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J Boos

Publications and source records attributed to J Boos.

At least 73 records · Page 4Linked to original sources
PubMed1995

Resistance to activated protein C (APCR) in children with acute lymphoblastic leukaemia--the need for a prospective multicentre study.

Activated protein C resistance (APCR), usually due to the Arg506-->Gln point mutation of the factor V gene, has emerged as the most important hereditary cause of venous thromboembolism. Using an aPTT based method in the presence of APC, together with a DNA technique based on the polymerase chain reaction, we investigated 65 leukaemic children and 65 age-matched healthy controls for the presence of this mutation. In both groups three children showed APCR. All six children showed the common factor V gene mutation, Arg506-->Gln. Although no child in the control group presented with thrombosis, all three children with acute lymphoblastic leukaemia had thromboembolic events. Whether the poor anticoagulant response to activated protein C in leukaemic children treated with prednisone, vincristine, daunorubicin and asparaginase affects the risk of thrombotic events requires a more extensive multicentre study.

Adolescent↗
PubMed1995

Steady-state levels and bone marrow toxicity of etoposide in children and infants: does etoposide require age-dependent dose calculation?

PURPOSE: Most pediatric treatment protocols specify dose calculations for cytostatic drugs based on body-surface area (BSA). However, for children less than 1 year of age, calculation guidelines vary. Normally, reduced dosages are recommended with calculations based on body weight (BW). However, the optimal dose for infants should take age-dependent and drug-specific pharmacokinetic parameters into account. PATIENTS AND METHODS: The current investigation focused on the effects of different dose-reduction rules on the steady-state levels (Css) of etoposide and related bone marrow toxicity. One hundred seventy three treatment courses in 78 children on a 96-hour continuous infusion schedule were monitored for Css (determined by high-performance liquid chromatography [HPLC]), and 100 courses were documented in detail with regard to dose calculation (125 mg/m2, 4.17/kg, or 2/3 x 4.17/kg) and toxicity. RESULTS: Dose calculation on the basis of BSA led to Css of 4.9 +/- 1.2 micrograms/mL, which on the basis of BW was 3.5 +/- 1.1 micrograms/mL and 1.95 +/- 0.6 micrograms/mL (2/3.kg-dose), respectively. However, conversion of the latter levels to those expected with the regular square-meter-dose, resulted in values of 4.7 +/- 1.4 micrograms/mL and 4.2 +/- 1.2 micrograms/mL (/125 mg/m2). Lower etoposide Css levels resulted in less pronounced thrombocyte and WBC nadirs in the respective groups. The dose-calculation rules for infants, therefore, decreased both dose-intensity and related toxicity. Etoposide clearance rates related to BW (0.8 +/- 0.3 mL/min/kg) or BW (19 +/- 6 mL/min/m2) did not show any differences between children and infants, even in the age range of 3 to 12 months. CONCLUSION: In the case of etoposide, special dose-calculation guidelines for infants are not substantiated by age-dependent pharmacokinetics or tolerance.

Adolescent↗
PubMed1994

Unilateral nephrectomy and cisplatin as risk factors of ifosfamide-induced nephrotoxicity: analysis of 120 patients.

PURPOSE: This study was performed to identify risk factors of ifosfamide-induced renal damage. PATIENTS AND METHODS: Renal function was assessed in 120 patients at a minimum of 3 months after completion of chemotherapy including ifosfamide. The cumulative ifosfamide dose ranged from 2 to 95 g/m2 (median, 30 g/m2). Ten patients had undergone unilateral nephrectomy; combination cytostatic treatment included cisplatin in 51 and methotrexate in 57. Sixty-eight patients had received gentamicin treatment. The glomerular filtration rate was estimated using the Schwartz formula. Proximal tubular function was assessed by the percent reabsorptions of glucose and 16 amino acids, the fractional excretion of sodium, and the fractional reabsorption of phosphate. In addition, the serum bicarbonate level was measured. RESULTS: Proximal tubular dysfunction--with a predominance of renal amino acid (66.3%) and phosphate loss (38.3%)--was much more frequent than both glomerular impairment and acidosis. Seven patients were identified as having renal Fanconi's syndrome, and generalized tubulopathy was noted in another 15 patients. Ifosfamide-induced nephrotoxicity was dose-dependent, with a weak linear inverse correlation between cumulative ifosfamide dose and fractional phosphate reabsorption. Unilateral nephrectomy proved to be the single most important risk factor (odds ratio for the development of renal Fanconi's syndrome, 11.4), but cisplatin also significantly enhanced ifosfamide-mediated nephrotoxicity. Methotrexate, gentamicin, and patient age at primary diagnosis had no influence on renal function. CONCLUSION: Ifosfamide chemotherapy should probably be restricted in patients after unilateral nephrectomy.

