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Biomedical subjects

S M Yule

Publications and source records attributed to S M Yule.

18 recordsLinked to original sources
PubMed1999

Cyclophosphamide metabolism in children with Fanconi's anaemia.

Although patients with Fanconi's anaemia (FA) exhibit a heightened sensitivity to DNA cross-linking agents, modified doses of CY continue to be used in their conditioning prior to BMT. We measured the pharmacokinetics and metabolism of CY in six children with FA using an established high performance thin layer chromatography technique. CY doses ranged between 5 and 20 mg/kg (median 10 mg/kg). The median CY clearance was 0.6 l/h/m2 (range 0.4-1.1 l/h/m2), t1/2 was 8.1 h (range 6.7-9.5 h) and volume of distribution was 0.19 l/kg (range 0.16-0.34 l/kg), respectively. These results contrast with those previously reported from a comparable group of non-FA children in whom the median CY clearance was 3.2 l/h/m2 (range 2-5 l/h/m2) (P = 0.035), t1/2 was 2.4 h (range 2-3.8 h) (P = 0.035) and volume of distribution 0.5 l/kg (range 0.26-0.95 l/kg) (NS). Unlike the control group in whom the presence of inactive metabolites of CY was common, metabolites could not be found in any FA patient. The enhanced sensitivity of children with FA to CY may in part result from altered drug metabolism.

Bone Marrow Transplantation↗
PubMed1999

The effect of fluconazole on cyclophosphamide metabolism in children.

Fluconazole is increasingly used in children receiving chemotherapy. Many of these patients are being treated with cyclophosphamide, which must undergo hepatic metabolism to produce active alkylating species. As a consequence of the cytochrome P-450 inhibitory properties of fluconazole, a potential interaction exists between these two agents that could influence the therapeutic effect of cyclophosphamide. To investigate this interaction, a retrospective case series of patients was chosen from a population of children with a previously established profile of cyclophosphamide metabolism. Twenty-two children who were not receiving other therapy known to influence drug metabolism were selected and analyzed in terms of fluconazole treatment; of these, nine were receiving fluconazole and thirteen were identified as controls. Study design was not randomized. The plasma clearance of cyclophosphamide was lower in patients receiving fluconazole [mean(SD) 2.4(0.71) versus 4.2(1.2) l/h/m2, p =.001]. In vitro studies were performed to characterize the interaction between fluconazole and cyclophosphamide in six human liver microsomes. The concentration of fluconazole required to reduce the production of 4-hydroxycyclophosphamide to 50% of control values (IC50) varied between 9 and 80 microM (median 38 microM). Further studies of the effect of fluconazole on 4-hydroxycyclophosphamide production in vivo are warranted to determine whether this interaction reduces the therapeutic effect of cyclophosphamide in clinical practice.

Adolescent↗
PubMed1997

Recurrent pneumomediastinum and pneumothorax in Langerhans cell histiocytosis.

Pneumothorax is an unusual complication of pulmonary Langerhans cell histiocytosis. We report three children who developed recurrent intrathoracic air leaks. In one case, bilateral pneumothoraces may have been precipated by intermittent positive pressure ventilation during general anaesthesia. Chemical pleurodesis was unsuccessful in preventing recurrence of pneumothoraces in two children. The use of extracorporeal membrane oxygenation as an alternative to intermittent positive pressure ventilation in children with respiratory failure from Langerhans cell histiocytosis is discussed.

Adolescent↗
PubMed1997

High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. PATIENTS AND METHODS: Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. RESULTS: There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). CONCLUSION: The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.

Adolescent↗
PubMed1997

Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children.

