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Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 253 records · Page 14Linked to original sources
PubMed1997

An improved limited sampling method for individualised busulphan dosing in bone marrow transplantation in children.

Busulphan (BU) pharmacokinetic (PK) studies in children undergoing bone marrow transplantation suggest that individual BU dosing may be necessary to optimise BU systemic exposure. Optimising BU systemic exposure may improve outcome and decrease toxicity in BMT. Because of practical limitations in obtaining blood from children and for financial reasons, a limited sampling method (LSM) is needed. However, such methods for BU have not been validated in children. In the present study, we individualized oral BU dosing in 10 children to target an area under the curve of BU (BU AUC) of 900-1400 microM/min based on BU AUC(0-infinity) calculated from nine serum BU concentrations performed after a BU test dose of 40 mg/m2. We validated a LSM using 3 BU concentrations to determine AUC. Six of nine patients studied (one patient non-evaluable), required their doses modified (3, lower; 3, higher). The mean percent dose change was 26.2% (range -33.3% to +45.3%). Our three sample LSM BU AUC(0-infinity) (1098 +/- 344, mean +/- 1 s.d.) correlated highly with our nine sample BU AUC(0-infinity) (1132 +/- 389, Pearson r = 0.98, P = 0.0001) and was not significantly different by t-test (P = 0.3). The mean percentage difference between the three sample LSM AUCs and the nine sample AUCs in each of our patients was 7.5%, (range -10.99% to +9.4%). Trough levels correlated extremely well with AUC (r = 0.95, P = 0.0001). Individual BU dosing, based on AUC, is necessary in most children to achieve targeted levels of BU therapy. An LSM of three BU concentrations performed at 0.5 h, 1 h and 6 h post-BU test dose closely predicts the AUC calculated from nine sampling points.

Alkylating Agents↗
PubMed1997

Immune function in patients with beta thalassaemia receiving the orally active iron-chelating agent deferiprone.

Short-term deferiprone may reduce body iron in some patients with thalassaemia major. Concerns regarding potential immunosuppressive effects of deferiprone have been raised from results of animal studies and case reports in humans. We studied immune function in 57 thalassaemia patients: 36 treated with deferiprone (L1; CP020) and 21 treated with desferrioxamine (DFO). Circulating B lymphocytes were increased in all patient groups. No differences were detected between treatment groups in percentages of circulating lymphocytes, concentrations of IgG, IgM or IgA, specific antibody titres, complement levels, or in vitro lymphocyte proliferation. No clinically important infections were observed in any patient. These data suggest that no clinical or laboratory changes consistent with immuno-suppression or immunodeficiency are observed during deferiprone therapy.

Adolescent↗
PubMed1997

Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis.

To determine the relative risk for major malformations associated with antihistamine (H1 blockers) exposure in the first trimester of pregnancy, a literature search of all studies examining the association between antihistamines and major malformations for the period 1960 to 1991 was conducted, followed by meta-analysis. Odds ratio was calculated using the Mantel-Haenszel method. Twenty-four controlled studies met the inclusion criteria with more than 200,000 participating women. The summary odds ratio of major malformations associated with antihistamines taken during the first trimester was 0.76 (95% CI: 0.60-0.94). This analysis indicates that H1 blockers used mainly for morning sickness during the first trimester do not increase the teratogenic risk in humans and may, in fact, be associated with a protective effect. More study is needed to verify the possibility that by preventing vomiting, antihistamines may ensure better metabolic conditions to the fetus and thus may reduce some birth defects. Alternatively, it is possible that pregnancies characterized by vomiting are associated with better outcome due to other reasons, such as hormonal status or placental function. Women suffering from morning sickness which is not controlled by nonpharmacological methods can safely use antihistamines.

Abnormalities, Drug-Induced↗
PubMed1997

Salivary measurement of deferiprone concentrations and correlation with serum levels.

Deferiprone (L1) is the first clinically available oral iron chelator and it has been proven to be effective for the treatment of transfusional iron overload in thalassemic patients. Because many of these patients have impaired compliance with their medications, effective means of continuous monitoring of compliance are crucial. Saliva drug monitoring has the potential advantage of an easy, noninvasive approach, assuming that it represents serum levels. However, drugs have variable correlations between saliva and serum concentration. We compared serum and saliva levels of L1 at various time points after ingestion of a 75 mg/kg/day dose in nine thalassemic patients. A highly significant correlation between serum-free L1 and saliva levels (r = 0.97, p = 0.0003) was found. Pharmacokinetic profiles were similar using serum and saliva monitoring. We conclude that saliva can be substituted for serum in monitoring L1 levels.

