Biomedical subjects

Gideon Koren

Publications and source records attributed to Gideon Koren.

At least 199 records · Page 11Linked to original sources

PubMed2003

Monitoring lithium in breast milk: an individualized approach for breast-feeding mothers.

Lithium is a drug of choice for the management of bipolar disorder, a disease frequently affecting women in their childbearing years. Unfortunately, this drug has typically been contraindicated in nursing women. Data in humans are limited with respect to the use of this drug in lactating women, and early reports suggest high excretion into milk. The purpose of this report was to verify the excretion of lithium into human milk and to assess infant safety after breast-feeding. The authors found wide interpatient variability in lithium dose offered to the infant through breast milk (from 0% to 30% of maternal weight-adjusted dose), indicating that therapeutic drug monitoring of lithium in milk and/or in infant's blood, coupled with close monitoring of adverse effects, is a rational approach. Since therapeutic drug monitoring of lithium is routine, physicians caring for these women and infants should be encouraged to individualize their recommendations.

Bipolar Disorder↗

PubMed2003

Discrepancies between ordered and delivered concentrations of opiate infusions in critical care.

OBJECTIVES: We sought to test the assumption that the measured concentrations of medication infusions are within pharmaceutical standards (+/-10% of intended concentrations) and whether, at the time the infusion was mixed, the professional background of persons preparing the infusion or the unit for which the infusion was prepared were related to the observed variation. DESIGN, SETTING, AND PARTICIPANTS: This prospective, observational study was conducted in the neonatal and pediatric intensive care units of a university-affiliated tertiary pediatric center. Morphine infusions prepared for clinical use were randomly sampled over a 7-month period. Those with no error between labeled and ordered concentration were further analyzed. High-performance liquid chromatography was used to determine the concentration of morphine infusions. The primary outcome was a difference of >10% between ordered and measured concentrations. MEASUREMENTS AND MAIN RESULTS: The measured concentration of 65% of the 232 infusions was >10% different from the ordered concentration (95% confidence interval, 58-71%). The concentrations of 6% of infusions represented two-fold errors (95% confidence interval, 3-9%). The difference was normally distributed around zero, suggesting a cumulative effect of random errors, rather than a systematic bias. The time that the infusion was prepared, the professional background of the persons preparing the infusion, and the unit for which the infusion was mixed were not significant predictors of discrepancy (p =.74, analysis of variance). CONCLUSIONS: The concentration of two thirds of infusions prepared for clinical use was outside accepted industry standards. These findings are likely to be broadly representative of intravenous drug administration in hospitalized children and pediatric pharmacokinetic studies. Further study of the causes and clinical impact is required.

Critical Care↗

PubMed2003

Verapamil metabolites: potential P-glycoprotein-mediated multidrug resistance reversal agents.

Multidrug resistance in cancer chemotherapy frequently correlates with overexpression of the P-glycoprotein drug transporter. Attempts to reverse P-glycoprotein-mediated multidrug resistance with racemic verapamil or its less toxic (R)-enantiomer have been complicated by cardiotoxicity. The objective of this study was to investigate the effects of the major verapamil metabolite, norverapamil, as well as the PR-22 and D-620 metabolites, on P-glycoprotein-mediated drug transport. We measured the basolateral-to-apical fluxes of the P-glycoprotein substrates digoxin and vinblastine in the presence and absence of verapamil, (R)-norverapamil, (S)-norverapamil, racemic norverapamil, PR-22, or D-620 across confluent monolayers of Madin-Darby canine kidney (MDCK) cells that express P-glycoprotein on their apical membranes. Verapamil and norverapamil nonstereospecifically inhibited the renal tubular secretion of digoxin and vinblastine similarly in a dose-dependent manner. However, there was no decrease in the cellular accumulation of digoxin and vinblastine, suggesting that neither verapamil nor norverapamil prevent the substrates from entering the MDCK cells. Furthermore, the norverapamil metabolite P-22 also inhibited the secretion of these P-glycoprotein substrates. Our results suggest that the verapamil metabolites norverapamil and PR-22, which are less cardiotoxic than the parent compound, have comparable inhibitory abilities to verapamil (norverapamil greater than PR-22) and may be useful in reversing resistance to P-glycoprotein substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Regional upregulation of Kv2.1-encoded current, IK,slow2, in Kv1DN mice is abolished by crossbreeding with Kv2DN mice.

