Getting the facts straight.
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Abnormalities, Drug-Induced↗
Biomedical subjects
G Koren
Publications and source records attributed to G Koren.
Gastric-outlet obstruction induced by prostaglandin therapy in neonates.
BACKGROUND: An infusion of prostaglandin E1 is widely used to maintain patency of the ductus arteriosus in neonates with congenital heart disease. After gastric-outlet obstruction was recognized in several infants who received prostaglandin E1, we studied the association between the drug and this complication. METHODS: We evaluated all neonates who received prostaglandin E1 in our hospital between October 1, 1989, and September 30, 1991, for clinical, radiologic, or pathological evidence of acute gastric-outlet obstruction. RESULTS: Of the 74 neonates evaluated, 65 had no signs of gastric obstruction and were considered normal; 5 had clinical and radiologic or pathological evidence of gastric obstruction consistent with the presence of antral mucosal hyperplasia. The remaining four neonates had clinical signs of gastric obstruction, but no radiologic or pathological examinations were performed. The 5 neonates with antral hyperplasia had received prostaglandin E1 for longer periods (mean [+/- SD] duration, 569 +/- 341 hours) than the 65 normal neonates (54 +/- 58 hours, P less than 0.001) or the 4 neonates with clinical signs of gastric obstruction (119 +/- 60 hours, P less than 0.05). The cumulative dose of prostaglandin E1 was higher in the neonates with antral hyperplasia (2982 +/- 1392 micrograms per kilogram of body weight) than in the normal neonates (279 +/- 270 micrograms per kilogram, P less than 0.001) or the neonates with signs of gastric obstruction (528 +/- 306 micrograms per kilogram, P less than 0.01). In two neonates with antral hyperplasia, the cessation of therapy lessened the gastric-outlet obstruction. CONCLUSIONS: The administration of prostaglandin E1 to neonates can cause gastric-outlet obstruction due to antral hyperplasia. Neonates who receive prostaglandin E1 at recommended doses for more than 120 hours should be closely monitored for evidence of antral hyperplasia.
Alprostadil↗
Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia.
In patients with thalassemia intermedia in whom hyperabsorption of iron may result in serious organ dysfunction, an orally effective iron-chelating drug would have major therapeutic advantages, especially for the many patients with thalassemia intermedia in the Third World. We report reduction in tissue iron stores and normalization of serum ferritin concentration after 9-month therapy with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in a 29-year-old man with thalassemia intermedia and clinically significant iron overload (SF 2,174 micrograms/L, transferrin saturation 100%; elevated AST and ALT, abnormal cardiac radionuclide angiogram) who was enrolled in the study with L1 75 mg/kg/day after he refused deferoxamine therapy. L1-Induced 24-hour urinary iron excretion during the first 6 months of therapy was (mean +/- SD, range) 53 +/- 30 (11 to 109) mg (0.77 mg/kg), declining during the last 3 months of L1 to 24 +/- 14 (13-40) mg (0.36 mg/kg), as serum ferritin decreased steadily to normal range (present value, 251 micrograms/L). Dramatic improvement in signal intensity of the liver and mild improvement in that of the heart was shown by comparison of T1-weighted spin echo magnetic resonance imaging with images obtained immediately before L1 administration was observed after 9 months of L1 therapy. Hepatic iron concentration decreased from 14.6 mg/g dry weight of liver before L1 therapy to 1.9 mg/g liver after 9 months of therapy. This constitutes the first report of normalization of serum ferritin concentration in parallel with demonstrated reduction in tissue iron stores as a result of treatment with L1. Use of L1 as a therapeutic option in patients with thalassemia intermedia and iron overload appears warranted.
Adult↗
[Red man syndrome after vancomycin].
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Drug Eruptions↗
The effects of cardiac transplantation and cyclosporine therapy on digoxin pharmacokinetics.
