Formation of the Organization of Teratology Information Services (OTIS). The OTIS Executive Committee.
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Information Services↗
Biomedical subjects
G Koren
Publications and source records attributed to G Koren.
Fetal outcome following intrauterine amantadine exposure.
Amantadine hydrochloride is a well-known antiviral agent that has been used for the prevention of influenza A2, the treatment of Parkinson disease, and, more recently, multiple sclerosis. However, very few data exist about its use in pregnant women. We report a 34-year-old woman who had used amantadine to prevent relapse of her multiple sclerosis throughout two of her pregnancies who subsequently delivered two normal infants. We review the available animal data and two other human pregnancy exposure reports.
Adult↗
Misinterpretation of iron-binding capacity in the presence of deferoxamine.
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Animals↗
Decreased protein binding of salicylates in Kawasaki disease.
Because patients with Kawasaki disease have low serum concentrations of salicylates despite high doses, and because the free (unbound) drug is responsible for the pharmacologic effects of salicylates, we assessed salicylate protein binding in patients with Kawasaki disease. During the acute phase of the disease, protein binding of salicylate in 36 children with Kawasaki disease was 73 +/- 12%, significantly lower than during the subacute phase (90.4 +/- 8.7%; p less than 0.0005). Mean serum albumin concentration was 29.2 +/- 6.4 gm/L during the acute phase and 36.7 +/- 7.8 gm/L during the subsequent subacute phase (p less than 0.005). Salicylate protein binding was affected independently by both serum albumin and total salicylate levels. During the acute phase of Kawasaki disease, children had an average twofold increase in free salicylate compared with normoalbuminemic control subjects. A nomogram has been devised to derive free salicylate levels from the known total salicylate and serum albumin concentrations.
Acute Disease↗
Tissue plasminogen activator for the treatment of thromboembolism in infants and children.
We report our experience with the use of tissue plasminogen activator to treat 12 infants and children with various thromboembolic states after conventional thrombolytic agents had failed. The dosage range was between 0.1 to 0.5 mg/kg per hour. Complete clot dissolution occurred in seven cases after 2 hours to 3 days of therapy. Partial clot dissolution and clinical improvement were noted in another four patients. Bleeding complications were noted in 6 of the 12 patients and included bruising, oozing from various venipuncture sites, and bleeding; these complications were controlled by clinically available means. In all cases with bleeding the dose rate was in the higher range (0.46 to 0.50 mg/kg per hour). In one patient, restlessness, agitation, and screaming were noted during administration of tissue plasminogen activator and when it was reinstituted. We conclude that tissue plasminogen activator is effective in inducing clot lysis in children. Because the effective dose appears to overlap with those causing bleeding, we recommend that a dose of 0.1 mg/kg per hour be started and increased gradually if clot dissolution does not occur, with close monitoring for bleeding.
Adolescent↗
Assessing pain and analgesia with a lidocaine-prilocaine emulsion in infants and toddlers during venipuncture.
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Anesthetics, Local↗
Relationship between the pharmacokinetics and iron excretion pharmacodynamics of the new oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one in patients with thalassemia.
Single-dose and steady-state pharmacokinetics of the new oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1) were studied in 14 patients with thalassemia and correlated with iron excretion. Food prolongs the rate of absorption of L1, but it does not affect significantly the extent of absorption measured by the area under the plasma concentration-time curve. Similarly, it does not affect the chelation potential of the drug. The mean elimination half-life of the drug is 3 hours, suggesting that a divided dose every 8 hours may assure better chelation. Our steady-state studies reveal that urinary iron excretion is independently influenced by body iron load (measured by ferritin levels) and by steady-state trough concentrations of the drug. While patients were receiving an unchanged regimen of 75 mg/kg/day, we have detected a gradual and significant decrease in trough concentrations in the presence of unchanged patients' compliance monitored by the Medication Event Monitoring System, diaries, and pill count. These findings suggest self-induction of L1 metabolism or decreased absorption during long-term therapy. Because of the concentration-dependent iron excretion, patients may need increasing doses to achieve negative iron balance.