Deferiprone↗
PubMed1997

Correlation of morphine sulfate in blood plasma and saliva in pediatric patients.

This study sought to determine whether saliva concentrations of morphine correlate with plasma levels of morphine in pediatric patients receiving morphine analgesia for severe pain, and to evaluate whether the measurement of saliva morphine concentrations would be a useful, noninvasive, clinical tool to diagnose systemic exposure to morphine. Fifteen pediatric patients were enrolled; for the control group, 18 adult volunteers were recruited. Patients received continuous morphine drips to ameliorate pain caused by a sickle cell vasoocclusive crisis (range, 10-40 micrograms/kg.h). Control subjects were randomized into those receiving acetaminophen with either 8 mg (n = 13) or 30 mg (n = 5) of codeine. All participants fasted at least 2 hours before sample collection. Blood and saliva samples were collected simultaneously. All samples were analyzed by radioimmunoassay for morphine. There was no correlation between saliva and plasma morphine concentrations in either the patients receiving intravenous morphine (r = 0.04, P = 0.89) or in the controls receiving codeine (r = 0.43, P = 0.08). There was no observed difference in the mean counts per minute (CPM) for saliva samples in the pH range 3.96 to 8.06. Saliva concentrations of morphine cannot be used to predict the plasma concentration of morphine in children or adults. However, the concentration of morphine in saliva may be used as a qualitative indicator of systemic exposure to morphine in a subject.

Adolescent↗
PubMed1997

Is saliva suitable for therapeutic monitoring of anticonvulsants in children: an evaluation in the routine clinical setting.

Studies performed in the research setting suggested that saliva instead of blood may be used for therapeutic drug monitoring (TDM) of anticonvulsants in children. This is an attractive alternative because its collection is painless, and simpler and cheaper than blood drawing. Citric acid stimulation of saliva secretion facilitates sampling in the youngest patients. The aim of the study was to evaluate the suitability of saliva in routine TDM of anticonvulsants in infants and children with epilepsy. Blood and saliva samples were obtained simultaneously during routine TDM in 170 patients on chronic anticonvulsant drug therapy attending a neurology clinic. Saliva, plasma total, and plasma free concentrations of anticonvulsants were measured by high-performance liquid chromatography and enzyme multiplied immunoassay technique. Strong and highly significant correlations between saliva and plasma concentrations were found over a wide range of concentrations for carbamazepine, phenytoin, clobazam, and desmethylclobazam, and for phenobarbital in children > or = 8 years of age (r = 0.90 to 0.97; p < 0.001). Correlations between saliva and plasma concentrations were poor for phenobarbital in children < 8 years of age and for valproate. Correlations between saliva and plasma-free anticonvulsant concentrations were equal or only slightly better than between saliva and plasma total concentrations. Citric acid-stimulated saliva constitutes a convenient alternative for TDM of carbamazepine and phenytoin therapy in pediatric patients and of phenobarbital in children > or = 8 years of age.

Adolescent↗
PubMed1997

Controlled pilot study of rapid amphotericin B infusions.

This pilot study compared the toxicity of a one hour with a four hour amphotericin B infusion in children. There were more severe chills in the former group on the first day of infusion, and more hypotension in the latter group over the study duration.

Adolescent↗
PubMed1997

Current management of the neonatal abstinence syndrome: a critical analysis of the evidence.

OBJECTIVE: To systematically and critically analyse and summarise the published evidence for the rational choice of pharmacologic treatment of the neonatal abstinence syndrome (NAS), a frequently observed condition in neonates born to mothers who are dependent on physically addicting drugs. DESIGN: Studies comparing different pharmacological agents for the treatment of NAS were identified utilising MEDLINE and additionally the references cited in pertinent articles. The identified studies were critically analysed regarding their study designs and outcome measures. The reported data for the comparative efficacy of the drugs were summarised and evaluated. RESULTS: Fourteen studies were identified, most of them comparing treatment of NAS with phenobarbital, paregoric or diazepam. However, none of these studies was conducted in a double-blind fashion. Frequently, treatment allocations were not properly randomised. Prenatal drug exposure varied and was often not sufficiently verified. Outcome measures and their evaluations differed widely. Due to the different study objectives and flaws in study design, a combined analysis of the published data in the form of a meta-analysis was not deemed possible. When attempting to compare efficacy, diazepam appears to be less efficacious in treating NAS than phenobarbital or paregoric. The relative efficacy of paregoric and phenobarbital appears to depend upon the antenatal exposure of the neonate and on the outcome measure of the study. Only two studies evaluate the efficacy of pure opioids, none of them in direct comparison to paregoric. It remains questionable whether paregoric, which contains the central stimulant camphor and a large amount of alcohol, should be the opioid of choice for the treatment of NAS. CONCLUSION: Most published studies were conducted prior to the development of clinical epidemiology and modern study design and thus yielded only very limited comparative data on the benefits of different treatment protocols. There is very little evidence regarding the efficacy of different pharmacological therapy regimens to treat NAS. More studies are required to produce the evidence needed to allow a rational choice between treatment modalities of NAS and thus to ensure optimal care of the neonates suffering from this condition.