Overexpression of a truncated Kv1.1 channel transgene in the heart (Kv1DN) resulted in mice with a prolonged action potential duration due to marked attenuation of a rapidly activating, slowly inactivating potassium current (I(K,slow1)) in ventricular myocytes. Optical mapping and programmed electrical stimulation revealed inducible ventricular tachycardia due to spatial dispersion of repolarization and refractoriness. Here we show that a delayed rectifier with slower inactivation kinetics (I(K,slow2)) was selectively upregulated in Kv1DN cardiocytes. This electrical remodeling was spatially restricted to myocytes derived from the apex of the left ventricle. Biophysical and pharmacological studies of I(K,slow2) indicate that it resembles Kv2-encoded currents. Northern blot analyses and real-time PCR revealed upregulation of Kv2.1 transcript in Kv1DN mice. Crossbreeding of Kv1DN mice with mice expressing a truncated Kv2.1 polypeptide (Kv2DN) eliminated I(K,slow2). In summary, our data indicate that the spatially restrictive upregulation of Kv2.1-encoded currents underlies the increased dispersion of the repolarization observed in Kv1DN mice.

4-Aminopyridine↗

PubMed2003

In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype.

Mutations in cardiac voltage-gated K+ channels cause long QT syndrome (LQTS) and sudden death. We created a transgenic mouse with a long QT phenotype (Kv1DN) by overexpression of a truncated K+ channel in the heart and investigated whether the dominant negative effect of the transgene would be overcome by the direct injection of adenoviral vectors expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. End points at 3-10 days included electrophysiology in isolated cardiomyocytes, surface ECG, programmed stimulation of the right ventricle, and in vivo optical mapping of action potentials and repolarization gradients in Langendorff-perfused hearts. Overexpression of Kv1.5 reconstituted a 4-aminopyridine-sensitive outward K+ current, shortened the action potential duration, eliminated early afterdepolarizations, shortened the QT interval, decreased dispersion of repolarization, and increased the heart rate. Each of these changes is consistent with a physiologically significant primary effect of adenoviral expression of Kv1.5 on ventricular repolarization of Kv1DN mice.

4-Aminopyridine↗

PubMed2003

A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy.

OBJECTIVES: Trazodone and nefazodone are phenylpiperazine antidepressants. Currently, there are no adequate, well-controlled studies on the fetal safety of these drugs. Our primary objective was to determine whether the use of trazodone or nefazodone during pregnancy is associated with an increased risk for major malformations. Secondary outcomes of interest included rates of spontaneous and therapeutic abortions, rates of premature labour, and birth weight. METHODS: Pregnant women from 5 centres who had been exposed to these drugs (n = 147) were enrolled in the study during their first trimester. We compared the women with 2 groups of women who took either other antidepressant drugs (n = 147) or nonteratogenic drugs (n = 147). All the women were followed up after delivery to ascertain pregnancy outcome and the health of the baby. RESULTS: We have completed 147 follow-ups. There were 121 (82.4%) live births, 20 (13.6%) spontaneous abortions, and 6 (4%) therapeutic abortions. Of the live births, there were 2 (1.6%) major malformations. In all cases, drug exposure occurred during the first trimester, with 52 (35%) of the women using these drugs throughout pregnancy. The mean gestational age at birth was 38 weeks (SD 4.2), and the mean birth weight was 3306.34 g (SD 655). We found no statistically significant differences among the 3 groups in any of the endpoints of interest that we examined. Of the sample, 58 women were exposed to trazodone, and 89 were exposed to nefazodone. CONCLUSION: Our results suggest that these drugs do not increase the rates of major malformations above the baseline rate of 1% to 3%.

Antidepressive Agents, Second-Generation↗

PubMed2003

Vitamin E: the evidence for multiple roles in cancer.

