Prior breastfeeding experience and infant feeding at discharge among women with pregestational diabetes mellitus.

OBJECTIVE: To compare multiparous women with pregestational diabetes mellitus (PGDM) with and without prior breastfeeding (BF) experience and to ascertain their infants' feeding type during hospitalization and at discharge. METHODS: A retrospective cohort study of 304 women with PGDM who delivered at ≥34 weeks gestational age (GA). Prior BF experience and infant feeding preference was declared prenatally. At discharge, BF was defined as exclusive or partial. RESULTS: BF experience and no experience groups were similar in diabetes type 1 and 2, race and number of pregnancies. Women with no experience had more spontaneous abortions (35 vs 27%), fewer term deliveries (51 vs 61%) and living children (median 1 vs 2). In the current pregnancy, mode of delivery: vaginal (36 & 37%), cesarean (64 & 63%), birthweight (3592 & 3515 g), GA (38 & 37 w), NICU admission (14 & 11%) and hypoglycemia (44 & 43%) were similar. Women with experience intended to BF (79 vs 46%), their infants' first feeding was BF (64 vs 36%) and had lactation consults (96 vs 63%) more often than those without experience. At discharge, women with BF experience were different in rate of exclusive BF (33 vs 11%), partial BF (48 vs 25%) and formula feeding (19 vs 64%). CONCLUSION: Prior BF experience leads to better BF initiation rates while the absence of BF experience adds a risk for BF initiation failure. A detailed BF history could provide insight into obstacles that lead to unsuccessful BF experiences and may help define appropriate preventive or corrective strategies.

Determinants of undernutrition in rural communities of a protected area in Gabon.

OBJECTIVE: To understand how access to natural resources may contribute to nutrition. DESIGN: In each of the two major seasons, data were collected during a 7 d period using observations, semi-structured interviews, anthropometric measures and a weighed food consumption survey. SETTING: Four rural communities selected to represent inland and coastal areas of the Gamba Complex in Gabon. SUBJECTS: In each community, all individuals from groups vulnerable to malnutrition, i.e. children aged 0-23 months (n 41) and 24-59 months (n 63) and the elderly (n 101), as well as women caregivers (n 96). RESULTS: In most groups, household access to natural resources was associated with household access to food but not with individual nutritional status. In children aged 0-23 months, access to care and to health services and a healthy environment were the best predictors of length-for-age (adjusted R2: 14%). Health status was the only predictor of weight-for-height in children aged 24-59 months (adjusted R2: 14%). In women caregivers, household food security was negatively associated with nutritional status, as was being younger than 20 years (adjusted R2: 16%). Among the elderly, only nutrient adequacy predicted nutritional status (adjusted R2: 5%). CONCLUSION: Improving access to care and health for young children would help reverse the process of undernutrition. Reaching a better understanding of how the access of individuals to both food and other resources relate to household access could further our appreciation of the constraints to good nutrition. This is particularly relevant in women to ensure that their possibly important contribution to the household is not at their own expense.

Nutritional status and dietary adequacy in rural communities of a protected area in Gabon.

OBJECTIVE: As part of a larger study designed to understand how to protect the food and nutrition security of individuals living in a protected area of Gabon, we assessed their nutritional status and its relationship to dietary adequacy and health status. DESIGN: A 7 d food consumption survey was conducted during each of the two major seasons using a weighing method. Data were also collected on weight, height and health of individuals as well as on sociodemographic characteristics and potential determinants of the nutrition situation. SETTING: Four rural communities were intentionally selected to represent both inland and coastal settings and access to food markets. SUBJECTS: Approximately 500 individuals representing over 90% of the population of these communities participated in the survey during each season. RESULTS: Undernutrition was present in the area, particularly among children <5 years of age and the elderly. Health was generally good and under-fives were most frequently ill. Energy, Fe and vitamin A requirements of individuals were generally not satisfied; the opposite was true for protein. The estimated prevalence of inadequate intakes of energy and vitamin A was very high in most age groups. Global nutrient adequacy was associated with nutritional outcome. CONCLUSIONS: Individuals do not eat enough and breast-feeding practices are poor. Many suffer from undernutrition, particularly young children and the elderly. The results confirm the need to investigate the determinants of this poor nutrition situation to ensure that protection of natural resources will not be associated with harm to the well-being of the population.

