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Biomedical subjects

Gideon Koren

Publications and source records attributed to Gideon Koren.

At least 127 records · Page 7Linked to original sources
PubMed2004

How physicians perceive and utilize information from a teratogen information service: the Motherisk Program.

BACKGROUND: Teratogen information services have been developed around the world to disseminate information regarding the safety of maternal exposures during pregnancy. The Motherisk Program in Toronto, Canada, fields thousands of these inquiries per year. Our primary objective was to evaluate the perception and utilization of information received from us by physicians. Our secondary objective was to examine their information seeking behavior, in particular regarding teratogen information. METHODS: A one page survey was sent to physicians who had called Motherisk for information concerning pregnancy exposures in the previous 30 days for three months. Among the questions that were asked were demographics, which included gender, years in practice, specialty, information resources, and how they utilized the information received from Motherisk. RESULTS: We received 118/200 completed questionnaires (59% response rate). The mean age of the respondents was: 42 +/- 9 years, mean years of practice was: 14 +/- 8 years, males: 46(38%) and females 72(62%) and 95(80%) were family physicians. 56(48%) researched their question prior to calling Motherisk, 106(91%) and passed on the information received to their patient verbatim. The top four resources for information were: 1) The CPS (PDR), 2) textbooks, 3) journals and 4) colleagues. Only 8% used the Medline for gathering information. CONCLUSIONS: Physicians feel that a teratogen information service is an important component in the management of women exposed to drugs, chemicals, radiation and infections diseases etc. during pregnancy. Despite the advent of the electronic age, a minority of the physicians in our survey elected to use electronic means to seek information.

Adult↗
PubMed2004

Effects of age, gender and holding on pain response during infant immunization.

Determinants of infant pain responses are important when assessing the efficacy of analgesics. In a randomized controlled trial, 106 infants aged 2 to 6 months were positioned either supine (SUP) on the examination table or held (HLD) by a parent during routine immunization in a community pediatric office. There was no difference between the SUP and HLD infants in duration of crying, facial grimacing or visual analogue scale (VAS) pain scores. Similarly gender did not affect pain response. In contrast, 2-month-old infants displayed more pain during immunization than did 4 or 6-month-old infants.

Age Factors↗
PubMed2004

Welcome to cyberspace.

In April 2004, The Canadian Journal of Clinical Pharmacology has become the first peer review, Medline journal in therapeutics to have free access on the Internet. The address is www.cjcp.ca.

Access to Information↗
PubMed2004

Placental handling of fatty acid ethyl esters: perfusion and subcellular studies.

The measurement of fatty acid ethyl esters (FAEE) in neonatal meconium is a novel test to confirm prenatal ethanol exposure. The origin of FAEE in the maternal-placental-fetal unit is not known. The objectives of this study were to investigate whether FAEE are transferred and metabolized by the human placenta. Isolated placental cotyledons were perfused with a mixture of four FAEE (palmitic, stearic, oleic, and linoleic acid ethyl esters) commonly detected in the meconium of neonates exposed to ethanol in utero, and the transfer of FAEE to the fetal unit was investigated in the absence and presence of albumin. The metabolic degradation of FAEE by human placental microsomes was subsequently determined. FAEE disappeared from the maternal circulation but remained undetectable in the fetal unit following perfusions. The addition of albumin had no effect on FAEE transfer. The unrecoverable fraction of individual FAEE in the perfusion system accounted for >50% of the initial amount used, suggesting significant metabolic degradation. Subcellular studies documented the enzymatic degradation of FAEE by placental microsomes (mean Km, 35-95 microM; Vmax, 0.6-1.8 nmol/min/mg for individual FAEE). FAEE at levels found in alcoholics that are originated from the mother are not transferred to the fetus because they are taken up and degraded extensively by the human placenta. Hence, FAEE detected in neonatal matrices are likely produced by the fetus from ethanol that has been transferred to and metabolized by the fetus, rendering FAEE a powerful direct biomarker reflective of true fetal exposure to ethanol in utero.

Albumins↗
PubMed2004

Single-channel recordings of a rapid delayed rectifier current in adult mouse ventricular myocytes: basic properties and effects of divalent cations.

