Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 199 records · Page 11Linked to original sources

PubMed1998

Sequential use of intravenous and oral acyclovir in the therapy of varicella in immunocompromised children.

BACKGROUND: Immunocompromised children are at risk for disseminated varicella infections. Standard management involves hospitalization and intravenous acyclovir for 7 to 10 days. This approach is expensive, is inconvenient and may not be necessary. We undertook a pilot study to assess the safety and efficacy of an alternative approach that utilized a combination of intravenous (i.v.) followed by oral (p.o) acyclovir in a cohort of immunocompromised children. METHODS: The cohort consisted of 26 immunocompromised children between the ages of 1.5 and 12.7 years (mean, 6.3). Therapy was commenced with i.v. acyclovir (1500 mg/m2/day in 3 divided doses). Concurrent management included holding or reducing immunosuppressive therapy (by 50%) and administering varicella-zoster immunoglobulin in 69% (11 of 16) of cases where exposure to chickenpox was recognized. Patients were eligible to switch to p.o therapy after receiving a minimum of 48 h of i.v. acyclovir therapy provided they were afebrile; had no new lesions for 24 h; had no internal organ involvement and were able to tolerate oral medications. Patients were observed in hospital for a further 24 h and then discharged provided they remained well. Oral acyclovir was continued for a total of 7 to 10 days (i.v. plus p.o). RESULTS: Of the 26 patients 25 were successfully switched from i.v. to p.o after 4.1 +/- 1.2 days (mean +/- SD) (range, 2.3 to 6) Children had fever for a mean of 2.0 +/- 1.6 days (range, 0 to 5) and developed new lesions for 2.9 +/- 0.7 days (range, 2 to 4). All 25 patients switched to p.o therapy had resolution of their disease and no patient required resumption of i.v. therapy. CONCLUSIONS: The sequential use of i.v. followed by p.o acyclovir is feasible in the treatment of varicella in immunocompromised children and results in a reduction in duration of intravenous therapy and hospitalization.

Acyclovir↗

PubMed1998

A model for the prediction of digoxin-drug interactions at the renal tubular cell level.

Digoxin-drug interactions are relatively common causes of digitalis toxicity. Recently, the clinical importance of the renal tubular secretion of digoxin has been proven by documenting drug interactions at this level. The authors describe a model using cultured renal tubular cell monolayers that can be used to predict drug interactions with the cardiac glycoside. This model accurately documents known clinical digoxin interactions such as those with verapamil and propafenone. The common feature of these interactions is that they involve P-glycoprotein substrates (e.g., digoxin, vincristine, vinblastine) or inhibitors (e.g., quinidine, cyclosporine). In the case of the newly described interaction of digoxin with itraconazole, the model preceded the emergence of clinical cases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Clinical relevance of therapeutic drug monitoring of digoxin and gentamicin in the saliva of children.

Digoxin and gentamicin are widely used in pediatric medicine, and therapeutic monitoring is mandatory because of their narrow margin of safety and wide interpatient and intrapatient pharmacokinetic variabilities. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is often difficult. In 11 children treated with digoxin for various cardiac conditions, and in 24 children treated with gentamicin (14 patients were administered gentamicin three times a day, and 10 once-daily), drugs levels were measured in plasma and saliva. There was no correlation between plasma total or free digoxin concentrations and saliva levels, precluding the clinical use of the saliva test for digoxin. No correlation was found between plasma gentamicin concentrations and saliva levels when the drug was administered three times a day; however, good correlation was found when the drug was administered once-daily (r2 = 0.89, p < 0.0001). Saliva may be used as a noninvasive method of measuring gentamicin serum concentrations to guide dosage adjustments in patients administered the drug once-daily.

Anti-Bacterial Agents↗

PubMed1998

Diagnosing intrauterine exposure to cocaine by hair testing: six years of clinical use.

Intrauterine exposure to cocaine results in a variety of perinatal and long-term neurobehavioral sequlae. Maternal history and neonatal urinalysis miss most instances of exposure. After establishing the high sensitivity, specificity, and predictive value of neonatal hair testing for cocaine, the authors embarked on a study to evaluate the clinical use of the test. Between October 1991 and September 1997, they assessed the presence of cocaine in 509 hair samples; 422 were from neonates and were based on clinical suspicion of intrauterine exposure, although history and urine test results were negative. Thirty-two percent were positive, a rate fivefold higher than the incidence found by the authors in population-based studies. Neonates referred by children's aid workers had significantly higher percentages of positivity (60%). Because neonatal hair grows only during the last 4 months of pregnancy, positive neonatal hair test results reflect maternal addiction, and this warrants close follow-up of the baby after release because of the high rate of postnatal risks secondary to suboptimal parental care and because of the proven perinatal risks inflicted by the drug itself.

