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Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 433 records · Page 24Linked to original sources
PubMed1992

A randomized, double-blind comparison of lumbar epidural and intravenous fentanyl infusions for postthoracotomy pain relief. Analgesic, pharmacokinetic, and respiratory effects.

Although epidural opioids frequently are used to provide postoperative analgesia, several articles have suggested that the analgesia after epidural fentanyl is similar to that after an equal dose of fentanyl given intravenously. To address this issue further, 29 postthoracotomy patients were studied in a randomized, double-blinded trial comparing a lumbar epidural fentanyl infusion with an intravenous fentanyl infusion for analgesia, plasma fentanyl pharmacokinetics, and respiratory effects for 20 h postoperatively. In all patients in both groups, good analgesia was achieved (pain score less than 3, maximum 10) over a similar time course, although the patients receiving epidural infusion required a significantly larger fentanyl infusion dose than did the patients receiving intravenous infusion (group receiving epidural fentanyl infusion: 1.95 +/- 0.45 micrograms.kg-1.h-1; group receiving intravenous fentanyl infusion: 1.56 +/- 0.36 micrograms.kg-1.h-1; P = 0.0002). The time course for the plasma fentanyl concentrations was similar in the two groups, and plasma fentanyl concentrations were not significantly different at any sampling period (T7-T20; group receiving epidural fentanyl infusion: 1.8 +/- 0.5 ng/ml; group receiving intravenous fentanyl infusion: 1.6 +/- 0.6 ng/ml; P = 0.06). Similarly, calculated clearance values for the two groups were not significantly different (group receiving epidural fentanyl infusion: 0.95 +/- 0.26 l.kg-1.h-1; group receiving intravenous fentanyl infusion: 0.87 +/- 0.25 l.kg-1.h-1; P = 0.3). Both groups demonstrated a similar degree of mild to moderate respiratory depression postoperatively, which was assessed with continuous respiratory inductance plethysmography and sequential arterial blood gas analysis. Side effects (nausea, vomiting, pruritus) were mild and did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Therapeutic drug monitoring of retinoids.

Retinoids are natural or synthetic compounds related to vitamin A. They are successfully used in the treatment of dermatological disorders. However, one of the limiting factors in the use of retinoids is their huge teratogenic potential. The investigation into the pharmacokinetics and metabolism of retinoids has encountered many difficulties due to lack of suitable techniques to deal with these labile compounds. Because of the teratogenic nature of the retinoids, the sensitivity of the assay is of utmost importance. We report a systematic comparison between two high-performance liquid chromatographic methods used to monitor levels of etretinate and its metabolites acitretin and 13-cis-acitretin in plasma. Our analysis suggests that the column-switching method is superior owing to smaller variability in results and its simplicity. We also describe our therapeutic drug monitoring program for counseling women of reproductive age following etretinate or acitretin exposure. Presently, labeling of etretinate in North America suggests that women should refrain from conception for an undetermined length of time. Assessment of serum concentrations over time is beneficial in defining the length of period to postpone conception.

Acitretin↗
PubMed1992

Postmortem redistribution of morphine in rats.

Because morphine is often found in the postmortem (PM) blood samples of patients treated with or abusing the drug, its causation in death has to be considered. The possibility of PM redistribution of the opioid drug has not been studied previously. We treated adult Wistar rats with 4 mg/kg of morphine i.m. and measured cardiac cavity levels at the time of death, by killing (2 h postdose) 24 and 96 h PM. Morphine concentrations rose from 41.4 +/- 13.2 ng/ml at death to 111.9 +/- 66.6 ng/ml at 24 h (p = 0.00036), with no additional increase at 96 h (98.7 +/- 21.7 ng/ml). After death there was accumulation of endogenous substances cross-reacting with the morphine radioimmunoassay. Although these attribute only 3% to total accumulation of morphine, they may complicate interpretation of morphine "readings" in patients who had not received the drug. Our study suggests that after death there is substantial redistribution of morphine. Elevated PM levels cannot necessarily by interpreted as representing antemortem concentrations.