Most patients needing cardiac transplantation are treated with digoxin for heart failure. Because of its narrow therapeutic range, even recommended doses of digoxin may cause severe toxicity. Several drugs, including quinidine, amiodarone, verapamil, and propafenone can interact with digoxin, leading to toxic accumulation of the glycoside. The authors have recently reported two cases of severe digitalis toxicity after the initiation of cyclosporine treatment in patients awaiting cardiac transplantation. A preliminary study on two additional patients suggested that cyclosporine reduced the plasma clearance and volume of distribution of digoxin. To assess the mechanism of this interaction, the authors studied digoxin pharmacokinetics in patients awaiting cardiac transplantation and again after the surgery, during chronic cyclosporine therapy. To separate the effects of transplantation and cyclosporine on digoxin pharmacokinetics, pharmacokinetic studies were subsequently performed in dogs to allow controlled experimental conditions for evaluation of the digoxin-cyclosporine interaction.
Administration, Oral↗
Hair analysis of cocaine: differentiation between systemic exposure and external contamination.
Cocaine has been shown to accumulate in hair of admitted users. Before using this test to verify cocaine use, however, it is crucial to differentiate between systemic exposure and external contamination from being in contact with crack smoke. In the present studies, the authors document that pyrolysis of crack results in hair accumulation of cocaine, but not its benzoylecgonine metabolite, whereas after admitted cocaine use both species are detectable in hair. External contamination with crack smoke is washable, whereas systemic exposure is not. The authors suggest these two criteria to distinguish systemic exposure from external contamination.
Animals↗
The perception of teratogenic risk of cocaine.
While there has been a substantial increase in recreational use of cocaine by young adults, conclusive evidence for cocaine teratogenicity in humans is lacking, and even those believing the drug is teratogenic agree that the rates are quite small. While counseling pregnant women on their teratogenic risk, it was our impression that there is an unrealistically high perception of reproductive risk of cocaine. We wished to quantify the perception of teratogenic risk of cocaine by the public, physicians, and by pregnant women who were counseled following gestational exposure to the drug. Women taking cocaine during the first trimester of pregnancy (n = 54), controls with post secondary education (n = 30), and physicians (n = 30) were asked, using a visual analogue scale, to quantify the teratogenic risk of cocaine and the tendency to terminate/continue the pregnancy after first trimester exposure; in the case of the "public" and physicians this was a hypothetical question. Both physicians and the controls perceived cocaine to be teratogenic (13.4 +/- 11% risk of major malformations by physicians, and 56.5 +/- 22.8% by the "public"). The controls believed cocaine to be as hazardous as thalidomide (57.2 +/- 25.6% risk for thalidomide). Asked whether they would wish to terminate such pregnancy in their family, most physicians (56%) and the controls (70%) had a greater than 50% tendency to terminate.(ABSTRACT TRUNCATED AT 250 WORDS)
Abnormalities, Drug-Induced↗
Iphosphamide-induced nephrotoxicity in children.
The nephrotoxic potential of iphosphamide was evaluated in a retrospective analysis of all children receiving the drug at The Hospital for Sick Children in Toronto. The 25 children exhibiting nephrotoxicity did not receive more cycles or higher doses per square metre than the 78 with normal renal function. Similarly, the two groups received comparable doses and number of cycles of sodium 2-mercaptoethanesulphonate, and had similar rates of exposure to nephrotoxic drugs (except for cis-platinum). Children exhibiting nephrotoxicity were significantly younger (78.1 +/- 64.1 months) than those having normal kidney function (103.8 +/- 66.6 months) (P less than 0.05). Children exhibiting nephrotoxicity were more likely to have received cis-platinum prior to the iphosphamide (10/25, 40%) than those with normal renal function (14/73, 18%) (P less than 0.05). Nephrotoxicity was associated with a significant effect on growth. Careful follow-up of renal function should take place in children receiving iphosphamide, with special attention paid to children younger than 5 years of age and those who have received cis-platinum.
Antineoplastic Combined Chemotherapy Protocols↗
Maternal and fetal effects of intravenous patient-controlled fentanyl analgesia during labour in a thrombocytopenic parturient.
