Showing papers by "Gideon Koren published in 1989"

Experimental evidence for vortex-glass superconductivity in Y-Ba-Cu-O.

Abstract: We demonstrate experimentally the existence of a continuous phase transition between a normal and a true superconducting phase (with zero linear resistivity) in epitaxial films of Y-Ba-Cu-O in strong magnetic fields fields, {ital H}{much gt}{ital H}{sub {ital c}1}. The nonlinear {ital I}-{ital V} curves show scaling behavior near the transition and the relevant critical exponents are extracted. These exponents are consistent with values expected for freezing into a superconducting vortex-glass phase.

Determination of gestational cocaine exposure by hair analysis.

Abstract: Drug self-reports are often unreliable and standard blood and urine tests detect only recent cocaine use. Since cocaine is deposited in hair, we have applied a radioimmunoassay to hair extract to detect past cocaine use. Hair from 16 adult users was positive for benzoylecgonine, in the presence of negative findings from urine screening tests. Benzoylecgonine in admitted heavy users averaged 8775 ng/g of hair (range, 640 to 29 089 ng/g of hair), whereas in occasional users it averaged 624 ng/g of hair (range, 32 to 1210 ng/g of hair). Benzoylecgonine was not detected in hair of 21 adults who reported no use of cocaine ever and whose urine samples were negative for the metabolite. Neonatal hair from seven infants whose mothers were known cocaine users averaged 5430 ng of benzoylecgonine per gram of hair (range, 200 to 27500 ng/g of hair). Hair from two infants 2.5 and 3.5 months of age averaged 6050 ng of benzoylecgonine per gram of hair. However, values were negative for infants 1 year and older, corresponding to loss of fetal hair in the few months after birth. Because studies reporting reproductive risks of cocaine compare exposed and nonexposed groups, validation of drug-free status of control subjects is extremely important. Hair analysis may remedy the disadvantages of currently used methods and may identify intrauterine exposure to cocaine in babies when a maternal drug history is not available or of doubtful truthfulness. (JAMA. 1989;262:3328-3330)

Topical skin anesthesia for venous, subcutaneous drug reservoir and lumbar punctures in children.

Abstract: A new topical anesthetic ointment (EMLA, "eutectic mixture of prilocaine and lidocaine was studied in a double-blind, placebo-controlled trial to evaluate its efficiency in alleviating pain associated with venous, subcutaneous drug reservoir and lumbar punctures in children. Pain intensity was scored by the children themselves, using a visual analogue scale in which 0 corresponded to absence of sensation and 10 to the worst imaginable painful sensation. Venipunctures were performed on 18 children (6.1 to 12.2 years of age) equally divided in the study and control groups; EMLA cream was associated with lesser pain scores than those with placebo (means +/- SD: 2.8 +/- 2.4 vs 6.8 +/- 2.1, P less than .01). A crossover trial was used in the studies of subcutaneous drug reservoir and lumbar punctures, eight children (6.1 to 15.1 years of age) were tested for subcutaneous drug reservoir punctures; pain induced by this procedure was rated at 3.9 +/- 2.2 with placebo compared with 1.2 +/- 1.8 with EMLA cream (P less than .04). In lumbar punctures (14 children studied, 5.5 to 15.3 years of age), EMLA cream was again associated with less pain (1.9 +/- 1.9) than was placebo (5.6 +/- 3.0, P less than .01). It was concluded that the use of EMLA cream substantially reduces pain caused by venous, subcutaneous drug reservoir, and lumbar punctures in children and may therefore be offered to young patients, particularly those repeatedly submitted to such procedures.

Determinants of recall and recall bias in studying drug and chemical exposure in pregnancy.