Animals↗
PubMed1992

Oxygen therapy in sickle cell disease.

The effect of oxygen therapy on the number of irreversibly (ISC) and reversibly (RSC) sickled cells was studied in patients with sickle cell anemia. Inhalation of 50% oxygen in patients who were not in crisis produced a significant fall in RSCs and a lesser fall in ISCs. Twenty-five subjects in sickle cell crisis were chosen at random to receive either oxygen (15 patients) or air (10 patients). Those who received oxygen showed a significant reduction in RSCs, but not in ISCs. No significant change in RSCs or ISCs occurred in the group who received air. Despite the reduction in RSCs in the oxygen-treated group, there was no significant difference between the air and oxygen groups in the duration of severe pain, opioid administration, and hospitalization. It was also observed that crisis was associated with arterial desaturation and a reduction in the number of RSCs. We conclude that, although RSCs may be involved in the pathophysiology of sickle cell crisis, reduction in RSCs by oxygen therapy in these studies did not result in any reduction in the duration of crisis.

Adolescent↗
PubMed1992

Growth failure and bony changes induced by deferoxamine.

We reviewed the linear growth and growth plate morphology in all children with homozygous beta thalassemia followed in Toronto, for whom monthly height percentiles were available before, and for a 36-month period after, the initiation of nightly subcutaneous deferoxamine therapy. All patients were less than 7 years of age when begun on deferoxamine, and had received nightly deferoxamine for a minimum of 36 months. Marked abnormalities of the metaphyseal growth plate were readily observed in the distal ulnar, radial, and tibial metaphyses in 11 of 37 patients in whom a significant decline in mean height percentile was also noted. (In 10 of these 11 patients, height was less than the 15th percentile after 36 months.) These 11 patients had received a significantly greater (p less than 0.025) initial and average daily dose of deferoxamine, and had maintained a significantly lower (p less than 0.025) mean serum ferritin concentration over the 36 months, than the remainder of the cohort. To determine whether deferoxamine played a causative role in growth failure, growth in patients who began deferoxamine before the age 2 years was compared to that of patients who began after age 5 years, for the period between 2 and 5 years of age. Only patients begun on deferoxamine prior to age 2 years demonstrated a significant (p less than 0.01) decline in height percentile by the third year, implicating deferoxamine therapy as the cause of growth failure. We conclude that both the decline in height percentile and the bony changes observed in well-chelated patients are directly related to deferoxamine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1992

Cyclosporin and quinidine inhibition of renal digoxin excretion: evidence for luminal secretion of digoxin.

We studied the in vivo luminal and contraluminal uptake of [3H]digoxin in dog kidney using the single-pass multiple indicator dilution method. A bolus tracer of 125I-albumin (plasma reference), creatinine, or L-[14C]glucose [extracellular reference (ecf)] and [3H]digoxin (or [3H]ouabain) was injected into the left renal artery, and timed serial samples were collected from the left renal vein (basolateral uptake) and left and right ureters (luminal uptake). [3H]ouabain was excreted solely by filtration and exhibited saturable and irreversible binding at the basolateral surface. Uptake of [3H]digoxin across the basolateral membrane was large and nonsaturable. Despite urine flow-dependent reabsorption and approximately 20% protein binding, the urine recovery ratio for [3H]-digoxin/glomerular (ecf) marker was 0.97 +/- 0.04 (n = 29), indicating net digoxin secretion. After intravenous infusions of cyclosporin in Cremophor EL (0.5-3.5 microM), the urine recovery ratio decreased in a dose-dependent manner from control values of 1.13 +/- 0.06 (n = 12) to 0.62 +/- 0.03 (n = 14). There was no change in the relative renal vein recovery. Left renal artery infusion of quinidine (37.5 micrograms.min-1.kg-1) decreased the relative urine recovery of [3H]digoxin by 46% (n = 6) but had no effect on postglomerular extraction. Cyclosporin and quinidine are known inhibitors of P-glycoprotein. But digoxin did not compete with [3H]azidopine for binding in rat brush-border membranes or membranes prepared from the multidrug-resistant cell line CHRC5. The exact mechanism for renal digoxin secretion remains to be determined, but our results point to a luminal localization of this secretory system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Comparison of methods for prediction of nephrotoxicity during development.

