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Biomedical subjects

J Boos

Publications and source records attributed to J Boos.

At least 37 records · Page 2Linked to original sources
PubMed1999

Pharmacokinetic dose adjustment of Erwinia asparaginase in protocol II of the paediatric ALL/NHL-BFM treatment protocols.

Native forms of asparaginase stem from different biological sources. Previously reported data from children treated with Erwinase showed significantly lower trough levels and pharmacokinetic dose intensity than after E. coli-derived preparations. Hence, schedule optimization was initiated to achieve relevant serum activities. 21 children on reinduction therapy received Erwinase on Mondays, Wednesdays and Fridays for 3 weeks (9 x 20000 IU/m2 i.v.) instead of 4x 10 000IU/m2 of E. coli asparaginase (twice weekly for 2 weeks). Asparaginase trough activities were measured as the primary parameter, targeting 100-200 IU/I after 2 d and >50 IU/l after 3 d. Concurrently, asparagine trough concentrations were monitored. The mean trough activity was 156+/-99 IU/l, with 2/108 samples showing no detectable activity. Regarding trough levels per individual (three or more measurements/patient), means ranged from 52+/-29 to 276+/-114 IU/l (20 patients, 106 samples), with nine, six, and five children inside, below, and above the target range, respectively. The mean 3 d trough activity was 50+/-39 IU/l (20 patients, 51 samples). In 11 of these samples no activity was measurable. Mean trough activities calculated per individual ranged from < 20-84+/-30 IU/l (14 patients, 42 samples) with seven children below the target limit of 50 IU/l and asparagine concentrations <0.2 - 1.5microM. We concluded that an increased dose of 9x20000 IU/m2 of Erwinia asparaginase within 3 weeks resulted in a pharmacokinetic dose intensity comparable to former observations made with 4 x 10 000IU/m2 of the E. coli product Crasnitin which is no longer marketed. High interindividual variability and the phenomenon of 'silent' inactivation necessitate monitoring wherever possible.

Antineoplastic Agents↗
PubMed1999

Population pharmacokinetic approach to compare oral and i.v. administration of etoposide.

The antitumor effect of etoposide (ETO) may be related to duration of exposure to a relatively low serum level while myelosuppression may be dependent on peak ETO serum levels. With regard to such therapeutic ranges, duration of exposure to predefined plasma ETO concentration ranges and the related AUC (expressed as percent of total AUC, pAUC) were used to compare pharmacokinetic profiles after oral and short time i.v. (1 h infusion) administration of identical ETO doses (100 mg/m2). Patients included in this study received i.v. (18 patients, short-term infusions) or oral (16 patients) ETO on different treatment schedules. Plasma ETO concentrations were determined by HPLC and population pharmacokinetic parameters were calculated (P-Pharm 1.4). Despite an 'apparent bioavailability' of 59%, oral administration of ETO was associated with the same time of exposure to a predefined 'therapeutic range' of 0.5-3 mg/l and a significantly higher pAUC compared to i.v. administration. By contrast, time of exposure to the probably more myelotoxic concentration range above 3 mg/l was significantly shorter and the related pAUC was highly significantly lower after oral than after i.v. administration. These findings demonstrate that oral ETO therapy is at least equivalent to short time i.v. therapy in terms of achieving specific target concentration ranges and avoiding peak concentrations.

Administration, Oral↗
PubMed1998

Capillary electrophoretic drug monitoring of methotrexate and leucovorin and their metabolites.

High-dose methotrexate is an important element of treatment protocols in childhood acute lymphocytic leukemia or osteosarcoma. A capillary electrophoretic method has been developed to measure peak levels and the metabolite pattern in patients with delayed methotrexate elimination. It serves to determine plasma levels of methotrexate, leucovorin and their metabolites, 7-hydroxymethotrexate, 2,4-diamino-N10 -methylpteroic acid and 5-methyltetrahydrofolic acid. For the determination of high concentrations (>10 microM) protein precipitation by acetonitrile will suffice for sample preparation. All other samples undergo solid-phase extraction and upgrading on C18 columns. Aminopterin, a therapeutic antecedent of methotrexate, serves as internal standard. Detection is done on a UV detector with a 300 nm filter. Five hundred microl of serum are needed to determine 0.2 microM of a specified substance (0.5 microM 5-methylterahydrofolic acid) with good precision and accuracy. For peak levels, 20 microl of capillary serum are sufficient.

