Search PubMed⌕ Search

Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 487 records · Page 27Linked to original sources
PubMed1991

Monitoring adverse drug reactions in pregnancy and lactation; the motherisk model.

The Motherisk Program represents a new clinical approach to the problems of estimating reproductive risk following exposure to drugs, chemicals and radiation. While the primary goal is to provide a much needed service to women and their physicians, a prospective database enables us to collect information on pregnancy outcome following exposure to agents on which there are no data.

Adverse Drug Reaction Reporting Systems↗
PubMed1991

The transport of digoxin across the perfused human placental lobule.

The cardiac glycoside, digoxin, is clinically used to treat fetal tachyarrhythmias and congestive heart failure. The time course of digoxin transfer across the human placenta was studied by dually perfusing an isolated lobule of the human placenta in vitro. Viability of the placental preparation was validated by measuring the rates of glucose and oxygen consumption, lactate production and synthesis of the protein hormone, chorionic gonadotropin. Following administration of 5 ng/ml digoxin to the maternal circulation, digoxin appeared in the fetal circulation within 5 min. The disappearance of digoxin from the maternal circulation was biexponential and best fit a two-compartment pharmacokinetic model. Mean calculated volume of the central compartment (257 +/- 6.3 ml) was consistent with the actual volume of the in vitro maternal circulation (246 +/- 7.4 ml). The half-life of the distribution phase was 9.7 +/- 3.3 min, and half-life of the terminal elimination phase was 362 +/- 83 min. After 30 min of perfusion, the amount of digoxin leaving the maternal circulation and appearing in the fetal circulation was constant at a fetomaternal mass ratio of 0.36 +/- 0.04. This ratio was maintained through to the end of the 3-hr experiment. All of the digoxin leaving the maternal circulation could be accounted for either in the fetal circulation or bound to placental tissue. The time to achieve equal concentrations on both sides of the placenta was estimated to be 268 +/- 34 min. These data are consistent with in vivo data obtained in humans, and support the relevance of using the in vitro placental perfusion model to obtain information regarding placental drug transfer in humans.

Digoxin↗
PubMed1991

Pregnancy-induced changes in drug metabolism in epileptic women.

The pharmacokinetics of antiepileptic drugs may be altered during pregnancy, resulting in decline of serum concentrations and subsequent suboptimal control of seizures. We investigated changes which may occur during pregnancy in hepatic drug handling by comparing metabolic ratios of 15 pregnant epileptic women to 15 nonpregnant epileptic women, as well as 10 pregnant nonepileptic and 10 nonpregnant nonepileptic controls. We used the caffeine test to describe several enzyme activities: P450 1A2, xanthine oxidase, n-acetyltransferase and hydroxylation. For this end, ratios were calculated among a number of metabolites of the main demethylation pathway of caffeine. In addition, we measured D-glucaric acid excretion for specific characterization of antiepileptic drug metabolism. Paired comparison of epileptic women in late pregnancy and six to eight weeks post partum revealed statistically significant decreases in P450 1A2, xanthine oxidase and n-acetyltransferase activities, and a significantly increased hydroxylation activity during pregnancy. Twenty-one of the 30 epileptic women (70%) were found to be fast acetylators, whereas the normal distribution in the nonepileptic control groups was 50%. Excretion of D-glucaric acid was significantly increased in all epileptic patient groups as compared to the matched nonepileptic control groups. Importantly, it was also significantly increased in the pregnant nonepileptic control group as compared to the nonpregnant nonepileptic women. Overall, our results suggest that enzymatic pathways involved in antiepileptic drug metabolism tend to be increased during pregnancy as a potential cause for observed lower serum concentrations of these drugs.

Adult↗
PubMed1990

Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients.