The impact of paediatric tracheostomy on both patient and parent.

OBJECTIVE: We set out to assess the impact of paediatric tracheostomy, performed in a central London hospital, on patients and their families. METHODS: We conducted structured interviews with caregivers of tracheostomised children using the Pediatric Tracheotomy Health Status Instrument during all in-patient admissions for airway endoscopy over a 6-month period. RESULTS: Completed questionnaires were received from 26 caregivers, 7 (27%) of whose children had been successfully decannulated. Carers reported adverse effects on all aspects of their quality of life, including sleep, relationships, social life and ability to work. The families included in the study had gross household incomes below the mean for SE London. There is a shortfall in the provision of home nursing when compared with the needs of the caregivers. CONCLUSIONS: Tracheostomy has wide ranging effects on the quality of life of both the patient and their caregivers. We identified the need for better pre-operative preparation where possible, and greater support for such families in the community.

Molecular characterization of IRF3 and IRF7 in rainbow trout, Oncorhynchus mykiss: functional analysis and transcriptional modulation.

Interferon regulatory factors (IRF) 3 and 7 in mammals are known to be crucial in regulating the type I interferon (IFN) response to viral infection as part of transcriptional complexes binding to IRF-binding elements (IRF-Es) and interferon stimulatory response elements (ISREs) within IFN and interferon-stimulated genes (ISGs). Here we report the sequencing and characterization of full-length cDNA homologues of rainbow trout (rt)IRF7 and, for the first time in fish, IRF3. RtIRF3 consists of 2127 bp with a 159 bp 5'-UTR-containing two upstream AUGs and a 573 bp 3'-UTR. RtIRF7 was found to be 2055 bp, with a 102 bp 5'-UTR and a 705 bp 3'-UTR. The open reading frames (ORFs) translate into 464 amino acid and 415 amino acid proteins, respectively, each possessing a putative DNA-binding domain (DBD) containing a tryptophan cluster, which is characteristic of all IRF family members. The presence of putative IRF association domain (IAD)s, serine-rich C terminal domains (poorly conserved in trout IRF3), and phylogenetic analysis places the two genes in the IRF3 subfamily. Both genes were found to be upregulated by poly I:C, type I recombinant rainbow trout (r) IFN (second isoform, type I rIFN), type II rIFN (rIFNgamma), LPS, and rIL-1beta in the trout macrophage cell line, RTS-11. Poly I:C and type I rIFN also induced IRF3 and IRF7 expression in a trout fibroblast cell line (RTG-2). Transient transfection of RTG-2 cells with each IRF fused to GFP revealed a predominant cytoplasmic distribution found most intensely around the nucleus and, to a lesser extent, within cell nuclei. Transient transfection of rtIRF3 in the Mx-1-luciferase reporter cell line, RTG-P1, revealed a modest increase in luciferase activity relative to the vehicle control, which was lost in cells over-expressing a DBD-truncated form of rtIRF3. Both full-length and DBD-truncated forms of rtIRF7 increased reporter activity relative to the control, although to a non-significant extent. Electromobility shift assays (EMSAs) did not reveal a specific interaction between each IRF and the ISRE element found in the Mx-1 promoter, although the Mx-1 ISRE bound specifically to endogenous transcriptional complexes. These data support the premise that rtIRF3 and rtIRF7 are important molecules in the regulation of antiviral responses in fish, with the impact of rIFNgamma on rtIRF3/7 expression implying a role for these IRFs in immune processes other than type I IFN-driven antiviral responses.

Transcriptome response following administration of a live bacterial vaccine in Atlantic salmon (Salmo salar).