Antimetabolites, Antineoplastic↗
PubMed1998

Therapeutic drug monitoring of doxorubicin in paediatric oncology using capillary electrophoresis.

A method for the determination of doxorubicin and its main metabolite doxorubicinol in human plasma is described. Two different sample preparation procedures are applied depending on the expected concentration: To monitor the peak plasma levels, 10 microL of plasma are deproteinated with acetonitrile. After centrifugation, the supernatant is directly applied to the capillary by hydrodynamic injection. For the determination of lower amounts of doxorubicin and its main metabolite doxorubicinol 100 microL of plasma is extracted by liquid-/liquid extraction with chloroform. After evaporation of the organic phase, the sample is reconstituted in acetonitrile/water (95/5 v/v) and injected into the capillary by electrokinetic injection. Idarubicin serves as the internal standard. Laser-induced fluorescence detection with an Ar-ion laser emitting at 488 nm and a 520 nm cut-off filter is used for detection. The accuracy of the method was calculated to be 3.0% at higher concentrations and 15.0% at the limit of quantification. Reproducibility data are in accordance to the generally accepted criteria for bioanalytical methods. The limit of quantification is 2 microg/L, enabling us to monitor doxorubicin plasma levels for several days after application. Noninvasive blood sampling (from the fingertip) using heparinized capillaries was found to be a simple and convenient procedure and provides reproducible data. Initial results show high interindividual variability in doxorubicin peak plasma levels.

Antibiotics, Antineoplastic↗
PubMed1998

Augmentation of 1-beta-D-arabinofuranosylcytosine (Ara-C) cytotoxicity in leukaemia cells by co-administration with antisignalling drugs.

The ribonucleotide reductase inhibitors hydroxyurea (HU), arabinosyl-2-fluoroadenine (F-Ara-A) and 2-chlorodeoxyadenosine (2-CdA) and the antisignalling drugs all-trans retinoic acid (ATRA), staurosporine and quercetin have been reported to enhance the cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C). We tested the hypothesis that the ara-C-sensitising potency of the antisignalling agents is equipotent with that of the ribonucleotide inhibitors. The cytotoxicity, determined by the 3-(4,5 dimethylthiazol-2-yl-)5 diphenyltetrazolium bromide (MTT) assay, of combinations of ara-C with the agents named above was compared in the leukaemia cell lines HL-60, ara-C-resistant HL-60 (HL-60/ara-C) and U937. Furthermore, a range of protein tyrosine kinase inhibitors, genistein, CGP 52411, tyrphostin A48 and nordihydroguaiaretic acid (NDGA), for which ara-C-sensitisation has hitherto not been described, were included in the study. All three cell types acquired increased sensitivity to ara-C when co-incubated with HU or ATRA, but their ara-C sensitivity was not affected by quercetin or genistein. 2-CdA, CGP 52411, tyrphostin A48, staurosporine and NDGA were active as sensitisers against ara-C in HL-60 cells, CGP 52411 and tyrphostin A48 also in HL-60/ara-C cells, and 2-CdA, staurosporine and NDGA also in U937 cells. F-Ara-A increased ara-C toxicity in HL-60/ara-C and U937 cells. To address the mechanism of the observed sensitisation, the influence of agents with ara-C-sensitising properties on ara-C-induced apoptosis was investigated in HL-60 cells as measured by cell shrinkage, DNA loss and DNA fragmentation. HU, ATRA, tyrphostin A48 and NDGA augmented apoptosis induced by ara-C as assessed by all three indicators. CGP 52411 decreased the effect of ara-C on apoptotic indicators after incubation for 4 h, but not after 12 h. The results suggest that ATRA, CGP 52411, tyrphostin A48, staurosporine and NDGA may be suitable alternatives to the clinically applied ribonucleotide reductase inhibitors as modifiers of ara-C cytotoxicity in the treatment of acute myeloid leukaemia.