There is accumulating evidence that vitamin E may have different roles in the prevention and treatment of cancer. The purpose of this review is to summarize and evaluate this evidence and to suggest future avenues of research. A comprehensive literature review of vitamin E and cancer was conducted. Articles were organized into the following categories: 1) cancer prevention, 2) direct antineoplastic activity, 3) augmentation of chemotherapy effects, and 4) attenuation or treatment of chemotherapy toxicity. The evidence was systematically evaluated using guidelines developed by the U.S. Preventative Services Task Force. There is evidence to suggest that those individuals with higher serum vitamin E levels and those receiving vitamin E supplementation have a decreased risk of some cancers, including lung, prostate, stomach, and gastrointestinal carcinoma. However, these results differed depending on the study design and the population studied. There is insufficient evidence to support anticancer activity and attenuation of chemotherapy toxicity by vitamin E. Vitamin E is likely to be important in the prevention of some cancers. The therapeutic role of vitamin E is poorly understood. Further research will be required before routine use of vitamin E in patients with cancer can be advocated in the clinical setting.

Case-Control Studies↗

PubMed2003

Milk transfer and neonatal safety of tacrolimus.

OBJECTIVE: To report the first case of tacrolimus measurement in human milk following maternal dosing in a woman who breast-fed while taking the medication. CASE REPORT: A 32-year-old white woman who had taken tacrolimus 0.1 mg/kg/d throughout pregnancy contacted the Motherisk Program at 35 weeks' gestation inquiring about the safety of breast-feeding during maternal tacrolimus therapy. After benefit-risk assessment, the mother decided to breast-feed the baby. METHODS: Manually expressed milk samples were collected over 12 hours following the first tacrolimus dose of the day; pre-dosing and 1-hour post-dosing blood concentrations were also determined. The samples were analyzed for tacrolimus by tandem-mass spectrometry. Breast milk and blood samples were collected at steady-state. RESULTS: The highest and mean concentrations of tacrolimus in milk were 0.57 and 0.429 ng/mL, respectively. From these measurements, the exclusively breast-fed infant would ingest, on average, 0.06 micro g/kg/d, which corresponds to 0.06% of the mother's weight-adjusted dose. Given the low oral bioavailability of tacrolimus, the maximum amount the baby would receive is 0.02% of the mother's weight-adjusted dose. The milk-to-blood ratios of tacrolimus at pre-dosing and 1-hour post-dosing concentrations were calculated to be 0.08 and 0.09, respectively. At 2.5 months of age, the infant was developing well both physically and neurologically. COMMENT: This report is the first to measure tacrolimus concentrations in established human milk using tandem-mass spectrometry to detect drug while the infant was exclusively breast-fed by the mother, and in which the infant's growth and development were reported. CONCLUSIONS: Our results suggest that maternal therapy with tacrolimus for liver transplant may be compatible with breast-feeding.

Adult↗

PubMed2003

Prediction of milk/plasma concentration ratio of drugs.

OBJECTIVE: The milk to plasma (m/p) concentration ratio of drugs is used to estimate the amount of drug offered to the suckling infant. Published literature was reviewed to identify drugs for which sufficient data exist for calculation of m/p ratio and to examine whether the existing empiric data agree with the published method of Atkinson for mathematical prediction of m/p ratios based on physiochemical characteristics. METHODS: Using a comprehensive reference text, we identified studies reporting sufficient data to calculate m/p ratio based on the AUC for milk and plasma. Subsequently, we calculated the m/p ratio with Atkinson's formula based on pKa, lipophilicity, and protein binding. We then correlated the empiric versus predicted (calculated) m/p ratios. RESULTS: Of 192 drugs of which at least some data on milk accumulation have been published, there were sufficient data to quantify m/p ratios for only 69 medications (78 studies). There was no significant correlation between the empiric m/p ratios and the predicted values using the Atkinson's model. CONCLUSIONS: Reliable data on m/p concentration ratios exist for few medications. Presently, there is no appropriate model to predict milk concentrations of drugs in humans.

Area Under Curve↗

PubMed2003

Celecoxib in human milk: a case report.