Antibacterial responses have been studied in Atlantic salmon following an acute intra peritoneal injection of a genetically attenuated (aroA(-)) strain of Aeromonas salmonicida known to elicit protective immunity. Three tissues were studied for transcriptional changes, the liver, head kidney and the gill. RNA was collected from fish 6, 12, 24 and 48 h following infection or at the same time points from fish injected with PBS as non-infected control. PCR-select cDNA subtraction libraries were constructed from pooled 24 and 48 h post infection RNA to identify up-regulated mRNAs. One thousand four hundred and eighty six cDNA clones were sequenced from enriched cDNA libraries, of which 71% had significant homologies to known functional proteins. Many of these clones have previously been un-characterised in Atlantic salmon. A salmonid cDNA microarray was used to further analyse the gene expression profile as the library construction in itself does not answer the dynamics of the response. The greatest increase in expression identified in the array analysis was a liver antibacterial peptide, hepcidin that was increased 11-fold following the challenge. A panel of clones were chosen for semiquantitative reverse transcriptase PCR from all time points sampled. These results indicated there were both temporal differences and tissue differences in the transcriptional response to bacterial exposure, potentially of relevance to the establishment of protection.

Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: final results of a multicenter compassionate use trial.

The recombinant urate oxidase, rasburicase (Elitek, Sanofi-Synthelabo, Inc.), has recently received regulatory approval for the prevention and treatment of hyperuricemia in children with leukemia, lymphoma, and solid tumors. Prior to approval, 682 children and 387 adults in the US and Canada received rasburicase on compassionate-use basis. Uric acid concentration declined rapidly in both adult and pediatric patients after rasburicase treatment. Similar responses were observed in patients treated with subsequent courses. Possible drug-related adverse events, including allergic reactions, were uncommon. These data confirm that rasburicase is effective and safe for the treatment and prophylaxis of children and adults with malignancy-associated hyperuricemia.

Modulation of the cytotoxic effect of cyclopentenylcytosine by its primary metabolite, cyclopentenyluridine.

Cyclopentenylcytosine (CPE-C), a synthetic cytidine analogue with significant preclinical antitumor activity against both solid tumor xenografts and 1-beta-D-arabinofuranosylcytosine resistant murine leukemia cell lines, will soon enter phase I clinical trials. Unlike 1-beta-D-arabinofuranosylcytosine which is activated by deoxycytidine kinase, the enzyme responsible for the phosphorylation of CPE-C is uridine/cytidine kinase. Preclinical pharmacokinetic studies of CPE-C in nonhuman primates revealed that the primary route of elimination in this species was deamination to cyclopentenyluridine (CPE-U), an inhibitor of uridine/cytidine kinase. Since CPE-C is likely to be deaminated in humans, we investigated the modulating effect of CPE-U on the in vitro cytotoxicity of CPE-C in Molt-4 lymphoblasts. Concurrent exposure of cells to cytotoxic concentrations of CPE-C and 50 microM CPE-U resulted in the rescue of 50% of cells and exposure to CPE-U concentrations in excess of 100 microM resulted in the rescue of greater than 90% of cells. Progressive attenuation of the rescue effect was observed with delayed administration of CPE-U and no cells were rescued when addition of CPE-C was delayed for more than 2 h. At the intracellular level it was observed that the formation of the cytotoxic metabolite, cyclopentenylcytosine triphosphate, was blocked by increasing concentrations of CPE-U presumably secondary to inhibition of uridine/cytidine kinase by CPE-U. Although CPE-U can modulate the cytotoxic effects of CPE-C in vitro, the minimum CPE-U levels that are required for modulation coupled with the available preclinical pharmacokinetic data from nonhuman primates suggests that this modulation is not likely to impact on the antitumor effects of CPE-C in humans.

Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates.