Abstract: Case-control studies on effects of durgs in pregnancy rely heavily on maternal recall. At the Motherisk Program in Toronto we counsel women during early pregnancy on the risk of drug and chemical exposure; subsequently, we follow up the outcome of pregnancy after birth. This cohort has given us an opportunity to assess the magnitude of recall of early pregnancy exposure and determinants likely to affect it in 145 consecutive cases. The mean recall of exposure identity was 62%, while accurate recall of timing of exposure was 37% and of dosage 24%. Exposures that prompted the clinic visit, chronic therapeutic exposures, environmental agents, and known teratogens were recalled significantly better than were other exposures. Accurate report of smoking was significantly higher than of alcohol use (79.4% vs. 59%, respectively, P = .0002). The number of agents consumed by the pregnant woman negatively correlated with her recall; mean recall of 1 agent was 85% vs. only 40% recall of 4 agents. Women ≥ 30 years of age recalled significantly worse (mean ± SEM, 52 ± 4%) than women younger than 30 (70 ± 4%), P = .002) despite a similar mean number of exposures. No difference in mean recall was found between women having normal (n = 112) or adverse pregnancy outcome (n = 33). There was a recall bias in reporting alcohol consumption; postnatally, women with adverse outcome tended to report significantly less than the amount initially reported by them.

Acute changes in renal function associated with deferoxamine therapy.

Abstract: In three patients who received intravenous deferoxamine there was a twofold to eightfold increase in plasma creatinine level and a parallel decrease in creatinine clearance that resolved when treatment with the drug was discontinued. In two thalassemic patients, diuresis was evident by urine output exceeding fluid intake. The mechanism was studied in dogs that exhibited an acute and significant decrease in inulin and para-aminohippuric acid clearances induced by intravenous deferoxamine. Saline diuresis could prevent the decrease in the glomerular filtration rate but not the decrease in renal blood flow caused by deferoxamine. Deferoxamine induced an acute increase in the fractional excretion of sodium, potassium, chloride, phosphate, and urate, which may explain the relative diuresis observed in two of the patients. In a subsequent experiment, ferrioxamine induced an increase in the fractional excretion of sodium and chloride but did not affect the glomerular filtration rate and renal blood flow. Our studies suggest that adequate hydration may be needed to preserve renal hemodynamics during intravenous deferoxamine therapy. Repeated measurements of renal function should accompany treatment with this agent.

Vancomycin pharmacokinetics in very low birth weight neonates.

Abstract: The pharmacokinetics of vancomycin hydrochloride was studied in 12 very low birth weight infants. The gestational age (mean +/- SD) was 25.9 +/- 1.3 weeks and body weight was 769.2 +/- 151.5 g at the time of initiation of the study. Vancomycin was infused over a period of 60 minutes in a dosage of 14.2 +/- 3.2 mg/kg once daily in 10 patients, twice daily in 1 patient and every 36 hours in 1 patient for a mean of 10.5 +/- 4.9 days. Serial blood samples were obtained and the concentration time data were fitted to a one-compartment open model using the ADAPT computer program. A significant positive correlation was found between postconceptional age and vancomycin clearance (P less than 0.005) and between vancomycin elimination half-life and plasma creatinine (P less than 0.01). A negative correlation existed between plasma creatinine and vancomycin clearance (P less than 0.005), between postconceptional age and plasma creatinine (P less than 0.005) and between vancomycin half-life and postconceptional age (P less than 0.01). On the basis of these findings a vancomycin dosage of 15 mg/kg every 24 hours for infants less than 1000 g should yield concentrations within the accepted therapeutic range. This susceptible population requires frequent monitoring of vancomycin concentrations because of the high degree of interpatient variability and the continuous maturation of renal function.

The nephrotoxic potential of drugs and chemicals. Pharmacological basis and clinical relevance.