Adolescent↗
PubMed1993

Development of hypertension in neuroblastoma during therapy: a case report.

A case of stage 4 neuroblastoma that developed excessive hypertension on day 120 of chemotherapy is presented. The tumor initially had responded well to chemotherapy; however, while the tumor mass decreased, plasma and urine catecholamines and the blood pressure increased. The plasma concentrations of noradrenaline, adrenaline, and dopamine increased to 26.4, 1.8, and 36.2 micrograms/l, respectively. The profile of catecholamine metabolites changed: on day 150 of therapy, noradrenaline, adrenaline, and dopamine levels were increased, whereas HVA and VMA levels were decreased when compared to day 1 of therapy. The only residual neuroblastoma tissue visible on MIBG scintigraphy on day 150 of treatment was a metastasis in the left tibia which was irradiated with 24 Gy. The adrenaline concentration in the left femoral vein was twice as high compared to the right femoral vein. A treatment, possibly radiation-associated tumor cell alteration resulting in a different catecholamine production, is discussed.

Abdominal Neoplasms↗
PubMed1993

Trofosfamide metabolism in different species--ifosfamide is the predominant metabolite.

Trofosfamide (TRO) belongs to the group of oxazaphosphorines and is a congener of cyclophosphamide (CYC) and ifosfamide (IFO). The precondition for the cytotoxic effect of all oxazaphosphorines is their metabolic activation by "ring" oxidation at the hepatic mixed-function oxidase system. In addition, an inactivating metabolic pathway ("side chain" oxidation) is known for CYC and IFO. The metabolic pattern of the substances gains special interest in the discussion of a growing incidence of side effects. Therefore, the in vitro biotransformation of TRO was studied. Liver microsomes were prepared from different species, including the rat, rabbit, and mouse as well as from one human sample. Microsomal proteins were incubated for various periods and concentrations of TRO and its metabolites were analyzed by reversed-phase high-performance liquid chromatography (HPLC). In vitro metabolism resulted in the formation of activated metabolites by hydroxylation at position 4. In addition, side-chain oxidation resulted in the formation of IFO and CYC. IFO was the predominating metabolite of this pathway, with a 5- to 6-fold excess being noted as compared with CYC in rats and mice. The rabbit species showed similar CYC and IFO formation; in the single human sample, only IFO could be detected. In rats, the Michaelis constant (Km) for biotransformation to IFO was 398 microM, with the maximal volume (Vmax) being 70.8 nmol 120 min-1 mg protein-1, the corresponding values for biotransformation to CYC were 348 microM and 13.30 nmol 120 min-1 mg protein-1. On the basis of its structural similarity and the current knowledge of oxazaphosphorine metabolism, CYC was expected to be the main metabolite of TRO. The predominance of IFO was unexpected, but the observed metabolic profile promises numerous interesting aspects for the clinical use of TRO.

Animals↗
PubMed1993

Is there a relationship between cytarabine pharmacokinetics and keratitis?--A case report.

While on therapy for acute myeloid leukemia, a 15-year-old girl developed extensive punctate keratitis of both eyes following high-dose cytarabine therapy (HD-Ara-C). Pharmacokinetic monitoring showed an increase of the Ara-C plasma levels up to twice the steady-state level within 10 minutes after discontinuation of the Ara-C infusion. Calculations of Ara-C plasma half-life, plasma clearance and volume of distribution were within the expected range. Owing to the short half-life of Ara-C in blood due to rapid deamination, varying infusion velocities will result in markedly varying plasma levels. Higher peak plasma levels lead to proportionally higher diffusion into compartments like tears, aqueous humor and cerebrospinal fluid. In compartments which lack noteworthy deaminase activity, dose intensity will be much more enhanced than in plasma. Peak plasma levels, therefore, may be associated with multifold local toxicity without concurrent increase of hematological toxicity. Especially when the drug is given in small volumes of infusion, these considerations should be taken into account. Precise control of infusion parameters and application of artificial tears for dilution of the Ara-C concentration on the corneal surface should be part of keratitis prophylaxis.