Adolescent↗
Outcome of pregnancy after first trimester exposure to H2 receptor antagonists.
H2 antagonists are widely prescribed medications and are often consumed by women who are unaware of being pregnant. In 23 cases reported to the Motherisk program there were two spontaneous abortions, two therapeutic abortions, 18 normal births, and one infant with a large hemangioma of the upper right eyelid. The hemangioma was removed without incident. Our data suggest that cimetidine and ranitidine may not be teratogenic risk in humans.
Abnormalities, Drug-Induced↗
Pregnancy outcome following first trimester exposure to chloroquine.
Although the use of chloroquine (C) and hydroxychloroquine (HC) in the treatment of malaria prophylaxis during pregnancy is probably safe, the use of much higher doses for treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis during pregnancy has been controversial. We analyzed the cases of 24 pregnant women with a total of 27 pregnancies who had taken these drugs during their first trimester of pregnancy. C and HC were given in 11 patients with SLE, three with rheumatoid arthritis, and four for malaria prophylaxis. Most of these women had already been on antimalarial drugs for 1 to 172 months prior to pregnancy (mean, 32.2 months). Of the 27 pregnancies, 14 resulted in normal full-term deliveries, six were aborted due to severe disease activity or social conditions, three were stillbirths, and four pregnancies resulted in spontaneous abortions. No congenital abnormalities were detected in the 14 live births at ages between 9 months and 19 years (mean, 5.3 years). All these children are physically and developmentally normal with no clinical evidence of eye or hearing defects. The seven pregnancies that were associated with fetal loss occurred particularly in patients who had active SLE, although stillbirth and spontaneous abortion occurred also in patients with rheumatoid arthritis and in two of the three patients who had been treated prophylactically for malaria. Although of the 215 reported pregnancies with C and HC exposure, including our study, only seven (3.3%) had congenital abnormalities, the risk associated with antimalarials may be cumulative and further studies are needed to elucidate the safety of this drug later in pregnancy.
Abnormalities, Drug-Induced↗
Hepatitis B vaccine in pregnancy: maternal and fetal safety.
Perinatal transmission of hepatitis B (HB) virus occurs if the mother has had acute HB infection during late pregnancy or in the first months postpartum, or if the mother is a chronic HB antigen carrier. Vertical transmission from chronic carriers exceeds 90% and accounts for up to 40% of the world chronic carriers in endemic areas. Hepatitis in pregnancy is not associated with increased abortion rate, stillbirth, or congenital malformation. However, prematurity seems to be increased if hepatitis is acquired in the last trimester. Sixty percent of pregnant women who acquire acute HB infections at or near delivery will transmit the HB virus to their offspring. Although infection is rarely symptomatic, 70 to 90% of the babies will remain chronically infected into adult life and be prone to cirrhosis and hepatocellular carcinoma. Because of such high risks and the safety and efficacy (seroconversion 90 to 100%) of HB vaccine in preventing HB infection, it is recommended that HB vaccine be given to pregnant women at high risk. However, its safety to the fetus is not well documented. Only one human study reports the safety and efficacy of Heptavax, but only when administered (to 72 pregnant women) in the last trimester of pregnancy when embryopathy cannot occur. We report pregnancy outcome in ten women, mostly health care personnel or patients traveling to endemic areas exposed to the vaccine during the first trimester of pregnancy. No congenital abnormalities were observed and all the infants are physically and developmentally normal for their ages at 2 to 12 months. Although small, this cohort suggests safe use of the vaccine in early pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
A high-performance liquid chromatographic method for the measurement of the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one in human plasma.