Abstract: Scores of drugs in common clinical use are capable of inflicting various degrees of damage to the kidney. Similarly, a large number of widely employed chemicals may adversely affect renal tissue as part of their toxic potential. A xenobiotic may damage the kidney by more than one mechanism. For example, NSAIDs may cause decreased renal perfusion, interstitial nephritis, primary glomerulopathy and/or altered potassium homeostasis. A large number of drugs and chemicals inflict their damage on the renal tubular cell secondary to intracellular accumulation to concentrations substantially higher than in the plasma or in other tissues. These include aminoglycosides, mercury and carbon tetrachloride and cephaloridine. Drug-induced interstitial nephritis is characterised by inflammatory lesions of the renal interstitium developed after at least 7 to 10 days of therapy. The immunological nature of this reaction is suggested by the associated fever, maculopapular rash and arthralgia observed in some of the patients. Although eosinophilia, eosinophiluria, and raised blood IgE levels are characteristic, immunoglobulins are not deposited in renal tissue, and the basic mechanism has not been elucidated. Renal biopsy demonstrates oedema and interstitial inflammatory reaction, mainly with lymphocytes, monocytes, eosinophils and plasma cells. Less frequent, vasculitis of small vessels or granulomatous reaction may develop, leading to necrotising glomerulonephritis. The drugs most commonly causing acute interstitial nephritis are methicillin, ampicillin, cephalosporins, rifampicin (rifampin), sulphonamides, phenindione and allopurinol. Other penicillins, NSAIDs, phenytoin, thiazides and frusemide (furosemide) are less frequently associated with this syndrome. Drugs and chemicals may affect renal function by pharmacologically decreasing glomerular filtration rate and/or renal blood flow. These include the NSAIDs, radiological contrast media and cyclosporin. Normal renal function depends upon an intact glomerular apparatus. Many drugs and chemicals are capable of damaging the glomerulus, causing its increased permeability to large molecules such as proteins. Several drugs including d-penicillamine, thiopronine, captopril, pyrithioxine and methimazole, are believed to exert their damage through their sulfhydryl group which bind with high affinity to glomerular structures. A variety of xenobiotics or their metabolites may be deposited in the renal tubule causing obstruction of urine flow and a secondary damage to tubular epithelium. Sulphonamides, methotrexate and ethylene glycol are good examples.(ABSTRACT TRUNCATED AT 400 WORDS)

Pregnancy outcome following first trimester exposure to cocaine in social users in Toronto, Canada

Abstract: Studies of drug-dependent women reveal high rates of adverse fetal effects of cocaine. However, no data are available on the effect of the chemical in social users who discontinue cocaine upon realizing they are pregnant. We report the results of the first phase of a prospective study examining the outcome of pregnancy in women seeking counseling from the Motherisk Program in Toronto. Of 25 women seen in our clinic for 1st trimester cocaine exposure, 92% reported use of less than 10 g of cocaine and 36% reported marijuana use. Other illicit drug use was rare; cigarette and alcohol use was common. The study group did not experience adverse pregnancy outcome above the rate expected in the general population. There were 23 single births 1 pair of twins, and 1 spontaneous abortion. Birth weight and gestation were within normal limits. Only 1 child had a major malformation, syndactyly. Infant development was within normal limits, as measured by developmental milestones. All children are scheduled for assessment using the Bayley Scales of Infant Development. The results of the BSID will be compared to results from a cannabis-exposed control group and a no-drug control group.

Relationship between the pharmacokinetics and the analgesic and respiratory pharmacodynamics of epidural sufentanil.

Abstract: To establish the relationships between epidural sufentanil analgesia and respiratory effects and to determine the pharmacokinetics of the drug, 22 adult patients undergoing thoracotomy were put into a randomized, double-blind study and received either 30, 50, or 75 micrograms per dose in 20 ml normal saline solution. Repeated doses were given on request for the 24-hour study period. There was a weak but significant nonlinear correlation between length of effective analgesia and the cumulative dose of the drug (r = 0.26, p less than 0.001). In 12 of 22 patients, the maximal length of effective analgesia was reached before the last dose and the effect tended to taper off thereafter. The mean maximal length of effective analgesia was 4.69 +/- 0.32 hours (mean +/- SEM), whereas the length of effective analgesia with the last dose was only 3.34 +/- 0.46 hours (p less than 0.0005). There was a significant correlation between the peak serum concentrations of sufentanil during the dose interval and the length of effective analgesia (r = 0.44, p less than 0.0001). Area under the concentration-time curve was proportional to the size of the epidural dose, and with all three doses tested there was a gradual accumulation of sufentanil in the serum. Mean time-to-peak concentration (tmax) increased with repeated doses (p less than 0.05). Mean serum concentration of sufentanil during periods of slow respiratory rate (0.47 +/- 0.05 ng/ml) was significantly higher than during episodes without adverse respiratory effects (0.37 +/- 0.05 ng/ml, p less than 0.05). The above data suggest that an important part of the analgesic and adverse effects of sufentanil are mediated centrally, after this opioid is absorbed systemically.