Drugs with nephrotoxic potential are continuously introduced into perinatal and pediatric medicine, and assessment of their relative toxicity is important. We compared different methods of assessment of renal damage during development in an attempt to establish their relative sensitivity, age and dose dependence. Newborn, 6- to 8-day-old and adult rats were treated for 7 days with intramuscular gentamicin (5, 10 or 20 mg/kg/day) or amikacin (5, 20 or 40 mg/kg/day). Renal damage was assessed by serum and urine creatinine, urine N-acetyl beta-glucosaminidase and beta 2-microglobulin, cortical sphingomyelinase in vivo and in vitro and morphologic changes in light and electron microscopy. As expected, there was a dose-dependent damage, with gentamicin being more nephrotoxic than amikacin, and with newborn rats more resistant. The light- and electron-microscopic assessment were more sensitive than all other methods, followed by urinary N-acetyl glucosaminidase and then by beta 2-microglobulin. Sphingomyelinase changes occurred only at the highest doses of gentamicin.

Aging↗
PubMed1992

Salivary excretion of drugs in children: theoretical and practical issues in therapeutic drug monitoring.

Studies suggest that saliva could be used instead of blood in the therapeutic monitoring of many drugs. This has distinct advantages in pediatrics and neonatology as saliva sampling is painless and spares blood. Stimulation of saliva secretion with a chemical stimulus (i.e. citric acid applied over the tongue) facilitates the study of younger patients. Secretory and reabsorptive processes which take place in the ductal system of the salivary glands, and the rate of flow of the secretion play major roles in the determination of the concentration of solutes in saliva. Drug passage into saliva follows the general principles of movement of drugs across biologic membranes. Only the unbound fraction of the drug in plasma is available for diffusion into saliva and a relationship exists between saliva pH and the saliva/plasma concentration ratio of many polar drugs (tolbutamide, propranolol, procainamide, etc.). However, deviations from the pH theory exist and the inter -and intra-individual variations in saliva/plasma concentration ratios of salicylate and procainamide cannot be explained solely on the basis of fluctuations of salivary pH; on the other hand, a useful relationship exists between plasma and saliva phenobarbital concentrations with no need to correct for saliva pH. The use of stimulated saliva has several advantages over resting saliva: a larger volume of the sample is obtained, the pH gradient between plasma and saliva is smaller, the variability in saliva/plasma concentration ratios of some drugs is narrowed, and less specimens are too viscous or discolored to allow drug analysis. Thorough rinsing of the mouth is required prior to saliva sampling as remnants of orally administered medicines may contaminate saliva specimens and give spuriously high values. Deviation from a simple but strict methodology accounts for some of the discrepancies found in the literature. Studies in children uniformly recommend saliva for therapeutic monitoring of phenytoin, carbamazepine and phenobarbital. Saliva sampling for therapeutic monitoring of ethosuximide, primidone and digoxin in infants and children, and of theophylline and caffeine in the neonate is promising, but little pediatric experience is available as yet. The value of saliva in therapeutic monitoring of theophylline in children is still controversial. Little of highly polar compounds such as aminoglycosides, and of polar highly protein bound drugs such as valproic acid is present in saliva. More data are still needed on the excretion of drugs in saliva in infants and in acutely ill children, and few data exist in the premature and full-term neonate.

Child↗
PubMed1992

The effects of impaired liver function on the elimination of antineoplastic agents.