The rapidly delayed rectifier current (I(Kr)) has been described in ventricular myocytes isolated from many species, as well as from neonatal mice. However, whether I(Kr) is present in the adult mouse heart remains controversial. We used cell-attached patch-clamp recording in symmetrical K(+) solutions to assess the presence and behaviour of single I(Kr) channels in adult mouse cardiomyocytes (mI(Kr)). Of 314 patches, 158 (50.1%) demonstrated mI(Kr) currents as compared with 131 (42.3%) for the I(K1) channel. Single mI(Kr) channel activity was rarely observed at potentials positive to -10 mV. The slope conductance at negative potentials was 12 pS. Upon repolarization, ensemble-averaged mI(Kr) showed slow deactivation with a biexponential time course. A selective I(Kr) blocker, E-4031 (1 microm), completely blocked mI(Kr) channel activity. Extracellular Ca(2+) and Mg(2+) at physiological concentrations shifted the activation by approximately 30 mV, accelerated deactivation kinetics, prolonged long-closed time, and reduced open probability without affecting single-channel conductance, suggesting a direct channel-blocking effect in addition to well-recognized voltage shifts. HERG subunits expressed in Chinese hamster ovary cells produced channels with properties similar to those of mI(Kr), except for the more-negative activation of the HERG channels. Despite the abundant expression of mI(Kr), single-channel events were rarely observed during action-potential clamp and 5 microm E-4031 had no detectable effect on the action potential parameters, confirming that mI(Kr) plays at best a minor role in repolarization of adult mouse cardiomyocytes, probably because the modulatory effects of divalent cations prevent significant mI(Kr) opening under physiological conditions.

Animals↗
PubMed2004

Child neurodevelopmental outcome and maternal occupational exposure to solvents.

BACKGROUND: Many women of reproductive age are employed in industries involving exposure to organic solvents. Animal toxicological studies and human case reports demonstrate that high exposure to solvents causes neurodevelopmental toxicity in exposed offspring. Data from occupationally exposed women and their children are few. OBJECTIVE: To compare the cognitive, language, and motor performance and the behavioral achievements of children whose mothers were exposed occupationally to organic solvents during pregnancy with those of a matched unexposed control group. PARTICIPANTS: Thirty-two pregnant women occupationally exposed to organic solvents were recruited during pregnancy and followed up. Their offspring (age range, 3-9 years) were tested for cognitive functioning (IQ), language, visual-motor functioning, and behavioral functioning and were compared with a matched unexposed control group that was recruited and tested in a similar manner. Examiners were blinded to the exposure status. RESULTS: Mothers occupationally exposed to organic solvents did not differ significantly from matched controls in demographic variables. After controlling for potential confounding because of maternal IQ and maternal education, children exposed in utero to organic solvents obtained lower scores on subtests of intellectual, language, motor, and neurobehavioral functioning. CONCLUSIONS: In utero exposure to organic solvents is associated with poorer performance on some specific subtle measures of neurocognitive function, language, and behavior. Reducing exposure in pregnancy is merited until more refined risk assessment is possible. Further studies that address exposure to specific solvents, dose, and gestational timing of exposure are needed.

Case-Control Studies↗
PubMed2004

Is lack of morning sickness teratogenic? A prospective controlled study.

BACKGROUND: Case-control studies have suggested that the nausea and vomiting of pregnancy (NVP) may have a protective effect against specific malformations. These suggestions have been interpreted as if the lack of NVP may put mothers at an increased teratogenic risk. METHODS: A prospective, cohort-controlled study was done comparing pregnancy outcome in women not experiencing NVP with those experiencing NVP at two levels of clinical severity. Women who called the Motherisk program about first-trimester exposure to drugs and who had not experienced NVP were included as the study group. The NVP Healthline enrolled two control groups of women with NVP treated with a doxylamine-pyridoxine combination for morning sickness. These women were exposed during the first trimester of gestation to either higher than the standard dose (5-12 tablets/day) or a standard dose (1-4 tablets/day) of doxylamine-pyridoxine. The women in all three groups were followed up four to six months after the expected date of birth to ascertain pregnancy outcomes and child health. RESULTS: There were no major malformations among offspring of 130 women not experiencing NVP. There were two major malformations among 246 women experiencing NVP. The two control groups of women with NVP had similar distributions of gestational ages, birth rates, as well as rates of miscarriages and stillbirths, as in the no-NVP group. CONCLUSIONS: This study did not show an association between lack of NVP and an increase in the overall rates of major malformations.

Adult↗
PubMed2004

Recall bias of the symptoms of nausea and vomiting of pregnancy.

OBJECTIVE: Nausea and vomiting of pregnancy is the most common medical condition in pregnancy. Relatively little research has been conducted on this condition, and much of it is based on women's reports. Determinants that affect women's reports of their nausea and vomiting of pregnancy symptoms have not been elucidated. The purpose of this study was to assess the accuracy of recall by women of their symptoms of nausea and vomiting of pregnancy. STUDY DESIGN: Two hundred women who called the Motherisk nausea and vomiting of pregnancy counseling line in Toronto were asked about the severity of their nausea and vomiting of pregnancy symptoms with the use of the pregnancy unique quantification of emesis and nausea system (PUQE). The patients were asked the same questions again during a follow-up call, which took place up to 16 weeks later. RESULTS: There was a recall (or reporting) bias for nausea and vomiting, with women reporting significantly more severe symptoms during their follow-up call than they had reported originally. Multivariate analysis revealed that the severity of the symptoms affected the accuracy of recall positively, whereas the time that has elapsed affected it negatively. CONCLUSION: Retrospective evaluation of nausea and vomiting of pregnancy symptoms may produce a recall bias, which may distort the evaluation of the therapeutic effectiveness of antiemetics.