Cocaine-Related Disorders↗

PubMed1998

Evidence-based pain management for infants.

The impact of pain on infants has been the topic of increasing research interest over the past decade. Although pain is now known to be stressful and the source of immediate and long term consequences, inadequate progress has been made in infant pain management. Research evidence provides the basis for effective pain management. However, the quality of the evidence, inconsistent findings, and the perceived lack of clinical relevance may have hindered the utilization of research on infant pain management in clinical practice. Reconceptualization of the definition of pain, increased methodologic rigor, validated assessment approaches, and systematic reviews of research studies on pain management may provide the opportunity for improved pain management using evidence-based practice.

Anesthetics, Local↗

PubMed1998

Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study.

Concerns regarding the teratogenicity of fluoroquinolones have resulted in their restricted use during gestation. This is despite an increasing need for their use due to emerging bacterial resistance. The objectives of the present investigation were to evaluate pregnancy and fetal outcomes following maternal exposure to fluoroquinolones and to examine whether in utero exposure to quinolones is associated with clinically significant musculoskeletal dysfunctions. We prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that for 200 controls matched for age and for smoking and alcohol consumption habits. Controls were exposed to nonteratogenic, nonembryotoxic antimicrobial agents matched by indication, duration of therapy (+/- 3 days), and trimester of exposure. Rates of major congenital malformations did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk, 0.85; 95% confidence interval, 0.21 to 3.49). Women treated with quinolones had a tendency for an increased rate of therapeutic abortions compared with the rate among women exposed to nonteratogens (relative risk, 4.50; 95% confidence interval, 0.98 to 20.57), resulting in lower live-birth rates (86 versus 94%; P = 0.02). The rates of spontaneous abortions, fetal distress, and prematurity and the birth weight did not differ between the groups. Gross motor developmental milestone achievements did not differ between the children of the mothers in the two groups. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.

Abnormalities, Drug-Induced↗

PubMed1998

Errors by paediatric residents in calculating drug doses.

BACKGROUND: Errors in calculating drug doses in infants and small children can cause morbidity and mortality, especially with agents exhibiting a narrow therapeutic window. A previous study from this institution has detected potential life threatening errors in calculations performed by trainees while writing prescriptions. OBJECTIVES: To verify whether the true incidence of trainees' errors in prescribing can be explained by impaired calculation skills in written tests. SETTING: A tertiary paediatric hospital; educational rounds for core paediatric residents. METHODS: Two anonymous written tests, which included calculations of doses similar to those performed at the paediatric bedside; one was conducted in 1993 and one in 1995. RESULTS: Thirty four paediatric residents participated in 1993 and 30 in 1995. A substantial number of trainees in both years committed at least one error. In general, there was no correlation between the length of training (0 to 4 years) and likelihood of making a mistake. Three trainees in 1993 and four in 1995 committed 10-fold errors. These seven residents committed significantly more errors than the rest of the group in each of the tests separately. All seven were in their first two years of training, and six were in their first year of residency. CONCLUSIONS: A substantial proportion of paediatric trainees make mistakes while calculating drug doses under optimal test conditions. Some trainees commit 10-fold errors, which may be life threatening. The results of these anonymous tests suggest that testing of calculations skills should be mandatory, and appropriate remedial steps should follow to prevent paediatric patients receiving wrong drug dosages.

Clinical Competence↗

PubMed1998

Empirical examination of the ability of children to consent to clinical research.

This study examined the quality of children's assent to a clinical trial. In subjects younger than 9 years of age, understanding of most aspects of the study was found to be poor to non-existent. Understanding of procedures was poor in almost all subjects. In addition, voluntariness may have been compromised in many subjects by their belief that failure to complete the study would displease others. If the fact that a child's assent has been obtained is used to justify the exposure of that child to the potential harm of a non-therapeutic blood sample, the assent must be meaningful. In the nutrition study observed here, the quality of the assent of children younger than 9 years of age was very poor. The assent therefore did not provide a valid justification for requesting a blood sample from these children. This study indicates that most children younger than 9 years of age cannot be expected to consent or assent to clinical research in a meaningful way. The current age of 7 years for initiating assent (in addition to parental consent) is possibly not appropriate and should be reconsidered.

Adaptation, Psychological↗

PubMed1998

The efficacy of diazepam in the treatment of acute iron overload in rats.