Adolescent↗
PubMed1992

[Solid phase-sample preparation of ifosfamide and chloroethyl metabolites in biological material. 1. Determination in plasma and urine].

The cytostatic drug ifosfamide (IFF) and its main metabolites 2-dechloroethyl ifosfamide (2-D-IFF) and 3-dechloroethyl ifosfamide (3-D-IFF) were isolated from the plasma matrix with high recovery by solid phase extraction using Bakerbond C18-cartridges. A further cleaning of the extracts is not necessary. An effective separation of IFF and metabolites from interfering compounds present in urine samples prior gc was performed with Extrelut-1 and dichloromethane/isopropanol (95:5, v/v). The described assays may be used for pharmacokinetic studies as well as drug monitoring in the clinical laboratory.

Humans↗
PubMed1992

Investigation of the variability of etoposide pharmacokinetics in children.

PROBLEM: The interindividual variation of etoposide pharmacokinetics under different therapeutic schedules and the rationale of dose reduction in young children and newborns were investigated in the present study. PATIENTS AND METHODS: We evaluated pharmacokinetic parameters during short-term infusion in 21 therapy cycles (18 children) on different therapeutic schedules (66-200 mg/m2). In 33 patients state levels (Css) during continuous infusion of 125 mg/m2/96 h were analyzed by an HPLC-method. RESULTS: During short-term infusion half-life (3.3 +/- 0.7 h) and total body clearance (26 +/- 6 ml/min/m2) showed a relatively narrow range. Calculation of the area under the curve was standardized to a dosage of 100 mg/m2 (AUC/[100 mg/m2]). The AUC then was 68 +/- 17 (micrograms.h/ml)/(100 mg/m2) with a coefficient of variation of 25%. In the subgroup of 10 patients who received 150 mg/m2 the AUC was 106 +/- 15 micrograms.h/ml with only 14% coefficient of variation. In children < 2 years, pharmacokinetic parameters were within the normal range. Calculation of the doses the short-term infusion per kg resulted in a dose reduction or 31% (mean, n = 5) and in 22% (mean) lower AUC's. With continuous infusion of 125 mg/m2 etoposide the interpatient variability was greater with a 33% coefficient of variation of the Css (4.4 +/- 1.4 micrograms/ml; n = 24). Calculation of the doses per kg (age < 1 year) or 2/3.kg resulted in reduced Css. Standardization of these levels showed Css (125 mg/m2) of 4.6 +/- 1.4 micrograms/ml and a coefficient of variation of 31%. CONCLUSIONS: Interpatient variability of etoposide pharmacokinetics at least during short-term infusion is limited. Dose reduction is not substantiated in children < 2 years by our pharmacokinetic data.

Child↗
PubMed1992

Acute myelogenous leukaemia in children under 2 years--experiences of the West German AML studies BFM-78, -83 and -87. AML-BFM Study Group.

Clinical, morphological, immunological, cytogenetical and prognostic features of 84 children under 2 years of age with AML in studies AML-BFM-78, -83 and -87 were retrospectively analysed. There was a high incidence of acute monoblastic leukaemia (FAB M5) (41 patients--49%) and acute megakaryoblastic leukaemia (FAB M7) (study AML-BFM-87: five patients--13%) in this age group. Acute monoblastic leukaemia was associated with hepatosplenomegaly, extramedullary organ manifestations and chromosomal abnormalities involving 11q23. The probability of an 11-year event-free survival of all patients under 2 years of the three studies combined was 39% (SD 6%). While the event-free survival rates of patients aged 2 years and older could be improved in studies AML-BFM-83 and -87 compared with study AML-BFM-78, overall prognosis in children under 2 years in the three consecutive studies remained unchanged. The event-free survival rate of children with acute monoblastic leukaemia in both age groups was comparable (7 yr-EFS (AML-BFM-83 and -87): much less than 2 years--43% (SD 9%), =/much greater than 2 years--33% (SD 9%); P much greater than 0.5). This also applied to other risk groups. In conclusion, taking the high incidence of acute monoblastic and megakaryoblastic leukaemia in children under 2 years into account, no significant differences between children under 2 years or older children concerning response to therapy and overall prognosis could be evaluated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Urinary excretion of the enantiomers of ifosfamide and its inactive metabolites in children.