The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) was compared with that of subcutaneous desferrioxamine in 26 patients with transfusional iron overload. Immediately after red-cell transfusion, 20 patients were randomised to receive either desferrioxamine (50 mg/kg daily as a 12 h subcutaneous infusion), or L1 (50 mg/kg daily by mouth). Patients were evaluated during treatment with the other drug after transfusion the next month. Mean (SD) daily urinary iron excretion was lower during L1 than during desferrioxamine (12.3 [6.7] vs 18.2 [15.3] mg/day). In 5 patients the dose of L1 was raised from 50 to 75 mg/kg daily; mean urinary iron excretion rose from 13.8 (7.0) mg/day to 26.7 (17.8) mg/day, comparable with that during desferrioxamine (24.9 [24.3] mg/day). Faecal iron excretion rose slightly over baseline in 6 patients studied during L1 administration (from 8.5 [0.9] mg/day to 12.2 [0.9] mg/day). Pharmacokinetic studies showed an elimination half-life for L1 of 117-237 min. Studies in dogs and in volunteers showed no absorption of the L1-iron complex, excluding a contribution of absorption of intraluminal complexes of L1 and food iron to urinary iron excretion. Further animal toxicity testing is needed before L1 can be studied in a broader group of patients.

Adolescent↗
PubMed1990

Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children.

BACKGROUND: Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse. METHODS: To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted. RESULTS: There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005). CONCLUSIONS: Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Lead exposure among mothers and their newborns in Toronto.

Recent studies have suggested that a fetal blood lead level of 0.48 mumol/L (much lower than 1.21 mumol/L, which is the level previously believed to be toxic to the developing brain) may impair brain development permanently. We measured the maternal and umbilical cord blood levels of lead and free erythrocyte protoporphyrin (FEP) among 95 consecutive mother-infant pairs to determine whether neonates in Toronto are in the high-risk group. There was a significant correlation between the maternal and the cord blood lead levels (r = 0.59, p less than 0.0001). Most (99%) of the infants had cord blood lead levels below 0.34 mumol/L; in 11 cases the levels were below the detection limit of 0.01 mumol/L. The cord blood FEP levels were higher than the maternal levels. The US Centers for Disease Control, Atlanta, currently finds acceptable a blood FEP level of 0.62 mumol/L among children up to 10 years of age; however, this is not applicable to newborns since their higher FEP levels apparently reflect immature heme synthesis and increased erythrocyte volume rather than lead poisoning. Our data suggest that living in Toronto does not impose increased teratogenic risk from intrauterine exposure to lead; however, residents in high-risk areas should be followed up.

Adult↗
PubMed1990

Diurnal variation in the pharmacokinetics and myelotoxicity of mercaptopurine in children with acute lymphocytic leukemia.

During their maintenance therapy, children with acute lymphoblastic leukemia are treated with a daily dose of mercaptopurine for several years. A recent retrospective analysis has suggested that administration of the drug in the evening results in a better prognosis. We compared the disposition pharmacokinetics of mercaptopurine administered in the morning vs in the evening in 13 children with acute lymphoblastic leukemia. Elimination half-life of mercaptopurine was significantly longer in the evening than during the day (423 +/- 142 minutes vs 176 +/- 22 minutes, mean +/- SEM). The area under the concentration-time curve (AUC0-infinity) was significantly larger in the evening (24,713 +/- 3536 ng/mL per minute vs 17,120 +/- 1474 ng/mL per minute). These differences were even more pronounced when comparing the area under the curve of the postdistributive phase (AUC300 min-infinity, 7724 +/- 2955 ng/mL per minute in the evening vs 2597 +/- 712 ng/mL per minute during the day). In a second study, 12 children with acute lymphoblastic leukemia receiving mercaptopurine in the morning had their medication administration switched to the evening. Within 2 weeks there was a sharp fall in peripheral white blood cell counts in all patients (from 4.1 x 10(9)/L to 2.2 x 10(9)/L) mainly due to a drop in polymorphonuclear lymphocytes (from 2.78 x 10(9)/L to 1.05 x 10(9)/L). We conclude that the diurnal variations of mercaptopurine disposition result in clinically important myelotoxicity of the drug.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Prevention of unnecessary pregnancy terminations by counselling women on drug, chemical, and radiation exposure during the first trimester.

