PubMed Health⌕ Search

Biomedical subjects

E Giesbrecht

Publications and source records attributed to E Giesbrecht.

15 recordsLinked to original sources
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↗
PubMed1991

Diurnal variation of methotrexate disposition in children with acute leukaemia.

There is recent evidence that survival is improved when maintenance therapy for acute lymphocytic leukaemia in children is given at night. We have examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In 6 children with leukaemia there was a significant fall in methotrexate plasma clearance at night (from 5.6 to 4.7 ml.kg-1.min-1). Renal clearance of methotrexate tended to fall at night and unbound renal clearance fell significantly (from 17.5 to 8.5 ml.min-1.kg-1 P less than 0.05). Creatinine clearance did not exhibit diurnal variation, whereas there was a significant fall in the non-glomerular clearance of methotrexate (from 14.8 to 6 ml.min-1.kg-1). Since methotrexate is a weak organic acid, its tubular secretion depends on urinary pH. At night urinary pH is more acidic, and this may result in more reabsorption and hence reduced renal clearance.

Acute Disease↗
PubMed1991

Decreased protein binding of salicylates in Kawasaki disease.

Because patients with Kawasaki disease have low serum concentrations of salicylates despite high doses, and because the free (unbound) drug is responsible for the pharmacologic effects of salicylates, we assessed salicylate protein binding in patients with Kawasaki disease. During the acute phase of the disease, protein binding of salicylate in 36 children with Kawasaki disease was 73 +/- 12%, significantly lower than during the subacute phase (90.4 +/- 8.7%; p less than 0.0005). Mean serum albumin concentration was 29.2 +/- 6.4 gm/L during the acute phase and 36.7 +/- 7.8 gm/L during the subsequent subacute phase (p less than 0.005). Salicylate protein binding was affected independently by both serum albumin and total salicylate levels. During the acute phase of Kawasaki disease, children had an average twofold increase in free salicylate compared with normoalbuminemic control subjects. A nomogram has been devised to derive free salicylate levels from the known total salicylate and serum albumin concentrations.

Acute Disease↗
PubMed1990

Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children.

BACKGROUND: Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse. METHODS: To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted. RESULTS: There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005). CONCLUSIONS: Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Diurnal variation in the pharmacokinetics and myelotoxicity of mercaptopurine in children with acute lymphocytic leukemia.

During their maintenance therapy, children with acute lymphoblastic leukemia are treated with a daily dose of mercaptopurine for several years. A recent retrospective analysis has suggested that administration of the drug in the evening results in a better prognosis. We compared the disposition pharmacokinetics of mercaptopurine administered in the morning vs in the evening in 13 children with acute lymphoblastic leukemia. Elimination half-life of mercaptopurine was significantly longer in the evening than during the day (423 +/- 142 minutes vs 176 +/- 22 minutes, mean +/- SEM). The area under the concentration-time curve (AUC0-infinity) was significantly larger in the evening (24,713 +/- 3536 ng/mL per minute vs 17,120 +/- 1474 ng/mL per minute). These differences were even more pronounced when comparing the area under the curve of the postdistributive phase (AUC300 min-infinity, 7724 +/- 2955 ng/mL per minute in the evening vs 2597 +/- 712 ng/mL per minute during the day). In a second study, 12 children with acute lymphoblastic leukemia receiving mercaptopurine in the morning had their medication administration switched to the evening. Within 2 weeks there was a sharp fall in peripheral white blood cell counts in all patients (from 4.1 x 10(9)/L to 2.2 x 10(9)/L) mainly due to a drop in polymorphonuclear lymphocytes (from 2.78 x 10(9)/L to 1.05 x 10(9)/L). We conclude that the diurnal variations of mercaptopurine disposition result in clinically important myelotoxicity of the drug.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Effect of endogenous digoxin-like substances on the interpretation of high concentrations of digoxin in children.

The objective of this study was to assess the effect of endogenous digoxin-like substances on the interpretation of excessive concentrations of digoxin in children. After the development of a high-pressure liquid chromatography (HPLC) method for digoxin in our laboratories, we analyzed sera of children in whom the fluorescence polarization immunoassay identified potentially toxic concentrations of the glycoside (greater than 3 nmol/L; 2.3 ng/ml). Sixteen of them were receiving long-term digoxin therapy, and one had an accidental overdose. The immunoassay yielded significantly higher concentrations (4.1 +/- 1.2 nmol/L; 3.2 +/- 0.9 ng/ml) than the HPLC method (3.3 +/- 1.6 nmol/L; 2.6 +/- 1.2 ng/ml; p less than 0.01). In five cases (30%) these differences were clinically significant because administration of digoxin had been discontinued in the presence of true digoxin concentrations within the therapeutic range and the lack of clinical toxic effects. These data suggest that therapeutic drug monitoring using immunoassays of digoxin may be too inaccurate to detect potential toxic effects, and that much more weight should be focused on clinical monitoring. The HPLC method for assay of digoxin is extremely meticulous and will not become clinically available; therefore the development of better immunoassays should be encouraged.