Antimetabolites, Antineoplastic↗
PubMed1998

Use of L-asparaginase in childhood ALL.

Owing to the high efficacy of L-asparaginase in the treatment of acute lymphatic leukaemia the enzyme was introduced into the chemotherapy schedules for remission induction of this disease shortly after results of large-scale clinical trials had become available. Since asparaginase monotherapy was associated with a high response rate but short remission duration, the enzyme is currently employed within the framework of combination chemotherapy schedules which achieve treatment response in about 90% and long-term remissions in the majority of patients. Recently initiated clinical trials have still confirmed the eminent value of asparaginase in the combination chemotherapy of acute lymphatic leukaemia and of some subtypes of non-Hodgkin lymphoma, and its important role as an essential component of multimodal treatment protocols. Despite the unique mechanism of action of this cytotoxic substance which shows relative selectivity with regard to the metabolism of malignant cells, some patients experience toxic effects during asparaginase therapy. Immunological reactions toward the foreign protein include enzyme inactivation without any clinical manifestations as well as anaphylactic shock. Severe functional disorders of organ systems result from the impaired homeostasis of the amino acids asparagine and glutamine. The changes affecting the proteins of the coagulation system have considerable clinical impact as they may induce bleeding as well as thromboembolic events and may be associated with life-threatening complications when the central nervous system is involved. Risk factors predisposing to thromboembolic complications are hereditary resistance against activated protein C and any other hereditary thrombophilia. Other organ systems potentially affected by relevant functional disorders are the central nervous system, the liver, and the pancreas, with patients who have a history of pancreatic disorders carrying an especially high risk of developing pancreatitis. Studies on the mechanisms of action and the occurrence of resistance phenomena have shown that a treatment response may only be expected if the malignant cells are unable to increase their asparagine synthetase activity to an extent providing enough asparagine to the cell; one may thus conclude that the enzyme-induced asparagine depletion of the serum constitutes the decisive cytotoxic mechanism. Independent of the asparagine depletion related cytotoxicity however, there are other mechanisms of clinical relevance like induction of apoptosis. Besides this, further influences on signal transduction cannot be excluded. Only few publications have dealt with the question of minimum trough activities to be ensured before each subsequent asparaginase dose in order to maintain uninterrupted asparagine depletion under treatment, and answers to this problem are not definitive. Clinical studies using enzymes from E. coli strains indicate that a trough activity of 100 U/l will suffice for complete asparagine depletion of the fluid body compartments with the preparations studied. These findings have been transferred to enzymes from other E. coli strains as well as those isolated from Erwinia chrysanthemi and to the PEG-conjugated E. coli asparaginases. It might be desirable to countercheck the results for confirmation or correction. The dosage and administration schedule of the various enzyme preparations required for complete asparagine depletion over a period of time have been insufficiently defined. While pharmacokinetic studies showed clinically relevant differences in biological activity and activity half-lives for enzymes from different biological sources, the findings of recently published clinical trials indicate that the therapeutic efficacy is affected when different asparaginase preparations are given by identical therapy schedules. (ABSTRACT TRUNCATED)

Antineoplastic Agents↗
PubMed1998

Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia.

Although treatment of childhood acute myelogenous leukemia (AML) has substantially improved in the last 15 years, in nearly half of the patients disease recurs. The aim of this study was to establish the prognosis of relapsed childhood AML and to identify prognostic factors for achievement of second remission and survival. From February 1988 to July 1996, 134 children with first relapse of AML were reported to the study center of the AML-BFM group. 102 patients treated intensively to induce second remission were prospectively followed. With various regimens, complete remission was achieved in 52 of 102 patients (51%), 27 children were alive in median 2.5 years (range, 0.4-7 years) after relapse. Disease-free survival was observed in seven of 16 patients transplanted from a matched sibling donor, one of four after matched unrelated bone marrow transplantation, 10 of 22 after autologous transplantation and five of nine patients after chemotherapy alone (two patients were lost to follow-up). Time until relapse reflecting the duration of first remission is the only variable correlating CR and survival rates. Defining early relapse as less than 1.5 years from diagnosis to relapse resulted in a 5-year survival of 10%, s.e. 5% for early relapses and 40%, s.e. 10% for late relapses (P-logrank test, 0.0001). Duration of first remission is a strong predictor for achievement of second CR and survival. It should be considered in reporting results of experimental therapies.