The use of intravenous (i.v.) patient-controlled fentanyl analgesia during labour in a parturient with unexplained thrombocytopenia (70 x 10(3).ml-1) is described. The patient self-administered boluses of 25 micrograms of fentanyl with a lock-out interval of ten min. In addition, a concurrent fentanyl infusion of 25 micrograms.hr-1 was given. Effective analgesia was achieved during labour and a total of 1025 micrograms of fentanyl was infused over 11 hr 55 min until delivery of a vigorous infant with Apgar scores of 9 after one and five min. Respiratory depression or undue sedation were not observed in the mother either during labour or in the post-partum period. At birth, maternal total plasma fentanyl concentration was 1.11 ng.ml-1, whereas neonatal umbilical total plasma fentanyl concentration was 0.43 ng.ml-1. Newborn plasma protein binding of fentanyl was lower compared to the mother (63% vs 89%). Thus, free fentanyl concentrations (0.16 ng.ml-1) were identical in the mother and newborn at delivery.
Adult↗
Maternal and fetal outcome after breast cancer in pregnancy.
We compared 118 women with breast cancer (119 pregnancies) with 269 nonpregnant control subjects matched on important prognostic factors. The distribution of breast cancer stages among the 118 pregnant women was compared with that among 5115 cases of breast cancer in women of reproductive age. Fetal outcome was compared with that of a control group matched for maternal age. Women having breast cancer in pregnancy were 2.5 times more likely to have metastatic disease (95% confidence interval 1.1 to 5.3) and had a significantly lower chance of having stage I disease (p = 0.015). Survival of pregnant women did not differ from that of the controls. Birth weights of babies born to women with breast cancer were significantly lower than those of control babies after gestational age was adjusted for (3010 +/- 787 vs 3451 +/- 515 gm, p = 0.016). The two stillbirths in 85 pregnancies that continued to term (2.4%) was not statistically different from the 1.1% rate for Ontario. We analyzed all 223 births occurring in women who had any form of cancer in the same hospital during the same 30 years. There were 10 stillbirths among these 223 cases (4.4%), significantly more than expected in Ontario (p less than 0.0005; relative risk of 4.23 with 95% confidence interval 2.0 to 7.8). Our data suggest that pregnant women are at a higher risk of presenting with advanced disease because pregnancy impedes early cancer detection.
Abortion, Spontaneous↗
Accumulation of cocaine in maternal and fetal hair; the dose response curve.
Cocaine and its major metabolites are incorporated into hair during the growth of the shaft and stay there for the whole life of the hair. Cocaine crosses the placenta and its metabolites for example Benzoylecgonine (BZ), have been found in neonatal urine, meconium and hair. In order to utilize hair measurements of cocaine as a biological marker of systemic exposure, we conducted both animal and human investigations on the dose response characteristics of this phenomenon. Our data suggest that both maternal and fetal accumulation of cocaine and its metabolite follow a linear pattern within the clinically used doses. Similarly, a good correlation was observed in animals between maternal dose and fetal hair accumulation.
Animals↗
Course of pregnancy and fetal outcome following maternal exposure to carbamazepine and phenytoin: a prospective study.
This prospective study followed the pregnancy course of epileptic women at the Motherisk Program of The Hospital for Sick Children, Toronto. We compared fetal outcome of women treated with carbamazepine (CBZ), those treated with diphenylhydantoin (phenytoin, DPH), and a drug-free control group. Seizures were reported in 15 pregnancies; in a subgroup of 9 women without change in drug or schedule, an increase in seizure frequency was evident in 6, a decrease in 1, and no change in 2, regardless of the drug taken. Of 23 children exposed to CBZ in utero, one was born with a lumbar myelomeningocele and multiple congenital anomalies. Of 21 children exposed to DPH, there was one case of severe developmental delay and four with minor features of fetal hydantoin syndromes (FHS). The three groups did not differ in birth weights or gestational ages of the babies. Although much more experience is needed, as a result of this study and other similar reports, Motherisk now offers women treated with CBZ diagnostic tests to detect neural tube defects during the second trimester of pregnancy.
Abnormalities, Drug-Induced↗
A quality assurance program for teratogen information services.
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Counseling↗
Maternal and foetal outcome following Hodgkin's disease in pregnancy.
The peak incidence of Hodgkin's disease occurs during the reproductive age, and its association with pregnancy is at a rate of between 1:1,000-1:6,000. We studied the effects of Hodgkin's Disease on the course and survival of 48 women who had Hodgkin's Disease and who were pregnant, and compared their outcome with non-pregnant matched women who were of similar stage of disease, age at diagnosis, and calenderic year of treatment. Twenty-year survival of pregnant women with Hodgkin's Disease was not different from that of their matched controls. Pregnant women with Hodgkin's Disease had similar distribution of stages to the controls.