OBJECTIVE: To critically review available data on the disposition of cancer chemotherapy in patients with hepatic dysfunction, and to derive at dose recommendation. DATA SOURCES: All published studies in English. STUDY SELECTION: Both human and animal studies. DATA SYNTHESIS: The available studies were sequentially qualitatively described and critically discussed. CONCLUSIONS: The liver is responsible for the metabolism and elimination of many anticancer agents. Their accumulation during hepatic insufficiency may expose the patient to increased risk of drug toxicity. A variety of clinical methods have been described to estimate the need to decrease doxorubicin dose according to degree of hepatic failure to avoid serious toxicity. In some studies prospective ascertainment of clinical indices such as hepatic enzymes and bilirubin was successful in preventing doxorubicin-induced hepatotoxicity. Liver dysfunction has a major impact on cyclophosphamide pharmacokinetics. However, because such impairment leads to less production of the active aldophosphamide, fewer adverse effects were observed in hepatically impaired patients. Vinca alkaloids are extensively metabolized by the liver and excreted in the bile. Systemic exposure to these drugs is inversely correlated to the degree of hepatic failure measured by serum alkaline phosphatase. Although hepatic metabolism is a major route of elimination of fluorouracil, the kidney also plays an important role in its elimination. It has been suggested to reduce its dose in cirrhotic patients. Available pharmacokinetic data and their clinical implications are also discussed for azathioprine, mercaptopurine, etoposide, epirubicin, amsacrine, cytarabine, and other less-studied drugs. Recommendations for dose adjustments are presented and discussed.

Animals↗
PubMed1992

Pain perception and effectiveness of the eutectic mixture of local anesthetics in children undergoing venipuncture.

The emulsion of lidocaine and prilocaine (EMLA) is effective in preventing the pain of venipuncture in children. It is therefore important to identify children who could benefit the most from EMLA. We studied the safety and feasibility of two methods of application of EMLA (patch and cream) in a randomized, open-label trial of EMLA patch versus EMLA cream in 160 children with chronic diseases undergoing venipuncture. EMLA patch or cream was applied 60 to 120 min before puncture. Pain was assessed by the children using a visual analogue score. Children also scored the pain of their last puncture and the pain of removing the tape. EMLA patch and cream had similar efficacy (visual analogue scores for the venipuncture were 8.5 +/- 16 and 9.5 +/- 17 out of 100, respectively). Side effects occurred in similar frequencies in the two groups. Adhesiveness of the patch was less effective than that of the cream with Tegaderm. Age was a major determinant of pain perception; younger children recalled more severe pain in their previous puncture. Children recently diagnosed had higher visual analogue scores than those with a long history of chronic disease. We concluded that EMLA patch and cream have a similar efficacy in children undergoing venipuncture. Young children recently diagnosed with chronic disease are most likely to benefit from EMLA.

Adolescent↗
PubMed1992

Chronopharmacology of methotrexate pharmacokinetics in childhood leukemia.

Survival has been shown to improve when maintenance therapy for acute lymphocytic leukemia in children is given at night rather during the day. We examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In a crossover study, we determined the pharmacokinetics of intravenous methotrexate at 10:00 and 21:00 h in six children with standard or high-risk leukemia. During the study, children refrained from concomitant drugs (6-mercaptopurine and trimethoprim sulfamethoxazole). There was a significant fall in methotrexate plasma clearance at night (from 5.6 +/- 3 ml/min/kg to 4.7 +/- 2.3 ml/min/kg p < 0.05). Renal clearance of methotrexate tended to decrease at night and unbound renal clearance decreased significantly (from 17.5 +/- 1.7 ml/min/kg to 8.5 +/- 3.6 ml/min/kg p < 0.05). Creatinine clearance did not exhibit diurnal variation, when comparing two 12-h collections, but there was a significant decrease in the nonglomerular clearance of methotrexate (from 14.8 +/- 5.2 to 6 +/- 4 ml/min/kg). Because it is a weak organic acid, the tubular secretion of methotrexate depends on urinary pH. At night urinary pH is more acidic. This may result in more reabsorption and hence reduced renal clearance.