The precondition for the antineoplastic effect of ifosfamide (ifo) is the oxidation of the oxazaphosphorine ring system, which contains a chiral centre at the phosphorous atom. This "ring oxidation" leads to the formation of alkylating mustard via several steps. A second metabolic pathway produces the cytostatically inactive metabolites 2- and 3-dechloroethyl-ifosfamide (2-d- and 3-d-ifo). The urinary excretion of the optical isomers of unmetabolised ifo and of 2- and 3-d-ifo, which represents the amount of ifo that has not been activated, was investigated by capillary gas chromatography for 18 treatment cycles in 14 children on various therapeutic schedules. The total cumulative excretion in 12 completely sampled cycles ranged from 27% to 50% of the ifo dose. Between 14% and 34% of the dose could be detected as ifo; 9% to 29%, as 3-d-ifo; and 2% to 8%, as 2-d-ifo. At 24 h after the end of therapy, excretion was nearly complete. Without exception, slightly more R-ifo (53%-61%) than S-ifo was excreted. S-2-d-ifo (50%-73%) was the main 2-d-metabolite. S-3-d-ifo (deriving from R-ifo) predominated in 6 of 14 children and R-3-d-ifo, in 8. Enantiomer-specific excretion increased after the end of infusion (up to 73% for R-ifo and 27% for S-ifo). We demonstrated stereospecific metabolism of ifo in children, with two different patterns of side-chain oxidation being observed. There was no evidence of important stereospecific ring oxidation in most children. A benefit should not be expected from the therapeutic application of pure enantiomers.

Adolescent↗
PubMed1991

A simple isocratic ion-pair high-performance liquid chromatographic determination of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate for intracellular drug-monitoring and in vitro incubation assays.

A sensitive isocratic ion-pair HPLC method using a reversed-phase C18 column and phosphate buffer at pH 6 for the determination of the cytotoxic intracellular anabolite 1-beta-D-arabinofuranosylcytosine-triphosphate (Ara-CTP) of the antineoplastic drug cytarabine in leukaemic cells in vivo is described. Simultaneous determination of the physiological nucleotide deoxycytidine-triphosphate is possible. The recovery from cells is greater than 90%, the limit of detection is 25 ng ml-1 (51 nM l-1) and about 10 pM mg-1 cell protein. Extraction procedure and pitfalls are discussed. The method enables intracellular drug monitoring of Ara-CTP with standard HPLC equipment.

Arabinofuranosylcytosine Triphosphate↗
PubMed1989

Vitamin K-dependent coagulation parameters during the first six days of life: incidence of PIVKA II in newborns.

The vitamin K-dependent carboxylation of the prothrombin precursor PIVKA II (protein induced by vitamin K absence analogous to Factor II) is essential for the synthesis of prothrombin. The noncarboxylated precursor is found in peripheral blood in the presence of vitamin K deficiency. In this study prothrombin time, Factor II and Factor VII activity, and PIVKA II were investigated in 57 newborns without vitamin K prophylaxis in order to assess their vitamin K status. Two-dimensional immunoelectrophoresis demonstrated the presence of PIVKA II in 21% of the newborns, predominantly on the second day. The PIVKA-II positive group showed significantly lower prothrombin times than the PIVKA II-negative group. An oral dose of 3 mg vitamin K (Konakion) was administered to 35 healthy newborns in a second group with the first feeding. On the second day of life, these infants showed significantly higher vitamin K-dependent laboratory parameters than the group not given vitamin K; only 9% of the treated infants were positive for PIVKA II.

Biomarkers↗
PubMedDate not supplied

[Improved treatment results in children with AML: Results of study AML-BFM 93].

