PubMed Health⌕ Search

Biomedical subjects

G Ehninger

Publications and source records attributed to G Ehninger.

At least 181 records · Page 10Linked to original sources
PubMed1995

Treatment of steroid-resistant graft-versus-host disease after allogeneic bone marrow transplantation with anti-CD3/TCR monoclonal antibodies.

Acute graft-versus host disease (GVHD), one of the major complications of allogeneic bone marrow transplantation (BMT), occurs in 30-50% of all patients transplanted from HLA-identical sibling donors and in 50-80% of all patients transplanted from an unrelated or HLA-mismatched family donor, despite GVHD prophylaxis with methotrexate and cyclosporin. We report our experience with OKT3/BMA031 treatment in 14 patients with severe steroid-resistant GVHD following allogeneic BMT. Three of 5 patients treated in the early post-transplant period with OKT3 remitted and 2 of 3 became long-term survivors. Two patients treated for extensive chronic GVHD showed only minor responses. Five of 7 patients treated with BMA031 showed a partial remission; no complete remission was seen after treatment with this antibody. Shortly after the introduction of OKT3 or BMA031 therapy a rapid decline of the lymphocyte count, especially the CD3+ subset, was observed coinciding with a relative increase of CD56+ lymphocytes and of gamma/delta TCR+ T cells. Increasing numbers of CD3+ lymphocytes preceded recurrence of acute GVHD in three patients. In contrast, persisting CD3-lymphocytopenia was associated with complete clearance of acute GVHD. The incidence of infectious complications following OKT3 or BMA031 therapy was high (42%). Thus, to improve treatment results of severe acute GVHD, prophylactic or pre-emptive strategies are required to reduce the rate of fatal viral and fungal infections.

Acute Disease↗
PubMed1995

Biotransformation of CI-937 in primary cultures of rat hepatocytes. Formation of glutathione conjugates.

The anticancer drug 7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]- ethyl]-5-[[2-(methylamino)ethyl]amino]anthra[1,9-c,d]pyrazole- 6(2H)-one dihydrochloride (CI-937) is 1 of 3 anthrapyrazole derivatives chosen for phase I and phase II clinical trials. Although the chemical structure of CI-937 signals a contribution of redox reactions in the pharmacology of the drug, a study concerning the biotransformation of CI-937 is still missing. Incubations of primary cultures of rat hepatocytes with CI-937 result in the formation of three glutathione conjugates and a glucuronic acid conjugate. The structures of the glutathione conjugates have been established by reference synthesis with activated horseradish peroxidase and HPLC-MS-MS and two-dimensional NMR measurements. The glucuronic acid derivative of CI-937 has been identified by MS. The formation of the glutathione conjugates in cells establishes the ability of the drug to form covalent bonding to intracellular nucleophilic targets. The conjugation with glutathione has been rationalized by oxidative activation of CI-937, yielding an electrophilic intermediate that finally reacts with glutathione.

Animals↗
PubMed1995

Remission of a lymphoproliferative disorder occurring after second BMT from an unrelated donor in a 5-year-old boy with severe aplastic anemia.

A 5-year-old boy with severe aplastic anemia failed to respond to cyclosporine (CYA), prednisolone and antilymphocyte globulin (ALG). No suitable sibling marrow donor was available, but an HLA-matched unrelated donor was identified. The patient was conditioned with cyclophosphamide (CY), 50 mg/kg/day for 4 days, total nodal irradiation (8 Gy), and ALG 30 mg/kg/day for 3 days. GVHD prophylaxis consisted of daily CYA, methotrexate (MTX) and ALG. The patient failed to achieve sustained engraftment. He was reconditioned with high-dose prednisolone and anti-T lymphocyte monoclonal antibody OKT3. The boy was reinfused with the same donor marrow on day 0 (+49/first BMT). No GVHD prophylaxis was given the second time. He received G-CSF on days 0 to +20 after the second transplant. Full engraftment was achieved on day +16 (+65). However, on day +31 (80) he developed a biopsy-proven B cell lymphoproliferative disorder (BLPD). After the OKT3 administration was stopped and treatment with ganciclovir and high-dose immunoglobulin was initiated, the BLPD resolved and the patient was discharged on day +50 (99). He is currently well with a functioning graft 266 (305) days posttransplant, with no sign of GVHD.

Anemia, Aplastic↗
PubMed1994

Detection and separation of the anthrapyrazole CI-941 and its metabolites in serum and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic method using ion-pairing chromatography on reversed-phase C18 material with a mobile phase of acetonitrile-water (19:81, v/v) containing 5 mM 1-pentanesulfonic acid was developed for the detection and separation of the anthrapyrazole CI-941 (I) and its metabolites. After sample clean-up with solid-phase extraction, I and its metabolites were measurable at a wavelength of 491 nm. A detection limit of 5 ng/ml was achievable for I. The dicarboxylic acid derivative and the isomers of the monocarboxylic acid derivative could be separated. Application of the method to a human pharmacokinetic study showed two and four metabolites of I in serum and urine respectively.

