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Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 343 records · Page 19Linked to original sources
PubMed1995

Influence of food on the bioavailability of oral methotrexate in children.

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 mumol/l.h after po fasting, po fed, and iv administration, respectively. The maximum serum MTX concentration (Cmax) was 0.65 +/- 0.33 and 0.39 +/- 0.18 mumol/l after po fasting and po fed administration, respectively (p = 0.0022). The time to Cmax 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.

Administration, Oral↗
PubMed1995

Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation.

PURPOSE: We evaluated the efficacy of a new lidocaine-prilocaine cream in preventing premature ejaculation. MATERIALS AND METHODS: An open pilot, unblinded study was done using lidocaine-prilocaine cream in 11 healthy, married men with premature ejaculation without organic or erectile problems. The patients were instructed to apply 2.5 gm. of the cream 30 minutes before sexual contact and to cover the penis with a condom. Patients were asked to grade the effect of the cream on ejaculation after each application. RESULTS: There was a significant improvement in premature ejaculation statistically and clinically. Five patients graded the result as excellent compared to baseline, 4 graded it as better and 2 claimed to have no change compared to ejaculation before use of the cream. No adverse effects were noted. CONCLUSIONS: These promising results should prompt a large double-blind placebo-controlled trial. If confirmed, this therapy may be a breakthrough in the treatment of the most common form of male sexual dysfunction.

Adult↗
PubMed1994

Neurodevelopment of adopted children exposed in utero to cocaine.

OBJECTIVE: To assess the neurodevelopment of adopted children who had been exposed in utero to cocaine. DESIGN: A case-control observational study. PARTICIPANTS: Twenty-three children aged 14 months to 6.5 years exposed in utero to cocaine and their adoptive mothers, and 23 age-matched control children not exposed to cocaine and their mothers, matched with the adoptive mothers for IQ and socioeconomic status. SETTING: The Motherisk Programme at The Hospital for Sick Children, Toronto, a consultation service for chemical exposure during pregnancy. MAIN OUTCOME MEASURES: Height, weight and head circumference at birth and at follow-up, and achievement on standard tests of cognitive and language development. RESULTS: Compared with the control group, children exposed in utero to cocaine had an 8-fold increased risk for microcephaly (95% confidence interval 1.5 to 42.3); they also had a lower mean birth weight (p = 0.005) and a lower gestational age (p = 0.002). In follow-up the cocaine-exposed children caught up with the control subjects in weight and stature but not in head circumference (mean 31st percentile v. 63rd percentile) (p = 0.001). Although there were no significant differences between the two groups in global IQ, the cocaine-exposed children had significantly lower scores than the control subjects on the Reynell language test for both verbal comprehension (p = 0.003) and expressive language (p = 0.001). CONCLUSIONS: This is the first study to document that intrauterine exposure to cocaine is associated with measurable and clinically significant toxic neurologic effects, independent of postnatal home and environmental confounders. Because women who use cocaine during pregnancy almost invariably smoke cigarettes and often use alcohol, it is impossible to attribute the measured toxic effects to cocaine alone.

Adoption↗
PubMed1994

Survival in medically treated patients with homozygous beta-thalassemia.

