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S S de Graaf

Publications and source records attributed to S S de Graaf.

12 recordsLinked to original sources
PubMed1995

Vincristine disposition in children with acute lymphoblastic leukemia.

Vincristine (VCR) has been widely used to treat childhood malignancies for over thirty years, but its plasma disposition has not yet been well-defined. Therefore, we conducted a pharmacokinetic study of VCR in 17 children with acute lymphoblastic leukemia (ALL) receiving the first dose of VCR. A new high-performance liquid chromatographic assay was used for the measurement of VCR in plasma. A two-compartment pharmacokinetic model was fit to the data by nonlinear least-squares regression. Estimated pharmacokinetic parameters were highly variable; mean (S.D.) volume of distribution at steady-state was 360 (176) L.m-2; total body clearance was 431 (238) ml.min-1.m-2, and elimination half-life was 823 (390) min. These results were compared to data from eight adults with lung cancer. Mean volume of distribution in adults and children were similar, but VCR clearance was significantly larger in children (P = 0.01), resulting in a significantly longer elimination half-life in the adults (P < 0.01). We conclude that administration of a standard dosage of VCR to children with ALL results in a highly variable systemic drug exposure, which may have implications for the oncolytic effect and/or toxicity in individual patients. Comparison of data from children and adults suggests that VCR elimination rate is a function of age; this could account for more severe neurotoxicity in older patients. However, it cannot be excluded that differences between the children and adults may be due to other variables than age. Future studies should focus on the possible influence of multidrug resistance modulating agents on VCR pharmacokinetics and on pharmacokinetic-pharmacodynamic relationships in individual patients.

Analysis of Variance↗
PubMed1994

Pharmacokinetics of vincristine in children and adolescents with acute lymphocytic leukemia.

We studied the pharmacokinetics of vincristine in children with acute lymphocytic leukemia by means of a specific high-performance liquid chromatographic assay with ultraviolet and electrochemical detection and a limited sampling strategy. Our objectives were to characterize the disposition of vincristine in pediatric patients, to determine clinical, demographic, or biochemical variables related to variability in vincristine pharmacokinetic parameters, and to assess the relationship between pharmacokinetic parameters and vincristine neurotoxicity. Plasma samples were collected at 5 and 30 minutes, and 1, 3, and 24 hours after a rapid intravenous injection during 3 minutes. Vincristine-induced neurotoxicity was retrospectively evaluated by chart review. Pharmacokinetic studies were completed for 64 doses in 54 children between 2 months and 18 years of age (median, 4.3 years), including 2-month-old monozygous twin girls. Vincristine clearance, estimated by Bayesian methods, was highly variable, with a mean (SD) clearance of 19.9 (14.9) ml/min per kilogram or 482 (342) ml/min per square meter. Mean clearance for all subjects was faster than in published studies of adults, which may be related in part to the greater specificity of the assay used in our study, as well as to age-related differences in drug disposition. Vincristine-associated neurotoxicity was frequent but mild and was not predicted by vincristine systemic exposure; however, neurotoxicity may have been underestimated. Clearance in one patient who received concomitant treatment with pentobarbital exceeded the 75th percentile for all patients, and four of five patients receiving concomitant histamine2 antagonists had clearances below the 25th percentile for all subjects, suggesting that drugs that induce or inhibit hepatic cytochrome P-450 enzymes may affect vincristine disposition. Further studies are needed to identify the factors responsible for interpatient variability in vincristine disposition and to develop improved dosing guidelines.

Adolescent↗
PubMed1990

Relationship between dose rate of [6RS]Leucovorin administration, plasma concentrations of reduced folates, and pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon adenocarcinoma xenografts.

