Ara-CMP-Stearate (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate, YNK 01, Fosteabine) is the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a phase I study in patients with ...advanced low-grade non-Hodgkin lymphomas or acute myeloid leukemia, the pharmacokinetic parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Frankfurt, Germany) were determined by HPLC analysis. Seventy-two hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Stearate was administered over 14 days by daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/day and was escalated in subsequent patients to 200 mg/day and 300 mg/day. Plasma and urine concentrations of Ara-CMP-Stearate, Ara-C and Ara-U were measured during the initial treatment phase and within 72 h after the end of the 14-day treatment cycle. So far six patients have been treated with 100 mg/day, three with 200 mg/day and another six with 300 mg/day. One patient was treated consecutively with 100 mg, 300 mg and 600 mg. Fitting the results of the plasma concentration measurements of Ara-CMP-Stearate to a one-compartment model, the following pharmacokinetic parameters were obtained (average and variation coefficient VC). Ara-CMP-Stearate dose-independent parameters: lag time = 1.04 h (0.57); tmax = 5.72 h (0.30); t1/2 = 9.4 h (0.36). Dose-dependent parameters: at 100 mg: AUC = 1099 ng/h/ml (0.31); concentration(max) = 53.8 ng/ml (0.28); at 200 mg: AUC = 2753 ng/h/ml (0.32); concentration(max) = 154.8 ng/ml (0.46); at 300 mg: AUC = 2940 ng/h/ml (0.66); concentration(max) = 160.0 ng/ml (0.59). The long lag time and late tmax can be explained by resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500 pg/ml). Pharmacokinetic parameters of Ara-C following Ara-CMP-Stearate application showed the following characteristics: t1/2 = 24.3 h (0.39); AUC (100 mg) = 262 ng/h/ml (0.93); AUC (200 mg) = 502 ng/h/ml (0.87); AUC (300 mg) = 898 ng/h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemolysis after intravenous administration, it was not possible to determine its bioavailability by comparing the AUC after oral and i.v. application. Instead, the renal elimination of Ara-U, as the main metabolite of Ara-C was measured during the first 72-h period and after the last application.
Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy at an improved quality of life. These perspectives ...are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under the curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicin in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24-h trough levels shows high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4 - 445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two-fold from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r=0.78, indicating that the interindividual variations of idarubicin AUC reflects differences in absorptions rather than metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24-h trough level shows such an excellent correlation (r=0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24-h trough level may allow the assessment of the impact of interindividual variations in AUC of clinical outcome and toxicity.
A new platin compound, oxaliplatin, has significant activity in advanced colorectal carcinomas. However, its pharmacokinetics
have not been characterized adequately yet. This study extensively ...analyzes the pharmacokinetics of both ultrafiltrable (free)
and protein-bound platin in 13 patients receiving 130 mg/m 2 oxaliplatin as a 4-h infusion in combination with 375 mg/m 2 5-fluorouracil as a 24-h infusion for advanced colorectal carcinomas. The interpatient variability was very low for all parameters
analyzed. The levels of free platin decreased triphasically, with a mean terminal half-life of 27.3 ± 10.6 h. The area under
the time-concentration curve was 20.17 ± 6.97 μg·h/ml and the total and renal clearances amounted to 222 ± 65 and 121 ± 56
ml/min, respectively. The values for the volume of distribution and for the maximum concentration at the end of infusion were
349 ± 132 liters and 1612 ± 553 ng/ml, respectively. On the basis of the simulation of the plasma levels and the urinary excretion
of platin following the long-term administration of oxaliplatin as a constant-rate and a chronomodulated infusion, additional
analyses are warranted to fully characterize the pharmacokinetics of the drug in these settings.
Paraneoplastic pemphigus (PP) is an autoimmune disease, which is frequently associated with non‐Hodgkin's lymphoma. Autoantibodies against components of the cytoplasmic plaque of epithelial ...desmosomes are usually present in the sera and are believed to play a major pathogenic part in acantholysis and suprabasal epidermal blistering. However, another typical histological feature of PP, interface dermatitis with keratinocyte dyskeratosis, is shared with skin diseases that involve epithelial damage mediated by T cells. Here, we present the detailed characterization of the cutaneous T‐cell response in a patient with PP and demonstrate a selective epidermal accumulation of activated CD8+ T cells together with an increased local production of interferon‐γ and tumour necrosis factor‐α, and a strong expression of HLA‐DR and ICAM‐1 on keratinocytes. Apoptosis was identified as a key mechanism of keratinocyte death, and appeared independent of the FAS/FAS ligand (FAS‐L) pathway, as epidermal expression of FAS was not increased compared with normal skin, and FAS‐L was undetectable on the protein and mRNA level. Triple therapy with high‐dose corticosteroids, cyclophosphamide and intravenous immunoglobulins reduced levels of pemphigus‐like autoantibodies and reversed the cutaneous inflammatory reaction leading to long‐standing clinical remission. Our findings support the concept of a major contribution of cytotoxic T lymphocytes to the immunopathology of paraneoplastic pemphigus.