Analgesics, Opioid↗
PubMed1997

Clinical utilization of the neonatal hair test for cocaine: a four-year experience in Toronto.

BACKGROUND: There has been a steady increase in the number of newborns affected by maternal drug use. Cocaine and its metabolites cross the placenta and have been routinely measured in neonatal urine; however, due to the short half-life of the drug many exposed fetuses have negative urine tests. We have developed a neonatal hair test for measuring cocaine and its metabolites by radioimmunoassay. Since the validation of this test we prospectively evaluated its clinical utility by physicians, hospital nurseries and social welfare agencies who requested neonatal hair analysis to verify clinical suspicion of maternal cocaine use during pregnancy. OBJECTIVE: The objective of the present research was to establish the sensitivity of the hair test in validating clinical suspicion of in utero exposure to cocaine in the presence of negative urine test. HYPOTHESIS: We hypothesized that the use of the hair test in cases of clinical suspicion but negative urine test will yield a substantially higher rate of positivity than expected in the general population. DESIGN: Between October 1991 and April 1995 we prospectively analyzed a total of 192 neonatal hair samples to confirm clinical suspicions of intrauterine exposure to cocaine. Of these, 10 did not have sufficient hair to analyze for cocaine metabolites. RESULTS AND DISCUSSION: Fifty-five (30%) of the remaining 182 were positive for cocaine metabolite. This rate was 5.5-fold higher than the 5.5% found by us in a population-based research study in three nurseries in Toronto (p < 0.001), thus documenting the efficiency of this test in confirming clinical suspicions of fetal exposure to cocaine. Benzoylecgonine concentrations in this cohort were 2-fold higher than among positive cases in a previous population-based screening study (p = 0.0001) indicating that when clinical suspicions prompted physicians to test neonatal hair, they identify a subgroup of heavy cocaine users, who are probably at higher perinatal risks.

Cocaine↗
PubMed1997

Interactions of clobazam with conventional antiepileptics in children.

Clobazam is a 1,5-benzodiazepine effective in antiepileptic therapy of children and adults. Presently it is mainly used as adjuvant therapy for intractable seizures. Our objective was to evaluate the effect of clobazam on the apparent clearance of other antiepileptic drugs at steady state, and to determine the factors that determine the plasma levels of clobazam and its active metabolite N-desmethylclobazam. Patients were 74 children with intractable seizures who received treatment with clobazam at our institution as part of the Canadian Cooperative Clobazam Study Group during the years 1987 to 1991. Serum concentrations of clobazam, N-desmethylclobazam, and of concomitant antiepileptic drugs were monitored and prospectively collected. The effect of clobazam treatment on the apparent clearance steady state of the other antiepileptic drugs was determined by statistical comparison of the clearances of each drug before and after initiation of clobazam treatment using Wilcoxon's signed rank test. The effects of dosage, age, and concomitant antiepileptic therapy on the levels of clobazam and N-desmethylclobazam was assessed by multivariate analysis. Response to treatment and incidence of adverse effects were evaluated for each conventional antiepileptic drug to possibly identify favorable or unfavorable combinations with clobazam. Whereas the clearances of most conventional antiepileptics are not affected by cotherapy with clobazam, the apparent clearances of valproic acid and primidone are significantly reduced in the presence of clobazam. Serum concentrations of clobazam increased with dosage and age, and decreased with phenobarbital cotherapy. Serum concentrations of N-desmethylclobazam significantly correlated with clobazam serum levels, age, or clobazam dosage and were significantly increased by cotherapy with phenytoin or carbamazepine. None of the concomitantly used drugs were associated with increased or decreased rate of seizure control. Twelve patients experienced mild adverse drug effects that were not associated with particular cotherapy, clobazam dose, or plasma concentrations. When clobazam is added to a therapy regimen that includes valproic acid, the patient should be closely followed for possible adverse drug reactions caused by elevated valproic acid serum concentrations, and monitoring of valproate serum levels should be considered. When clobazam doses are gradually increased to achieve an optimal clinical effect, the interactions with phenobarbital, carbamazepine, and phenytoin do not necessitate therapeutic drug monitoring of clobazam or N-desmethylclobazam, because there is a large therapeutic window and a poor correlation between plasma concentrations and therapeutic efficacy.