Although both cyclophosphamide (CP) and ifosfamide (IF) are used in the treatment of central nervous system tumors, little is known about the concentration of either drug or their metabolites in the cerebrospinal fluid (CSF) of children. The concentrations of the parent oxazaphosphorine and its principal metabolites were measured simultaneously in the plasma and CSF of 25 children. Twenty-one patients received CP for the treatment of either acute lymphoblastic leukemia, non-Hodgkin's lymphoma, or medulloblastoma, and 4 children received IF for the treatment of rhabdomyosarcoma. A high degree of interpatient variation was seen in terms of the CSF concentration of CP and the CSF:plasma ratio. The CSF:plasma ratio was greater for IF than for CP (P < 0.001). In contrast to IF, where the majority of metabolites was measured in the CSF, no child receiving CP had detectable metabolites. Children receiving dexamethasone had lower concentrations of CP in the CSF (P = 0.04). The CSF:plasma ratio for isophosphoramide mustard was greater than that for either parent drug or any other metabolite. These results demonstrate that IF enters the CSF to a greater extent than CP in children. The ability of both IF and CP and their metabolites to cross the blood-brain barrier may be reduced by dexamethasone.

Adolescent↗
PubMed1996

Intrasubject variation in children of ifosfamide pharmacokinetics and metabolism during repeated administration.

The aim of this study was to investigate intrasubject variability in ifosfamide (IFO) pharmacokinetics and metabolism which may influence clinical effect, since the pharmacology of this drug is dependent on metabolism. A group of 11 patients (ages 1-16 years) were studied on at least two occasions. IFO, 9 gm-2 was administered as a continuous infusion over 72 h. Plasma and urine samples were collected and concentrations of IFO and its metabolites were determined. Comparisons were made between courses in the same subject, allowing for differences in age and prior IFO treatment. There was a wide variation in drug (twofold) and metabolite (up to tenfold) AUCs between courses in the same patient. Although some patients did show an increase in clearance between courses (up to threefold), there was no significant consistent change in overall pharmacokinetics among the different courses studied in the same patient. There was a significant decrease (up to 63%) in the AUC of the inactive metabolite 3-dechloroethylifosfamide (3-DCI) in later courses compared with the first course studied (P = 0.032, paired t-test). This was matched by an increase in the AUC of the total dechloroethylated metabolites with course (P = 0.015, paired t-test). None of the other metabolites measured showed any consistent change in plasma or urine levels between courses. Overall, the AUC of parent drug correlated with age (r2 = 0.86, P = 0.011), and postinfusion half-life correlated with plasma bilirubin (r2 = 0.89, P = 0.007). This study demonstrated large and seemingly unpredictable intrasubject variability in IFO pharmacokinetics and metabolism during repeated administrations. Investigations relating the clinical effects of IFO to pharmacokinetics and metabolism must take this variation into account.

Adolescent↗
PubMed1996

Cyclophosphamide pharmacokinetics in children.

1. Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2. A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-1 m-2 and volume of distribution varied between 0.26 and 1.48 1 kg-1. 3. The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4. Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.51 h-1 m-2 (P = 0.001) presumably as a result of CYP450 enzyme induction. 5. Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6. Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.

Adolescent↗
PubMed1995

Cyclophosphamide metabolism in children.

The alkylating agent cyclophosphamide is a prodrug which is metabolized in vivo to produce both therapeutic and toxic effects. Cyclophosphamide metabolism was investigated in 36 children with various malignancies. Concentrations of cyclophosphamide and its principal metabolites were measured in plasma and urine using a quantitative high-performance TLC method. The results indicated a high degree of inter-patient variation in metabolism. In contrast to previous adult studies on urinary metabolites, plasma carboxyphosphamide concentrations did not support the existence of polymorphic metabolism. Plasma concentrations of dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide in plasma was strongly associated with dexamethasone pretreatment and was also accompanied by a high clearance of the parent drug. Interpatient differences in metabolism reflect individual levels of enzyme expression and may contribute to variation in clinical effect.

Adolescent↗
PubMed1995

Solid alveolar rhabdomyosarcoma with a t(2;13).

