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Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 145 records · Page 8Linked to original sources
PubMed1999

Proactive approach for the evaluation of fetal safety in chemical industries.

Women, their families, and employers are concerned about potential fetal risks that may be associated with occupational exposure to chemicals. In an attempt to quantify potential fetal risks in the petroleum industry, we conducted a literature review of selected chemical compounds to which Imperial Oil Limited (IOL) female personnel may be exposed. Medline, Toxline, and Dissertation Abstracts databases were utilized to search for all research papers published in any language from 1966-1996. Chemical exposures in these papers were compared to IOL chemical exposure indices from a specific refinery and chemical plant. In total, 559 studies obtained from the literature search related to the chemicals used in a specific refinery and chemical plant. Of these, only 21 studies explicitly stated some sort of exposure level for the various chemicals. Most of the selected female reproductive toxicology studies summarized explicitly stated chemical exposure levels: either as parts per million, stratifying as to number of days of exposure, or as estimates of the percentage of the threshold limit value. On comparing the occupational literature that presented either actual or estimated values of chemical exposure dose with the IOL routine rating factors in IOL's Products and Chemicals Divisions, we found that IOL chemical exposure levels overall were lower than those reported in the literature to be associated with fetal risks. A new proactive approach is presented to inform female workers and their families of the relative safety/risk of routine occupational exposures. This approach allows for the mitigation of the misperception of teratogenic risk and unjustified fears associated with it.

Air Pollutants, Occupational↗
PubMed1999

Intrauterine exposure to clomiphene and neonatal persistent hyperplastic primary vitreous.

A 4-year-and-10-month-old girl was diagnosed shortly after birth with persistent hyperplastic primary vitreous (PHPV). Her mother took clomiphene 100 mg daily for approximately 4 weeks and discontinued the drug once she had a positive pregnancy test. The exact time of gestation was not clear. Clomiphene is an estrogen antagonist effective in the treatment of anovulation. Various ocular side effects have been described in women taking the drug, including decreased vision, mydriasis, flashing lights, central scotoma, photophobia, diplopia, allergic reactions, retinal vasospasms, detachment posterior vitreous, and possibly posterior subcapsular cataracts. These occur in 1.5-10% of patients taking clomiphene. The potential effects of clomiphene on the fetus have been investigated in five animal studies. Cataracts were observed in fetal mice and rats, but not in monkeys. In humans, a case of congenital retinal aplasia was described. The possibility of clomiphene-induced congenital PHPV should be considered, especially in pregnant women who are taking a high and prolonged dose.

Animals↗
PubMed1999

Meta-analytic review of the clinical effectiveness of oral deferiprone (L1).

OBJECTIVE: To summarize efficacy and effectiveness in iron overloaded patients treated with the orally active iron chelator deferiprone also known as L1 or, using meta-analysis of the literature. METHODS: We reviewed the literature, searching Medline and Embase databases, as well as reviews and other literature on the topic. Inclusion criteria were: original clinical trials reporting results for serum ferritin concentration (SF), hepatic iron concentration or urinary iron excretion (UIE). Efficacy data had to have been reported after > or =3 months of treatment. Data were combined using a random effects model (Cochrane) modified for use with single groups to produce a point estimate and a 95% confidence interval. To summarize the clinical effectiveness, overall proportion of patients where deferiprone was able to reduce serum ferritin was calculated. We also examined average (mg x l(-1)) serum ferritin levels over the reported time (mean) and absolute decrease from the baseline after therapy. To summarize efficacy, success was defined as the proportion of patients who achieved UIE of 25 mg per day or 0.5 mg x kg(-1) x day(-1), which equals the average amount received from monthly blood transfusions. We also calculated the overall average level (mg per day) of UIE over the reported time of therapy (mean). As part of a sensitivity analysis, data were analyzed for two ranges of deferiprone dosage: < or = 50 mg x kg(-1) x day(-1) and > or =75 mg x kg(-1) x day(-1). RESULTS: Of 83 identified references, nine clinical trials met our inclusion criteria, providing data for 129 iron overloaded patients. After a mean of 16 months of therapy (range 6.4 36 months) with 66.4 mg x kg(-1) x day(-1) (mean) of deferiprone, 75.5% of highly iron overloaded patients had a decrease in serum ferritin from baseline. The average drop in serum ferritin of 0.8 mg x l(-1) was 23.5% from baseline. The overall average UIE for therapy was 28.8 mg per day in patients receiving > or = 75 mg x kg(-1) x day(-1) over 8.5 months of therapy. At the same dosage, more than half of the patients (51.8%) achieved negative iron balance. When studies with patients receiving lower dosage (< or = 50 mg x k(-1) x day(-1)) were included, the success rate was 45.1%. CONCLUSION: Overall, deferiprone has clinical efficacy in achieving negative iron balance and reducing body iron burden in highly iron overloaded patients. After an average of 16 months of deferiprone in doses > or = 75 mg x kg(-1) x day(-1), most patients had a decrease in ferritine concentration.