Topotecan, a water soluble semisynthetic analogue of camptothecin, is a topoisomerase I inhibitor that has recently entered phase II clinical trials. Topotecan has shown significant preclinical activity in refractory murine tumors and in human tumor xenograft models. In addition, objective antineoplastic activity has been observed in recent adult phase I clinical trials. Topotecan is unstable in solution and is rapidly and spontaneously converted to a less active open ring form which predominates at physiological pH. This study was undertaken to better define the pharmacokinetic behavior of this highly unstable compound in both plasma and cerebrospinal fluid (CSF) and to measure the degree of CSF penetration of this novel antineoplastic agent. Three nonhuman primates with indwelling Ommaya reservoirs received 10 mg/m2 i.v. topotecan administered as a 10-min infusion. Frequent plasma and CSF samples were obtained and immediately extracted and assayed with a reverse phase high performance liquid chromatography assay to quantitate the concentration of topotecan (lactone). Samples were then acidified and reinjected to quantitate total drug (lactone ring plus open ring). Peak plasma concentrations of topotecan ranged from 0.27 to 0.45 microM. Plasma disappearance of the lactone ring was biexponential with a distribution half-life (t1/2 alpha) of 22 +/- 5 min and an elimination half-life (t1/2 beta) of 1.3 +/- 0.1 h. Total body clearance of topotecan was 72.1 +/- 15.8 liters/h/m2. The volume of distribution at steady state was 88.6 +/- 33.2 liters/m2. Peak CSF concentrations of topotecan occurred at 30 min following drug administration and ranged from 0.044 to 0.074 microM. CSF disappearance paralleled that in plasma. The mean ratio of the area under the CSF concentration-time curve to that in plasma was 0.32 (range, 0.29 to 0.37). The mean CSF penetration of topotecan exceeds 30%, which is significantly greater than the penetration of most structurally similar chemotherapeutic agents. The impact of chemotherapy on the survival of patients with primary or metastatic central nervous system malignancies is very limited. Therefore, this novel antineoplastic agent is an excellent candidate for further study in patients with high risk or refractory central nervous system tumors.

A pharmacokinetic model of topotecan clearance from plasma and cerebrospinal fluid.

We present a physiological pharmacokinetic model that describes the plasma and cerebrospinal fluid (CSF) concentrations of topotecan [(S)-9-dimethylaminomethyl-10-hydroxyamptothecin hydrochloride, SK&F 104864-A, NSC 609699] following i.v. and intraventricular administrations in monkeys. The model consists of three physical spaces: the CSF, the plasma, and a body compartment. The model incorporates such processes as reversible conversion of topotecan lactone to an inactive hydroxy acid form, microvascular exchange between CSF and plasma, bulk CSF flow, exchange between plasma and body compartments, and elimination of drug from the plasma compartment. Several parameters in the model were obtained from published literature on the physiology of the monkey. The model was then fit to the plasma and CSF data to deduce the other parameters. Calculated clearances of topotecan lactone and total drug from the CSF after intraventricular injection were 3.9 and 2.2 ml/h, respectively. Clearances of topotecan lactone and total drug from the plasma following a 10-min infusion were 26.3 liters/h/m2 and 17.8 liters/h/m2, respectively. The calculated ratios of the area under the concentration curve in the CSF following i.v. infusion to the area under the concentration curve in plasma were 0.11 and 0.19 for topotecan and total drug, respectively, indicating significant CSF penetration. The volume of distribution was 0.77 liters/kg, which represents distribution in a volume approximating total body water. The forward and reverse rate constants for the lactone-to-hydroxy acid conversion were 1.0 and 0.29 h-1, respectively. Comparison of the clearances (normalized to body surface area) with values reported for mice and humans shows reasonable similarity across species. This pharmacokinetic model may help guide future development and refinement of clinical protocols, especially in the treatment of diseases of the central nervous system.

Pharmacokinetics and metabolism of cyclopentenyl cytosine in nonhuman primates.

The plasma and cerebrospinal fluid pharmacokinetics of cyclopentenyl cytosine (CPE-C) were studied following i.v. bolus and continuous i.v. infusion in male rhesus monkeys. Following an i.v. bolus dose of 100 mg/m2 plasma elimination of CPE-C was biexponential with a mean t1/2 alpha of 8.4 min, a mean t1/2 beta of 36 min, and a total clearance (CLTB) of 662 ml/min/m2, which is 5- to 10-fold higher than clearance rates in rodents and dogs. Less than 20% of the total dose of CPE-C was excreted unchanged in the urine. The remainder was excreted as the inactive deamination product cyclopentenyl uridine (CPE-U). The ratio of the areas under the plasma concentration versus time curves of CPE-U to CPE-C was 7.0 +/- 2.4 following i.v. bolus CPE-C. The cerebrospinal fluid:plasma ratios of CPE-C and CPE-U were 0.08 and 0.30, respectively. Continuous i.v. infusion of CPE-C was compared to continuous infusion of 1-beta-D-arabinofuranosylcytosine in two monkeys. Steady state plasma concentrations, normalized to a dose of 12.5 mg/m2/h of CPE-C and an equimolar dose of 1-beta-D-arabinofuranosylcytosine, were 2.1 and 0.53 microM, respectively. The steady state concentrations of their corresponding uridine metabolites (CPE-U and 1-beta-D-arabinofuranosyluridine) were 8.2 and 15.5 microM. The rapid elimination of CPE-C by deamination in the primate resulted in a much higher CLTB and considerably lower total drug exposure than in rodents and dogs that clear CPE-C at a much lower rate by renal excretion. These significant interspecies differences in the disposition of CPE-C should be considered in the selection of a starting dose and schedule for human trials and suggest that a pharmacologically directed dose escalation scheme should be used in the planned phase I studies.

Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion.

Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatric patients with refractory malignancies. A phase I and pharmacokinetic study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities, the incidence and severity of other toxicities, and the pharmacokinetics of topotecan in children. Twenty-nine patients received 42 courses of i.v. topotecan administered as a 24-h continuous infusion every 21 days at doses ranging from 2.0 to 7.5 mg/m2. Dose-related hematological toxicity was the dose-limiting toxicity. Leukopenia, neutropenia, and thrombocytopenia occurred sporadically at the 3.0- to 5.5-mg/m2 dose levels, but at 7.5 mg/m2 4 of 5 patients experienced dose-limiting thrombocytopenia (grade 4) and 2 of 5 had dose-limiting neutropenia (grade 4). No other dose-limiting toxicities were observed. Nausea and vomiting were mild and occurred in < 20 and 10% of patients, respectively. Grade 2 hematuria occurred in one patient. No objective responses were observed. Pharmacokinetic studies revealed a linear relationship between the steady-state topotecan concentration and dose. The mean steady-state concentration at the MTD was 18.2 +/- 3.7 nmol/liter and the total body clearance was 28.3 +/- 6.5 liters/h/m2. Elimination was biexponential with a t1/2 alpha of 14.4 +/- 1.8 min and a t1/2 beta of 2.9 +/- 1.1 h. The recommended starting dose for phase II pediatric trials is 5.5 mg/m2. Although this dose exceeds the MTD identified in heavily pretreated adult patients receiving topotecan on the same schedule, it is less than the MTD for minimally pretreated adult patients. Therefore, dose escalation to 7.5 mg/m2 in phase II pediatric trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.

A phase I trial of amifostine (WR-2721) and melphalan in children with refractory cancer.

Melphalan has a steep dose-response curve, but the use of high doses results in unacceptable myelosuppression. Strategies to circumvent this dose-limiting myelosuppression would allow for the administration of higher, more effective doses of melphalan. Amifostine (WR-2721) has been shown in preclinical studies to protect the bone marrow from the myelotoxicity of melphalan, and in clinical trials, to protect from the myelotoxicity of other alkylating agents. A Phase I trial of the combination of amifostine and melphalan was performed in children with refractory cancers to: (a) define the acute toxicities of amifostine and its maximum tolerated dose (MTD); and (b) to determine whether the dose of melphalan could be safely escalated when administered in combination with amifostine. Amifostine was administered i.v. as a 15-min infusion 30 min before melphalan. The starting dose of amifostine was 750 mg/m2, with planned dose escalations in 30% increments. Melphalan was administered as a 5-min infusion using the previously defined MTD in heavily pretreated patients, 35 mg/m2, as the starting dose. The dose of melphalan was escalated by 30% increments. Nineteen patients, ranging in age from 3 to 24 years (median, 15 years), were entered on trial. The dose of amifostine was escalated to 2700 mg/m2, which is approximately 3-fold higher than the adult recommended dose, without reaching a MTD. Fifteen patients experienced nondose-limiting (< 25%), transient decreases in blood pressure after the amifostine infusion. Other nondose-limiting toxicities of amifostine included mild nausea and vomiting, flushing, anxiety, diarrhea, and urinary retention. Six patients, three each at the 2100 and 2700 mg/m2 amifostine dose levels were treated with an escalated dose of melphalan (45 mg/m2). All of these patients experienced grade 4 neutropenia (< 500/mm3), and five of six patients had grade 4 thrombocytopenia. The duration of this dose-limiting myelosuppression exceeded 7 days in four of six patients. Although no dose-limiting (grade 3 or 4) toxicity was attributed to amifostine, significant anxiety and reversible urinary retention occurred at the two highest amifostine dose levels. A dose of 1650 mg/m2 for pediatric Phase II trials is recommended. High doses of amifostine, however, do not appear to allow for escalation of melphalan beyond its single agent MTD of 35 mg/m2.

Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration.

PURPOSE: Intralumbar methotrexate is one of the primary therapeutic modalities for the prevention and treatment of meningeal leukemia. However, methotrexate distribution to the ventricles is limited and highly variable following intralumbar dosing, and cytotoxic concentrations of methotrexate are not always achieved or sustained in the ventricular CSF. We used a nonhuman primate model to determine the effect of body position on the caudal distribution of an intralumbar dose of methotrexate. METHODS: Methotrexate (1.0 mg) was administered by intralumbar injection to four animals, which were then immediately placed either in an upright sitting position or in a prone position for 1 hour, then upright. Each animal served as its own control and was studied in each position on at least one occasion. RESULTS: The mean peak ventricular methotrexate concentration was 0.12 mumol/L (range, 0.091 to 0.20) in animals that were immediately placed upright, compared with 2.81 mumol/L (range, 0.21 to 8.9) in animals that remained prone for 1 hour. The mean area under the concentration-versus-time curves (AUC) was 0.51 mumol/L.h (range, 0.26 to 1.1) in the upright animals and 12.0 mumol/L.h (range, 0.9 to 35.4) in the prone animals. CONCLUSION: Maintaining a prone position for 1 hour after an intralumbar dose increased the peak methotrexate concentration and drug exposure in ventricular CSF. CSF drug distribution following intralumbar therapy can be influenced by body position after the injection.

Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of all-trans-retinoic acid (ATRA) administered on an intermittent oral schedule with interferon-alpha2a (IFN-alpha2a) in children with refractory cancer, and whether the marked reduction in plasma ATRA concentrations observed with chronic daily oral dosing could be circumvented with an intermittent dosing schedule. PATIENTS AND METHODS: Thirty-three children with refractory cancer (stratified by age, < or = 12 and > 12 years) were treated with ATRA 3 consecutive days per week and IFN-alpha2a 3 x 10(6) U/m2 5 consecutive days per week, both repeated weekly. The starting dose of ATRA was 60 mg/m2/d divided into three doses, with planned escalations to 90 and 120 mg/m2/d. Because severe headaches have been noted to occur on the initial day of ATRA administration, only two of three doses of ATRA were administered on day 1 of each week. RESULTS: Pseudotumor cerebri or dose-limiting headache was observed in two of five patients older than 12 years treated at the 120-mg/m2/d dose level and in one of six < or = 12 years at the 90-mg/m2/d level. Other non-dose-limiting toxicities of ATRA included reversible elevations in hepatic transaminases and triglycerides, dry skin, cheilitis, and nausea/vomiting. One child with recurrent neuroblastoma had an objective response of 6 months' duration, and one with recurrent Wilms' tumor had histologic maturation of multiple tumors. This intermittent schedule allowed for exposure to relatively high plasma concentrations of ATRA on a repetitive basis. Following 30-mg/m2 doses, the ATRA area under the concentration-time curve (AUC) decreased from 96 +/- 14 micromol/L/min on day 1 to 26 +/- 24 micromol/L/min by day 3 of drug administration, but on day 1 of the fourth consecutive week of therapy, the AUC averaged 110 +/- 16 micromol/L/min. The recommended pediatric phase II dose of ATRA administered on this schedule is 90 mg/m2/d. CONCLUSION: An intermittent schedule of ATRA administration appears to circumvent the low plasma drug exposure that is a result of the sustained upregulation of metabolism when this drug is administered on a chronic daily schedule. Based on the results of this trial, a phase II trial of ATRA/IFN-alpha2a in neuroblastoma and Wilms' tumor using this schedule is in progress.

Phase I trial of intrathecal liposomal cytarabine in children with neoplastic meningitis.

PURPOSE: We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children >/= 3 years of age with advanced meningeal malignancies. PATIENTS AND METHODS: Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients. RESULTS: Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE: A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS: A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS: Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION: The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma.

PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. PATIENTS AND METHODS: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. RESULTS: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. CONCLUSION: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.