Adolescent↗
PubMed1997

Mechanism of anaphylactoid reactions: improper preparation of high-dose intravenous cyclosporine leads to bolus infusion of Cremophor EL and cyclosporine.

BACKGROUND: During a Phase I/II trial of high-dose intravenous cyclosporine, a high incidence of anaphylactoid reactions was observed. Epidemiologic investigations revealed that the occurrence of anaphylactoid reactions was significantly associated with improper mixing during preparation of the infusions. It was hypothesized that improper mixing during the preparation of the infusion may have caused initial bolus infusions of the vehicle, Cremophor EL. These inadvertent bolus infusions may have caused the anaphylactoid reactions. OBJECTIVE: To investigate the effect of different mixing techniques on the distribution of the components of cyclosporine concentrate for infusion: cyclosporine, Cremophor EL, and ethanol in the infusions administered to the patients. METHODS: Infusions were prepared in a similar fashion as those administered to study patients enrolled in a high-dose cyclosporine therapy protocol. Samples were collected at defined time points of the infusions. Concentrations of cyclosporine and Cremophor EL were spectrophotometrically determined; ethanol concentrations were measured enzymatically. RESULTS: Cyclosporine and Cremophor EL concentrations were up to ninefold higher than intended during the first 10 minutes of the infusions that were not appropriately mixed. In contrast, the concentrations of cyclosporine and Cremophor EL were similar to the intended concentrations in all of the well-mixed infusions. CONCLUSIONS: Inappropriate mixing of high-dose cyclosporine infusions can lead to initial bolus infusion of cyclosporine and Cremophor EL. Bolus infusions of Cremophor EL have been associated with anaphylactoid reactions. Thus, through mixing of high-dose cyclosporine infusions may be important to reduce the possibility of life-threatening anaphylactoid reactions.

Anaphylaxis↗
PubMed1997

Pharmacokinetic changes during pregnancy and their clinical relevance.

The dynamic physiological changes that occur in the maternal-placental-fetal unit during pregnancy influence the pharmacokinetic processes of drug absorption, distribution and elimination. Pregnancy-induced maternal physiological changes may affect gastrointestinal function and hence drug absorption rates. Ventilatory changes may influence the pulmonary absorption of inhaled drugs. As the glomerular filtration rate usually increases during pregnancy, renal drug elimination is generally enhanced, whereas hepatic drug metabolism may increase, decrease or remain unchanged. A mean increase of 8 L in total body water alters drug distribution and results in decreased peak serum concentrations of many drugs. Decreased steady-state concentrations have been documented for many agents as a result of their increased clearance. Pregnancy-related hypoalbuminaemia, leading to decreased protein binding, results in increased free drug fraction. However, as more free drug is available for either hepatic biotransformation or renal excretion, the overall effect is an unaltered free drug concentration. Since the free drug concentration is responsible for drug effects, the above mentioned changes are probably of no clinical relevance. The placental and fetal capacity to metabolise drugs together with physiological factors, such as differences acid-base equilibrium of the mother versus the fetus, determine the fetal exposure to the drugs taken by the mother. As most drugs are excreted into the milk by passive diffusion, the drug concentration in milk is directly proportional to the corresponding concentration in maternal plasma. The milk to plasma (M:P) ratio, which compares milk with maternal plasma drug concentrations, serves as an index of the extent of drug excretion in the milk. For most drugs the amount ingested by the infant rarely attains therapeutic levels.

Animals↗
PubMed1997

Therapeutic drug monitoring principles in the neonate. National Academy of CLinical Biochemistry.

Therapeutic drug monitoring in the newborn infant is necessary because dose requirements differ greatly from those for older children. These differences stem from major changes in kinetic disposition at the absorption, distribution, and elimination phases. The small blood volume of neonates makes them sensitive to iatrogenic blood loss. Similarly, the small size of these patients means that medication errors frequently lead to morbidity and even mortality. The clinical laboratory must set up strict, high-standard, carefully updated guidelines to ensure the safety of infants who need drug therapy at this very vulnerable phase of their lives.

Drug Monitoring↗