While conducting studies on the prevention of mortality from acute iron intoxication in rats, diazepam, given to prevent animal suffering, was observed to be associated with reduced mortality in a limited number of animals. The objective was to assess whether diazepam reduces mortality following acute iron intoxication in rats. Survival of rats was compared among groups receiving (i) orally 612 mg/kg iron alone (LD60), (ii) iron with a subcutaneous injection of 2.5 mg/kg diazepam (DZ), or (iii) iron, DZ with 800 mg/kg deferiprone intraperitoneal injections. The administration of DZ decreased mortality from 60 to 16% (p < 0.001). The addition of deferiprone to DZ resulted in zero mortality (p < 0.05 compared with the DZ group) over the study period. The administration of DZ was not associated with decreased iron absorption or increased urinary iron excretion, whereas the administration of deferiprone did result in urinary iron excretion. Microscopic examination suggests that diazepam administration may be associated with lower intracellular accumulation of iron. In conclusion, diazepam reduces mortality from iron overdose in rats through a yet unidentified mechanism, although the drug does not inhibit iron absorption or enhance urinary iron removal.

Acute Disease↗

PubMed1998

Measurement of heart rate and Q-T interval in the conscious mouse.

Transgenic mouse models provided a powerful tool to evaluate the physiological significance of altered quantities or characteristics of specific gene products, such as cardiac ion channels. We have developed a system to record and analyze changes in the electrocardiogram in the mouse using an implantable telemetry system. The R-R and Q-T intervals were measured on individual beats and on signal-averaged complexes derived from 1, 2, or 4 s of contiguous data each hour during a 24-h period in three male and three female FVB mice. Duration of averaging had minimal effect on the measured Q-T. The Q-T interval was shown to be related to the square root of the R-R interval, and an appropriate formula for a rate-corrected Q-T interval (Q-Tc) was derived. Ketamine anesthesia was shown to markedly increase duration and variability in R-R, Q-T, and Q-Tc intervals. In conscious animals, variability in Q-T was low across animals and over time, suggesting that this should be a sensitive model for detection of changes in the Q-T interval in transgenic mice with ion channel defects.

Animals↗

PubMed1998

Efficacy of amlodipine in pediatric bone marrow transplant patients.

The calcium antagonist amlodipine may have the potential for expanded use in children owing to its physiochemistry and pharmacokinetic profile that facilitates once-daily dosing in a liquid formulation. Its safety and efficacy have not been previously evaluated in children. A retrospective analysis of 15 pediatric bone marrow transplant patients who had amlodipine incorporated into their antihypertensive drug regimen reveals significantly lower blood pressure as compared with baseline therapy (123.5+/-2.1 mmHg and 117.2+/-2.2 mmHg, systolic blood pressure before and during amlodipine, P<0.05; 81.5+/-1.8 mmHg and 75.5+/-2.6 mmHg, diastolic blood pressure before and during amlodipine, P<0.05). Amlodipine provided improved blood pressure control in this cohort and may provide a valuable pharmacologic alternative for treatment of pediatric hypertension.

Adolescent↗

PubMed1998

Pregnancy outcome following first trimester exposure to sumatriptan.

We prospectively compared pregnancy outcome after exposure to sumatriptan with that of disease-matched controls and nonteratogen controls. There were no differences in the rates of live births, spontaneous abortions, therapeutic abortions, or major birth defects among the three groups. This first prospective report suggests that the use of sumatriptan during organogenesis is not associated with an apparent increased risk of major birth defects.

Adult↗

PubMed1998

A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates.

