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Biomedical subjects

J Boos

Publications and source records attributed to J Boos.

At least 55 records · Page 3Linked to original sources
PubMed1996

Simultaneous determination of all-trans-, 13-cis- and 9-cis-retinoic acid, their 4-oxo metabolites and all-trans-retinol in human plasma by high-performance liquid chromatography.

All-trans-retinoic acid (all-trans-RA) and 13-cis-retinoic acid (13-cis-RA), due to their effects on cell differentiation, proliferation and angiogenesis, improved treatment results in some malignancies. Pharmacokinetic studies of all-trans-RA and 13-cis-RA along with monitoring of retinoic acid metabolites may help to optimize retinoic acid therapy and to develop new effective strategies for the use of retinoic acids in cancer treatment. Therefore, we developed a HPLC method for the simultaneous determination in human plasma of the physiologically important retinoic acid isomers, all-trans-, 13-cis- and 9-cis-retinoic acid, their 4-oxo metabolites, 13-cis-4-oxoretinoic acid (13-cis-4-oxo-RA) and all-trans-4-oxoretinoic acid (all-trans-4-oxo-RA), and Vitamin A (all-trans-retinol). Analysis was performed on a silica gel column with UV detection at 350 nm using a binary multistep gradient composed of n-hexane, 2-propanol and glacial acetic acid. For liquid-liquid extraction a mixture of n-hexane, dichloromethane and 2-propanol was used. The limits of detection were 0.5 ng/ml for retinoic acids and 10 ng/ml for all-trans-retinol. The method showed good reproducibility for all components (within-day C.V.: 3.02-11.70%; day-to-day C.V.: 0.01-11.34%). Furthermore, 9-cis-4-oxoretinoic acid (9-cis-4-oxo-RA) is separated from all-trans-4-oxo-RA and 13-cis-4-oxo-RA. In case of clinical use of 9-cis-retinoic acid (9-cis-RA) the pharmacokinetics and metabolism of this retinoic acid isomer can also be examined.

Chromatography, High Pressure Liquid↗
PubMed1996

Determination of paclitaxel in biological fluids by micellar electrokinetic chromatography.

A method has been developed for the determination of paclitaxel (Taxol) in plasma and urine using capillary electrophoresis with sodium dodecyl sulfate as additive in the run buffer. The samples are extracted and preconcentrated with tert.-butyl methyl ether. Taxotere has been used as the internal standard. The limit of detection of paclitaxel is 20 ng/ml. In comparison to high-performance liquid chromatography, the capillary electrophoresis method is simple and needs less organic solvents.

Acetonitriles↗
PubMed1996

Intracellular retention of cytosine arabinoside triphosphate in blast cells from children with acute myelogenous and lymphoblastic leukemia.

The importance of the cellular pharmacokinetics of cytarabine triphosphate (ara-CTP) with regard to therapeutic efficacy is well established. In vitro and in vivo monitoring of pharmacokinetic parameters of leukemic blast cells were initiated in order to contribute to the pharmacological basis of optimal ara-C treatment strategies. Peripheral or bone marrow blast cells from 66 leukemic patients [51 acute myelogenous leukemia (ALL), 15 acute lymphoblastic leukemia (AML) were separated and incubated with ara-C for 1 hour and in ara-C-free medium for another 3 hours, and the intracellular formation and retention of ara-CTP was measured. In eight children who received continuous ara-C infusion for induction treatment, the ara-CTP concentration in circulating blast cells was monitored in vivo. The in vitro values observed in this assay corresponded to the cellular levels monitored in vivo. The ara-CTP retention differed clearly among the individual groups, as classified by immunophenotype at the time of the initial diagnosis: non-T-ALL 67+/-25% (x+/-SD, n=33), T-ALL 37+/-15% (n=8), and AML 34+/-18% (n=14). The difference in ara-CTP retention between non-T-All and AML (P<0.05) as well as T-ALL (P<0.05) was significant. There was a tendency toward lower ara-CTP retention in relapsed as compared with newly diagnosed ALL, but the difference was not significant. The maximal accumulation of ara-CTP (after 1 hour incubation) was comparable in AML, T-ALL, non-T-ALL, and blast cells from children in relapse. The observed similarity of cellular accumulation in all groups and the significantly more rapid decrease in T-ALL and AML provide the pharmacokinetic rationale supporting the prolonged infusion duration for ara-C in these subgroups as an alternative to the intensification by high-dose ara-C schedules with short-term infusion.

Adolescent↗
PubMed1996

Therapy of childhood acute myelogenous leukemias.

