Biomedical subjects
Publications and source records attributed to G Koren.
Ketoconazole is known to inhibit the metabolism of cyclosporin through inhibition of cytochrome P-450. This pharmacological interaction was used in an 8-year-old renal transplant patient to successfully achieve therapeutic cyclosporin blood concentrations. The addition of ketoconazole to the cyclosporin regimen should be considered when difficulties are encountered in attaining satisfactory cyclosporin levels.
Three different experimental approaches were used to establish that the first transmembrane segment (S1) is important for K+ channel assembly. First, hydrodynamic analyses of in vitro translated Kv1.1 N-terminal domain containing the S1 segment coassembles to form homotetrameric complexes, whereas deletion of the S1 segment abolishes coassembly. Second, coimmunoprecipitation experiments of cotranslated Kv1.1 and Kv1.5 truncated polypeptides show that the S1 segment is essential for coimmunoprecipitation. Third, dominant negative experiments in Xenopus oocytes confirm that over-expression of either the S1 segment or the N-terminal domain is sufficient for abolishing the expression of functional Kv1.1 and Kv1.5 K+ channels. These data indicate that S1 segment plays an important role in the coassembly of homo- and heterotetrameric K+ channels.
OBJECTIVE: Our aim was to measure the transfer of cocaine and its major metabolite benzoylecgonine across the human term placenta. STUDY DESIGN: By means of in vitro perfusion of the human term placental cotyledon the transfer of these compounds was measured. RESULTS: The steady-state maternal-to-fetal transfer of cocaine (0.18 +/- 0.05 microgram/ml/min) was significantly greater than benzoylecgonine transfer (0.02 +/- 0.01 microgram/ml/min) (p < 0.05). When the perfused tissue was analyzed 32% +/- 7% of the maternal cocaine dose was retained by the placental tissue, whereas only 12% +/- 12% of the maternal benzoylecgonine dose was retained by the placental compartment. CONCLUSIONS: These results suggest (1) the placenta may serve as a depot for large amounts of cocaine, thus offering some degree of fetal protection after bolus administration; (2) fetal exposure may be prolonged by placental retention and subsequent release of cocaine and benzoylecgonine; and (3) benzoylecgonine does not cross the placenta as readily as does cocaine. Variability in placental handling of cocaine and benzoylecgonine may therefore determine fetal exposure to these agents.
PURPOSE: To determine whether use of lidocaine-prilocaine 5% cream (EMLA) decreases pain associated with diphtheria-pertussis-tetanus (DPT) vaccination in infants. METHODS: Randomize, double-blind, controlled trial in outpatient pediatric practice, Toronto, Ontario, Canada. Before vaccination, parents applied 2.5 gm of EMLA or placebo to the infant's leg and covered it with an occlusive dressing for at least 60 minutes. The infant received a 0.5 ml intramuscular injection of DPT at 2 degree to 8 degree C with a 1.6 cm 25-gauge needle; the infant was videotaped. The Modified Behavioral Pain Scale (MBPS) was used to assess baseline and postvaccination pain scores. Latency and duration of infant cry were also measured. RESULTS: A total of 49 evaluable infants received EMLA, and 47 infants received placebo. There were no significant differences in demographic data; mean age was 5 months; and 50% of the subjects were male. The median difference in pre-vaccination and postvaccination MBPS scores was lower for EMLA than for placebo (p = 0.001). The latency to the first cry was longer for subjects who were treated with EMLA (p = 0.0004)), but the total crying time was shorter (10.3 seconds vs 25.2 seconds; p = 0.027). Of the study group, 90% (45/50) of subjects treated with EMLA and 12% (6/49) of subjects treated with placebo had local skin reactions (p < 0.0001), mainly skin blanching. CONCLUSIONS: Pretreatment with EMLA decreases infant pain from DPT vaccinations. Application of these data is limited to healthy infants receiving DPT vaccinations.
We report a case of lack of fetal exposure to cocaine and benzoylecgonine as evidenced by meconium and hair analysis, but exposure to nicotine and its metabolite cotinine, after extensive maternal use of cocaine and nicotine. These data suggest that the mode of maternal use of cocaine and individual differences in placental handling of the drug may protect some fetuses, and highlight the need to address interpatient variability.
