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Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 181 records · Page 10Linked to original sources
PubMed1998

Characterization of a slowly inactivating outward current in adult mouse ventricular myocytes.

We recently have reported that suppression of the slowly inactivating component of the outward current, Islow, in ventricular myocytes of transgenic mice (long QT mice) overexpressing the N-terminal fragment and S1 segment of Kv1.1 resulted in a significant prolongation of action potential duration and the QT interval. Here we describe the detailed biophysical properties and physiological role of Islow by applying the whole-cell patch-clamp technique at both room temperature and 37 degreesC. This current activates rapidly with time constants ranging from 3.8+/-0.8 ms at -20 mV to 2.1+/-0.5 ms at 50 mV at room temperature. The half-activation voltage and slope factor are -12.5+/-2.6 mV and 7. 7+/-1.0 mV, respectively. The inactivation of this current is slow compared with the fast inactivating component Ito, with time constants of approximately 100 ms at 37 degreesC. The steady-state inactivation of Islow is not temperature-dependent, with half-inactivation voltages and slope factors of -35.1+/-1.3 and -5. 4+/-0.4 mV at 37 degreesC, and -37.6+/-1.8 and -5.8+/-0.6 mV at room temperature. Double exponentials were required to describe the time-dependent recovery of Islow from steady-state inactivation, with time constants of 233+/-34 and 3730+/-702 ms at 37 degreesC, and 830+/-240 and 8680+/-2410 ms at room temperature. Islow is highly sensitive to 4-aminopyridine but is insensitive to tetraethylammonium, alpha-dendrotoxin, and E-4031. Stimulation with action-potential waveforms under voltage-clamp mode revealed that this current plays an important role in the early and middle phases of repolarization of the cardiac action potential. We conclude that the biophysical properties and pharmacological profiles of Islow are similar to those of Kv1.5-encoded currents.

4-Aminopyridine↗
PubMed1998

Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies.

OBJECTIVE: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate. DESIGN: Meta-analysis. SETTING: Studies from 1966 to present. SUBJECTS: Studies were located with Medline, Embase, Reprotox, and from references of textbooks, reviews, and included articles. Included studies were original, concurrently controlled studies in any language. INTERVENTIONS: Data extraction and quality assessment were done independently and in duplicate. MAIN OUTCOME MEASURES: Maternal exposure to benzodiazepines in at least the first trimester; incidence of major malformations or oral cleft alone, measured as odds ratios and 95% confidence intervals with a random effects model. RESULTS: Of over 1400 studies reviewed, 74 were retrieved and 23 included. In the analysis of cohort studies fetal exposure to benzodiazepine was not associated with major malformations (odds ratio 0.90; 95% confidence interval 0.61 to 1. 35) or oral cleft (1.19; 0.34 to 4.15). Analysis of case-control studies showed an association between exposure to benzodiazepines and development of major malformations (3.01; 1.32 to 6.84) or oral cleft alone (1.79; 1.13 to 2.82). CONCLUSIONS: Pooled data from cohort studies showed no association between fetal exposure to benzodiazepines and the risk of major malformations or oral cleft. On the basis of pooled data from case-control studies, however, there was a significant increased risk for major malformations or oral cleft alone. Until more research is reported, level 2 ultrasonography should be used to rule out visible forms of cleft lip.

Abnormalities, Drug-Induced↗
PubMed1998

Use of misoprostol during pregnancy and Möbius' syndrome in infants.