Adolescent↗
PubMed1998

Chemically induced isomerization and differential uptake modulate retinoic acid disposition in HL-60 cells.

The successful introduction of 13-cis-retinoic acid (13-cis-RA) and all-trans-retinoic acid (all-trans-RA) in the chemoprevention and treatment of cancer along with the discovery of different retinoic acid receptors transactivated by different retinoic acid isomers resulted in a number of in vitro studies of the antitumor effects of single retinoic acid isomers. Since the formation of retinoic acid isomers with different receptor affinities might modulate retinoic acid response in vitro, we determined retinoic acid disposition in HL-60 cells and cell culture medium during incubation with 13-cis-, 9-cis-, and all-trans-RA. In medium, retinoic acids underwent a thiol-radical mediated isomerization resulting in a mixture of 13-cis-, 9-cis-, 9,13-di-cis-, and all-trans-RA. Except for the 9, 13-di-cis-RA, all isomers generated in medium were also detected in HL-60 cells. Whereas 9-cis-RA and 13-cis-RA showed similar cellular pharmacokinetics, all-trans-RA reached about fourfold higher concentrations in HL-60 cells compared to 9-cis-RA and 13-cis-RA. Due to its better uptake, all-trans-RA became the main isomer within cells as it was formed in the medium when incubated with 13-cis-RA and 9-cis-RA. Thus, due to the simple chemically induced isomerization and its profound influence on cellular retinoic acid concentrations, studies of the efficacy of single retinoic acid isomers in vitro should be interpreted with caution.

Biological Transport↗
PubMed1998

Excretion kinetics of ifosfamide side-chain metabolites in children on continuous and short-term infusion.

Ifosfamide (IFO) requires metabolic activation by hydroxylation of the ring system to exert cytotoxic activity. A second metabolic pathway produces the cytostatically inactive metabolites 2-dechloroethyl-ifosfamide (2-D-IFO) and 3-dechloroethyl-ifosfamide (3-D-IFO) under release of chloroacetaldehyde. This side-chain metabolism has been suggested to be involved in CNS- and renal toxicity. The total urinary excretion of ifosfamide and its metabolites was investigated during 23 cycles in 22 children at doses ranging from 400 mg/m2 to 3 g/m2. The kinetics of the excretion were compared following short-term and continuous ifosfamide infusion at a dosage of 3 g/m2. IFO and side-chain metabolites were analyzed by gas chromatography, the active metabolites by indirect determination of acrolein (ACR) and IFO mustard (IFO-M) with the NBP test. 59+/-15% of the applied dose could be recovered in the urine, 23+/-9% as unmetabolized IFO. The main metabolite was 3-D-IFO (14+/-4%) followed by isophosphoramide mustard (IFO-M) (13+/-4%) and 2-D-IFO (8+/-3%). Neither the total amount recovered nor the excretion kinetics of ifosfamide and side-chain metabolites showed obvious schedule dependency. The excretion kinetics of side-chain metabolites as well as unmetabolized IFO were nearly superimposable on short-term and continuous infusion. Even after 1-hour infusion there was a lag of 3 - 6 hours until dechloroethylation became relevant. Therefore, differences in toxicity and efficacy cannot be explained by an influence of the application time on the metabolic profile of ifosfamide.

Acetaldehyde↗
PubMed1998

Drug trials in pediatric oncology: a multi-facetted problem.

