Showing papers by "Gideon Koren published in 1995"

Iron-chelation therapy with oral deferiprone in patients with thalassemia major.

Abstract: Background To determine whether the orally active iron chelator deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) is efficacious in the treatment of iron overload in patients with thalassemia major, we conducted a prospective trial of deferiprone in 21 patients unable or unwilling to use standard chelation therapy with parenteral deferoxamine. Methods Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens or magnetic-susceptibility measurements. Detailed clinical and laboratory studies were used to monitor safety and compliance. Results The patients received deferiprone therapy for a mean (±SE) of 3.1±0.3 years. Ten patients in whom previous chelation therapy with deferoxamine had been ineffective had initial hepatic iron concentrations of at least 80 μmol per gram of liver, wet weight — values associated with complications of iron overload. Hepatic iron concentrations decreased in all 10 patients, from 125.3±11.5 to 60.3±9.6 μmol per gram (P<0.005), with values that wer...

Regulation of Vascular Endothelial Growth Factor in Cardiac Myocytes

Abstract: Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Fetal toxicology of environmental tobacco smoke.

Abstract: During the past decade, new evidence has been collected regarding the fetal risks of environmental tobacco smoke. Throughout gestation, the unborn baby is exposed to increasing concentrations of nicotine through maternal blood and gastrointestinal and skin absorption of the nicotine in the amniotic

Pemoline-associated fulminant liver failure : testing the evidence for causation

Abstract: Background Pemoline is a central nervous system stimulant used in treating children with attention deficit-hyperactivity disorder. Hepatotoxicity has been commonly reported in association with pemoline; however, only two reports of cases of fatal liver failure have been published. Objectives We report on a 14-year-old boy who received concomitant pemoline and methylphenidate in whom fulminant liver failure occurred and for whom liver transplantation failed. Other causes of fulminant liver failure were ruled out, and the liver biopsy was suggestive of drug toxicity. We estimated the probability that these three cases represent an increased risk of fulminant liver failure associated with pemoline. Results Based on the three known cases of fatal liver failure associated with pemoline use, we calculated that a child receiving pemoline has a relative risk of development of fulminant liver failure of 45.3 (95% confidence interval, 4.1 to 510). This highly significant association (p < 0.001) suggests causation. Conclusions Because pemoline has been widely used in recent years, further studies are needed to better quantify this risk in children with attention deficit-hyperactivity disorder. Clinical Pharmacology & Therapeutics (1995) 57, 696–698; doi:

Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: the causative role of improper dissolution of Cremophor EL.

Abstract: PURPOSEAn unusually high incidence of anaphylactoid reactions was observed during a phase I/II trial of high-dose intravenous cyclosporine (CsA) therapy to attenuate tumor multidrug resistance (MDR). Five of 21 children experienced severe anaphylactoid reactions shortly after initiation of the first or second CsA infusion. We hypothesized that improper dissolution of the vehicle Cremophor EL may have been a cause for these anaphylactoid reactions.METHODSAll nurses who had administered intravenous CsA were interviewed regarding their technique of preparing the infusion and the occurrence of an anaphylactoid reaction. The responses were statistically analyzed. The effect of various mixing techniques on the distribution of Cremophor EL in the infusion was experimentally evaluated. Different mixing techniques were used to assess their effect on the distribution of Cremophor EL in the solution.RESULTSAnalysis of the preparation techniques of the CsA infusion showed significant correlation between suboptimal mi...

The safety of nitrofurantoin during the first trimester of pregnancy: meta-analysis.

Abstract: Asymptomatic bacteriuria is common during pregnancy and may adversely affect both the mother and her fetus. Nitrofurantoin (NF) has been long recognized as an effective agent in both nonpregnant and pregnant women suffering from urinary tract infections. This meta-analysis was conducted in order to evaluate the safety of NF ingested during early pregnancy. Of twenty-two studies, only four met the inclusion criteria and their analysis could not demonstrate any significant correlation between NF ingestion and fetal malformation. The pooled odds ratio was 1.29 with 95% confidence interval 0.25-6.57. Although the number and quality of the studies included are limited, we thought it important to present the existing data. More extensive controlled studies are urgently needed in order to increase the significance of our study.