BACKGROUND: Patients with upper gastrointestinal ulceration may be treated with misoprostol, but it is not recommended for pregnant women because it may stimulate uterine contractions and cause vaginal bleeding and miscarriage. Recent data from Brazil, where misoprostol is used orally and vaginally as an abortifacient, have suggested a relation between the use of misoprostol by women in an unsuccessful attempt to terminate pregnancy and Möbius' syndrome (congenital facial paralysis) in their infants. METHODS: We compared the frequency of misoprostol use during the first trimester by mothers of infants in whom Möbius' syndrome was diagnosed and mothers of infants with neural-tube defects in Brazil. All diagnoses in infants were made between January 16, 1990, and May 31, 1996, by clinical geneticists at seven hospitals who also interviewed the mothers and recorded information about the administration of misoprostol, among other data. RESULTS: We identified 96 infants with Möbius' syndrome and matched them with 96 infants with neural-tube defects. The mean age at the time of the diagnosis of Möbius' syndrome was 16 months (range, 0.5 to 78), and the diagnosis of neural-tube defects was made within 1 week of birth in most cases. Among the mothers of the 96 infants with Möbius' syndrome, 47 (49 percent) had used misoprostol in the first trimester of pregnancy, as compared with 3 (3 percent) of the mothers of the 96 infants with neural-tube defects (odds ratio, 29.7; 95 percent confidence interval, 11.6 to 76.0). Twenty of the mothers of the infants with Möbius' syndrome had taken misoprostol only orally (odds ratio, 38.8; 95 percent confidence interval, 9.5 to 159.4), 20 had taken misoprostol both orally and vaginally, 3 had taken the drug vaginally, and 4 did not report how they took the drug. CONCLUSIONS: Attempted abortion with misoprostol is associated with an increased risk of Möbius' syndrome in infants.

Abortifacient Agents, Nonsteroidal↗
PubMed1998

Long-term neurodevelopmental risks in children exposed in utero to cocaine. The Toronto Adoption Study.

Children exposed in utero to cocaine are at risk for long-term neurobehavioral damage not just because of the drug itself; but also because of clustering of other health determinants, including low socioeconomic status, low maternal education, and maternal addiction, to mention a few. One methodologic approach to separate the direct neurotoxic effects of cocaine from these synergistic insults is to follow up a cohort of children exposed in utero to cocaine and given up for adoption to middle-upper class families. The Toronto Adoption Study, supported by Health Canada, has proven the direct neurotoxic effects of cocaine on IQ and language. These effects are mild to moderate as compared to those measured in children exposed in utero to cocaine and reared by their natural mothers.

Adoption↗
PubMed1998

Drugs in pregnancy.

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Abnormalities, Drug-Induced↗
PubMed1998

Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel.

Voltage-gated potassium channels control cardiac repolarization, and mutations of K+ channel genes recently have been shown to cause arrhythmias and sudden death in families with the congenital long QT syndrome. The precise mechanism by which the mutations lead to QT prolongation and arrhythmias is uncertain, however. We have shown previously that an N-terminal fragment including the first transmembrane segment of the rat delayed rectifier K+ channel Kv1.1 (Kv1.1N206Tag) coassembles with other K+ channels of the Kv1 subfamily in vitro, inhibits the currents encoded by Kv1.5 in a dominant-negative manner when coexpressed in Xenopus oocytes, and traps Kv1.5 polypeptide in the endoplasmic reticulum of GH3 cells. Here we report that transgenic mice overexpressing Kv1.1N206Tag in the heart have a prolonged QT interval and ventricular tachycardia. Cardiac myocytes from these mice have action potential prolongation caused by a significant reduction in the density of a rapidly activating, slowly inactivating, 4-aminopyridine sensitive outward K+ current. These changes correlate with a marked decrease in the level of Kv1.5 polypeptide. Thus, overexpression of a truncated K+ channel in the heart alters native K+ channel expression and has profound effects on cardiac excitability.

4-Aminopyridine↗
PubMed1998

Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study.

CONTEXT: Although a large number of women of reproductive age use new selective serotonin reuptake inhibitors (SSRIs) and half of all pregnancies are unplanned, no data exist on the safety of these agents for the human fetus. OBJECTIVE: To assess fetal safety and risk of fluvoxamine, paroxetine, and sertraline. DESIGN: A prospective, multicenter, controlled cohort study. SETTING: Nine Teratology Information Service centers in the United States and Canada. PATIENTS: All women who were counseled during pregnancy following exposure to a new SSRI and followed up by the participating centers. Controls were randomly selected from women counseled after exposure to nonteratogenic agents. MAIN OUTCOME MEASURES: Rates of major congenital malformations. RESULTS: A total of 267 women exposed to an SSRI and 267 controls were studied. Exposure to SSRIs was not associated with either increased risk for major malformations (9/222 live births [4.1%] vs 9/235 live births [3.8%] in the controls, relative risk, 1.06, 95% confidence interval, 0.43-2.62) or higher rates of miscarriage, stillbirth, or prematurity. Mean (SD) birth weights among SSRI users (3439 [505] g) were similar to the controls (3445 [610] g) as were the gestational ages (39.4 [1.7] weeks vs 39.4 [1.9] weeks). CONCLUSION: The new SSRIs, fluvoxamine, paroxetine, and sertraline, do not appear to increase the teratogenic risk when used in their recommended doses.