Female↗
PubMed2004

In vitro analysis of human transplacental transport of desmopressin.

OBJECTIVE: Desmopressin (DDAVP) therapy may be required during pregnancy, but there are limited data about its safety. We wished to verify whether DDAVP is transported across the human placenta. METHODS: Using the in vitro human placental cotyledon perfusion model, we performed serial measurements of maternal and fetal DDAVP concentrations. After introducing the drug into the maternal circulation at estimated baseline therapeutic (30 pg/ml) and supratherapeutic (16,000 and 60,000 pg/ml) concentrations, we measured the rate of transplacental drug transfer up to 2 h. RESULTS: There was no detectable transport of DDAVP at a 30 pg/ml concentration, and the maternal drug concentration remained stable over time. At a much higher maternal concentration of 60,000 pg/ml, the mean peak fetal DDAVP concentration was 2990 pg/ml, equivalent to 4.8% of the baseline maternal concentration. CONCLUSION: At a therapeutic maternal drug concentration, DDAVP does not appear to cross the placenta within detectable limits. At much higher drug concentrations, DDAVP may cross the placenta in a small amount. Future in vitro clinical studies should attempt to reproduce these findings.

Biological Transport↗
PubMed2004

Recent developments in meconium and hair testing methods for the confirmation of gestational exposures to alcohol and tobacco smoke.

The use of alcohol and tobacco is prevalent among pregnant women despite the well-known adverse effects of these substances imposed on the developing fetus and immense public health education efforts. Confirmation of gestational exposures to these compounds have relied mostly on maternal self-reporting, which is often underestimated because of guilt, embarrassment, and fear of punitive action. The presence of fatty acid ethyl esters in various biological matrices as a result of alcohol consumption initiated the development of neonatal screening tests for these emerging biological markers in meconium and hair. The levels of nicotine and cotinine in hair have long been used as objective indices for the quantification of exposure to active and passive smoking. Maternal segmental hair analysis in the study of pharmacokinetic changes in nicotine metabolism in the obstetric population is a novel application of this traditional analytical method. The latest developments and novel applications of meconium and hair testing for the confirmation of prenatal alcohol and tobacco exposure are discussed in this review.

Alcohol Drinking↗
PubMed2004

Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease.

BACKGROUND: The etiology of acute chest syndrome, the most severe complication of the sickle cell crisis, is unknown. OBJECTIVE: Our objective was to assess exposure to morphine as an etiologic factor for acute chest syndrome in sickle cell disease. METHODS: A post hoc analysis of a randomized controlled trial comparing oral with continuous infusion of morphine was performed. Children (aged 5-17 years) with sickle cell crisis were randomized to receive oral sustained-release morphine, 1.9 mg. kg(-1). 12 h(-1), or a continuous intravenous infusion of morphine at 0.04 mg. kg(-1). h(-1) by use of a double-blind, placebo-controlled design. In a subgroup of 15 patients, the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide were also studied. RESULTS: At baseline, demographic and physiologic characteristics were similar between groups. There were no differences in the number of previous rescue doses per day, painful sites per episode, physician contacts per year, and hospitalizations per year between treatment arms. There was a 2-fold higher morphine area under the concentration-time curve at steady state (AUC(ss)) and a 3-fold higher morphine-6-glucuronide AUC(ss) with oral morphine than with a continuous intravenous infusion of morphine (P <.001 and P <.006, respectively). New onset of acute chest syndrome was 3-fold more prevalent in the oral group (57%) versus the continuous intravenous infusion group (17%) (P <.001). CONCLUSIONS: The risk of acute chest syndrome is significantly associated with high systemic exposure to morphine and its active metabolite morphine-6-glucuronide after oral administration of slow-release morphine. Morphine may facilitate respiratory deterioration by eliciting a decrease in oxygen saturation, by inducing histamine release, or through an as-yet-unidentified mechanism. The safe systemic exposure to morphine in terms of area under the concentration-time curve should be further studied in children with sickle cell disease.

Acute Disease↗
PubMed2004

Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde: pharmacokinetic modeling for estimation of intracellular levels.