We discuss the case of a 32 year-old male with severe microcytic anemia (hemoglobin 2,9 g/dl) and megaloblastic changes in the bone marrow. The patient reported of substantial dietary weight loss. ...The family history was positive for beta-thalassemia. Previous blood work showed iron deficiency with mild anemia. Further work-up verified beta-thalassemia minor and revealed severely decreased vitamin B12 levels with positive anti intrinsic-factor antibodies, pathognomonic for autoimmune pernicious anemia. The paradoxon therefore dissolved as a pernicious anemia with megaloblastic changes with microcytic erythrocytes due to beta-thalassemia.
Acute myeloid leukemia (AML) is a rare disease of the hematopoietic stem cell leading to uncontrolled proliferation of immature progenitor cells. This results in a replacement of healthy ...hematopoiesis and in pancytopenia with corresponding symptoms (anemia, thrombo- and granulocytopenia). Diagnosis can reliably be confirmed by bone marrow aspiration, which also allows risk stratification by cytogenetic and molecular analysis. Therapy of AML that should preferentially be performed in clinical studies comprises induction therapy for achievement of complete cytomorphological remission (CR) and postremission strategies consisting of consolidation and maintenance therapy for eradication of residual blasts. The backbone of polychemotherapy is cytarabine and anthracyclines. Different regimens exist that achieve CR rates of 60-80%. As a consequence, pancytopenias up to 6 weeks will be experienced, that will lead to specific problems such as infections by atypical pathogens. To date, induction therapy will be performed independently of the individual risk constellation (with the exception of acute promyelocytic leukemia); however, postremission therapy is highly dependent on individual risk stratification. Besides conventional strategies, allogeneic stem cell transplantation has to be considered in certain risk groups depending on the availability of a matched donor. Taken together, cure can be achieved in about 40% of patients, however, with large interindividual variability.
Acute myeloid leukemia (AML) is a disease of mostly elderly patients who are often unable to undergo intensive intravenous chemotherapy. In an attempt to provide an all-oral regimen suitable for ...palliative treatment, we assessed the antileukemic efficacy of combination therapy of idarubicin 20 mg/m(2) (days 1, 3, and 5) and etoposide (EI) in increasing doses (75-125 mg/m(2)) on days 1-5. Eleven patients were included (median age 69 years, range: 56-77) with prognostically unfavorable characteristics (myelodysplastic syndrome, relapse, or unfavorable karyotypes). No complete remission and five partial remissions were observed whereas four patients had persistent leukemia. There were two patients who succumbed to early death. Median overall survival was 100 days (range: 8-493 days). Nonhematological toxicities were acceptable with nausea/vomiting being the predominant side effect. Hematological toxicity with grade III/IV aplasia was seen in all patients. In this study EI did not show convincing antileukemic efficacy and was unable to induce clinically useful complete remissions, with a substantial risk profile. In contrast to the situation of elderly patients with standard-risk AML in which similar oral treatment has shown promising activity, EI cannot be recommended for elderly patients with high-risk AML.
The biological mechanisms responsible for the association of specific karyotypes with prognosis in acute myeloid leukaemia (AML) remain largely unclear. A prospective study was performed to evaluate ...how far cytogenetically defined prognostic subgroups of AML differ in their proliferative activity as a potential mechanism for differential sensitivities to S‐phase‐specific induction chemotherapy comprising cytosine arabinoside (AraC). One hundred and eighty‐seven patients with de novo AML were included in the study; 25 patients with a favourable inv(16), t(8;21), t(15;17) karyotype, 99 with a normal karyotype, 29 with an unfavourable karyotype (−5, 5q–, −7, 7q–, complex aberrations) and 34 with cytogenetic aberrations of unknown prognostic significance (all others). The favourable group demonstrated the highest ex vivo proliferative activity (PA) (3·41 pmol/105 cells), significantly (P = 0·02) exceeding the unfavourable group with the lowest PA (0·72) and the group with a normal karyotype (1·06) or with karyotype of unknown significance (1·05) that both demonstrated an intermediate PA. Samples with a high PA (> median of the whole group) were more likely to produce interleukin 3, granulocyte macrophage colony‐stimulating factor (GM‐CSF), granulocyte CSF (G‐CSF) (56%, 43% and 50%) than cells with a low PA (33%, 36% and 36%; n.s.). The effect of priming by exogenous GM‐CSF or G‐CSF was significantly more pronounced in samples with a low PA than in rapidly proliferating samples (P < 0·01). For the whole group, a high PA was closely associated with an increased incorporation of AraC triphosphate (AraCTP) into the DNA (P < 0·0001). Clinically, a high PA was associated with a better complete remission (CR) rate in the normal (95% versus 62%) and the unfavourable group (75% versus 33%). The significant differences in proliferative activity between cytogenetic subgroups of AML are associated with increased cytosine arabinoside pharmacodynamics and constitute one potential mechanism for the different response of cytogenetic subgroups to AraC‐based induction therapy.