Influence of food on the bioavailability of oral methotrexate in children

Abstract: Objective. To determine the bioavailability of oral methotrexate (MTX) in patients with juvenile rheumatoid arthritis in the fasting and fed states. Methods. Each patient randomly received their usual weekly MTX dose either orally (po) after an overnight fast, po immediately after a breakfast of their choice, or intravenously (iv) on 3 consecutive weeks. Blood samples were taken at 0, 0.5, 1, 1.5, 2, 3, 4, and 6 h after po and 0, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, and 6 h after iv administration. Results. Fourteen patients (10 female) aged 2.8 to 15.1 yrs completed the study ; the results of 13 patients were evaluable. The mean elimination rate constant was 0.27 ± 0.065, 0.26 ± 0.067, and 0.25 ± 0.11 h -1 after po fasting, po fed, and iv administration, respectively. The total area under the serum concentration vs time curve was 1.87 ± 0.83, 1.50 ± 0.51, and 1.85 ± 0.80 μmol/l.h after po fasting, po fed, and iv administration, respectively. The maximum serum MTX concentration (C max ) was 0.65 ± 0.33 and 0.39 ± 0.18 μmol/l after po fasting and po fed administration, respectively (p = 0.0022). The time to C max was 0.94 ± 0.40 and 1.32 ± 0.68 h after po fasting and po fed administration, respectively (p = 0.1464). The bioavailability of oral MTX while fasting was 1.1 ± 0.51, while that after a meal was 0.88 ± 0.35 (p = 0.0211). Conclusion. These data indicate greater oral bioavailability of MTX in the fasting state. We recommend that children receive MTX on an empty stomach.

Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin

Abstract: The skin and liver may be targets for cytotoxicity induced by oxidative drug metabolites. We used human epidermoid A431 cells and human hepatoblastoma Hep G2 cells as the experimental model. The aim of the study was to investigate and evaluate the effect of silymarin on acetaminophen (APAP)-induced toxicity under controlled conditions. Silymarin is known to be a potent antioxidant that diminishes toxicity induced by a variety of other hepatotoxins (e.g. Amanita phaloides, algae's toxins, carbon tetrachloride). Glutathione (GSH) depletion was enhanced by adding to the medium buthionine sulfoximine [L-buthionine-(S,R)-sulfoximine, BSO]. Cells were incubated with high-concentration 5-20 mM APAP or alpha-(minimum essential medium for 2-24 h to evaluate the drug's ability to reduce cytoviability. Viability was then quantitated by metabolism of the tetrazolium dyes (MTT) and neutral red (NR). Cytoviability was 100% for controls. For Hep G2 treated for 24 h with 20 mM, APAP viability was 56.0% by MTT and 62.5% by NR. BSO-treated cells showed an enhanced cytotoxicity, determined by both assays. Administration of 0.5 mM silymarin reduced cytotoxicity significantly. In A431 cells, treatment with 20 mM APAP reduced viability by 57% (MTT) and 69% (NR) versus control (100%). BSO further decreased viability. Since incubation with silymarin showed significant protection against APAP toxicity, it can be considered a cytoprotective agent in this in vitro model of drug toxicity. GSH concentrations in both cell lines decrease significantly after exposure to 20 mM APAP, or 0.5 mM versus control (p < 0.05), and increased (p < 0.001) if incubated with APAP and silymarin. The protective effect could be through mitochondrial membrane stabilization and/or an increase in available GSH.

A crossover comparison of extended release felodipine with prolonged action nifedipine in hypertension.

Abstract: In a crossover design, control of blood pressure by extended release felodipine was compared with control by prolonged action nifedipine in 21 children with renal hypertension. Compliance with once daily felodipine was higher than with nifedipine, at 95.6 (SEM 2.7)% v 78.9 (6.0)% (p = 0.02). Mean diastolic blood pressure was lower during the day with felodipine than with nifedipine, at 77.6 (2.4) v 84.4 (2.8) mm Hg (p = 0.05). Similarly, blood pressure load (the percentage of the day during which the child had blood pressure exceeding the upper limits of normal for age) was lower for felodipine than for nifedipine: 43.5 (5.5)% v 61.3 (6.3)%. There was an opposite trend during the night, though this did not reach statistical significance. These data suggest that once a day felodipine is effective in children with hypertension. This may be because of improved compliance.

Effects of maternal epilepsy on children's neurodevelopment

Abstract: To assess the neurodevelopmental consequences of epilepsy during pregnancy, we compared offspring of mothers with epilepsy and closely matched controls. Children of mothers with epilepsy were exposed to phenytoin (n=29) or carbamazepine (n=29) monotherapies. All children received age-appropriate measures of psychometric intelligence, motor skills, cognitive abilities, language, and temperament. Results indicated that epilepsy during pregnancy is associated with lower psychometric intelligence and less adequate language skills. Children exposed in utero to phenytoin were affected at a younger age and particularly in their language development, whereas children exposed to carbamazepine only showed effects past age 3. Regression analyses indicated an effect only on language skills due to maternal 1Q and type of epilepsy. Although results are limited by small sample sizes, present findings suggest effects due to anticonvulsants regardless of seizure activity and more favorable outcome in children tre...

Experience with misoprostol therapy for NSAID gastropathy in children.