[6RS]Leucovorin (5-formyltetrahydrofolate; 5-CHO-H4PteGlu) administered in different regimens in combination with 5-fluorouracil (FUra) has increased the response rates to FUra in patients with colon adenocarcinoma. Using preclinical models of human colon adenocarcinomas as xenografts in immune-deprived mice, the effect of the rate of administration of racemic [6RS]leucovorin on the concentration-time profile of reduced folates in plasma, size of intratumor pools of 5,10-methylenetetrahydrofolates (CH2-H4PteGlun) and tetrahydrofolates (H4PteGlun), and the distribution of their polyglutamate species have been examined. Bolus injection i.v., or 4-h or 24-h infusion of [6RS]leucovorin (500 mg/m2) yielded similar concentration profiles of the biologically active [6S] and inactive [6R] isomers of 5-CHO-H4-PteGlu and 5-methyltetrahydrofolate (5-CH3-H4PteGlu) in mouse plasma to those previously reported in humans, but with more rapid elimination half-lives (t1/2 = 11 to 16 min, 23 to 41 min, and 30 to 35 min, respectively). Thus, reduced folates remained elevated in plasma during the period of [6RS]leucovorin administration. In HxELC2 and HxGC3 tumors, pools of CH2-H4PteGlun and H4PteGlun were increased from 350% to 700% of control, but only during [6RS]leucovorin infusion. Intracellular levels subsequently declined rapidly, similar to the loss of reduced folates from plasma. Increasing the rate of [6RS]leucovorin delivery by decreasing the time for administration from a 24-h to a 4-h infusion did not further increase the intratumor pools of CH2-H4PteGlun and H4PteGlun, suggesting saturation in the cellular metabolism of [6RS]leucovorin. In HxGC3 tumors, CH2-H4PteGlu4-5 were elevated more rapidly than in line HxELC2, which accumulated predominantly a shorter chain length species following i.v. bolus injection. During the 4-h infusion schedule, di- and triglutamate species in particular accumulated in both tumors with no elevation in CH2-H4PteGlu5 until the infusion was discontinued, when this species increased as the shorter chain length forms were declining. However, during the 24-h infusion of [6RS]leucovorin, CH2-H4PteGlu3-5 were elevated in tumors. Since these species have been reported to increase the binding affinity of [6-3H]5-fluorodeoxyuridine monophosphate ([6-3H]FdUMP) to thymidylate synthase, and intratumor pools of CH2-H4PteGlun and H4PteGlun were elevated during the 24-h infusion of [6RS]leucovorin, this was considered to be the preferred schedule for administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1989

Comparison of the conversion of 5-formyltetrahydrofolate and 5-methyltetrahydrofolate to 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon tumors.

Four hr infusions i.v. of [6RS]5-formyltetrahydrofolate ([6RS]5-CHO-H4PteGlu; 500 mg/m2) and [6RS]5-methyltetrahydrofolate ([6RS]5-CH3-H4PteGlu; 500 mg/m2) were compared for their relative effects on expansion of pools of 5,10-methylenetetrahydrofolates (CH2-H4PteGlun) and tetrahydrofolates (H4PteGlun) in two human colon adenocarcinoma xenografts in mice. Expansion of these pools by 253-661% of control and increase in predominance of di-, tri-, and tetra-glutamate species were observed during [6RS]5-CHO-H4PteGlu infusion. In contrast, only modest pool size expansion (148-164% of control) and limited modulation of polyglutamate species were detected in four tumor lines during infusion with [6RS]5-CH3-H4PteGlu. The data suggest that [6RS]5-CH3-H4PteGlu is less effective than [6RS]5-CHO-H4PteGlu as a precursor for pools of CH2-H4PteGlun and H4PteGlun in colon tumors.

Adenocarcinoma↗
PubMed1988

Phase I clinical trial of orally administered 4-demethoxydaunorubicin (idarubicin) with pharmacokinetic and in vitro drug sensitivity testing in children with refractory leukemia.

Fifteen children with acute leukemia in relapse, refractory to conventional therapy, were treated with idarubicin administered orally for 3 consecutive days in dosages ranging from 30 to 50 mg/m2 per day at 19- to 21-day intervals. Gastrointestinal complications, including nausea, vomiting, abdominal pain, diarrhea and stomatitis, were the major forms of dose-limiting toxicity, affecting the majority of patients at all levels of idarubicin dosage. Two patients who had received total-body irradiation for bone marrow transplantation developed life-threatening gastrointestinal toxicity suggestive of a radiation "recall" phenomenon. Echocardiographic evidence of depressed cardiac function, without clinical symptoms or signs, was noted in six of 11 patients, although the changes were judged to be significant in only one child. The maximal tolerated oral dose of idarubicin was 40 mg/m2 per day. The medium terminal plasma half-life of idarubicin was 9.2 h (range, 6.4-25.5 h). Both idarubicin and its metabolite, idarubicinol, accumulated during the 3 days of therapy. Among the five patients with acute nonlymphoblastic leukemia whose cells were tested for drug sensitivity in vitro, the idarubicin concentration resulting in 50% inhibition (IC50) of cluster and colony formation ranged from 1.6 x 10(-10) M to 5 x 10(-7) M. There was no obvious relationship between the IC50 for idarubicin and that for epirubicin or daunorubicin. Oral idarubicin produced definite antileukemic effects, clearing blast cells from the circulation in 13 of the 14 evaluable patients. Future studies should define an optimal dose schedule to circumvent the limiting gastrointestinal complications associated with this agent.