Administration, Oral↗
PubMed1999

Transfer of morphine across the human placenta and its interaction with naloxone.

The purpose of this investigation was to measure the transfer rate and clearance of morphine across the placenta with and without naloxone. Term human placental cotyledons were perfused in vitro. The placenta was perfused with 50 ng/mL of morphine in the absence (n=4) and presence (n=5) of 100 ng/mL of naloxone. Maternal and fetal samples were collected. Student's t-test or one-way repeated measures ANOVA were used for all comparisons. The maternal-to-fetal morphine transfer rate was 0.73+/-0.44 ng/mL/min in the morphine and 0.69+/-0.26 ng/mL/min in the morphine-naloxone experiments (p=0.89). The clearance of morphine was 0.89+/-0.39 mL/min without naloxone and 0.87+/-0.27 mL/min with naloxone (p=0.92). Final morphine concentrations in the morphine experiments were 9.78+/-6.17 ng/mL (maternal) and 3.43+/-2.14 ng/mL (fetal) and 10.04+/-3.89 ng/mL (maternal) and 4.16+/-1.64 ng/mL (fetal) in the morphine-naloxone experiments. Morphine readily crosses the term human placenta. Naloxone does not alter placental transfer or clearance of morphine, suggesting that transfer across the placental barrier is not altered by changes in vascular resistance. Placental retention of morphine prolongs fetal exposure to morphine.

Analgesics, Opioid↗
PubMed1999

Pregnancy outcome after gestational exposure to terfenadine: A multicenter, prospective controlled study.

BACKGROUND: Terfenadine is a selective, nonsedative, H(1)-blocker antihistamine used for a variety of allergic conditions. The widespread popularity of terfenadine and its use by many women in their reproductive age raises concerns regarding its safety during pregnancy. Presently, no prospective controlled study has addressed its safety during gestation. OBJECTIVE: We sought to determine whether terfenadine use during pregnancy is associated with an increased risk of major malformations, decreased birth weight, perinatal complications, or developmental delays. METHODS: A multicenter, prospective controlled study was performed. Pregnant women exposed to terfenadine during gestation were matched with control subjects exposed to drugs not known to adversely affect pregnancy outcome. The primary end point was the incidence of major malformations. Secondary outcomes of interest were pregnancy outcome, rates of preterm delivery, birth weight, and developmental milestones. RESULTS: One hundred eighteen women were exposed to terfenadine during pregnancy. Among those exposed during the first trimester (n = 65), rates of major malformations in the terfenadine group did not differ from rates in their matched control subjects (0% vs 2%; relative risk, 0.57; 95% confidence interval, 0.06-5.39; P =.53). The birth weight in the terfenadine-exposed newborns was significantly lower compared with that in their matched control subjects (3335 +/- 582 vs 3499 +/- 617 g; P =.04). However, the rates of birth weight below 2500 g and birth weight below the 10th percentile for gestational age were not different between the groups. Univariate and multiple regression analysis revealed that none of the terfenadine therapy-related factors (daily dose, duration of therapy, and trimester of exposure) had a significant predictive effect on birth weight. Gestational age at delivery, rates of preterm deliveries, and developmental milestones were comparable between the groups. CONCLUSIONS: On the basis of the limited sample size of this study, it appears that terfenadine is not associated with a 6-fold or greater increased incidence of major malformations. Terfenadine use during gestation was not associated with increased rates of prematurity or developmental delays. Further studies will be needed to confirm the finding of lower birth weight in newborns exposed to terfenadine.

