy have developed complications at birth.” 2 These complications were seen as consistent with withdrawal symptoms or a direct adverse effect by the antidepressant on the baby. We believe those recommendations are only partially evidence-based and may put the depressed mother-to-be and her baby at an unreasonable health risk. This paper presents a brief discussion of the pattern of neonatal symptoms observed after maternal use of selective serotonin or serotonin–norepinephrine reuptake inhibitors (SSRIs or SNRIs, respectively).

Pregnancy outcome following first trimester exposure to sumatriptan

We prospectively compared pregnancy outcome after exposure to sumatriptan with that of disease-matched controls and nonteratogen controls. There were no differences in the rates of live births, spontaneous abortions, therapeutic abortions, or major birth defects among the three groups. This first prospective report suggests that the use of sumatriptan during organogenesis is not associated with an apparent increased risk of major birth defects.

Pregnancy outcomes following gabapentin use: Results of a prospective comparative cohort study

Objectives: Our objectives were to 1) determine whether first-trimester use of gabapentin is associated with an increased risk for major malformations; 2) examine rates of spontaneous abortions, therapeutic abortions, stillbirths, mean birth weight and gestational age at delivery; and 3) examine rates of poor neonatal adaptation syndrome following late pregnancy exposure. Methods: The study design was prospective. Women were included who initially contacted the services between 5 and 8 weeks with a comparison group of women exposed to nonteratogens, collected in a similar manner. Results: We have data on 223 pregnancy outcomes exposed to gabapentin and 223 unexposed pregnancies. The rates of major malformations were similar in both groups (p = 0.845). There was a higher rate of preterm births (p = 0.019) and low birth weight <2,500 g (p = 0.033) in the gabapentin group. Among infants who were exposed to gabapentin up until delivery, 23 of 61 (38%) were admitted to either the neonatal intensive care unit or special care nursery for observation and/or treatment, vs 6 of 201 (2.9%) live births in the comparison group (p < 0.001). There were 2 cases of possible poor neonatal adaptation syndrome in neonates exposed to gabapentin close to delivery, compared with none in the comparison group, although it must be noted that these infants were concomitantly exposed to other psychotropic drugs. Among the women who took gabapentin, the major indications were pain (n = 90; 43%) and epilepsy (n = 71; 34%); the remainder were for other indications, mostly psychiatric. Conclusion: Our results suggest that although this sample size is not large enough to make any definitive conclusions, and there was no comparator group treated with other antiepileptic drugs, gabapentin use in pregnancy does not appear to increase the risk for major malformations. This finding and the increased risk for low birth weight and preterm birth require further investigation.

Translational Research in Pediatrics: Tissue Sampling and Biobanking

Translational research is expanding and has become a focus of National Research funding agencies, touted as the primary avenue to improve health care practice. The use of human tissues for research on disease etiology is a pillar of translational research, particularly with innovations in research technologies to investigate the building blocks of disease. In pediatrics, translational research using human tissues has been hindered by the many practical and ethical considerations associated with tissue procurement from children and also by a limited population base for study, by the increasing complexities in conducting clinical research, and by a lack of dedicated child-health research funding. Given these obstacles, pediatric translational research can be enhanced by developing strategic and efficient biobanks that will provide scientists with quality tissue specimens to render accurate and reproducible research results. Indeed, tissue sampling and biobanking within pediatric academic settings has potential to impact child health by promoting bidirectional interaction between clinicians and scientists, helping to maximize research productivity, and providing a competitive edge for attracting and maintaining high-quality personnel. The authors of this review outline key issues and practical solutions to optimize pediatric tissue sampling and biobanking for translational research, activities that will ultimately reduce the burden of childhood disease.

Physicians' attire as perceived by young children and their parents: the myth of the white coat syndrome.

Objective To determine if young children have a preference regarding whether physicians do or do not wear a white coat Methods One hundred one children, ages four to eight years, and their parents were recruited from the outpatient setting of a pediatric referral center. Two pairs of photographs, the same man with and without a white coat and the same woman with and without a white coat, were shown to the children and their parents, and both were asked which of each pair they would like to have as their or their childs doctor, respectively. Parents filled out a questionnaire rating the appropriateness of various aspects of a physicians attire and appearance. Results The children selected the person in the white coat 69% of the time. The parents also selected the white coat more often (66%). On the questionnaire parents identified a name tag as the most appropriate item of dress followed by a white coat A groomed mustache and groomed beard were also rated favorably. Open-toed sandals, clogs, and shorts were rated negatively, while parents were neutral with respect to hospital greens, blouse and skirt or dress, and shirt and tie. Conclusions Physicians may wear a white coat without fear that they are negatively affecting their relationship with their pediatric patients four to eight years of age. The appropriateness of wearing a name tag is confirmed.

Adherence with drug therapy in pregnancy.

Available information suggests that nonadherence with medication is a common problem in pregnant women. Not taking prescribed drugs may have potentially negative consequences as patients may not achieve their therapeutic goal. In addition to the many factors that may influence medication-taking behaviour in the general population, unique challenges are encountered in pregnant women as both maternal health and fetal well-being must be considered. On the one hand, pregnant women may be motivated to keep their underlying disease under control, while, on the other hand, fear and anxiety regarding the potential harmful effects of their medication on their unborn child may result in poor adherence with needed medication. Providing evidence-based information, ideally preconceptually, regarding the effects of their medication during pregnancy may be important in avoiding misperceptions that lead to nonadherence.

Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: Pharmacokinetic characteristics

Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 +/- 2.6 (mean +/- S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 +/- 1.0 (range 0.5-2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m2 of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity.

Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers.

Objective To evaluate the palatability of 4 common flavoring vehicles (water, chocolate milk [CM], orange juice [OJ], and cola) combined with activated charcoal (AC) in pediatric volunteers. Design A single-blind taste test of 4 different vehicles (water, OJ, a cola drink, and CM) was conducted in healthy volunteer children. Each child tasted 1.25 mL of Charcodote® (0.2g/mL) mixed with 1.25 mL of each vehicle. Setting Palatability testing was conducted at the office of 1 of the authors. Participants Thirty children (16 male, 14 female), aged 6.5 ± 1.4 years (range 5–9 years). Outcome Measures After each test dose, each child rated its taste on a modified 10 cm visual analog scale incorporating a facial-hedonic scale. Each child was also asked for his/her overall preference. Results Taste scores (cm) were as follows: water 5.6 ± 1.8, OJ 5.4 ± 1.0, cola 7.6 ± 0.7, and CM 5.6 ± 0.8. There was a significant difference in the taste scores between the cola drink (P = 0.01) and the other 3 vehicles. The cola drink was also selected as the most preferred vehicle by 50% of the children as compared with 19.2% for CM and 15.4% for OJ. In contrast, water was selected as the least preferred vehicle by 36.4% of children versus 31.8% for CM and 27.3% for OJ. Only 4 children (15.4%) stated that water was their preferred vehicle, and only 1 child (4.5%) stated that cola drink was the least preferred drink. Conclusions Children rate the palatability higher and prefer charcoal given with a cola drink rather than with water. OJ and CM do not seem to improve the acceptability of charcoal.