1-Naphthylamine↗
PubMed1998

Electronic measurement of compliance with mercaptopurine in pediatric patients with acute lymphoblastic leukemia.

UNLABELLED: Twenty-four pediatric patients with acute lymphoblastic leukemia (ALL) on maintenance therapy were evaluated for their compliance with taking their prescribed doses of oral mercaptopurine (6-MP). PROCEDURE AND RESULTS: We utilized the Medication Event Monitoring System (MEMS; Aprex Corporation, Fremont, CA) for the study. Compliance was defined as the number of days doses were taken as a percentage of the total number of days doses were prescribed during the study period. The mean age of the patients was 7.3 years (range 2.6-17.2 (years). Patients were evaluated for a mean of 44 days (range 15-94 days). Thirty-three percent of patients (8) took less than 90% and 17% (4) took less than 80% of their prescribed pills. Eight patients were also evaluated for a difference in compliance between morning and evening administration. For the comparison of compliance between a morning vs. an evening schedule a tren toward improved compliance in the evening was found. Five patients had an increase and one patient a decrease in compliance with an evening schedule (differences ranged from 0.2% to 51.3%), with two patients having 100% compliance on both schedules. CONCLUSIONS: Our data raise concern that a significant proportion of pediatric patients are non-compliant with pill taking and demonstrate that the timing of administration of 6-MP in children with ALL may be crucial in some patients and supports the hypothesis that evening administration of 6-MP is associated with a lower risk of relapse.

Adolescent↗
PubMed1998

Pregnancy outcome following maternal organic solvent exposure: a meta-analysis of epidemiologic studies.

BACKGROUND: Evidence of fetal damage or demise from occupational organic solvent levels that are not toxic to the pregnant woman is inconsistent in the medical literature. The risk for major malformations and spontaneous abortion from maternal inhalation of organic solvent exposure during pregnancy was summarized using meta-analysis. METHODS: Medline, Toxline, and Dissertation Abstracts databases were searched to locate all research papers published in any language from 1996 to 1994. Included were studies that were case-control or cohort in design and indicated first trimester (or up to 20 weeks gestation for spontaneous abortion) maternal solvent exposure. A summary odds ratio (ORs) with 95% confidence intervals (CI) was calculated from research results combined by the Mantel-Haenszel method. RESULTS: In total, 559 studies were obtained from the literature search. Five studies for each outcome of interest qualified for inclusion in the analysis. The ORs for major malformations from five studies (n = 7,036 patients) was 1.64 (CI 1.16-2.30) and for spontaneous abortion from five studies (n = 2,899 patients) was 1.25 (CI 0.99-1.58). CONCLUSIONS: Maternal occupational exposure to organic solvents is associated with a tendency toward an increased risk for spontaneous abortion and additional studies may affect the trend. There is a statistically significant association with major malformations which warrants further investigation.

Abnormalities, Drug-Induced↗
PubMed1998

Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety.

Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady-state pharmacokinetics of isotretinoin and its major 4-oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady-state serum concentrations of isotretinoin was tested. The concentration-time data best fitted a two-compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady-state serum concentrations. There was no correlation between dose of isotretinoin and steady-state concentration, due to the large variability in apparent clearance. Values for elimination half-life (t1/2) of isotretinoin and its metabolite were 29+/-40 hours and 22+/-10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.

Abnormalities, Drug-Induced↗
PubMed1998

Intravenous and oral propafenone for treatment of tachycardia in infants and children: pharmacokinetics and clinical response.