BACKGROUND: The prognosis of patients with homozygous beta-thalassemia (thalassemia major) has been improved by transfusion and iron-chelation therapy. We analyzed outcome and prognostic factors among patients receiving transfusions and chelation therapy who had reached the age at which iron-induced cardiac disease, the most common cause of death, usually occurs. METHODS: Using the duration of life without the need for either inotropic or antiarrhythmic drugs as a measure of survival without cardiac disease, we studied 97 patients born before 1976 who were treated with regular transfusions and chelation therapy. We used Cox proportional-hazards analysis to assess the effect of prognostic factors and life-table analysis to estimate freedom from cardiac disease over time. RESULTS: Of the 97 patients, 59 (61 percent) had no cardiac disease; 36 (37 percent) had cardiac disease, and 18 of them had died. Univariate analysis demonstrated that factors affecting cardiac disease-free survival were age at the start of chelation therapy (P < 0.001), the natural log of the serum ferritin concentration before chelation therapy began (P = 0.01), the mean ferritin concentration (P < 0.001), and the proportion of ferritin measurements exceeding 2500 ng per milliliter (P < 0.001). With stepwise Cox modeling, only the proportion of ferritin measurements exceeding 2500 ng per milliliter affected cardiac disease-free survival (P < 0.001). Patients in whom less than 33 percent of the serum ferritin values exceeded 2500 ng per milliliter had estimated rates of survival without cardiac disease of 100 percent after 10 years of chelation therapy and 91 percent after 15 years. CONCLUSIONS: The prognosis for survival without cardiac disease is excellent for patients with thalassemia major who receive regular transfusions and whose serum ferritin concentrations remain below 2500 ng per milliliter with chelation therapy.

Adult↗
PubMed1994

Arthropathy in thalassaemia patients receiving deferiprone.

The iron chelator deferiprone (L1) reduces tissue iron stores in iron-loaded patients. Three of sixteen patients treated with deferiprone developed joint pain and swelling without evidence of systemic lupus erythematosus (SLE). Articular cartilage, synovial hypertrophy and iron deposition, and synovial lining cell proliferation, with no inflammatory or allergic reaction, were observed on synovial exploration and biopsy. Symptoms resolved partly or completely during continued drug administration. We hypothesise that deferiprone-induced shifts of iron to synovium resulted in tissue damage, accelerated by free-radical formation during incomplete complexation of iron and this bidentate chelator. This deferiprone-associated symptom complex is not associated with drug-induced SLE, and does not progress in severity during continued therapy.

Adolescent↗
PubMed1994

Simultaneous determination of lidocaine, prilocaine and the prilocaine metabolite o-toluidine in plasma by high-performance liquid chromatography.

An HPLC assay is described for the measurement of prilocaine and lidocaine (components of the local anesthetic cream EMLA) as well as the prilocaine metabolite, o-toluidine, in plasma. The method uses UV detection, is simple, sensitive and most important, only a single 200-microliters plasma sample is needed for simultaneous analysis of prilocaine, lidocaine and o-toluidine with a detection limit of 4 ng/ml. The plasma, together with the internal standard (bupivacaine) is extracted with diethyl ether under alkaline conditions, followed by the extraction of the analytes from the organic phase into dilute sulphuric acid. An aliquot of the acid extract is injected onto the HPLC system and the effluent is monitored by a UV detector.

Animals↗
PubMed1994

Iron-balance and dose-response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease.

Several life-threatening complications of the common disorder sickle cell disease require management with red blood cell transfusions and, hence, long-term iron-chelating therapy. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) has not previously been determined in patients with sickle cell disease. We compared the efficacy of L1 to that of standard-dose subcutaneous deferoxamine in four regularly transfused patients with homozygous sickle cell disease, who had evidence of severe iron overload and a history of poor compliance with deferoxamine. Determination of 24-hour urinary iron excretion conducted over 5 days immediately after transfusion showed that the mean daily urinary iron excretion induced by L1 at 75 mg/kg/d (0.48 +/- 0.23 mg/kg) was equivalent to that induced by deferoxamine at 50 mg/kg/d (0.39 +/- 0.06 mg/kg). In two of three patients studied, a significant (P < .025) increase in mean daily urinary iron excretion was achieved when the dose of L1 was increased to 100 mg/kg/d. Total iron balance studies, which quantitated both urinary and stool iron excretion on L1 and deferoxamine, determined that mean total daily iron excretion induced by deferoxamine (0.88 +/- 0.05 mg/kg) was significantly greater (P < .05) than that induced by L1 (0.53 +/- 0.17 mg/kg), attributable to the significantly greater stool iron excretion during deferoxamine treatment (0.50 +/- 0.16 mg/kg/d) compared with that measured during L1 treatment (0.12 +/- 0.08 mg/kg/d, P < .01). Stool iron excretion accounted for a significantly greater percentage of total iron excretion during deferoxamine treatment (59% +/- 20%) than during L1 treatment (23% +/- 14%, P < .01). These iron balance studies are the first to compare total iron excretion induced by L1 with that achieved by deferoxamine. They demonstrate that the mean total daily iron excretion during L1 treatment (0.53 +/- 0.17 mg/kg) is sufficient to maintain net negative iron balance in most regularly transfused patients with sickle cell disease. Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease.