Many women of reproductive age take the nonsteroidal antiinflammatory drug celecoxib. No data exist, however, regarding its transfer into human breast milk and safety for breastfed infants. We had the opportunity to obtain such data when a woman who was breastfeeding her infant daughter underwent emergency surgery to remove a gangrenous appendix. She received four doses of oral celecoxib 100 mg and did not breastfeed her daughter for 48 hours after taking the last dose. We analyzed samples of her breast milk and found a concentration of 133 ng/ml at approximately 5 hours after a 100-mg dose and an elimination half-life of 4.0-6.5 hours. This initial report, which should be substantiated and expanded, provides information that can help counsel parents about breastfeeding and celecoxib.

Adult↗

PubMed2003

Maternal-fetal transport of hypoglycaemic drugs.

Due to legal, ethical and monetary problems, drug studies in pregnancy are rare. Numerous pharmacokinetic and pharmacodynamic changes occur in pregnancy that can affect the efficacy and safety of drugs, and these are difficult to predict without appropriate studies. Drugs potentially useful and safe in pregnancy have to either not cross the placenta and/or be harmless to the fetus at clinically relevant concentrations. The first characteristic can be predicted using in vitro models such as the placenta perfusion model. In the case of glibenclamide (glyburide), in vitro experiments showed minimal maternal-fetal transfer, leading to completion of a successful clinical trial of this drug in gestational diabetes. Insulin, the main drug used in diabetes during pregnancy, has also been shown not to cross the placenta in vitro, as has insulin lispro. Animal insulin may cross the placenta when complexed with anti-insulin antibodies. Other sulphonylurea drugs (tolbutamide and chlorpropamide) have been shown to cross the placenta both in vitro and in vivo and to produce toxicity in the fetus. This review summarises the pharmacokinetic data available for hypoglycaemic drugs during pregnancy, as well as the potential role for the in vitro placenta perfusion model in the preclinical evaluation of drugs with potential usefulness in pregnancy.

Abnormalities, Drug-Induced↗

PubMed2003

Transfer of insulin lispro across the human placenta: in vitro perfusion studies.

OBJECTIVE: Insulin lispro (Humalog), a human insulin analog, has a more rapid onset, earlier peak, and shorter duration of glucose lowering activity than regular human insulin. However, it is not known whether insulin lispro crosses the human placenta and reaches the fetus. Therefore, the objective of the present study was to examine whether insulin lispro crosses the placenta using the technique of perfusing a human placental lobule in vitro. RESEARCH DESIGN AND METHODS: Term human placentae from uncomplicated pregnancies were obtained immediately after delivery. Insulin lispro, at concentrations ranging from 100 to 1000 micro U/ml, was introduced into the maternal reservoir. The maternal side of the placenta was perfused with constant concentration of lispro insulin; the fetal circulation was closed. Samples were drawn from both the maternal and fetal circulations at regular intervals. The appearance of insulin lispro in the fetal circulation was analyzed by a specific radioimmunoassay. RESULTS: No placental transfer of lispro could be detected during perfusion with 100 and 200 micro U/ml. In contrast, there was a small concentration-dependent transfer to the fetus at concentrations of 580 micro U/ml and higher, detectable after at least an hour of constant concentration of insulin lispro during perfusion. The rate of placental transfer was 0.019 micro U x min(-1) x g tissue(-1) at maternal levels of 580 micro U/ml and 0.045 micro U x min(-1) x g(-1) tissue at maternal levels of 1000 micro U/ml. Measuring lispro levels in 11 pregnant women revealed that a dose of 50 units may achieve serum concentrations >200 micro U/ml with apparent linear correlation between dose and levels. CONCLUSIONS: Insulin lispro is not likely to cross the placenta at a single standard dose. This study suggests that insulin lispro is unlikely to reach or harm the unborn baby.

Adult↗

PubMed2003

Taking St John's wort during pregnancy.

QUESTION: A 23-year-old patient of mine has been taking St John's wort for postpartum depression for about 2 years. She is now planning her second pregnancy. Is she or her fetus at risk if she continues to take the herbal therapy? ANSWER: Despite the widespread availability and use of St John's wort and extensive research on the herb, there are almost no data on reproductive safety. At this stage, therefore, St John's wort cannot be recommended as safe therapy during pregnancy.