To elucidate contribution of an active metabolite to overall clinical responses to propafenone, steady-state disposition of propafenone and its active metabolite and the clinical responses to treatment were examined in pediatric patients receiving intravenous or oral propafenone. There were more than ten-fold interindividual differences in apparent clearance, resulting in a wide range of the steady-state trough plasma concentrations of propafenone. The active metabolite, 5-hydroxypropafenone, was detected in four of the six patients receiving oral propafenone; however, two neonates receiving oral propafenone and all eight receiving intravenous propafenone had no detectable levels of 5-hydroxypropafenone in plasma. In nine patients for whom electrocardiographic (ECG) data were available, the PQ interval was significantly increased, whereas the QRS duration and the QTc interval were not. There was no close relationship between plasma concentrations of propafenone or 5-hydroxypropafenone and ECG parameters. Lack of good correlation between serum concentrations and clinical response precludes using a serum-concentration targeting strategy with propafenone therapy.

Administration, Oral↗
PubMed1998

The safety of omeprazole during pregnancy: a multicenter prospective controlled study.

OBJECTIVES: Our purpose was to determine whether omeprazole use during pregnancy is associated with an increased risk of malformations, spontaneous abortions, decreased birth weight, or perinatal complications. STUDY DESIGN: In a multicenter, prospective controlled study, pregnant women exposed to omeprazole during gestation were matched with controls exposed to nonteratogens and with disease-paired controls who used histamine blockers for similar indications. The primary end point was the incidence of major malformations. RESULTS: One hundred thirteen pregnant women were exposed to omeprazole during pregnancy. Rates of major malformations in the omeprazole group (4%) did not differ from controls exposed to nonteratogens (2%) (P = .68, relative risk = 1.94, 95% confidence interval 0.36 to 10.36) and disease-paired controls (2.8%). Birth weight, gestational age at delivery, preterm deliveries, and neonatal complications were comparable among the three groups. CONCLUSIONS: No association was found between exposure to omeprazole during the period of organogenesis and increased risk for major malformations. Exposure throughout pregnancy is not associated with increased risk of spontaneous abortions, decreased birth weight, or perinatal complications.

Abnormalities, Drug-Induced↗
PubMed1998

The safety of mesalamine in human pregnancy: a prospective controlled cohort study.

BACKGROUND & AIMS: Mesalamine is a first-line drug in the treatment of inflammatory bowel disease. Information regarding human pregnancy experience with mesalamine has been scarce and uncontrolled despite its frequent use in women of childbearing age. The aim of this study was to examine the fetal safety of mesalamine. METHODS: The Motherisk Program prospectively enrolled and followed up 165 women exposed to mesalamine during pregnancy, 146 of whom had first trimester exposure. Pregnancy outcome was compared with that of a matched control group, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in major malformations (1 of 127 [0.8%] for mesalamine vs. 5 of 131 [3.8%] for nonteratogenic controls; P = 0.23). There was an increase in the rate of preterm deliveries (13.0% for mesalamine vs. 4.7% for nonteratogenic controls; P = 0.02), a decrease in the mean maternal weight gain during pregnancy (13.1 +/- 6.3 kg for mesalamine vs. 15.6 +/- 6.0 kg for nonteratogenic controls; P = 0.0002), and a decrease in the mean birth weight (3253 +/- 546 g for mesalamine vs. 3461 +/- 542 g for nonteratogenic controls; P = 0.0005). There were no significant differences in the maternal obstetric history, rates of live births, miscarriages, pregnancy terminations, ectopic pregnancies, delivery method, or fetal distress between the groups. CONCLUSIONS: This study suggests that mesalamine does not represent a major teratogenic risk in humans when used in the recommended doses.

Adult↗
PubMed1998

Lack of cisplatin-ranitidine kinetic interactions: in vivo study in children, and in vitro study using dog renal brush border membrane vesicles.