Acute myelogenous leukemia (AML) accounts for approximately 20% of acute leukemias in children. Although AML is more resistant to chemotherapy than acute lymphoblastic leukemia (ALL), significant progress in improving outcome for AML patients has been achieved over the past 15 years. This can be attributed to intensification of chemotherapy, increased use of bone marrow transplantation, and improved supportive care. Thus 30-50% of children with AML achieve long-term event-free survival with current treatment strategies [61, 66, 85, 96]. This review gives an overview about the evolution of and rationale for current pediatric treatment protocols, with special emphasis on the German Berlin-Frankfurt-Münster (BFM) studies, and discusses new directions for the future.

Antineoplastic Agents↗
PubMed1996

Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations.

The antileukaemic enzyme L-asparaginase is used to achieve the greatest possible reduction in blood levels of the amino acid asparagine, an essential factor for the growth of leukaemic blasts. There are two main sources of the enzyme, E. coli and Erwinia. Faced with increasing reports of treatment complications, we established a programme to monitor enzyme activity and asparagine levels in serum, in children receiving treatment for acute lymphoblastic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL). Trough asparagine and asparaginase levels were measured in 49 children on induction treatment with different E. coli preparations (Asparaginase medac, Crasnitin) and in 52 children on re-induction (Asparaginase medac, Crasnitin, and, in the event of allergic reactions, Erwinase) just prior to each sequential application of 10000 U/m2 of asparaginase. Measurements were made by an enzyme assay and an HPLC method. During induction, both Escherichia coli preparations induced the desired reduction in asparagine, but the asparaginase activity with Asparaginase medac was significantly higher than with Crasnitin (median of trough levels 475 versus 74 U/l). Under re-induction treatment (median, Asparaginase medac 528 U/l, Crasnitin 49 U/l, and Erwinase < 20 U/l) complete asparagine depletion was recorded on day 3 in more than 90% of Asparaginase medac samples, more than 60% of Crasnitin samples and in 26% of Erwinase samples. The latter two groups included some children with unchanged asparagine levels and no measurable enzyme activity. Different asparaginase preparations are not readily interchangeable. When Asparaginase medac is used instead of Crasnitin, and identical dose will be associated with significantly higher enzyme activity, well above the level required for complete asparagine depletion. Clinical studies will need to specify both the preparation and the dose to be used. When substitution of an alternative drug is mandatory owing to allergic reactions, monitoring is advisable.

Adolescent↗
PubMed1996

Changes in coagulation and fibrinolysis in childhood ALL: a two-step dose reduction of one E. coli asparaginase preparation.

The influence of two different E. coli asparaginase (ASP) preparations on fibrinolytic proteins in childhood ALL was recently reported, demonstrating a clearly significant association between ASP activity and haemostatic changes. Since the Bayer preparation is no longer available for treatment of large series of patients with ALL, the present study was designed to prospectively evaluate coagulation and fibrinolytic changes in leukaemic children receiving different doses of Medac ASP, which is now available for treatment of childhood ALL. Leukaemic children in whom ASP Medac was administered at 3 d intervals in a two-step dose reduction (5000 IU/m2, n = 10; 2500 IU/m2, n = 15) were compared with children who had received Bayer ASP 10,000 IU/m2 in the same time schedule in a former randomized trial; at the same venipuncture, blood samples for coagulation studies were obtained before each ASP administration together with serum samples for pharmacokinetic monitoring. Compared with Bayer ASP 10,000 IU/m2, patients receiving Medac ASP 5000 IU/m2 showed significantly decreased values of fibrinogen, plasminogen, and alpha 2-antiplasmin, along with significantly enhanced thrombin generation. Improvement occurred in children treated with 2500 IU/m2 Medac ASP; alpha 2-antiplasmin and D-dimer no longer differed from the Bayer group. Since both patient groups showed complete asparagine depletion during the course of ASP administration, the lower dosage of 2500 IU/m2 administered at 3 d intervals should guarantee the specific metabolic therapy for ALL, leading to depletion of the circulating pool of asparagine.

Antineoplastic Agents↗
PubMed1995

Asparaginase decreases clotting factors in vitro: a possible pitfall?

L-Asparaginase treatment of leukemia patients causes hemostatic problems. To investigate whether L-asparaginase influences coagulation studies, 63 blood samples of 21 healthy male donors were incubated with L-asparaginase for 30 min at room temperature. After treatment with 100 IU/ml L-asparaginase plasma fibrinogen (P = 0.002), plasma antithrombin (P = 0.0002), plasma protein C (P = 0.0004), and plasma plasminogen (P = 0.0039) were decreased compared with controls. In contrast, a significant increase in plasma von Willebrand factor antigen (P = 0.08) and plasma thromboglobulin (P = 0.005) was observed. The decrease in plasma anti-thrombin (P = 0.001), plasma protein C (P = 0.0003), and plasma plasminogen (P = 0.0043) was also measurable after 0.05 IU/ml asparaginase treatment. The incubation with L-asparaginase was similar to the normal time from blood sampling to testing and hence the results suggest that L-asparaginase may directly attack proteins of the coagulation system during the interval between sampling and assay.

Adult↗
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↗