OBJECTIVE: Neonates routinely undergo painful cutaneous procedures as part of their medical treatment. Lidocaine-prilocaine 5% cream (EMLA) is a topical anesthetic that may be useful for diminishing the pain from these procedures. EMLA is routinely used in children and adults. There is substantial apprehension about its use in neonates because of concerns that it may cause methemoglobinemia. The objective of this review was to determine the efficacy and safety of EMLA as an analgesic for procedural pain treatment in neonates and provide evidence-based recommendations for clinical practice. METHODS: Systematic review techniques were used. Studies were identified using manual and computer-aided searches (Medline, EMBASE, Reference Update, personal files, scientific meeting proceedings). Behavioral (eg, facial action, crying) and physiologic (eg, heart rate, oxygen saturation, blood pressure, respiratory rate) outcome data from prospective nonrandomized controlled studies and randomized controlled trials in full-term and preterm neonates were accepted for inclusion to establish efficacy of EMLA. The risk of methemoglobinemia (defined as methemoglobin concentration >5% and requiring medical intervention) was estimated from all prospective studies. RESULTS: Eleven studies of the efficacy of EMLA were included in the analysis. Infant gestational age at the time of delivery ranged from 26 weeks to full-term. Two studies included data from both neonates and older infants. The following procedures were studied: circumcision (n = 3), heel lancing (n = 4), venipuncture (n = 1), venipuncture and arterial puncture (n = 1), lumbar puncture (n = 1), and percutaneous venous catheter placement (n = 1). Nine studies were randomized controlled trials. The total sample size for each study ranged from 13 to 110 neonates. The dose of EMLA used was 0.5 g to 2 g in 9 studies, and was not specified in the others. The duration of application ranged from 10 minutes to 3 hours. The three studies that investigated the efficacy of EMLA for decreasing the pain of circumcision used a randomized controlled trial design. All of them demonstrated significantly reduced crying time during the procedure in the infants in the EMLA group compared with the infants in the control group. Facial grimacing, assessed in two of the studies, was also significantly lower in the EMLA group. Using meta-analytic techniques, the heart rate outcome data for two studies was summarized. Increases in heart rate compared with baseline values were 12 to 27 beats per minute less for the EMLA group than in the placebo group during various stages of the surgical procedure. Three studies that investigated the pain from heel lancing were randomized controlled trials; the other was a nonrandomized controlled study. None demonstrated a significant benefit of EMLA for any of the outcome measures used to assess pain (ie, behavioral pain scores, infant crying, heart rate, blood pressure, respiratory rate, oxygenation parameters). One randomized controlled study of the pain from venipuncture showed that infants treated with EMLA had significantly lower heart rates and cry duration compared with infants treated with a placebo. In one nonrandomized study, a significantly lower behavioral pain score was observed for infants treated with EMLA compared with the control group. Infant heart rate, however, did not differ between the groups. In one randomized controlled study of pain from percutaneous venous catheter placement, EMLA resulted in a significantly lower increase in heart rate and respiratory rate. Behavioral pain scores were significantly lower during arterial puncture in one nonrandomized controlled study. EMLA did not reduce physiologic changes or behavioral pain scores in one randomized controlled trial in infants undergoing lumbar puncture. Meta-analytic techniques revealed that methemoglobin concentrations did not differ between EMLA-treated and placebo-treated infants (weighted mean di

Acute Disease↗

PubMed1998

Ifosfamide-induced nephrotoxicity in children: critical review of predictive risk factors.

Ifosfamide is widely used in the treatment of pediatric solid tumors. Its main adverse effects are various forms of renal tubular and glomerular damage. Many risk factors have been proposed to play a role in the development and severity of nephrotoxicity in children receiving ifosfamide, among which are 1) patient's age, 2) cumulative ifosfamide dose, 3) concurrent administration of cis or carboplatinum, 4) unilateral nephrectomy, and 5) method of ifosfamide administration. However, presently there is no consensus regarding the weight of each one of them. Therefore, we critically reviewed the major studies that have evaluated the different risk factors in an attempt to determine the relative importance of each. Cumulative ifosfamide doses of >/=60 g/m appears to be the most consistent independent predictor for both the development and the severity of nephrotoxicity, whereas a younger age (<5 years of age) was associated primarily with the more severe and chronic forms of proximal tubulopathy. Comparable incidence and severity forms of proximal tubulopathy among children who had been treated with cis platinum in addition to ifosfamide and those who had not indicate that platinums probably potentiate ifosfamide-induced renal damage rather than act as a major independent risk factor. Finally, although unilateral nephrectomy has been proposed as a significant risk factor in different studies, the relatively small number of nephrectomized children in these cohorts limit the strength of this association. To reduce the frequency and severity of ifosfamide-induced nephrotoxicity, it appears that cumulative doses of 60 g/m should be considered carefully, especially in children <5 years of age.

Adolescent↗

PubMed1998

Clinical pharmacology and therapeutic drug monitoring in neonates and children.

From a pharmacotherapy perspective, the process of development and growth represents an unstable and dynamic condition. Age-related changes in drug absorption, distribution, and metabolism among neonates, infants, and prepubescent children create a unique situation that may increase drug toxicity of some agents and protect from toxicity of other agents. Understanding the age-related changes in drug disposition that are relevant for therapeutic response and toxicity is essential for optimizing pharmacotherapy at different stages of childhood.

Absorption↗

PubMed1998

Pharmacokinetic predisposition to nicotine from environmental tobacco smoke: a risk factor for pediatric asthma.