Abstract: OBJECTIVE--To determine the effect of misoprostol, a synthetic prostaglandin E1 analogue, on the gastrointestinal tract (GIT) symptoms associated with non-steroidal anti-inflammatory drug (NSAID) administration and on the haemoglobin value, in children. METHODS--Retrospective chart review of children attending the paediatric rheumatology clinic at a tertiary referral hospital over a three year period, who were receiving NSAIDs and were prescribed misoprostol for treatment of GIT symptoms or anaemia. RESULTS--Twenty five children (mean age 12.0 (SD 2.8) (range 7-17) years were prescribed misoprostol (mean dose 308.4 (76.5) micrograms/m2/day; 9.8 (2.5) micrograms/kg/day) while NSAID therapy was continued. Of the 22 (88%) patients with GIT complaints, 18 (82%) had complete resolution of symptoms and two (9%) had some improvement. Four patients (18%) had a recurrence of symptoms after initial resolution while still receiving misoprostol. Misoprostol therapy was associated with a statistically significant increase in haemoglobin concentration (mean value before misoprostol 115 (18) g/l; after misoprostol 126 (15) g/l (p = 0.02)). The only adverse effect reported was self limited diarrhoea in one child. CONCLUSION--Misoprostol appeared to be effective in the treatment of GIT symptoms in children receiving NSAIDs and to result in significant increase in the haemoglobin concentration. Further prospective studies are needed to evaluate the role of misoprostol therapy for NSAID associated GIT complaints in the paediatric population.

A Double-Blind, Placebo-Controlled Trial of Transdermal Fentanyl After Abdominal Hysterectomy: Analgesic, Respiratory, and Pharmacokinetic Effects

Abstract: BackgroundA 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. MethodsTTSV patches releasing 50 μg/h (TTSF-50) or 75 μg/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. ResultsThere 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. ConclusionsApplication 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.

Evaluation of therapeutic drug monitoring of methotrexate in saliva of children with rheumatic diseases.

Abstract: Pediatric patients with leukemia, other malignancies, and rheumatological disease receive methotrexate chronically. Because of the documented correlation between methotrexate levels of compliance and clinical outcome, it is conceivable to verify appropriate systemic exposure to the drug. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is ethically limited. Our study shows poor correlation between serum total/free methotrexate concentrations and saliva levels, precluding the clinical use of this test.

Amphotericin-Induced Heart-Rate Decrease in Children

Abstract: We describe six children with acute decreases in heart rate temporally related to amphotericin B administration. All patients had achieved their maximal dose within 3 to 4 days. Heart-rate drops occurred as early as day 3 but could be delayed up to day 7 after start of therapy. The mean heart rate dropped from 104 ± 8/min (range 96 to 114) to 62 ± 8/min (range 48 to 72) (P= 0.0001). A slower heart rate than baseline was noted during the entire duration of drug administration, from 60 minutes of starting the infusion to 220 minutes (mean 120 ± 40) after discontinuation of the infusion. This reaction was noted in six of 90 (6.7%) patients who had amphotericin. These six children were compared with six age-matched children who received the drug but in whom such changes in heart rate did not develop. The method of administration of amphotericin B was similar in both patients and controls, starting with 0.25 mg/kg/day and increasing by 0.25 mg/kg/day up to 1 mg/kg/day. Children with heart-rate drop received am...

Penile absorption of EMLA cream in piglets: implications for use of EMLA in neonatal circumcision.

Abstract: EMLA (eutectic mixture of lidocaine and prilocaine) cream is currently not recommended for use in infants < 1 month of age because of the potential risk of methemoglobinemia as a result of the o-toluidine metabolite of prilocaine. We studied bioavailability and changes in methemoglobin levels following topical penile exposure to 1 g of EMLA cream for 1 hour in piglets. Lidocaine, prilocaine, and o-toluidine concentrations were measured simultaneously using a high-performance liquid chromatography method. The systemic bioavailability of EMLA was low: 4.0 +/- (SD) 4.7% for lidocaine (range 0-13.6; n = 8) and 7.2 +/- 5.7% for prilocaine (range 0-14.5; n = 8). The ratio between exposure to o-toluidine with EMLA versus intravenous administration (i.e., AUCEMLA/AUCIV; see text) was also low: 4.2 +/- 9.3% (range 0-28.6; n = 9). The mean maximum methemoglobin value after intravenous administration was 1.23 +/- 0.64% (range 0.5-3.0; n = 12) and after penile application 0.99 +/- 0.36% (range 0.5-2.0; n = 12). The methemoglobin value was elevated significantly above baseline after intravenous administration (p = 0.03), but not after penile application of EMLA. These findings suggest that penile administration of 1 g of EMLA may be safe for neonatal circumcision, but further study is required.