Adult↗

PubMed2003

Evaluation of eutectic lidocaine/prilocaine cream (EMLA) for steroid joint injection in children with juvenile rheumatoid arthritis: a double blind, randomized, placebo controlled trial.

OBJECTIVE: To evaluate the efficacy of eutectic lidocaine/prilocaine cream (EMLA) in reducing the pain associated with steroid joint injection in children with juvenile arthritis. METHODS: A randomized, double blind, placebo controlled parallel group trial. Thirty-one children (ages 8-18 yrs) scheduled for steroid injection into a knee were randomized into groups having either 2.5 g lidocaine/prilocaine cream or placebo cream applied to the injection site 60-90 min before the procedure. Patients assessed the pain associated with initial needle insertion and subsequent steroid injection using a 10 cm visual analog scale. RESULTS: No significant difference was found in the pain reported after needle insertion or steroid injection between the lidocaine/prilocaine cream group (n = 17) and the placebo group (n = 14). There was a trend toward an association of lower median scores with the pain of steroid injection in the lidocaine/prilocaine group (6 mm) compared with the placebo group (22 mm). CONCLUSION: Application of 2.5 g lidocaine/prilocaine cream for 60-90 min had no statistically significant analgesic effect on pain associated with injections of steroids into the knees of children with juvenile arthritis.

Adolescent↗

PubMed2003

Exposure to electromagnetic fields during pregnancy.

QUESTION: Several of my patients quote recent media coverage claiming that working with home appliances could increase the risk of misarriages. What is your advice? ANSWER: Two recent epidemiologic studies from California have suggested an increased risk of miscarriages associated with exposure to magnetic fields. Even if the threshold associated with such risk is a biologic and true risk (and not just an association), it does not appear to arise from typical use of hair dryers, microwave ovens, vacuum cleaners, and similar home appliances.

Abortion, Spontaneous↗

PubMed2003

Electric shock during pregnancy.

QUESTION: A 24-year-old patient of mine, who was 23 weeks pregnant at the time, suffered a minor electric shock while using her hair dryer. She said she felt the current in her right hand and she was wearing shoes. She was observed in an emergency room for several hours and then discharged home. Is her pregnancy or fetus at risk now or later in the pregnancy? ANSWER: There are conflicting reports on how harmful electric shock is to a fetus. The clinical spectrum of electrical injury ranges from a transient unpleasant sensation felt by a mother and no effect on her fetus to fetal death either immediately or few days later. Several factors, such as the magnitude of the current and the duration of contact, are thought to affect outcome. In this case, it appears the current did not travel through her abdomen. Recommendations for fetal monitoring after electrocution have been published.

Adult↗

PubMed2003

Anorexia nervosa during pregnancy.

QUESTION: A 22-year-old patient in my clinic was diagnosed with anorexia nervosa (AN) 7 years ago. She is now married and planning her first pregnancy. She is still underweight. What should she expect during pregnancy, and are there any implications for her unborn baby? ANSWER: Women with AN are at higher risk of complications during pregnancy, mainly because of low body weight. Apgar scores and birth weights of infants born to mothers with AN have been found to be significantly lower than those of infants born to healthy women. Rates of cesarean delivery, postnatal complications, and postpartum depression are higher among mothers with AN. Complications include hypothermia, hypoglycemia, infections, and increased rates of perinatal death. It is important to ensure appropriate intake of not only calories and proteins but also micronutrients, such as folic acid, to prevent neural tube defects.

Adult↗

PubMed2003

Effect of methotrexate on male fertility.

QUESTION: Several men with psoriatic arthritis have asked whether the methotrexate they take for rheumatoid arthritis will affect their fertility or the outcome of any of their partners' future pregnancies. What is known regarding risks to fertility and to fetuses? ANSWER: To date, there are no reports of adverse pregnancy outcomes among men exposed to methotrexate before conception. Opinions in the literature differ on the effects of methotrexate on male fertility. Several case reports and studies report no effect; others report reversible sterility. One limitation to several of these studies is the concurrent administration of other chemotherapeutic agents. Small studies reporting on methotrexate use with no other agents suggest no increased infertility. Motherisk is currently following men who are taking methotrexate alone for psoriatic arthritis to see whether it affects fertility.

Arthritis, Psoriatic↗