Neuroblastoma after prenatal exposure to phenytoin: cause and effect?

Abstract: We evaluated the causality of the association between intrauterine exposure to phenytoin and postnatal neuroblastoma using an in vitro lymphocyte toxicity assay for phenytoin-induced reactions in an unusual sibship. In addition, we investigated intrauterine phenytoin exposure in a case series of infants and children with neuroblastoma diagnosed over 17 years at our center. The response of lymphocytes from our index case with neuroblastoma exposed in utero to phenytoin was within the normal range, whereas the mother and a sibling with fetal hydantoin syndrome (FHS) exhibited an intermediate toxicity. None of the 188 cases of childhood neuroblastoma diagnosed between 1969 and 1988 had been exposed in utero to phenytoin, indicating that, statistically, the drug cannot be associated with neuroblastoma in more than two cases with this malignancy in our cohort, or in 1.5% of all cases of neuroblastoma. Although our data do not suggest an association between phenytoin in pregnancy and postnatal neuroblastoma, it is still possible that there is an increased risk for neuroblastoma in children with FHS.

Evaluation of a new method for the prevention of neonatal anemia.

Abstract: Blood sampling for diagnostic purposes is a major cause of neonatal anemia. We propose a new method of blood sampling which preserves the infant's erythrocytes. Upon drawing of 1.5-ml blood samples, the syringe is centrifuged and erythrocytes are injected back into the circulation. Using rabbits as an experimental model, we documented the efficiency of this method in decreasing the need for foreign blood transfusion. Results of a variety of laboratory tests performed with plasma obtained with the new method were identical to those achieved with whole blood. Subsequent testing did not show increased risk of contamination or bleeding phenomena secondary to heparin load. Red blood cells obtained by centrifugation were morphologically normal. This new method may be effective in reducing the need for foreign blood transfusions in neonates.

A high-performance liquid chromatographic method for the measurement of deferoxamine in body fluids.

Abstract: A high-performance liquid chromatography method for the analysis of deferoxamine (DFO) in 100 microliters of serum or plasma is described. The procedure involves the addition of the internal standard ciprofloxacin to the sample, followed by ultrafiltration to remove protein. The ultrafiltrate is then directly injected into the chromatography system. Separation is achieved using a reverse-phase mu Bondapak C18 column and a ternary solvent system (sodium phosphate:acetonitrile:methanol) running at 2.0 ml/min. Assay time is 10 min, and chromatograms show no interference from coadministered drugs during this period of time. Coefficients of variation were found to be less than 5%, and analytical recovery of DFO was 85%. Validation experiments in an experimental dog model and in patients with iron overload demonstrate that the method is appropriate for studying the pharmacokinetics of DFO in thalassemic patients receiving drug for the treatment of chronic iron overload.

Interpretation of elevated postmortem serum concentrations of digoxin in infants and children.