Acute Disease↗
PubMed1987

Dissociation of body weight and lean body mass during cancer chemotherapy.

Body weight and lean body mass are different reflections of the nutritional status of patients receiving cancer chemotherapy. In the present study, the relation between lean body mass and body weight during cytostatic treatment was investigated in 3 groups of newly-diagnosed children and young adults with acute lymphocytic leukemia, osteosarcoma, or a small round cell sarcoma. Body weight and lean body mass were determined before and after an initial period of cytostatic treatment. Lean body mass was derived from total body water volume, which was assessed by deuterium oxide dilution. A significant dissociation between body weight and lean body mass was observed in leukemia patients (n = 8, P = 0.008, paired t-test), and in osteosarcoma patients (n = 13, P = 0.001). No dissociation was found in patients with a small round cell sarcoma (n = 8, P = 0.839). We conclude that during cancer chemotherapy periodic assessment of body weight may give a false picture of the preservation of lean body mass. Considering the course of body weight alone may prevent the establishment of a timely diagnosis of malnutrition, which is mandatory for optimal supportive care.

Adolescent↗
PubMed1986

Influence of high-dose methotrexate on the distribution of body fluid volumes in the dog.

We studied the influence of high-dose methotrexate (HDMTX) on body fluid volumes in the dog, using indicator dilution techniques. In six healthy mongrel dogs total body water volume (TBW), extracellular water volume (ECW), body mass, and plasma osmolality were measured before and after infusion of both saline and HDMTX. TBW and ECW were determined simultaneously, using a double-indicator (D2O/ferrocyanide), single injection technique. In vitro experiments confirmed the reliability of ferrocyanide as an indicator for ECW, also in the presence of methotrexate. Results showed an increase in ECW after HDMTX (P = 0.029, paired Student's t-test), while TBW remained constant. Infusion of the same volume of isotonic saline in the control experiments did not result in any demonstrable change in either TBW or ECW. Therefore, infusion of HDMTX appears to cause a water shift from the intracellular to the extracellular compartment. Such a change in body water volumes may have implications for estimates of body composition and for pharmacokinetic studies in cancer patients receiving HDMTX.

Animals↗
PubMed1986

Acute circulatory effects of doxorubicin in the conscious dog.

Experimental work on the mechanisms of acute doxorubicin-induced cardiotoxicity may contribute to a better understanding of the clinical problem of cardiac failure after treatment with anthracycline derivatives. We studied aortic pressure and heart rate continuously for 1 h following a bolus injection of doxorubicin (1 mg/kg) in 7 dogs. In contrast with previous studies in intact animals, no anesthesia was used in order to eliminate possible interactions of doxorubicin with other drugs. One minute after doxorubicin injection a severe hypotension was observed, the average nadir in systolic and diastolic pressure being 62% and 42% of initial values. Surprisingly, the decrease in arterial blood pressure was not accompanied by cardiac acceleration. Doxorubicin, apparently interferes with the normal regulation of heart rate through the baroreceptor control system. Although several theories have been put forward regarding the mechanisms governing acute anthracycline cardiotoxicity, our knowledge of the phenomenon is still incomplete.

Akathisia, Drug-Induced↗
PubMed1985

Unexpected cure in metastatic rhabdomyosarcoma.

A 3 year old boy presented with a presumably incurable form of rhabdomyosarcoma. Conventional treatment for advanced stage rhabdomyosarcoma (chemotherapy plus radiotherapy) was not used and intensive chemotherapy alone was given, resulting in an apparent cure. Our treatment rationale is discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Dislocation of an artificial knee component due to extraordinary function.

A rare complication, namely dislocation of a knee component without fracture of the prosthesis and not caused by a trauma, is described in a patient who was treated for osteosarcoma of the femur. Probably the dislocation, which occurred 2 years postoperatively, was caused by an extraordinary function of this prosthesis. A partial revision of the prosthesis was performed. The newly designed knee component, which prevents dislocation, is described.

Child↗