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OBJECTIVE: To examine the effect of frequency of oral administration of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) on urinary iron excretion. HYPOTHESIS: Sustained serum concentrations of L1 will cause more iron chelation than the same daily dose given in larger but less frequent amounts. PATIENTS AND METHODS: Ten patients with thalassemia with a mean age of 20.9 +/- 4.7 years (range, 13 to 27 years), who were receiving regular treatment with 75 to 100 mg/kg/day oral L1, received 75 mg/kg/day L1 orally in equally divided doses: every 6 hours for 3 days and every 12 hours for 3 days. The two study periods occurred 1 month apart immediately after the monthly blood transfusions. Urine was collected for two consecutive 24-hour periods during each of the different schedules. Serial blood samples were collected from six patients over a 6-hour period and analyzed for total L1 and the L1 glucuronide metabolite concentrations. RESULTS: The patient's mean hemoglobin levels (138.8 +/- 12.5 and 139.0 +/- 11.6 gm/L) and ferritin levels (2856.4 +/- 2207.8 and 2890.0 +/- 2264.4 micrograms/L) were similar during the every-6-hour and every-12-hour L1 administrations, respectively. There was significantly more urinary iron excretion when L1 was administered every 6 hours (0.59 +/- 0.29 mg/kg/day) versus every 12 hours (0.40 +/- 0.26 mg/kg/day; p = 0.0129). Calculated 24-hour area under the plasma concentration-time curve of L1 was similar during the every-6-hour (7023.9 +/- 2637.8 mg.min/L) and every-12-hour (7050.1 +/- 1668.8 mg.min/L) experiments. CONCLUSIONS: These data suggest that the sustained presence of L1 in the blood results in greater chelation of iron than that observed with larger, less frequent doses.
BACKGROUND: A randomized, double-blind, placebo-controlled trial was conducted to assess the analgesic, pharmacokinetic, and clinical respiratory effects of 72-h application of two transdermal fentanyl (TTSF) patch sizes in patients undergoing abdominal hysterectomy. METHODS: TTSF patches releasing 50 micrograms/h (TTSF-50) or 75 micrograms/h (TTSF-75) fentanyl or placebo patches were applied to 120 women 2 h before abdominal hysterectomy under general anesthesia. Postoperatively, all patients had access to supplemental morphine using patient-controlled analgesia pumps. Each patient was attended continuously by a research nurse for 8 h on the night before surgery and for 84 h after patch application. The following data were collected: visual analog scale pain scores, supplementary analgesia, fentanyl plasma concentration (4-h intervals), continuous hemoglobin saturation (pulse oximetry), respiratory pattern (continuous respiratory inductive plethysmography), and adverse effects (nausea, vomiting, pruritus). Data analysis included analysis of variance, Kruskal-Wallis, and chi-squared. P < 0.05 was considered significant. RESULTS: There were no demographic differences among groups. Visual analog scale pain scores were significantly lower for the TTSF-75 group, and supplemental morphine was significantly decreased in the TTSF-75 group in the postanesthesia care unit and for both the TTSF-50 and the TTSF-75 group for 8-48 h postoperatively. Between 5 and 36 h, the TTSF groups had significantly increased abnormal respiratory pattern including apneic episodes (tidal volume of less than 100 ml for more than 15 s) and episodes of slow respiratory rate (less than 8 breaths/min persisting for more than 5 min) and significantly increased requirement for oxygen supplementation. Nine patients in the TTSF groups were withdrawn because of severe respiratory depression compared to none in the placebo group. No significant between-group differences were present in the incidence of nausea, vomiting, or pruritus. Although fentanyl plasma concentration was higher in the TTSF-75 group than in the TTSF-50 group, the differences were not significant. Fentanyl plasma concentration decreased significantly 48 h after patch application. CONCLUSIONS: Application of TTSF patches 2 h preoperatively is associated with moderate supplementary opioid requirements for analgesia in the early postoperative period and ongoing opioid supplementation for at least 72 h. Although good analgesia is the result of this combination therapy, it is associated with a high incidence of respiratory depression requiring intensive monitoring oxygen supplementation, removal of the TTSF patches in approximately 11% of the patients and opioid reversal with naloxone in approximately 8% of the patients.