The interactions between cisplatin and organic ions have been extensively investigated in animal models for the potential to reduce cisplatin cellular uptake and resultant nephrotoxicity. To further investigate the beneficial interaction clinically, we studied the effects of the organic cation, ranitidine, on the renal handling of cisplatin in children. In parallel, we examined the effects of cisplatin on the uptake kinetics of organic cations and anions by brush border membrane vesicles (BBMV) prepared from dog renal cortex. The results indicate that: 1) there is no measurable effect of ranitidine on renal clearance of cisplatin in children; and 2) BBMV uptake of anionic p-aminohippurate, but not cationic N-methylnicotinamide, is inhibited by cisplatin at concentrations of <1 mM. These findings suggest that cisplatin may not share transport systems with organic cations to a clinically significant degree. Assuming that renal tubular transport is a prerequisite for cisplatin nephrotoxicity, the lack of apparent kinetic interactions between cisplatin and organic cations may preclude clinical use of organic cations as a modality to prevent cisplatin nephrotoxicity.

Adolescent↗
PubMed1998

Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro.

Our objective was to study the characteristics of transfer and biotransformation of nicotine in the human term placenta. Nicotine transfer was studied by dually perfusing an isolated cotyledon of the human placenta in vitro. Nicotine metabolism to cotinine was investigated in intact tissue during perfusion and in placental microsomal fractions. Following the addition of nicotine (40 ng/ml) to the maternal side of the placenta, distribution into placental tissue (0.43 +/- 0.13 ng/ml/min) was three times higher than transfer to the fetal side of the placenta (0.15 +/- 0.01 ng/ml/min). The steady-state maternal-to-fetal transfer of nicotine was approximately 90% that of antipyrine (a marker of flow-dependent transfer). There was no evidence of nicotine metabolism to cotinine by intact placental tissue or in microsomal fractions. The observation that nicotine readily crosses the human placenta with no evidence of metabolism suggests that nicotine has the potential to cause adverse affects on the developing fetus.

Biological Transport↗
PubMed1998

Hypothetical framework for enhanced renal tubular secretion of drugs in cystic fibrosis.

Several clinical studies demonstrate reduced serum concentrations of renally excreted drugs in patients with cystic fibrosis (CF). To explain this phenomenon, we propose a model supporting increased proximal tubular secretion of certain drugs in individuals with CF. We hypothesize that the chloride channel located on the apical surface of renal proximal tubular cells and controlled by the cystic fibrosis transmembrane conductance regulator (CFTR) operates suboptimally in CF patients, and that the abnormal CFTR decreases Cl- reabsorption, resulting in an increased concentration of Cl- in the tubular lumen. We postulate that, in an effort to maintain homeostasis, luminal Cl- moves intracellularly in exchange for organic anions. The result of stimulating this anion exchanger is an increased rate of organic anion secretion by the renal tubule. Hence, due to enhanced tubular secretion, individuals with CF demonstrate increased tubular clearance of organic anion drugs, resulting in lower steady state serum concentrations.

Chlorides↗
PubMed1998

A prospective controlled multicentre study of clarithromycin in pregnancy.

Clarithromycin is a relatively new macrolide antibiotic with an action spectrum similar to that of erythromycin. Its main indications for use are for upper and lower respiratory and skin and soft tissue infections. Little is known about its safety in pregnancy, although animal reproductive studies found an increased rate of cardiovascular anomalies, cleft palate, and embryonic loss. Human data, limited to case reports and one small uncontrolled study, cannot allow evidence based counseling of pregnant women who were exposed to the drug before finding out they were pregnant. Pregnant women who had been counseled on the use of clarithromycin by five centers, were matched for age, smoking, and alcohol use with a control group of pregnant women who were exposed to nonteratogenic antibiotics. A total of 157 women were followed up. Of these, 122 were exposed to the drug in the first trimester. There were no significant differences found between the two groups in the rates of major and minor malformations; 2.3 versus 1.4% for major (p = 0.86) and 5.4 versus 4.9% for minor (p = 0.96). Spontaneous abortion rates in the exposed group was significantly different, higher (14%) than in the control group (7%) (p = 0.04). This first prospective controlled study of exposure to clarithromycin in pregnancy suggests that this agent does not increase the rate of major malformations above the baseline risk of 1-3%. The higher rate of reported spontaneous abortions, although still within the expected baseline rate, may warrant further study.

Anti-Bacterial Agents↗