Administration, Oral↗
PubMed1994

Hair concentrations of nicotine and cotinine in women and their newborn infants.

BACKGROUND: To date, no biological markers have been identified that can predict the extent of fetal exposure to the toxic constituents of cigarette smoke. A variety of xenobiotic agents have been shown to accumulate in growing hair. PATIENTS AND METHODS: We measured maternal and neonatal hair concentrations of nicotine and cotinine in 94 mother-infant pairs. Mothers who were active smokers, nonsmokers, and passive smokers and their infants were included. RESULTS: Mothers who were active smokers (n = 36) had mean (SEM) hair concentrations of 19.2 (4.9) ng/mg for nicotine and 6.3 (4.0) ng/mg for cotinine, significantly higher than concentrations in nonsmokers (n = 35) (1.2 [0.4] ng/mg for nicotine and 0.3 [0.06] ng/mg for cotinine, P < .0001). Infants of smokers had mean hair concentrations of 2.4 (0.9) ng/mg for nicotine (range, 0 to 27.3 ng/mg) and 2.8 (0.8) ng/mg for cotinine (range, 0 to 12.2 ng/mg), significantly higher than concentrations in infants of nonsmokers (0.4 [0.09] ng/mg for nicotine and 0.26 [0.04] ng/mg for cotinine, P < .01). Mothers with passive smoke exposure and their infants (n = 23) had significantly higher hair concentrations of nicotine (3.2 [0.8] ng/mg for mothers and 0.28 [0.05] ng/mg for infants) and cotinine (0.9 [0.3] ng/mg for mothers and 0.6 [0.15] ng/mg for infants) than nonsmoking mothers and their infants (P < .01). There was a significant correlation between maternal and neonatal hair concentrations of nicotine (r = .49, P < .001) or cotinine (r = .85, P = .0001). CONCLUSIONS: This is the first biochemical evidence that infants of passive smokers are at risk of measurable exposure to cigarette smoke. Hair accumulation of cigarette smoke constituents reflects long-term systemic exposure to these toxins and therefore may be well correlated with perinatal risks.

Adult↗
PubMed1994

Pediatric medication errors: predicting and preventing tenfold disasters.

Tenfold errors in pediatric doses are not uncommon. Because the needed volume of stock solution is generally small, even a tenfold higher volume may still appear deceivingly normal. Such errors are much less likely to occur in adults, because it would result in unacceptably large volumes of stock solution. Other sources of tenfold errors are communication difficulties with parents and illegible writing of orders by physicians. Testing health professionals may identify subgroups of individuals who are prone to commit such errors. Independent double checking of calculations and a mechanism to resolve disagreement is being practiced in most academic institutions. Transition to patient's unit dose is likely to decrease calculation errors, because pharmacists commit fewer errors. Hazardous drugs that are not required on a stat basis should be removed from the wards.

Adolescent↗
PubMed1994

Critical comparison of novel and existing methods of compliance assessment during a clinical trial of an oral iron chelator.