OBJECTIVES: To study the effect of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics of morphine in infants. DESIGN: A prospective, comparative study of morphine pharmacokinetics during and after ECMO. SETTING: The pediatric intensive care unit at a children's hospital. PATIENTS: Seven infants, aged 1 day to 12 months, requiring ECMO. INTERVENTION: Infusion of morphine. MEASUREMENT AND MAIN RESULTS: Steady-state concentrations of morphine were used to generate a morphine clearance rate. Plasma clearance rate of morphine increased from 0.574 +/- 0.3 L/kg/hr to 1.058 +/- 0.727 L/kg/hr after discontinuation of ECMO (p < .01). Two infants experienced a clinical picture consistent with opioid withdrawal. CONCLUSION: Infants requiring morphine after ECMO may require higher dose rates to maintain adequate sedation.
Maternal exposure to drugs and chemicals is increasingly being recognized as adversely affecting the developing fetus. To date, a very large number of fetuses have been exposed in utero to cocaine and cigarette smoke. Neonatal hair as a biological marker for fetal exposure in cocaine and nicotine has emerged as an excellent tool in correlating in utero exposure and outcome. However, a limiting factor is the sparsity of neonatal hair. We report on the first method that allows determination of both cocaine and nicotine as well as their metabolites in the same hair samples.
The objective of this study was to conduct an assessment of patient and parental preferences and an economic analysis of hospital costs in sampling blood and saliva for therapeutic drug monitoring (TDM). Costs and preferences were evaluated in the course of a study, which compared anticonvulsant concentrations in blood routinely drawn for therapeutic monitoring and in saliva in infants and children attending a pediatric neurology clinic. Parents of 84.8% of children, and half of the children, indicated a preference for saliva sampling over venous blood drawing. Children who had been on medications that required therapeutic monitoring for < 2 years were more likely to prefer saliva sampling as compared to those who were under treatment for > or = 2 years. Computation, based upon a basic assumption that a registered nurse obtained blood and a medical technician or a registered nurse assistant sampled saliva, indicated that for every 1,000 cases of changing from blood to saliva sampling, total cost savings would amount to $1,930 for cooperative children and $1,660 for infants and uncooperative children. This saving is equivalent to approximately 100 h of a registered nurse's initial salary. The important contributions to the differential cost were derived from the requirements for more highly trained individuals to take the blood sample and from the doubling time required for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)
Digitalis intoxication is a common problem, mainly because of the narrow margin of safety of digoxin. These patients may have concomitant renal failure. In patients who have renal failure and who have been treated with digoxin-Fab, the elimination of the digoxin-Fab complex is significantly delayed, and there is a risk of dissociation of the complex with rebound of free digoxin and recurrence of toxicity. The high molecular weight of digoxin and digoxin-Fab complex prevents its elimination by hemodialysis or continuous arteriovenous hemofiltration. A 3-day-old newborn with digoxin overdose and acute renal failure was treated with digoxin immune Fab and peritoneal dialysis. Low levels of total digoxin were measured in the dialyzate, indicating poor elimination of the digoxin-Fab complex through peritoneal dialysis.
1. We present a novel index for expressing the exposure of the infant to drugs in breast milk, which unifies two independent factors: a pharmacokinetic parameter, drug clearance, and a physiochemical parameter, i.e. milk-to-maternal plasma drug concentration ratio (M/P ratio). 2. During breast-feeding by a woman receiving therapeutic doses of a drug at steady state this index is given by: Exposure index = A x (M/P ratio)/CLI where A is a coefficient (10 ml kg-1 min-1) and CLI is drug clearance in the infant (ml kg-1 min-1). 3. This equation indicates a hyperbolic relationship between drug clearance and the exposure level of the breast-fed infant at a given M/P ratio of drug, emphasizing the importance of drug clearance as a determinant of infant exposure.