During the last decade several studies have shown that children whose parents smoke have higher rates of asthma. Recently, hair concentrations of cotinine have been shown to reflect systemic exposure to this constituent of smoke in both children and adults. At the present time it is not known, however, why some children exposed to passive smoking have asthma while others, similarly exposed, do not. The present study aimed at verifying whether asthmatic children are different from nonasthmatic children exposed to similar degrees of passive smoking in the way their bodies handle nicotine, a constituent of cigarette smoke. Seventy-eight asthmatic children were compared to 86 control children, all attending a consulting pediatric clinic in Toronto. A questionnaire completed by the parents and children detailed the daily number of cigarettes the child was exposed to and the identity of the smokers. Clinical data were extracted from the patients' charts. Urinary (corrected for creatinine) and hair concentrations of cotinine were measured by radioimmunoassays. The asthmatic and control children were of similar age, gender, and ethnic distribution, parental education, and socioeconomic status. Parents of asthmatic children tended to report a lower daily number of cigarettes (7.4 +/- 1.3/day vs. 11.2 +/- 2.3/day, p = 0.14), and this report agreed with the trend of urinary cotinine (47.1 +/- 9.1 ng/mg vs. 62.6 +/- 11.5 ng/mg, respectively). Conversely, children with asthma had on average twofold higher concentrations of cotinine in their hair (0.696 +/- 0.742 ng/mg) than control children (0.386 +/- 0.383) (p = 0.0001). In a similar manner, the hair:urine concentration ratio was significantly higher in children with asthma (0.028 +/- 0.002) than in their controls (0.18 +/- 0.003) (p = 0.0001). These results suggest that under exposure to similar amounts of nicotine, children with asthma have on average twofold higher systemic exposure to this constituent of cigarette smoke. These data suggest that out of all children passively exposed to environmental tobacco smoke, those who exhibit asthma have a higher systemic exposure to nicotine, possibly due to lower clearance rate. This is the first evidence of pharmacokinetic predisposition to environmental tobacco smoke as an etiological factor in pediatric asthma.

Adult↗

PubMed1998

Carbamazepine interference with an immune assay for tricyclic antidepressants in plasma.

BACKGROUND: Drug toxicological screening is commonly used as a diagnostic tool in patients with suspected toxic ingestion. False positive results due to cross-reactive compounds in drug assays may lead to misdiagnosis and mismanagement, especially when child abuse is suspected. CASE REPORT: Two of our patients with history of ingestion of carbamazepine were tested positive on screening with the tricyclic antidepressant immunoassay. The immunoassay's known cross-reactivity for carbamazepine is reportedly as low as 0.3%. Plasma samples of our patients were initially considered positive for tricyclic antidepressants because the cross-reaction of carbamazepine gave tricyclic antidepressant concentrations as imipramine equivalent sufficiently above the assay cut-off point (20 ng/mL). Later, confirmatory urine testing of both patients using high-performance liquid chromatography was negative for tricyclic antidepressants. CONCLUSION: This interference has significant clinical implications, and can be avoided on urine testing using a specific chromatographic assay such as high-performance liquid chromatography.

Adolescent↗

PubMed1998

Assessment of the effect of the oral iron chelator deferiprone on asymptomatic Plasmodium falciparum parasitemia in humans.

While the parenteral iron-chelating agent desferrioxamine B has anti-malarial activity in humans, the usefulness of an orally active chelator for this indication has not been investigated previously in vivo. We conducted a prospective, double-blind, placebo-controlled, cross-over trial of deferiprone (L1; CP20; 1,2-dimethyl-3-hydroxypyridin-4-one) in 25 adult Zambians with asymptomatic Plasmodium falciparum parasitemia. Deferiprone was administered daily for three or four days in divided doses of 75 or 100 mg/kg of body weight, dosages that are effective for treating iron overload. No reduction in asexual intra-erythrocytic parasites was observed during or after deferiprone treatment. The mean peak plasma concentration of deferiprone (108.9 +/- 24.9 micromol/L) achieved was within the range demonstrated to inhibit the growth of P. falciparum in vitro, but the systemic exposure as determined by the 24-hr plasma concentration-time curve would not be predicted inhibit growth in vivo. No evidence of deferiprone-associated hematological toxicity was noted in this short-term study of these subjects, all of whom had clinical evidence of normal body iron stores. Because of the risk of neutropenia and other adverse effects with higher doses or prolonged use of the chelator, additional trials of deferiprone as a sole anti-malarial agent would not seem to be justified. In contrast, further efforts are needed to develop other orally active iron-chelating agents specifically for their anti-malarial action.

Administration, Oral↗