Child↗
PubMed1992

Audiologic profiles of children with Kawasaki disease.

Kawasaki disease (KD) is an idiopathic vasculitis associated with systemic inflammation and profound immunoregulatory changes. Recent reports from Japan and the United States have documented the association of sensorineural hearing loss (SNHL) with acute KD. To further characterize the nature and prevalence of this complication, we prospectively evaluated the hearing of 40 consecutive patients with acute KD at a single institution. Standard audiometric procedures were used, including visual reinforcement audiometry and play audiometry. Auditory brainstem response (ABR) testing using clicks and tone pips (1000-4000 Hz) was performed in patients with abnormal or unreliable results on behavioral audiometry. Acoustic immittance measurements were obtained on all patients. Of the 23 males and 17 females (mean age 3.2 +/- 2.3 years, range 0.6-11.1 years), all but three were evaluated and treated with aspirin and intravenous gama globulin within 1 month of onset of fever. Seven children had test results suggesting sensorineural threshold shifts, 16 had normal hearing, and 14 had inconclusive hearing evaluations. Laboratory data in patients with hearing threshold shifts revealed significantly longer duration of fever (4.1 +/- 1.0 versus 1.9 +/- 0.5 days), and a tendency for higher temperatures and white blood cell counts at diagnosis compared to those with normal hearing. Results suggest that transient as well as persistent SNHL may be associated with the acute vasculitis of KD, and may be associated with laboratory markers indicating more severe systemic inflammation. Audiologic screening should be considered for all patients following KD.

Aspirin↗
PubMed1992

Biological markers of intrauterine exposure to cocaine and cigarette smoking.

We describe hair tests for assessment of fetal exposure to cocaine and cigarette smoking. Cocaine and its major metabolites are incorporated into hair during the growth of the shaft and stay there for the whole life of the hair. Cocaine crosses the placenta and its metabolite benzoylecgonine, has been found in neonatal urine, meconium and hair. In order to utilize hair measurements of cocaine as a biological marker of systemic exposure, we conducted both animal and human investigations on the dose response characteristics of this phenomenon. Our data suggest that both maternal and fetal accumulation of cocaine and its metabolite follow a linear pattern within the regularly used doses. Similarly, a good correlation was observed in animals between maternal dose and fetal hair accumulation. To date, no biological markers have been identified that can predict the extent of fetal exposure to the adverse effects of toxic constituents of cigarette smoke. We measured maternal and fetal hair concentrations of nicotine and cotinine in mother-infant pairs. Smoking mothers had a mean of 21.3 +/- 18 ng/mg hair nicotine and 6 +/- 9.2 ng/mg of cotinine, significantly more than nonsmokers (0.9 +/- 0.8 ng/mg nicotine and 0.3 +/- 0.5 ng/mg cotinine, p < 0.0001). Babies of smokers had a mean nicotine concentration of 6 +/- 9.2 ng/mg (range 0-27.3) and cotinine of 2.1 +/- 3.7 ng/mg (range 0-12.2), significantly more than babies of nonsmokers (nicotine 0.6 +/- 0.7 ng/mg and cotinine 0.2 +/- 0.5 ng/mg; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗
PubMed1992

Handling of digoxin and ouabain by renal tubular cells (LLC-PK1).

Digoxin is known to be secreted by renal tubular cells, but the mechanisms are still not fully understood. In this study, we examined renal tubular cell handling of digoxin and ouabain using LLC-PK1 cells, a model of proximal renal tubular cells. The cells were used in suspension for binding experiments and in monolayers on permeable filters for transport studies. The specific binding of digoxin to the cells, presumably to the ouabain binding site (i.e., membrane Na+,K(+)-ATPase), were characterized by Kd of 2.6 x 10(-7) M and Bmax (total number of specific binding sites) of 1.6 x 10(6)/cell. Kd and Bmax of ouabain binding were 1.3 x 10(-7) M and 1.9 x 10(6)/cell, respectively. In transport experiments, digoxin showed significantly higher flux than ouabain from the basolateral to the apical side across the cell monolayers. Importantly, this secretory transport was not inhibited by ouabain concentrations sufficient to block membrane Na+,K(+)-ATPase and to displace digoxin from the binding site on the enzyme (i.e., 10(-6) to 10(-4) M ouabain). However, the digoxin secretion was decreased by low temperature or excess digoxin in a concentration-dependent manner. These data suggest that digoxin undergoes unidirectional transport in favor of secretion, which does not involve its binding to the ouabain binding sites on membrane Na+,K(+)-ATPase.