OBJECTIVE: To measure acyclovir concentrations in the breast milk of a lactating woman using the drug for herpes zoster while nursing her 7-month-old infant. METHODS: The maternal dosage of acyclovir was 800 mg five times daily for seven days. Three random breast milk samples collected on the fifth and sixth days of therapy were analyzed for acyclovir concentrations with radioimmunoassay (RIA). RESULTS: Acyclovir concentrations in breast milk ranged from 18.5 mumol (4.16 micrograms/mL) to 25.8 mumol (5.81 micrograms/mL). An estimate of the infant's dosage ingested through nursing was 0.73 mg/kg/d, or approximately 1 percent of the maternal dose in milligrams/kilograms/day. The baby was nursed without any signs of adverse effects. CONCLUSIONS: Acyclovir was measured in clinically insignificant concentrations in the milk of a woman receiving large dosages for herpes zoster. Breast feeding continued without adverse effects to the nursing infant.
Inhaled pentamidine is used to treat Pneumocystis carinii pneumonia. Its potential effects on DNA have raised concerns about its safety for pregnant healthcare workers. We used a pharmacokinetic approach to estimate the fetal risks, based on the published data of pentamidine renal clearance and of urinary pentamidine concentrations in healthcare workers exposed to aerosolized pentamidine. The maximum pentamidine doses (intravenous equivalent) that healthcare workers were exposed to were calculated to be 9.8 micrograms/kg/d and 1.7 microgram/kg/d at the two different institutions reported. In parallel, based on animal data, we derived the intravenous-equivalent reference doses for embryolethality and for teratogenicity, the doses that can be viewed as tentative safe exposure levels. These analyses reveal that the exposure levels of a healthcare worker to aerosolized pentamidine are estimated to be in the vicinity of the teratogenic reference dose (4 micrograms/kg/d) and greater than the embryolethal reference dose (0.08 microgram/kg/d). Further improvement of the pentamidine administration technique and of environmental management in hospitals is warranted.
Non-Hodgkin's lymphoma (NHL) is infrequently diagnosed during pregnancy. Most NHL's complicating pregnancy are aggressive and disseminated. This presentation together with the possible teratogenecity of diagnostic methods dictate a limited staging workup during pregnancy. Although prognosis had been reported to be poor, there is recent evidence to suggest that when properly treated, pregnancy does not affect the course of lymphoma. The risk to the fetus can also be reduced by an appropriate therapeutic approach.
There has been an increasing use of cocaine in North America among women of reproductive age. The potential effects of cocaine on the fetus have raised serious concerns about the health of large numbers of children exposed in utero to the drug. Using neonatal hair and urine tests for benzoylegconine (BE), we quantified the incidence of fetal exposure to cocaine among 600 babies born in 3 nurseries in Toronto from 1990-91. A total of 37 babies (6.25%) tested positive for cocaine exposure by either hair test, urine test, or both. The hair test detected 33 cases and failed to identify 4 babies who had low urine concentrations of BE. The urine test failed to identify 76% of the cases. In downtown Toronto, the overall rate of fetal exposure to cocaine was 12.5% (25/200), significantly higher than in the 2 suburban nurseries (3%; 12/400). Babies are born with hair which has grown during the last trimester of pregnancy; hence, our analysis identifies women who have used cocaine long after they became aware of pregnancy. Our figures translate to more than 5,000 babies annually in the greater Toronto area who are cared for postnatally by mothers regularly using cocaine. Because history and urine testing during delivery fail to identify the majority of these cases, most of these children are not likely to receive the appropriate medical and social services and follow-up.
Using the pregnant woman as a means to medicate her fetus represents a new and exciting therapeutic approach in clinical pharmacology. In years to come, we will see an increase in the use of the currently accepted fetal therapies and an increase in the number of therapies available to the caregiver or clinician aimed at assisting the unborn child. The pharmacologist, through in vitro research that aids our understanding of the role of the placenta in fetal drug therapy, can contribute to the growth of this new field within the realm of obstetric medicine.