Adult↗
PubMed1999

Maternal cocaine use and cigarette smoking in pregnancy in relation to amino acid transport and fetal growth.

This review covers the weight of evidence that shows the association of cocaine and cigarette smoking in pregnancy with the impaired transplacental amino acid transport which might give rise to fetal growth restriction (IUGR). Vasoconstrictive effects of both cocaine and nicotine on the placental vasculature are clearly not the only cause for inhibition of placental amino acid uptake and transfer. In vitro studies strongly suggest that cocaine decreases the activity of placental amino acid transport system A and system N, and possibly system l and system y(+), while nicotine decreases the activity of system A. These findings are supported by cordocentesis studies in human IUGR pregnancies not resulting from drug abuse. More work is needed to be done in order to understand the potential additive or synergistic effect of cocaine and cigarette smoking on fetal growth and to determine the underlying cellular mechanisms of interaction with placental amino acid transporters.

Amino Acids↗
PubMed1999

Pregnancy outcome following first-trimester exposure to zopiclone: a prospective controlled cohort study.

BACKGROUND & AIM: Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic. To date, no published data exist regarding human pregnancy experience with zopiclone. The purpose of this study was to compare pregnancy outcome following first-trimester exposure to zopiclone with that of a matched control group of women, who were counseled for nonteratogenic exposure. METHODS: The Motherisk Program, the Toronto Teratogen Information Service, prospectively collected and followed up 40 women exposed to zopiclone during pregnancy. Pregnancy outcome was compared with that of a matched control group of women, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in the rate of major malformations (0 of 31 [0%] for zopiclone vs. 1 of 37 [2.7%] for nonteratogenic controls; p = 1). CONCLUSIONS: Our study, which is the first cohort on zopiclone use during embryogenesis, albeit small, suggests that zopiclone does not appear to be a major human teratogen. Larger studies are needed to establish its safety during pregnancy.

Abnormalities, Drug-Induced↗
PubMed1999

Management of pain from heel lance with lidocaine-prilocaine (EMLA) cream: is it safe and efficacious in preterm infants?

Hospitalized preterm infants undergo multiple painful heel lances. A two-phase, randomized, controlled trial was undertaken to determine the safety and efficacy of lidocaine-prilocaine 5% cream (EMLA, Astra Pharmaceuticals, L.P, Westborough, MA) for relieving pain from heel lance. One hundred twenty infants were randomly assigned to receive 0.5 g of EMLA or placebo cream for 30 minutes (Phase 1) or 60 minutes (Phase 2) before a routine heel lance. Efficacy was assessed using the Premature Infant Pain Profile (PIPP). Safety was determined by methemoglobin concentration 8 hours after EMLA application and by clinical signs of methemoglobinemia. No significant differences existed on PIPP scores between EMLA and placebo groups in Phase 1 (p < .480) or Phase 2 (p < .831). No infant had any clinical signs of methemoglobinemia. The mean methemoglobin concentration was 1.19% (.47). Approximately 10% of infants had minor skin reactions, and approximately 20% of EMLA-treated infants had blanching at the application site. The authors conclude that EMLA is safe but not efficacious for relieving pain from heel lance in preterm infants.

Anesthetics, Combined↗
PubMed1999

An investigation into variability in the therapeutic response to deferiprone in patients with thalassemia major.