Ifosfamide (IF) improves survival in children with solid tumors but causes a high rate of nephrotoxicity. We hypothesized that this is caused by an oxidative metabolite of IF, chloroacetaldehyde, which is produced locally by the cells of the renal tubule (RT). For this hypothesis to be viable, one must document that chloroacetaldehyde concentrations in the RT cell are consistent with levels shown to cause nephrotoxicity in experimental systems. Using pharmacokinetic modeling of experimental data, we show that the median level of chloroacetaldehyde in RT cells is 80 micromol/L, ranging from 35 to 320 micromol/L. These concentrations are consistent with levels shown experimentally to cause functional and structural RT damage and lends validity to the hypothesis that local renal production of chloroacetaldehyde causes nephrotoxicity.

Acetaldehyde↗
PubMed2004

Renal ontogeny of ifosfamide nephrotoxicity.

Ifosfamide-induced nephrotoxicity adversely affects the health and well-being of children with cancer. We have recently shown age-dependent nephrotoxicity induced by ifosfamide, with younger children (<3 years) substantially more vulnerable. The mechanisms leading to this age-related ifosfamide-induced renal damage have not been identified. Underlying this work is the hypothesis that renal ontogeny is involved in the expression and activity of the cytochrome P450 (CYP) enzymes responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. We evaluated renal CYP3A and 2B22 activity in pigs between the ages of 1 day and adulthood, as well as the metabolism of ifosfamide by renal microsomes to 2- and 3-dechloroethylifosfamide (2-DCEIF and 3-DCEIF, respectively). Kidney CYP3A messenger RNA expression peaked 15 to 60 days (0.7-76 +/- 0.19 CYP3A/actin ratio; P < 0.001). Subsequently, this level decreased to adult values (0.54 - 0.03 CYP3A/actin ratio; P = 0.04). Similarly, we detected an increase in the ifosfamide-metabolism rate between young (18 +/- 2 pmol/mg protein/min) and adult (12.2 +/- 0.17 pmol/mg protein/min) animals (P = 0.002). Ours is the first documentation of ontogeny of renal CYP3A and of renal ifosfamide metabolism. These data suggest that age-dependent ifosfamide nephrotoxicity is, at least in part, due to ontogeny in the production chloroacetaldehyde.

Acetaldehyde↗
PubMed2004

Elimination kinetics of ethanol in pregnant women.

To evaluate the pharmacokinetics of ethanol in the early second trimester of pregnancy, ethanol concentrations simultaneously measured in the maternal blood (EtOH-MB) and in the amniotic fluid (EtOH-AF) of six pregnant women were obtained from a previous study in which a single ethanol dose of 300mgkg(-1) body weight was administered orally. For maternal blood ethanol concentration, the kinetic equation was: [Formula: see text] where k(12) and k(21) are, respectively, the rate constant of ethanol transfer from either the central compartment to the peripheral compartment or vice versa; V(max)(EtOH)is the maximal velocity for ethanol oxidation; and K(m)(EtOH) is the concentration at which half of the maximal rate of ethanol elimination is reached. The maximum concentration of EtOH in AF was 60% lower than in MB (P=0.36). However, the AUC(0-3.5h) in AF was only 16% lower than the value for MB (P=0.059). The k(12) (0.20 =/- 0.26 h(-1)) was almost twice faster than k(21) (0, h(-1)). The V(max)(EtOH) was 237.6 +/- 71.5 microgml(-1)h(-1) and K(m)(EtOH) was 3.7 +/- 4.7 microgml(-1). Our results imply that in the early second trimester, ethanol metabolism is fast. However, ethanol clearance from the AF is slower than ethanol clearance in MB. This process is widely variable, and our findings may partially explain the wide variability of ethanol's toxic effects on the fetus.

Acetaldehyde↗
PubMed2004

Iron bioavailability in prenatal multivitamin supplements with separated and combined iron and calcium.

OBJECTIVE: To compare iron absorption of a prenatal multivitamin supplement containing both iron and calcium (HICA) to that of another multivitamin containing a lower iron dose and no calcium (LI). METHODS: In a crossover study, serum iron was measured in 12 healthy women administered HICA and LI separately on 2 different occasions. Blood samples were taken at 0, 1, 2, 3, 4, 6, and 8 hours after administration of each supplement. RESULTS: The values of the area under the concentration-time curve (AUC) were not significantly different between LI (79.1 +/- 36.0 micro M*h) and HICA (91.4 +/- 50.4 micro M*h) (P =.37). After standardizing the AUC for dose, the relative absorption over the 8-hour time period was significantly higher for LI (2.3 +/-.0 micro M*h/mg) than for HICA (1.5 +/- 0.8 micro M*h/mg) (P =.021). CONCLUSION: The absorption of iron from a low-iron-containing supplement was similar to that from a supplement with almost twice the amount of iron, due possibly to the exclusion of calcium in the LI product. Thus, while offering similar amounts of iron, the LI supplement may be better tolerated by women who are sensitive to iron-induced adverse effects.

Adolescent↗