In the field of childhood malignancies, the last 30 years have witnessed the advance of highly effective treatment regimens and high cure rates through the clinical application of a growing number of cytotoxic agents. The therapeutic success was mainly brought about by the empirically based joint efforts of cooperative clinical trials that employed effective cytotoxic drug combinations at the threshold of maximum tolerable toxicity. Systematic clinical drug trials, however, aimed at the approval of specific substances for use in pediatric oncology have been lacking. The following presentation will try to describe briefly the various facets of the problem involved in the systematic development of drugs for childhood malignancies as is manifested in Germany today.

Adolescent↗
PubMed1997

Modified total lymphoid irradiation and low dose corticosteroids in progressive multiple sclerosis.

In a double-blind prospective randomized trial, we assessed the efficacy and safety of modified total lymphoid irradiation (TLI) plus low dose prednisone (TLI-LDP) as compared to sham TLI plus identical prednisone therapy (sham TLI-LDP) in 46 patients with progressive forms of multiple sclerosis (MS). No significant difference existed between groups at study entry in patient age, sex, duration of MS, or disability status. However, following treatment, significantly fewer TLI patients showed a sustained one point decline in the Expanded Disability Status Scale, the primary study endpoint, as compared to the sham TLI group using the Kaplan-Meier Product-limit survival analysis, (P<0.005). Risk for relapse requiring treatment with intravenous methylprednisolone was reduced by 54% in the TLI-treated group (P<0.05). Significantly fewer TLI-LDP patients had gadolinium enhancing plus new T2-weighted lesions (P=0.018) when compared to the sham group post-treatment. There was also a substantial and significant decrease in blood lymphocytes in the TLI-LDP group when compared to either pretreatment values or to sham TLI-LDP through at least 12 months post-therapy. Side effects secondary to TLI were generally mild and well-tolerated. These results further support the hypothesis that TLI and systemic immunosuppression have a beneficial effect in progressive forms of MS.

Adult↗
PubMed1997

Determination of idarubicin and idarubicinol in plasma by capillary electrophoresis.

A rapid and sensitive capillary electrophoretic method for the determination of idarubicin and its metabolite idarubicinol in plasma has been developed and validated. Plasma is extracted by liquid-liquid extraction using chloroform. Idarubicin, idarubicinol and the internal standard daunorubicin can be separated in less than 5 min using a phosphate buffer of pH 5 with 70% acetonitrile. Laser-induced fluorescence detection with an Ar ion laser operated at 488 nm provides a sensitive and selective detection method without interferences from biological fluids. The small sample volume of 100 microl is of particular advantage for studies in pediatric oncology. The reproducibility of the method has been shown to be sufficient for drug monitoring or pharmacokinetic studies. The limit of quantification for idarubicin in plasma is 0.5 ng/ml.

Antibiotics, Antineoplastic↗
PubMed1997

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites.

To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m2 Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUCTrofo:AUCIfo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC(Ifo):AUC(Cyclo) 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechlorethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy.

Adolescent↗
PubMed1997

Changes in coagulation and fibrinolysis in childhood acute lymphoblastic leukaemia re-induction therapy using three different asparaginase preparations.

UNLABELLED: Recently we reported the influence of two different Escherichia coli asparaginase (ASP) preparations on fibrinolytic proteins in childhood acute lymphoblastic leukaemia (ALL) demonstrating a significant association between ASP activity and haemostatic alterations. The present study was designed for prospective evaluation of coagulation and fibrinolytic parameters in leukaemic children receiving different ASP preparations during the course of re-induction. Forty leukaemic children receiving ASP (Medac: n = 13; Bayer: n = 10; Erwinia: n = 17) at 3-day intervals during re-induction were enrolled in this study. Blood samples for coagulation studies were obtained before each ASP administration together with serum samples for pharmacokinetic monitoring. Compared with Medac ASP 10,000 IU/m2, patients receiving Bayer ASP or Erwinia ASP showed significantly higher fibrinogen values. Antithrombin and plasminogen showed normal values in children after Erwinia ASP. Alpha2-antiplasmin and D-Dimer were no different in the groups studied. Neither side-effects, nor sustained asparagine depletion was observed in the majority of children treated with Erwinia ASP. CONCLUSION: Data of this study show a down-regulation of coagulation proteins in children treated with Medac ASP, less pronounced in patients after Bayer or Erwinia ASP. Since children treated with Erwinia ASP showed no adequate asparagine depletion during the course of ASP therapy, a dose adjustment should be discussed to guarantee asparagine depletion, the specific metabolic therapy for ALL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukaemia.