Data suggest a large variability in the effectiveness of the orally active iron chelator, deferiprone, in inducing a sustained decrease in body iron to concentrations compatible with the avoidance of complications from iron overload. We analyzed 19 patients with thalassemia major who were undergoing long-term therapy with deferiprone (75 mg/kg/day every 8 hours). In seven of the 19 patients, hepatic iron concentration had been reduced or maintained at less than 7 mg/g of dry weight liver tissue, associated with no evidence of iron-induced toxicity (group A). In the remaining 12, hepatic iron concentration had either stabilized at higher than 7 mg/g of dry weight liver tissue, or increased to such concentrations during therapy with deferiprone (group B). We studied in these patients determinants that may explain such variability, including initial hepatic iron concentrations, compliance, transfusion index, pharmacokinetic characteristics of deferiprone, and plasma vitamin C status. Patients in group B showed significantly decreased plasma vitamin C concentrations compared with those in group A, who demonstrated normal levels (0.04 mg/dl [0.04-0.19 mg/dl] and 0.62 mg/day [0.44-1.05 mg/day], respectively; p = 0.02). A significant difference in apparent volume of distribution (Vd/F) had developed between the groups over time, with a higher Vd/F in group B (1.66 [0.681, group A] and 3.16 [0.811, group B]; p = 0.006). Group B had started with hepatic iron concentrations that were significantly higher than those of group A, a difference that became more pronounced over time. In the initial analysis, serum ferritin concentrations were also higher in group B. The two groups did not differ in the remaining factors. The initial hepatic iron concentrations predicted the slope of change in this value. Regression analysis suggested that patients with initial hepatic iron concentration of less than or equal to 7.22 mg/g of dry weight liver tissue are unlikely to further decrease while taking deferiprone 75 mg/kg/day. Vitamin C deficiency developed in patients in group B over time. Vitamin C is an important biologic cofactor that plays a role in the distribution of iron. The trend of increase in Vd/F of deferiprone over time may imply a compartment shift of iron stores to one less accessed by deferiprone. This study confirmed the effectiveness of deferiprone in heavily iron-loaded patients and provided evidence that its effectiveness decreases in proportion to liver iron load.

Adult↗
PubMed1999

Urine fingerprinting: detection of sample tampering in an opiate dependency program.

Methadone treatment programs commonly monitor patient compliance by screening urine samples for drugs of abuse. Our experience suggests that re-submission of urine samples (for example, providing a urine sample that is either not that of the patient or was previously submitted) is often used as a method of sample tampering. We have developed an algorithm that combines urine sodium, chloride, creatinine and pH values with urine drug screening results to effectively detect resubmitted samples. Given the widespread use of urine drug screening in drug and alcohol rehabilitation programs, we believe this technique has significant practical benefits. This technique may also have an application in forensic identification of duplicate samples.

Chromatography, High Pressure Liquid↗
PubMed1999

The effect of diazepam in the recovery of rabbits from acute acetaminophen intoxication.

We have recently shown that diazepam can reduce mortality of acute iron overdose in rats. The mechanism for that effect is not yet defined. Our objective in the present study was to assess whether diazepam can similarly reduce mortality of experimental acute acetaminophen intoxication. Survival of rabbits was compared among four groups receiving 3 g/kg (body weight) of acetaminophen (LD40) orally each, followed by: 1) nothing (group I), 2) one oral dose of 140 mg/kg N-acetylcystein (NAC) an hour later (group II), 3) intramuscular injection of 7 mg/kg diazepam (group III), 4) intramuscular injection of 7 mg/kg diazepam and one oral dose of 140 mg/kg NAC an hour later (group IV). 37.5% of rabbits in group I died after 16 hours, whereas none of the rabbits in group III died, (p = 0.04). No animal died during the 96-hour observation period in groups II and IV. Two and four hours post drug administration, acetaminophen plasma concentrations (APC) were significantly lower among rabbits in group III than in group I (p = 0.0007 and 0.01, respectively) and significantly lower among rabbits in group IV than in those in group II (p<0.0001 and p = 0.03, respectively). Acetaminophen plasma concentrations 2 hours after drug administration were also significantly lower among rabbits in group III than in those in group II (p = 0.0002). Seven and 24 hours after dosage, APC tended to be higher among rabbits in group III than in those in group I, but not significantly so. Administration of diazepam without NAC did not prevent liver and renal dysfunction. We conclude that early administration of diazepam in acute experimental acetaminophen overdose in rabbits reduced APC and mortality, probably by slowing intestinal motility, which resulted in delayed acetaminophen absorption from the gastrointestinal tract.