We report a child with a progressive "solid alveolar rhabdomyosarcoma" in whom analysis of tumor cells revealed a t(2;13) translocation characteristic of the classical alveolar subtype. Both subtypes of alveolar rhabdomyosarcoma are associated with a poor response to treatment and the occurrence of this translocation in both is suggestive of a common biologic origin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Comparison of continuous infusion and bolus administration of ifosfamide in children.

The pharmacological effects of ifosfamide (IFO) are dependent on its metabolism which may vary between different modes of administration. This was studied in 17 patients who received both a continuous infusion (9 g/m2 over 72 h) and repeated bolus administration (3 g/m2 every 24 h for 3 days). Concentrations of IFO and its metabolites were determined in plasma and urine. There was up to 70% less of the dechloroethylated metabolites in plasma following bolus administration compared to continuous infusion. Since dechloroethylation results in the formation of the toxic metabolite chloroacetaldehyde, this difference in metabolism may have an impact on the toxicity of IFO. There were no other consistent differences between the two modes of administration. Auto-induction of IFO metabolism, with an increase in dechloroethylated metabolites, was observed for both modes of administration. In conclusion, apart from dechloroethylation, there is little difference between these two modes of administration. However, during multiple cycles of IFO therapy such differences could have a significant effect.

Adolescent↗
PubMed1993

Pharmacokinetics and metabolism of ifosfamide administered as a continuous infusion in children.

The pharmacokinetics and metabolism of ifosfamide was investigated in a group of 16 pediatric patients (5 girls) aged 1-17 years. Each received a dose of 3 g/m2/day for up to 3 days by continuous infusion. Plasma and urine were collected, and concentrations of ifosfamide and its principal metabolites were determined by a quantitative high-performance thin layer chromatography method. During 3 days of continuous infusion, the plasma concentrations of parent drug decreased. This was accompanied by a continuous increase in dechloroethylated products in plasma but not in urine. Estimated pharmacokinetic parameters (clearance, volume of distribution, and half-life) were dependent on body size and age but not any other patient variable. Renal clearance was a relatively minor route of elimination for parent drug and corresponded to < 25% of glomerular filtration rate. Metabolite data from plasma and urine indicated a high degree of interindividual variation in metabolism. Comparison of metabolite recoveries in urine indicated a positive correlation between activation and inactivation routes of metabolism. Prior exposure to ifosfamide was associated with a higher recovery in urine of dechloroethylated metabolites. The severity of hematological toxicity was inversely correlated with glomerular filtration rate but not to parameters of ifosfamide metabolism. There was marked variation in levels of the carboxy metabolite, which could not be detected in the plasma of 5 subjects. However, evidence for a polymorphism in metabolism to this metabolite was weaker than that seen with the isomeric oxazaphosphorine cyclophosphamide. There appeared to be a higher clearance of ifosfamide in pediatric patients compared to adults. The significance of this, and of the variation in metabolism of ifosfamide, for clinical outcome remains to be established, but the increase in the dechloroethylation route of metabolism may be associated with an increased risk of toxicity.

Adolescent↗
PubMed1992

Chronic myelomonocytic leukemia with t(13;14) in a child.

Bone marrow cells from a child with chronic myelomonocytic leukemia showed an acquired, non-Robertsonian translocation between chromosomes 13 and 14, t(13;14)(q12.?2;q32.?3). This rearrangement has not previously been reported in childhood myeloproliferative or myelodysplastic disorders.

Child↗
PubMedDate not supplied

Small-bowel volvulus during treatment for renal tumors.

Intestinal obstruction as a result of postnephrectomy adhesions occurs in up to 7% of children treated for Wilms' tumor. The authors report two children who developed small-bowel volvulus during the treatment of their renal tumor. Both underwent urgent resection of their ischemic bowel with primary anastamosis and are long-term survivors. The risk of this complication may be increased in young children with bulky tumors who receive abdominal radiotherapy.

Child, Preschool↗