The enzyme asparaginase is an important element in the therapy of acute lymphoblastic leukaemia (ALL). The usual asparaginase dose as prescribed in the ALL-BFM-86/90 treatment protocol for the therapy of ALL is 10,000 IU/m2 at 3 d intervals and had been developed on the basis of the E. coli asparaginase preparation Crasnitin from the Bayer company. Using the described schedule the E. coli asparaginase preparation from the Medac company shows significantly higher biological activity than the Bayer preparation. These findings prompted an attempt to reduce the dose of the Asparaginase medac under careful pharmacokinetic and pharmacodynamic monitoring. At the first step of dose reduction in ALL treatment protocol I, 11 children received 5000 IU/m2 of Asparaginase medac. Another 15 children were given 2500 IU/m2 of the enzyme at the second step of dose reduction. Prior to each asparaginase dose, blood samples were taken to determine amino acids and trough enzyme activity. Concurrent with the asparaginase monitoring, the coagulation parameters were measured. 96% of samples from the first step of dose reduction (5000 IU/m2 every third day) showed complete L-asparagine depletion (< 0.1 microM), the median trough enzyme activity was 265 IU/l. At the second step of dose reduction (2500 IU/m2) complete L-asparagine depletion was seen in 97% of samples, and the median trough enzyme activity was 102 IU/l. Cerebrospinal fluid (CSF) depletion was complete in all samples tested (11/11). We concluded that an Asparaginase medac dose reduced from the usual 10000 IU/m2 down to 5000 IU/ m2 or 2500 IU/m2, applied at 3 d intervals, was sufficient to achieve complete L-asparagine depletion in serum. Changes of the fibrinogen levels was significantly less pronounced in the group on 2500 IU.

Adolescent↗
PubMed1997

Pharmacokinetics and drug monitoring of L-asparaginase treatment.

The enzyme L-asparaginase is an important component of the treatment protocols for Acute Lymphoblastic Leukemia (ALL). This enzyme is derived from different biological sources (E. coli and Erwinia chrysanthemi). An increasing number of hemorrhagic and thrombotic events prompted us to initiate a monitoring program for asparaginase treatment. Different asparaginase preparations were monitored in children on the ALL-BFM induction and reinduction treatment (10,000 U/m2 every 3-4 days). The different preparations resulted in significantly different trough levels of parameters of asparaginase activity, asparagine depletion, and coagulation. Not even the two preparations from E. coli were interchangeable: In a subsequent study, a mere 2500 U/m2 of the E. coli preparation Asparaginase medac resulted in trough levels comparable to 10,000 U/m2 of Crasnitin. The Erwinia preparation Erwinase, however, did not maintain measurable trough levels at the protocol schedule. We conclude that different L-asparaginase preparations are not readily interchangeable and that changes in the preparation, dosage or schedule require careful observation and possibly pharmacokinetic monitoring.

Antineoplastic Agents↗
PubMed1997

Trofosfamide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the oral treatment of cancer.

During the last decade, the oxazaphosphorine trofosfamide was underestimated partly due to its unsuitability for i.v. use. Oral daily doses of 150 mg were tolerated well and showed appreciable response rates in the treatment of lymphoma. Furthermore, activity in sarcoma and cancers sensitive to oxazaphosphorines in general seems probable, because ifosfamide is the main metabolite of trofosfamide. Due to its oral mode of application and good tolerance, trofosfamide will be an important option in view of the increasing demand for treatment regimens suited for an outpatient basis. Results of the major in vitro, in vivo and clinical studies are reported for evaluation of its significance in chemotherapy today.

Administration, Oral↗