Acetaminophen↗
PubMed1999

Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells.

P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a drug efflux pump. However, unclear is its integral quantitative role in the overall epithelial drug transfer, which also involves distinct diffusion processes in parallel and sequence. We used a simple three-compartment model to obtain kinetic parameters of each drug transfer mechanism, which can quantitatively describe the transport time courses of P-gp substrates, digoxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functionally single drug efflux pump in the apical membrane with diffusion across two membranes and intercellular junctions, is the least complex model with which to quantitatively reproduce the characteristics of the data. Interestingly, the model predicts that the MDCK apical membranes are less diffusion permeable than the basolateral membrane for both drugs and that the distribution volume of vinblastine is 10-fold higher than that of digoxin. Additional experiments verified these model predictions. The modeling approach is feasible to quantitatively describe overall kinetic picture of epithelial drug transport. Further model refinement is necessary to incorporate other modes of drug transport such as transcytosis. Also, whether P-gp solely accounts for the pump function in this model awaits more studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Hair analysis--a biological marker for passive smoking in pregnancy and childhood.

Passive smoking has been shown to adversely affect the health of infants and children. We used hair analysis for nicotine and its metabolite cotinine as a biological marker for exposure to smoking in these two groups. Using radioimmunoassay we measured maternal and fetal hair concentrations of nicotine and cotinine in the mother-infant pairs belonging to three different groups based on the mother's smoking habits. The three groups were: active smokers, passive smokers and nonsmokers. There was a significant correlation between maternal and neonatal hair concentration for both, nicotine and cotinine. Mothers and infants in the smoking groups, both active and passive, had significantly higher hair concentrations of both, nicotine and cotinine than in the control, nonsmoking group. In an older cohort, we compared two groups: 78 asthmatic children were compared to 86 healthy children exposed to similar degrees of passive smoking. By using objective, biological markers, our study aimed at verifying whether asthmatic children are different from nonasthmatic children in the way their bodies handle nicotine. Our results show, that, despite the fact that parents of asthmatic children tend to smoke a lower number of cigarettes per day, their children had an average twofold higher concentrations of cotinine in their hair then the control, nonasthmatic children. These studies document the importance of hair analysis as a tool for measuring exposure to cigarette smoke.

Adult↗
PubMed1999

Contamination of antibiotics resulting in severe pediatric methadone poisoning.

OBJECTIVE: To report an accidental contamination of antibiotic suspension by methadone that occurred in a retail Canadian pharmacy, leading to severe poisoning in a young child. CASE SUMMARY: A 4 1/2-year-old healthy Asian boy was prescribed amoxicillin suspension for cough and fever. Shortly after receiving the second dose of 5 mL he became drowsy and less responsive. On admission, he was arousable by deep pain, and pinpoint pupils were noted. A urine sample sent for a toxicology screen revealed the presence of methadone and its metabolite. Blood methadone concentrations were 0.23 and 0.14 mg/L, five and nine hours after the second dose of amoxicillin was given, respectively. The amoxicillin suspension was tested for methadone and was found to have a concentration of 2.4 g/L. The child gradually improved and was discharged on day 4 in good condition. The pharmacy in which the antibiotic was dispensed has been a dispensing center for a local methadone maintenance program, and methadone was accidentally mixed with the antibiotics. DISCUSSION: In this case, a near fatal outcome occurred when methadone was inadvertently mixed with antibiotics in a community pharmacy. A literature search revealed two previous reports of opiate toxicity in children following ingestion of oral antibiotic preparations. CONCLUSIONS: Prompt action is needed in Canadian pharmacies that dispense methadone in order to minimize such errors in the future. General practitioners, pediatricians, and emergency department physicians should recognize and suspect this rare cause of opiate toxicity in a child. In a patient presenting with a decreased level of consciousness and miosis, with or without respiratory depression, naloxone administration should be considered, whether or not a history of opioid ingestion is obtained.

Amoxicillin↗
PubMed1999

Relative efficacy of amethocaine gel and lidocaine-prilocaine cream for Port-a-Cath puncture in children.