The assessment of compliance is critical in the evaluation of the effectiveness of a new therapeutic agent. Fifteen patients with transfusion-dependent beta-thalassemia, many of whom had previously demonstrated erratic compliance with deferoxamine, were enrolled in a clinical trial of a new oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Their compliance with this medication was estimated by several existing methods and the novel Medication Event Monitoring System (MEMS). Overall compliance as assessed by the MEMS was 78.5 +/- 13.0% of prescribed doses taken, significantly lower than the corresponding rates calculated by pill counts and diaries (91.5 +/- 9.2% and 94.1 +/- 4.3%, respectively). However, several serious problems were encountered with the MEMS, mostly in the form of incorrect use of the device by the patients. Disclosure of the nature of the MEMS and the compliance monitoring process did not alter the rate of adherence with L1 therapy. Compliance as determined by pill counts did not differ between the 1st and 2nd 6-month periods. Although not reaching statistical significance, a trend towards better L1 compliance occurred in those patients in whom serum ferritin levels decreased. Patients who filled at least 50% of their diaries had significantly better compliance by pill counts than those who completed less than 50% of their diaries (95.9 +/- 4.1% and 86.5 +/- 11.1%, respectively). Steady-state L1 trough concentrations and 24-hour urinary iron excretion did not correlate with L1 compliance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Stereoselective pharmacokinetics of mefloquine in healthy Caucasians after multiple doses.

Mefloquine (MQ) is a chiral antimalarial agent effective against chloroquine-resistant Plasmodium falciparum. It is commercially available as a racemic mixture of the (+) and (-) enantiomers for oral administration. The pharmacokinetics of the (+) and (-) enantiomers of MQ were studied in eight healthy volunteers after administration of a first oral dose of 250 mg of racemic MQ and at steady state after 13 repeated doses of 250 mg given at 1-week intervals. Plasma samples were collected, and concentrations of each enantiomer were determined using a previously described achiral-chiral double column-switching liquid chromatographic method. At each time point, higher plasma concentrations values were found for the (-) enantiomer (p < 0.001). At steady state, Cmax values of (-)-MQ were higher than those of (+)-MQ (1.42 +/- 0.19 versus 0.26 +/- 0.05 mg/L; p < 0.001). Similarly, the plasma concentrations 7 days after the final dose were higher for (-)-MQ (1.01 +/- 0.26 versus 0.11 +/- 0.04 mg/L; p < 0.001). AUC values at steady state were also higher for (-)-MQ (197.3 +/- 36.7 versus 30.1 +/- 8.9 mg/L x h; p < 0.001). The terminal half-life values (T1/2beta) were longer for (-)-MQ (430.4 +/- 225.2 versus 172.8 +/- 56.5 h; p < 0.001). This study shows that the pharmacokinetics of MQ is highly stereoselective.

Adult↗
PubMed1994

Cisplatin protein binding in pregnancy and the neonatal period.

The most effective combination regimes for ovarian cancer contain cisplatin, but there is little knowledge about cisplatin use during pregnancy. The high protein binding of cisplatin means that small changes in protein binding result in large changes in the fraction of free drug. It is the free form of cisplatin that crosses the placenta and may contribute to fetal toxicity. The purpose of the present study was to compare protein binding of cisplatin in pregnant women, non-pregnant women, and newborn infants. We found that babies and pregnant women had significantly lower concentrations of both protein and albumin compared to non-pregnant women. Analysis of variance found overall significant differences in protein binding among the three groups over time (P < .05). Babies had statistically less cisplatin protein binding than non-pregnant women at 80 minutes and all time points thereafter (P < .05). In contrast, pregnant women had statistically less cisplatin protein binding than non-pregnant women at 3.3 and 8 hours (P < .05). Of interest, at 75.2 hours, the percentage of free cisplatin was 15% in babies as compared with 9% in non-pregnant women and 10% in pregnant women. This means that the fetus is exposed to 50% higher platinum levels at equal total concentration. Cisplatin protein binding significantly correlated with albumin concentrations at 3.3, 8, and 24 hours (P < .01). Our analysis reveals that pregnancy and fetal changes in cisplatin protein binding are caused in large part by lower albumin levels. The resulting higher levels of free drug in the mother and fetus may increase the risk of toxicity in both.

Adult↗