Phase I trial and pharmacokinetic study of pyrazoloacridine in children and young adults with refractory cancers.

PURPOSE: To define the maximum-tolerated dose (MTD), quantitative and qualitative toxicities, recommended phase II dose, and pharmacokinetics of pyrazoloacridine (PZA) administered as a 1- or 24-hour infusion in children and young adults with refractory cancers. PATIENTS AND METHODS: Twenty-two patients received PZA as a 1-hour infusion at doses of 380 mg/m2 (n = 3), 495 mg/m2 (n = 6), 640 mg/m2 (n = 6), and 835 mg/m2 (n = 7). An additional four patients received PZA as a 24-hour infusion at the MTD (640 mg/m2) for the 1-hour infusion schedule. Plasma samples were obtained for pharmacokinetic analysis in 17 patients. PZA concentration in plasma was measured by reverse-phase high-performance liquid chromatography (HPLC). A two-compartment pharmacokinetic model was fit to the PZA plasma concentration data. RESULTS: On the 1-hour infusion schedule, dose-limiting myelosuppression (neutropenia more than thrombocytopenia) was observed in two of seven patients at the 835-mg/m2 dose level. Myelosuppression did not appear to be ameliorated by prolonging the infusion to 24 hours. Nonhematologic toxicities were minor. Significant neurotoxicity, which was dose-limiting in adults treated with a 1-hour infusion of PZA, was observed in one patient treated at 640 mg/m2, but was not dose-limiting. There was marked interpatient variability in plasma PZA concentrations at all dose levels. The pharmacokinetic profile of PZA was characterized by an initial rapid decline (alpha half-life [t(1/2)alpha], 0.5 hours) followed by a prolonged elimination phase (t(1/2)beta, 30 hours). The volume of distribution at steady-state (Vd(ss)) was 700 L/m2 and the clearance was 300 mL/min/m2. There was no evidence of dose-dependent clearance. The area under the PZA concentration-time curve (AUC) correlated poorly with dose and was more predictive of the degree of myelosuppression than was PZA dose. CONCLUSION: PZA administered as 1- or 24-hour infusion is well tolerated by children and young adults. The dose-limiting toxicity (DLT) is myelosuppression. Neurotoxicity is not prominent in this age group. There was marked interpatient variation in plasma concentrations of PZA. The recommended dose for phase II studies is 640 mg/m2.

Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial.

PURPOSE: A phase I trial of docetaxel was performed to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities, and the incidence and severity of other toxicities in children with refractory solid tumors. PATIENTS AND METHODS: Forty-four children received 103 courses of docetaxel administered as a 1-hour intravenous infusion every 21 days. Doses ranged from 55 to 150 mg/m2, MTD was defined in heavily pretreated and less heavily pretreated (< or = 2 prior chemotherapy regimens, no prior bone marrow transplantation [BMT], and no radiation to the spine, skull, ribs, or pelvic bones) patients. RESULTS: Dose-related neutropenia was the primary dose-limiting toxicity. The MTD in the heavily pretreated patient group was 65 mg/m2, but the less heavily pretreated patients tolerated a significantly higher dose of docetaxel (maximum-tolerated dose, 125 mg/m2). Neutropenia and constitutional symptoms consisting of malaise, myalgias, and anorexia were the dose-limiting toxicities at 150 mg/m2 in the less heavily pretreated patients. Thrombocytopenia was not prominent, even in patients who experienced dose-limiting neutropenia. Common nonhematologic toxicities of docetaxel included skin rashes, mucositis, and mild elevations of serum transaminases. Neuropathy was uncommon. Peripheral edema and weight gain were observed in two of five patients who received more than three cycles of docetaxel. A complete response (CR) was observed in one patient with rhabdomyosarcoma, a partial response (PR) in one patient with peripheral primitive neuroectodermal tumor (PPNET), and a minimal response (MR) in two patients with PPNET. Three of the four responding patients were treated at doses > or = 100 mg/m2. CONCLUSION: The recommended phase II dose of docetaxel administered as a 1-hour intravenous infusion in children with solid tumors in 125 mg/m2. Because neutropenia was the dose-limiting toxicity and thrombocytopenia was mild, further escalation of the dose should be attempted with granulocyte colony-stimulating factor (G-CSF) support.