Animals↗
PubMed1992

Pregnancy outcome and infant development following gestational cocaine use by social cocaine users in Toronto, Canada.

To determine the effect of first trimester cocaine use on pregnancy outcome we conducted a prospective cohort study of 30 women admitting to social cocaine use (SCU) during early pregnancy, 20 users of cannabis during the first trimester and 30 matched recreational drug-free control subjects. The groups were of similar age, marital status, and obstetric history and were predominantly white. They were of similar socioeconomic status (SES), however the spouses of the cocaine users were of significantly lower SES than those of both control groups (p less than 0.005). The number of years of education of the cocaine users and the fathers of the SCU-exposed fetuses was significantly lower than that of the recreational drug-free control subjects (p = 0.004), however, female IQ was similar among the three groups (109.1 +/- 12.4 cocaine; 109.1 +/- 25.2 cannabis; 114.1 +/- 11.7 drug-free). Alcohol and cigarette use was greater among the cocaine users than among subjects of the recreational drug-free control group (p less than 0.025). Cocaine and the associated lifestyle were not associated with any adverse obstetric or neonatal endpoint (pregnancy weight gain, incidence of delivery complications, gestational age, birth weight, Apgar scores, and rates of major and minor malformations). There were no differences between groups in attaining developmental milestones. Mental and motor scores on the Bayley Scales of Infant Development and Vineland Adaptive Behavior Scales were identical among the three groups, studied at a mean of 19.7 months of age. We conclude that outcome of pregnancy of social cocaine users and subsequent infant physical and cognitive development are within normal limits at 1.6 years of age.

Adolescent↗
PubMed1992

Fetal outcome after in utero exposure to cancer chemotherapy.

BACKGROUND: Cancer is the second leading cause of death of women during the reproductive years, and its occurrence in pregnancy is between 0.07% and 0.1%. METHODS: To analyze the effect of cancer on pregnancy, we compared 21 pregnancies occurring during 30 years in women who received chemotherapy for their cancer with a control group matched for maternal age and composed of women not exposed to known teratogens or reproductive risks during pregnancy. RESULTS: Of 13 women exposed to chemotherapy during the first trimester, two of five whose pregnancies continued to term had major malformations in their infants, four had spontaneous abortions, and four had therapeutic abortions. Of four women with second-trimester exposure to chemotherapy, two had normal live births, one had a stillbirth, and one had a therapeutic abortion. All four pregnancies exposed to chemotherapy during the third trimester resulted in healthy live births. Infants exposed to chemotherapy had statistically significantly lower birth weights than their matched controls (2227 +/- 558 g vs 3519 +/- 272 g, P less than .001), due to both significantly lower gestational age and substantial intrauterine growth retardation (P less than .01). The trend for higher rate of stillbirth (1/11) agrees well with 10 stillbirths among all women with cancer in pregnancy without and with chemotherapy who gave birth (n = 223), when compared with the population of Ontario (P less than .0005). CONCLUSIONS: This study confirms the increased likelihood of spontaneous abortions and major birth defects when chemotherapy is used during embryogenesis, whereas such a risk is not apparent beyond the first trimester. Because of the higher risk of stillbirth and intrauterine growth retardation, women with cancer should be monitored closely by a high-risk obstetric unit to define the optimal time of delivery.

Abortion, Induced↗