1,2-Dimethyl-3-hydroxypyridin-4-one (CP020 or L1) is a novel oral iron chelator that has proved to be effective in animals and humans. A rapid, accurate, and sensitive high-performance liquid chromatography method is described for measuring L1 in human plasma using a Hypercarb 7 microns column and monitoring the column eluent by ultraviolet absorption at 280 nm. CP020 and the internal standard (CP094) were extracted into dichloromethane (2 x 5 ml) from plasma at neutral pH [0.25 ml of plasma + 0.75 ml of 60 mM 3-(N-morpholino)propanesulfonic acid buffer, pH 7.4]. The method proved to be linear (r2 = 0.998) in the clinical range of 0.5-50 micrograms/ml when 0.25 ml of plasma was used, with the coefficient of variation less than 10% even at the lower concentration range.
Adolescent↗
Compliance assessed by the Medication Event Monitoring System.
The accurate assessment of patient compliance is especially crucial in evaluating the efficacy of a new treatment. Because of the problems associated with parenteral desferrioxamine, the development of a safe, effective, and convenient iron chelator is of high priority. The high morbidity and mortality associated with iron overload requires careful evaluation of the ability of any new agent to promote long term effective iron chelation. Patients' compliance with an orally available chelating agent, 1,2,-dimethyl-3-hydroxypyrid-4-one (L1), that has been demonstrated to induce in vivo iron excretion equivalent to that of desferrioxamine during supervised short term administration, was examined. Compliance was assessed in seven patients by patient interview, by daily diaries reviewed monthly with each patient, and with the use of the Medication Event Monitoring System (MEMS) standard pill bottles with microprocessors in the cap that record the timing and frequency of bottle openings. L1 was dispensed in MEMS containers to the patients, who, unaware of their significance, recorded compliance using a daily diary. Overall compliance rate (% of prescribed doses taken) measured by MEMS was 88.7 +/- 6.8%. When 'doubling of doses' was accounted for, significantly poorer compliance with L1 was noted by MEMS (91.7 +/- 7.4%) than by patients' diaries (95.7 +/- 5.2%). There was no significant difference in patient compliance recorded between the first and last 30 day period of drug administration. MEMS can eliminate the confounding variable of erratic patient compliance in the evaluation of a new drug's efficacy. As MEMS cannot distinguish a missed dose from one doubled at the next bottle opening, the use of patient diaries is a useful adjunct to the accurate assessment of compliance and should be combined with the use of MEMS.
Administration, Oral↗
Maternal and fetal outcome after invasive cervical cancer in pregnancy.
Invasive carcinoma of the cervix is the most common gynecologic malignancy to occur during the reproductive years. To analyze the effects of pregnancy on the course and survival of invasive cervical cancer, we compared 40 women with invasive cervical cancer to 89 nonpregnant controls matched for age, calendric year of diagnosis, stage, and tumor type. Additionally, we compared the distribution of invasive cervical cancer stages among the 40 pregnant women with that among the 1,963 cases of invasive cervical cancer treated during the same 30 years in women less than 45 years of age registered in the same hospital. To evaluate pregnancy outcome, we compared babies born to women with invasive cervical cancer to babies born of women matched for maternal age and not exposed to known teratogens or reproductive risks during pregnancy. Thirty-year survival of pregnant women with invasive cervical cancer was identical to that of their matched controls. Women having invasive cervical cancer were 3.1 times more likely to be diagnosed with stage I disease (95% confidence interval, 1.6 to 6.2). Additionally, they had a significantly lower chance of being diagnosed with stages III and IV (P = .02). Babies born to women with invasive cervical cancer were similar in gestational age and rates of prematurity but had a lower birth weight than the matched controls. There were two stillbirths among the 24 pregnancies that continued to term (8%), not statistically different from the 1.1% rate for Ontario. Our data suggest that pregnancy per se does not adversely affect the survival of women with invasive cervical cancer. However, this study provides evidence that pregnant women are more likely to present with early disease because of regular, pregnancy-related obstetric exams. Moreover, there is an increased risk for stillbirth, which should lead to follow-up of these patients by a high-risk perinatal unit.
Adult↗
Toxic neonatal effects following maternal clomipramine therapy.