BACKGROUND: Lidocaine-prilocaine cream (EMLA) is currently standard therapy to alleviate procedural pain in children. One of the disadvantages of lidocaine-prilocaine is the need to wait for 60 minutes for adequate skin anesthesia. Amethocaine gel (Ametop) is a new topical anesthetic that requires a shorter application time for skin anesthesia. OBJECTIVES: To compare the relative efficacy and safety of amethocaine gel and lidocaine-prilocaine cream in children with cancer undergoing Port-a-Cath puncture and to determine which patient factors influence judgments about pain. METHODS: Randomized, blinded, crossover study. Each child received either 1 g of amethocaine gel for 30 minutes, preceded by a placebo gel for 30 minutes, or 1 g of lidocaine-prilocaine cream for 60 minutes. Children rated the pain using the faces scale, for which scores ranged from 0 to 5. Parents and attending nurse operators rated pain on a 10-cm visual analog scale. RESULTS: Thirty-nine children participated. The mean age was 10.2 years (range: 5-16 years), and 69% were male. There were no differences in mean pain assessments between amethocaine and lidocaine-prilocaine as rated by the children (2.0 vs 0.5), parents (2.6 vs 6.4), or nurse operators (2.0 vs 0.9). No serious adverse effects were detected with either preparation. Pain scores assigned by parents and children were not influenced by age, gender, duration of diagnosis, or anesthetic regimen (amethocaine versus lidocaine-prilocaine) in the child. Nurses, however, rated pain higher for younger children, and in males during pretreatment with lidocaine-prilocaine. CONCLUSION: Amethocaine achieves similar anesthesia to lidocaine-prilocaine during Port-a-Cath administration in children, with an application time that is half of lidocaine-prilocaine. Pain assessments were not influenced by age, gender, or duration of diagnosis of the child. Nurses may perceive that pain is greater for younger children and in males. lidocaine-prilocaine, amethocaine, pain, children, Port-a-Cath puncture.

Adolescent↗
PubMed1999

Treating allergic rhinitis in pregnancy. Safety considerations.

Allergic rhinitis affects approximately one-third of women of childbearing age. As a result, symptoms ranging from sneezing and itching to severe nasal obstruction may require pharmacotherapy. However, product labels state that medications for allergic rhinitis should be avoided during pregnancy due to lack of fetal safety data, even though the majority of the agents have human data which refute these notions. We present a systematic and critical review of the medical literature on the use of pharmacotherapy for the management of allergic rhinitis during pregnancy. Electronic databases and other literature sources were searched to identify observational controlled studies focusing on the rate of fetal malformations in pregnant women exposed to agents used to treat allergic rhinitis and related diseases compared with controls. Immunotherapy and intranasal sodium cromoglycate (cromolyn) and beclo-methasone would be considered as first-line therapy, both because of their lack of association with congenital abnormalities and their superior efficacy to other agents. First-generation (e.g. chlorpheniramine) and second-generation (e.g. cetirizine) antihistamines have not been incriminated as human teratogens. However, first-generation antihistamines are favoured over their second generation counterparts based on their longevity, leading to more conclusive evidence of safety. There are no controlled trials with loratadine and fexofenadine in human pregnancy. Oral, intranasal and ophthalmic decongestants (e.g. pseudoephedrine, phenylephrine and oxymetazoline, respectively) should be considered as second-line therapy, although further studies are needed to clarify their fetal safety. No human reproductive studies have been reported with the ophthalmic antihistamines ketorolac and levocabastine, although preliminary data reported suggest no association between pheniramine and congenital malformations. There are no documented epidemiological studies with intranasal corticosteroids (e.g. budesonide, fluticasone propionate, mometasone) during pregnancy; however, inhaled corticosteroids (e.g. beclomethasone) have not been incriminated as teratogens and are commonly used by pregnant women who have asthma. In summary, women with allergic rhinitis during pregnancy can be treated with a number of pharmacological agents without concern of untoward effects on their unborn child. Although the choice of agents in part should be based on evidence of fetal safety, issue of efficacy needs to be addressed in order to optimally manage this condition.

Animals↗