BACKGROUND: In the multicenter trial AML-BFM 93 daunorubicin or idarubicin was randomly applied in all patients during induction in combination with cytarabine and etoposide. After induction all patients were stratified to the standard or high risk group. To improve outcome in high risk patients high dose cytarabine and mitoxantrone (HAM) was introduced. The placing of HAM as either the 2nd or 3rd therapy block was randomized to evaluate the efficacy and toxicity accordingly. PATIENTS AND METHODS: 471 children with de novo AML entered the trial AML-BFM 93 (161 standard risk, 310 high risk). RESULTS: Overall, 387 of 471 (82 %) patients achieved remission, 5-year survival, event free survival (EFS), and disease free survival were 60 % SE 3 %, 51 % SE 2 % and 62 % SE 3 %, respectively. Idarubicin-based induction resulted in a significantly better blast cell reduction in the bone marrow on day 15 (25 of 144=17 % patients with > 5 % blasts compared to 46 of 149=31 % patients after daunorubicin, pchi(2)=0.01). This was, however, mainly seen in high risk patients treated with idarubicin (19 % vs. 38 %, pchi(2)=0.007). Cardiotoxicity, WHO grade 1 - 3 shortening fraction reduction after induction occurred in 6 % patients in both arms. In the total group of patients probabilities of five years event-free survival and disease-free survival were similar for patients treated with daunorubicin or idarubicin. However, in patients presenting with more than 5 % blasts on day 15 there was a trend for a better outcome after treatment with idarubicin (p logrank 0.06). Outcome in high risk patients was superior in study 93 compared to study 87 (remission rate and 5-year pEFS in study AML-BFM 93 vs. study 87: 78 % vs. 68 %, p=0.007, and 44 % vs. 31 %, p logrank=0.01). The placing of HAM as the 2nd or 3rd therapy block was of minor importance. However, patients who received the daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Compared to study AML-BFM 87 treatment results in study AML 93 improved significantly in high risk patients. This can partly be contributed to the better response on day 15 after idarubicin induction but is mainly due to the introduction of HAM.

Acute Disease↗
PubMedDate not supplied

Meeting report: pharmacology in pediatric oncology. Summary of the 10th international expert meeting of the Kind Philipp Foundation for leukemia research, June 10 - 13, 2001 at the Schloss Reisensburg, Günzburg an der donau.

The Kind-Philipp foundation invited a group of international experts from academia, industry, and regulatory institutions to discuss aspects of new drug development in pediatric oncology. The current design, conduct and infrastructure of clinical trials in Europe and the United States, recent regulatory changes of drug development, and the impact of the likely availability of more targeted anti-cancer agents on drug development for pediatric cancers were discussed. This included a review of risk factors, surrogate markers, novel targets, and new anti-cancer agents for pediatric cancers. A special effort was made to define the requirements of well performed clinical trials, including target evaluation, trial design, use of pharmacokinetic (PK) studies, surrogate markers, ethical, and statistical aspects. The greater need for collaboration beyond the National level was recognized.

Child↗
PubMedDate not supplied

[Liposomal daunorubicine combined with cytarabine in the treatment of relapsed/refractory acute myeloid leukemia in children].

BACKGROUND: First-line treatment in AML commonly included high cumulative doses of anthracyclines with an increasing risk of cardiotoxicity. Liposomal daunorubicin (L-DNR) is thought to be less cardiotoxic without impairment of efficacy. METHODS: The AML-BFM REZ 97 study included two reinduction blocks with L-DNR (2 x 60 mg/m (2) n = 38, since 2/1999 3 x 60 mg/m (2) n = 31) combined with cytarabine (500 mg/m (2) 4 d). Children who achieved a second blast clearance were allocated to allogeneic stem cell transplantation either from a matched related (MRD) or a matched unrelated donor (MUD). Lack of a donor justified haploidentical SCT in early relapse (1st remission < 1 year) and autologous SCT in late relapse. PATIENTS: Between 1/1997 and 9/2001, 69 children were enrolled in the AML-BFM 97 relapse study. The median duration of first remission was 0.9 years. Forty-one patients had a remission of less than one year, 28 of more than a year. RESULTS: 46 children (67 %) achieved a second remission, defined as clearance of blasts in bone marrow and at least a partial hematological reconstitution. Seventeen of these children are alive (12 of 25 children receiving allogeneic SCT (MFD/MUD); 1 of 8 children after haploidentical SCT; 1 of 4 patients after autologous SCT and 3 of 9 patients treated with chemotherapy only). Further three children without 2nd remission survived after MFD-SCT (n = 2) or chemotherapy (n = 1; follow-up 0.3 to 0.7 years). Duration of first remission remains a significant prognostic factor. The pharmacokinetic investigation showed a high overall AUC of 234.6 mg/l h at a dose of 60 mg/m (2), and a volume of distribution of 1.98 l/m (2), which is much lower in comparison to conventional Daunorubicin. Regarding toxicity, the combination of L-DNR and cytarabine followed by SCT was feasible in experienced centers, however, acute complications like infection or septicemia in aplasia, mucositis and GvHD were common. By contrast, no clinical relevant cardiotoxicity was seen so far, but definitive results in long-term cardiotoxicity await a longer follow-up. In conclusion, L-DNR/cytarabine treatment induced a 2nd remission in most of the children with relapsed or refractory AML. It has to be followed by allogeneic SCT which enables long-term survival.

Adolescent↗