As part of a new approach to counselling pregnant women concerned about antenatal exposure to drugs, chemicals, or radiation, we measured their tendency to terminate their pregnancy by using a visual analogue scale (VAS). Analysis of 78 cases where women had less than 50% tendency to continue pregnancy before they were advised by us reveals that 61 decided to continue their pregnancy after the consultation (57 normal, healthy infants, four miscarriages) and 17 terminated. Women who continued their pregnancy significantly changed their tendency after we discussed relevant information with them (from 34.3 +/- 2.5% to 84.5 +/- 3.3%, P less than 0.00001), whereas most of those who eventually terminated pregnancy did not change their tendency to continue pregnancy beyond the 50% mark (from 24.8 +/- 5.4% to 45.1 +/- 9.8%) (P greater than 0.1). Only two of the women who terminated their pregnancy were exposed to teratogenic drugs; however, in most other cases, other obvious reasons, unrelated to the exposure in question, were identified by the women as leading reasons for termination. An appropriate intervention in early pregnancy can prevent unnecessary pregnancy terminations by correcting misinformation and thereby decreasing the unrealistically high perception of risk by women exposed to nonteratogens.

Abortion, Induced↗
PubMed1990

Maternal spermicide use and adverse reproductive outcome: a meta-analysis.

A meta-analysis was performed to determine whether the literature provides evidence that periconceptual or postconceptual maternal use of spermicides is detrimental to the developing fetus. Nine studies that investigated teratogenicity met the inclusion criteria. The Mantel-Haenszel summary odds ratio was 1.02 (95% confidence interval = 0.78 to 1.32). The chi 2 analyses was 0.10 for significance from unity (p = 0.748) and 8.73 for homogeneity of effects (p = 0.365). Studies comparing specific abnormalities with other abnormalities also indicated no association (odds ratio = 0.96; 95% confidence interval = 0.72 to 1.28). Studies investigating other adverse events (spontaneous abortion, stillbirth, reduced fetal weight, prematurity, or increased incidence of female births) showed similar negative results. Cohen's d, the overall effect size as determined by Tukey's jackknife method, was -0.001 (95% confidence interval = -0.018 to 0.017). These results indicate that maternal use of spermicides is not associated with adverse fetal outcomes. Meta-analysis adds quantitative support for conclusions from traditional reviews of the subject.

Female↗
PubMed1990

Lumbar epidural fentanyl infusions for post-thoracotomy patients: analgesic, respiratory, and pharmacokinetic effects.

Ten patients undergoing a thoracotomy were studied for 24 hours postoperatively to determine the effects of a continuous lumbar epidural fentanyl infusion on postoperative pain, arterial blood gases (ABG), respiratory pattern (respiratory inductive plethysmography, RIP), and fentanyl plasma concentration (CONC). Patients served as their own controls because RIP and ABG data were obtained the night prior to surgery during sleep. Epidural fentanyl was administered as a bolus of 1.5 micrograms/kg followed by an infusion of 1.0 micrograms/kg/h started 1 hour after induction. Insufficient analgesia was treated with a bolus of 0.5 micrograms/kg and an infusion increase of 0.25 micrograms/kg/h. Postoperative assessment included RIP, ABG, CONC, and visual analog pain score (PS). The average infusion rate postoperatively was 1.47 +/- 0.08 micrograms/kg/h (114.3 +/- 8.3 micrograms/h). A mean PS of 2.1 +/- 0.3 was achieved; however, there was a delay in attaining this. There was no significant incidence postoperatively of apnea or slow respiratory rate. A significant but clinically insubstantial increase in PaCO2 and decrease in pH occurred. A steady state CONC of approximately 2.0 ng/mL was reached after 9 hours. The PS correlated with CONC in half the patients (0.60 less than r less than 0.86), indicating a systemic component may have contributed to the analgesic effect.

Adult↗