Adult↗
Clinical use of the Medication Event Monitoring System: a new window into pediatric compliance.
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Adolescent↗
A randomized, double-blind comparison of lumbar epidural and intravenous fentanyl infusions for postthoracotomy pain relief. Analgesic, pharmacokinetic, and respiratory effects.
Although epidural opioids frequently are used to provide postoperative analgesia, several articles have suggested that the analgesia after epidural fentanyl is similar to that after an equal dose of fentanyl given intravenously. To address this issue further, 29 postthoracotomy patients were studied in a randomized, double-blinded trial comparing a lumbar epidural fentanyl infusion with an intravenous fentanyl infusion for analgesia, plasma fentanyl pharmacokinetics, and respiratory effects for 20 h postoperatively. In all patients in both groups, good analgesia was achieved (pain score less than 3, maximum 10) over a similar time course, although the patients receiving epidural infusion required a significantly larger fentanyl infusion dose than did the patients receiving intravenous infusion (group receiving epidural fentanyl infusion: 1.95 +/- 0.45 micrograms.kg-1.h-1; group receiving intravenous fentanyl infusion: 1.56 +/- 0.36 micrograms.kg-1.h-1; P = 0.0002). The time course for the plasma fentanyl concentrations was similar in the two groups, and plasma fentanyl concentrations were not significantly different at any sampling period (T7-T20; group receiving epidural fentanyl infusion: 1.8 +/- 0.5 ng/ml; group receiving intravenous fentanyl infusion: 1.6 +/- 0.6 ng/ml; P = 0.06). Similarly, calculated clearance values for the two groups were not significantly different (group receiving epidural fentanyl infusion: 0.95 +/- 0.26 l.kg-1.h-1; group receiving intravenous fentanyl infusion: 0.87 +/- 0.25 l.kg-1.h-1; P = 0.3). Both groups demonstrated a similar degree of mild to moderate respiratory depression postoperatively, which was assessed with continuous respiratory inductance plethysmography and sequential arterial blood gas analysis. Side effects (nausea, vomiting, pruritus) were mild and did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Therapeutic drug monitoring of retinoids.
Retinoids are natural or synthetic compounds related to vitamin A. They are successfully used in the treatment of dermatological disorders. However, one of the limiting factors in the use of retinoids is their huge teratogenic potential. The investigation into the pharmacokinetics and metabolism of retinoids has encountered many difficulties due to lack of suitable techniques to deal with these labile compounds. Because of the teratogenic nature of the retinoids, the sensitivity of the assay is of utmost importance. We report a systematic comparison between two high-performance liquid chromatographic methods used to monitor levels of etretinate and its metabolites acitretin and 13-cis-acitretin in plasma. Our analysis suggests that the column-switching method is superior owing to smaller variability in results and its simplicity. We also describe our therapeutic drug monitoring program for counseling women of reproductive age following etretinate or acitretin exposure. Presently, labeling of etretinate in North America suggests that women should refrain from conception for an undetermined length of time. Assessment of serum concentrations over time is beneficial in defining the length of period to postpone conception.
Acitretin↗
Postmortem redistribution of morphine in rats.
Because morphine is often found in the postmortem (PM) blood samples of patients treated with or abusing the drug, its causation in death has to be considered. The possibility of PM redistribution of the opioid drug has not been studied previously. We treated adult Wistar rats with 4 mg/kg of morphine i.m. and measured cardiac cavity levels at the time of death, by killing (2 h postdose) 24 and 96 h PM. Morphine concentrations rose from 41.4 +/- 13.2 ng/ml at death to 111.9 +/- 66.6 ng/ml at 24 h (p = 0.00036), with no additional increase at 96 h (98.7 +/- 21.7 ng/ml). After death there was accumulation of endogenous substances cross-reacting with the morphine radioimmunoassay. Although these attribute only 3% to total accumulation of morphine, they may complicate interpretation of morphine "readings" in patients who had not received the drug. Our study suggests that after death there is substantial redistribution of morphine. Elevated PM levels cannot necessarily by interpreted as representing antemortem concentrations.
Animals↗