Clomipramine is a chlorinated tricyclic antidepressant commonly used in the treatment of depression (1). The drug is widely prescribed in Europe and Canada and has been recently approved for use in the USA. Its safety during pregnancy and breastfeeding, however, has not been fully established. Very few reports on its effect on the fetus and neonate have been published (2,3). We report a case of a mother treated with clomipramine during pregnancy, and the side effects observed in the infant. The correlation between plasma clomipramine concentrations in the baby's blood and clinical effects are described. Subsequently, we present the pregnancy outcome of five prospectively collected cases.
Adult↗
Renal handling of cisplatin: interactions with organic anions and cations in the dog.
Cis-diamminedichloroplatinum (II) (cisplatin CDDP) is an extremely potent chemotherapeutic agent. Its efficacy, however, is hindered by the cumulative dose-dependent nephrotoxicity which can lead to permanent renal impairment. The mechanisms of the renal transport of cisplatin are not clear. As a first step towards understanding the renal handling of cisplatin we studied its renal clearance in dogs, as well as the effects of organic anion and cation administration on cisplatin. Our results document net tubular secretion of cisplatin. Both an organic anion (probenecid) and cations (quinidine, cimetidine, ranitidine) significantly decreased renal clearance of free CDDP without affecting GFR.
Animals↗
The effects of subcutaneous deferoxamine administration on renal function in thalassemia major.
To assess the effects of deferoxamine (DFO) on the kidneys, we studied 27 patients with thalassemia major on chronic subcutaneous (s.c.) DFO therapy. In 41% of the patients glomerular filtration rate (GFR) values were above the normal range. In a previous study similar findings were reported for thalassemia patients who did not receive DFO. The subcutaneous administration of DFO was associated with a clinically significant decrease in GFR in 40% of the patients and in a mild decrease in another 40%. In all cases of severe decreases in GFR, it tended to return to baseline values upon discontinuation of DFO. There was a significant increase in urine volume during DFO therapy. These changes are consistent with our previous observation in humans and dogs receiving high dose i.v. DFO, albeit milder.
Adolescent↗
Effects of age and cardiac shunts on the measured uptake of nitrous oxide in children.
The uptake of nitrous oxide (N2O) was calculated by using a new application of pharmacokinetics involving cumulative fractional expired N2O concentration at 90 percent steady state. The effect of age on N2O uptake was investigated in 33 normal children undergoing non-cardiac surgery. Uptake was also investigated in 17 children with right-to-left cardiac stunts and 18 children with left-to-right shunts undergoing corrective or palliative cardiac surgery. There was a significant correlation of N2O elimination half-life (T1/2) with age for normal children (p less than 0.001), and for children with right-to-left (p less than 0.001) or left-to-right (p = 0.05) shunts. Elimination T1/2 in children with left-to-right shunts correlated significantly with the calculated shunt fraction (p less than 0.05). By providing a useful means for comparison, this method of measuring N2O uptake permits determination of the effects of age, weight and cardiac shunts on the uptake kinetics of N2O.
Age Factors↗
Captopril pharmacokinetics, blood pressure response and plasma renin activity in normotensive children with renal scarring.
We studied blood pressure response, plasma renin activity (PRA) and captopril pharmacokinetics in 8 children receiving orally 0.7 mg/kg of the drug. The drug increased PRA in all patients, in 5 to abnormally high levels. Peak captopril concentrations were achieved between half an hour and 2 h, and ranged between 100 and 547 ng/ml. Mean elimination half-time (T1/2) was 1.5 h, ranging between 0.98 and 2.3 h. There was a significant positive correlation between the area under the curve (AUC) and elimination T1/2 of the drug. There was a significant inverse correlation between AUC or elimination T1/2 and percent change in diastolic blood pressure; the 2 children who had no change in diastolic blood pressure had the largest AUC and the lowest apparent clearance of captopril. The kidney is the major site of captopril's pharmacological action. It is possible that longer retention of captopril in the plasma, evidence by larger AUC, may reflect less captopril available to modulate renin activity in the kidney.
Administration, Oral↗