Abstract: The relationship between excessive postmortem digoxin concentrations (greater than 6.4 nmol/L) and administered dose, and antemortem levels and time of sampling after death were determined in 27 digitalized children who died in our hospital between March 24, 1981 and September 1, 1983. In all 27 cases, postmortem concentrations were higher than antemortem levels (9.5 +/- 2.5 nmol/L and 3.12 +/- 1.72 nmol/L, respectively). In none of these patients was there clinical or electrocardiographic evidence of digitalis toxicity. There was a significant correlation between antemortem and postmortem determinations, and between time of sampling after death and postmortem concentration. Positive correlation existed between antemortem or postmortem concentrations and dose per kilogram. The degree of elevation in digoxin levels was uniform in most cases, and the likelihood of elevation falling in the range 3.5 to 7.0 nmol/L was 66%. If the estimated concentration of digoxin at the time of death was taken as baseline, in 75% of cases the subsequent elevation was between 5.3 and 8.3 nmol/L (mean, 6.5 +/- 1.1 nmol/L). Digoxin concentrations measured in newborn infants not receiving digoxin were significantly higher after death (1.5 +/- 0.3 nmol/L) than in age-matched living infants not receiving digoxin (0.5 +/- 0.3 nmol/L). These data indicate that the size of antemortem dose, the time of sampling after death, and existence of endogenous digoxinlike factors affect postmortem readings of digoxin levels. Consequently, excessive postmortem determinations cannot be directly interpreted as proof of toxic antemortem levels.

Interpretation of excessive levels of inhaled tobramycin.

Abstract: De mauvaises conditions de prelevement de sang au bout du doigt chez un enfant entrainent des concentrations excessivement elevees de Tobramycine. Le prelevement par voie intraveineuse et en prenant des precautions pour empecher l'exposition de la peau au medicament permettent de trouver des concentrations valables

The state of pediatric clinical pharmacology: an international survey of training programs.

Abstract: Clinical Pharmacology and Therapeutics (1989) 46, 489–493; doi:10.1038/clpt.1989.175

Peace of Mind During Pregnancy

Abstract: Between 40% and 90% of all women in the Western world use at least one medication during pregnancy. Since the thalidomide tragedy, every drug has been viewed as a potential teratogen. In fact, only roughly 20 xenobiotics are proved human teratogens. In a recent study conducted in Toronto, Canada, we showed that women consulting the Motherisk program (an antenatal consultation service for drug, chemical, and radiation exposures) assign themselves a 25% teratogenic risk when exposed to nonteratogenic drugs. Clearly, there is a need for authoritative information on the risk of exposure to drugs, chemicals, radiation, or infection in pregnancy. Although it is facile to say, "Do not use during pregnancy," more than 50% of the women contacting the Motherisk program do so after realizing that conception occurred while being exposed to the agent in question. For these women, the notion "do not use during pregnancy" may easily translate to "terminate

The effects of mannitol diuresis on digoxin and phenobarbital handling by the kidney: implications for tubular reabsorption and secretion of the cardiac glycoside.

Abstract: The effect of mannitol diuresis on the renal clearance of digoxin and phenobarbital was studied in dogs. Mannitol diuresis significantly increased the clearance of digoxin and the ratio digoxin: inulin clearances (from 0.7 +/- 0.2 to 1.1 +/- 0.25). The increase in phenobarbital: inulin clearance ratio was significantly higher than the increase in the digoxin: inulin clearance ratio (4.9 fold vs 1.66 fold) (p less than 0.005). Mannitol diuresis did not significantly affect inulin clearance, nor digoxin protein binding during the experimental period while there was a significant increase in PAH clearance. Significant correlations were found between urine flow rate and digoxin renal clearance or digoxin: inulin clearance ratio. The increase in the ratio drug: inulin clearance with diuresis correlated inversely with the initial ratio; animals with more predominant net reabsorption had a higher increase in ratio. These studies suggest that the mannitol-induced increase in digoxin clearance stems from a combination of increased renal blood flow enhancing digoxin secretion, and increased urine flow rate inhibiting its reabsorption. We conclude that urine flow rate and renal blood flow are important determinants of the renal clearance of digoxin, independent of GFR. Any study assessing the effect of pathophysiological states or drug interactions on digoxin renal clearance must control for these factors.

Enhanced flux creep and nonequilibrium optical response in YBaCuO epitaxial films

Abstract: Two novel flux creep related phenomena in YBa 2 Cu 3 O 7−δ films are presented: a sharp onset of nonequilibrium optical response and a thermally activated electrical resistivity with logarithmic current dependence of the activation energy. This nonlinear current dependence is significantly different from the predictions of the standard flux creep model.