Adolescent↗
PubMed1989

An evaluation of the Kodak Ektachem clinical chemistry slide for theophylline.

We evaluated the Kodak Ektachem clinical chemistry slide for assay of theophylline. Assay precision and accuracy were acceptable in the therapeutic range although precision was poor at low levels of theophylline. The assay performed well with patients' samples using the Abbott TDx as the reference procedure but, as indicated by the manufacturer, uremic samples gave a positive bias, particularly in the therapeutic range. Finally, the significant bias observed with Quality Control material, probably due to matrix sensitivity, is a possible drawback.

Humans↗
PubMed1989

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

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.

Animals↗
PubMed1988

Effects of quinidine on the renal tubular and biliary transport of digoxin: in vivo and in vitro studies in the dog.

Quinidine is known to inhibit the renal clearance of digoxin without affecting glomerular filtration rate. The renal interaction between these drugs was investigated by a combination of in vivo and in vitro methods. The uptake of digoxin by brush border membrane vesicles was not affected by quinidine. Similarly, digoxin did not inhibit the uptake of the cation N-methylnicotinamide by these vesicles and did not alter the binding kinetics of digoxin to the Na+, K+-adenosine triphosphatase by the antiluminal membrane vesicles. By using the in vivo multiple indicator dilution technique transtubular transport of digoxin was documented; renal-artery infusion of quinidine did not affect the recovery of digoxin in the renal vein or urine. Clearance studies documented that the decrease in the renal clearance of digoxin is paralleled by a significant fall in renal blood flow evidenced by a decrease in p-aminohippuric acid clearance. It is concluded that quinidine inhibits the renal excretion of digoxin not by competition at the tubular cell membrane level, but rather by decreasing renal blood flow. A parallel decrease in biliary clearance of digoxin is documented and may suggest a similar mechanism.

Animals↗
PubMed1987

Receptor radioligand system for measuring digoxin activity.

The purpose of this study was to develop and evaluate a receptor radioligand assay (RRA) for the measurement of digoxin, its metabolites, and endoxin and to compare the results of this assay with those of a fluorescence polarization immunoassay (FPIA) for digoxin. The within-run coefficients of variations for the RRA at digoxin concentrations of 2.0 and 5.0 nmol/L were 21 and 10%, respectively. Serum samples collected from 33 volunteers (not on digoxin medication) measured in the RRA resulted in levels less than 1.23 nmol/L digoxin equivalents (1.23 nmol/L is the lower level of sensitivity for this system). Serum samples collected from 29 patients receiving digoxin for therapeutic purposes and measured in the RRA gave a mean of 3.39 nmol/L digoxin equivalents. The samples collected from the patients receiving digoxin were also measured using FPIA with a mean of 1.75 nmol/L digoxin. The interference of progesterone, 11-alpha-hydroxyprogesterone, cortisone, and six digoxin metabolites on the binding of 3H-ouabain in the RRA was also evaluated.

Animals↗
PubMed1986

A study of lipid effects on the digoxin immunoassay and on the binding to and activity of Na+/K+-ATPase.

The present study has examined the cross-reactivity of fatty acids and mono- and di-glycerides in the fluorescence polarization immunoassay for digoxin. The ability of these compounds to inhibit 86Rb uptake by the erythrocyte as well as their ability to displace 3H-ouabain from membrane-bound dog kidney ATP-ase was also assessed. Some unsaturated fatty acids (palmitoleic, palmitelaidic, oleic, linoleic, linolelaidic, linolenic, gamma-linolenic and arachidonic) were found to cross-react significantly in the digoxin immunoassay and to inhibit 3H-ouabain binding to membrane-bound Na+/K+-ATPase. Of the monoglycerides studied mono-11-eicosenoin was found to cross-react in the digoxin immunoassay, inhibit red cell 86Rb uptake and displace 3H-ouabain from its receptor, membrane-bound Na+/K+-ATPase. Two other monoglycerides, 1-monolinoleoyl and 1-monolinolenoyl glycerides, were able to displace 3H-ouabain from membrane-bound Na+/K+-ATPase, but had no effect on the digoxin immunoassay or on red cell 86Rb uptake.

Animals↗