ABSTRACT
Plasma and cellular pharmacokinetics of m-AMSA were investigated in 5 patients with acute leukemia, using HPLC. The pharmacokinetic data served as a guideline for in vitro toxicity tests on clonogenic bone marrow cells. m-AMSA was administered as a 3-hour intravenous infusion of 100 mg/m2. Median plasma and nucleated blood cell peak concentrations were 1.25 and 6.36 micrograms/ml followed by biphasic elimination with a median T1/2 alpha alpha of 1.6 h and 0.3 h and a median T1/2 beta of 5.0 h and 5.0 h respectively. Median plasma and cellular area under the curve (AUC) for a 24-h period amounted 6.2 micrograms.h/ml and 49.8 micrograms.h/ml respectively. In vitro cellular uptake was maximal at least within 30 minutes. No differential toxicity for CFU-GM and CFU-L was observed in relation to exposure time. Median IC50 for CFU-GM and CFU-L was 2.2, 1.8 and 1.6 micrograms/ml after incubation periods of resp. 0.08, 4 and 24 h. The corresponding m-AMSA concentration x time products to achieve 50% inhibition (IAUC50) were 0.18, 7.2 and 38.4 micrograms.h/ml, respectively. 48-h prestimulation of the clonogenic bone marrow cells with Human Placenta Conditioned Medium increased sensitivity (median 1.7 x) after 4 h incubation with mAMSA. Short exposure provides maximal, concentration-related, cellular uptake, resulting in effective inhibition of growth of clonogenic bone marrow cells.
Subject(s)
Amsacrine/pharmacokinetics , Amsacrine/toxicity , Hematopoietic Stem Cells/drug effects , Leukemia, Myeloid/blood , Leukemia, Myeloid/pathology , Acute Disease , Adult , Amsacrine/blood , Blast Crisis/blood , Blast Crisis/pathology , Bone Marrow/pathology , Bone Marrow Cells , Cell Division/drug effects , Cell Survival/drug effects , Cells, Cultured , Colony-Forming Units Assay , Dose-Response Relationship, Drug , Female , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/pathology , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Tumor Cells, Cultured , Tumor Stem Cell AssayABSTRACT
PURPOSE: Treatment options for patients with chronic myeloid leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT) are limited. Treatment with lymphocytes from the original marrow donor and the influence on the malignant clone was studied in these patients. PATIENTS AND METHODS: Seven patients with CML that had relapsed after BMT with T-cell-depleted grafts were treated. Six patients received leukocyte infusions from the original marrow donor. One patient received a second BMT with unseparated marrow from the same sibling donor. Chimerism was studied using erythrocyte and cytogenetic markers. Residual leukemic cells were monitored by cytogenetic analysis of the Philadelphia (Ph) chromosome and by polymerase chain reaction (PCR) of the breakpoint cluster region/Abelson (BCR-ABL) fusion gene. RESULTS: In five patients with hematologic relapse, the Ph chromosome disappeared 1 to 3 months after the leukocyte infusions. Cytogenetic analysis and in situ hybridization (ISH) showed only donor cells during further follow-up. Four to five patients became negative for the BCR-ABL translocation by PCR. Graft-versus-host disease (GVHD) always preceded response and was severe in two patients. One patient with cytogenetic relapse showed no response after leukocyte infusions. GVHD after second BMT was of moderate severity. One year after second BMT, PCR for the BCR-ABL translocation was negative. CONCLUSION: Infusion of donor leukocytes is an effective treatment with a low mortality in patients with CML relapsed after BMT with a T-cell-depleted graft. Longer follow-up and more patients will be needed to know whether cure will be permanent.
Subject(s)
Bone Marrow Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Leukocyte Transfusion , Adult , Erythrocytes/immunology , Female , Fusion Proteins, bcr-abl/genetics , Graft vs Host Disease/etiology , Humans , Immunophenotyping , Infusions, Intravenous , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/surgery , Male , Middle Aged , Philadelphia Chromosome , Polymerase Chain Reaction , Recurrence , Time Factors , Transplantation, HomologousABSTRACT
More than half of new mothers may be affected by mood disorders after childbirth. Possible causes and recommended management depend on the type of disorder and its severity. In this article, Dr Knops discusses recognition, prevention, and management of three types of postpartum mood disorders as well as the need for support for a woman and her family at this vulnerable time.
Subject(s)
Affective Disorders, Psychotic , Family Practice/methods , Mood Disorders , Puerperal Disorders , Affective Disorders, Psychotic/diagnosis , Affective Disorders, Psychotic/epidemiology , Affective Disorders, Psychotic/therapy , Counseling , Diagnosis, Differential , Family/psychology , Female , Humans , Marriage/psychology , Mood Disorders/diagnosis , Mood Disorders/epidemiology , Mood Disorders/therapy , Mother-Child Relations , Primary Prevention/methods , Prognosis , Puerperal Disorders/diagnosis , Puerperal Disorders/epidemiology , Puerperal Disorders/therapy , Risk Factors , Social SupportABSTRACT
With the use of A SEP-PAK Alumina N cartridge, peptide fractions containing the hydroxamate moiety have been isolated from tumour-tissue homogenate. It is therefore postulated that N-hydroxypeptides might play a role in the accumulation of gallium-67 in tumours. The biodistribution of several 67Ga-labelled hydroxamate peptide fractions is determined. Although their biodistribution differs from that of 67Ga-citrate no enhancement in tumour accumulation is observed indicating that they do not act like tumour-specific siderophores.
Subject(s)
Gallium Radioisotopes/metabolism , Hydroxamic Acids/isolation & purification , Peptides/isolation & purification , Rhabdomyosarcoma/metabolism , Animals , Biological Transport , Male , Rats , Rats, Inbred Strains , Tissue DistributionABSTRACT
The biodistribution of 67Ga-labelled complexes of some mono- and di-N-hydroxyamino acid derivatives and of two siderophores (trihydroxamates) were evaluated in Rhabdomyosarcoma-bearing rats. It was found that the mono- and dihydroxamates could not enhance the tumour-localizing properties of 67Ga-citrate, while the 67Ga-labelled trihydroxamates showed very rapid urinary excretion.
Subject(s)
Gallium Radioisotopes , Hydroxamic Acids , Rhabdomyosarcoma/diagnostic imaging , Animals , Chelating Agents , Deferoxamine/analogs & derivatives , Ferrichrome/analogs & derivatives , Radionuclide Imaging , Rats , Sarcoma, Experimental/diagnostic imaging , Tissue DistributionABSTRACT
[18F]-5-fluorocytosine was prepared by reaction of [18F]-acetylhypofluorite with cytosine in acetic acid and was isolated in an overall radiochemical yield of 20%. Tissue distribution studies in sarcoma-bearing rats indicated in vivo stability, limited tissue uptake and rapid urinary excretion.