Anthraquinones↗
PubMed1994

Drug-induced changes in the expression of MDR-associated genes: investigations on cultured cell lines and chemotherapeutically treated leukemias.

The induced expression of multiple drug resistance (MDR)-associated genes as a direct response of tumor cells to antineoplastic drugs could be an important factor influencing the success of cancer chemotherapy. We investigated the effects of such compounds on mdr1/P-glycoprotein (P-gp) gene expression and drug sensitivities in the T-lymphoblastoid human cell line CCRF-CEM and MDR sublines. Thereby, we observed that actinomycin D or adriamycin administered at sublethal concentrations induced increases of mdr1 mRNA levels and resistance within 72 h. Furthermore, on leukemia cell samples collected before and after chemotherapy we checked by a complementary DNA polymerase chain reaction (cDNA-PCR) approach for similar alterations in the relative expression levels of the MDR-associated genes (a) mdr1/P-gp (b) mrp (MDR related protein), and (c) the topoisomerase II isoforms alpha and beta. We found a concomitant increase in mdr1 and mrp gene expression combined with a decreased expression of topoisomerase II alpha in the course of the second relapse of an acute lymphoblastic leukemia (ALL). This points to the emergence of at least three different MDR mechanisms in this type of leukemia unresponsive to chemotherapy. A chronic myeloid leukemia (CML) in blast crisis, however, showed combined increases in mdr1 (about 20-fold) and mrp (about four fold) gene expression after intense but unsuccessful chemotherapy over a 6-month period. Our results indicate the occurrence of induced resistance in vitro and in vivo and suggest a contribution of the newly identified ATP-binding cassette (ABC) transporter MRP in MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

[CT and HR-CT in the diagnosis of pulmonary complications of bone marrow transplantation].

The aim of this prospective study was to compare conventional and high resolution CT for demonstrating pulmonary complications. 23 patients treated by bone marrow transplantation were included in the study between December 1990 and August 1991. These patients were examined radiologically at regular intervals following the transplants. In 9 patients lung changes were detected by CT: there were pneumonic infiltrates, including one CMV pneumonia, two cases of mild parenchymal fibrosis, two cases of extensive lung fibrosis and one of miliary tuberculosis. The advantages and disadvantages of conventional and high resolution techniques are discussed in relation to our findings.

Adult↗
PubMed1994

Synthesis and structural elucidation of biliary excreted thioether derivatives of mitoxantrone.

1. Hplc-MS coupling has been used for the identification of thioether derivatives of the anticancer agent mitoxantrone in the bile of pig. 2. Three biologically relevant new thioether derivatives of mitoxantrone have been synthesized by a horseradish peroxidase-catalysed reaction. 3. The thioether derivatives have been characterized by means of ion-spray tandem mass spectrometry and nmr spectrometry including two-dimensional techniques. 4. The carbon-sulphur bond formation takes place at the hydroquinone moiety of the anthraquinone skeleton pointing to the importance of a tautomeric equilibrium between different species of the oxidized drug. 5. The occurrence of the synthesized compounds in biological systems suggests a metabolic pathway that may be relevant for the cytotoxicity of mitoxantrone (oxidative activation).

Animals↗
PubMed1994

Incidence of local CMV infection and acute intestinal GVHD in marrow transplant recipients with severe diarrhoea.

Intestinal biopsy samples derived from 22 consecutive patients with severe diarrhoea (> 1.5 1/day for 3 or more consecutive days) following allogeneic BMT were analysed for the local presence of cytomegalovirus (CMV) and histological and immunohistological alterations described as typical for acute graft-versus-host disease (GVHD). Seventeen patients showed extensive histopathological lesions typical for acute intestinal GVHD grade > I, 14 marked GVHD-related immunohistological alterations. In intestinal biopsies from 10 of these 22 patients CMV-DNA was detected using PCR- and in situ hybridisation techniques. In 7 of these 10 CMV-DNA positive samples CMV protein expression and in 5 cytomegalic cells were demonstrated. CMV could predominantly be shown in biopsies obtained from the ascending colon and/or the terminal ileum. All 10 patients with local CMV infection showed severe histopathological and immunohistological alterations described as typical for acute intestinal GVHD. Five of seven patients with a CMV-positive intestinal biopsy showed marked improvement of lower gastrointestinal tract disease on antiviral therapy. Five of seven patients lacking local presence of CMV but with severe histopathological lesions responded to therapy with high-dose steroids. Thus, PCR screening for CMV and histopathological analysis may help to treat lower intestinal disease in the marrow transplant recipient early and effectively.

Adolescent↗
PubMed1994

New approaches to the prophylaxis and treatment of bacterial and fungal infections in allogeneic marrow transplant recipients.

Bacterial and fungal infections continue to be a major threat to bone marrow transplant recipients. While standardized approaches to empiric therapy with early inclusion of antibiotics active against Gram-positive organisms and against fungi may have improved the outcome of these patients during the past decade, other developments (e.g. increasing number of patients in older age groups, unrelated donors, mismatch transplants) may even have increased the problem. Current approaches to the prophylaxis and treatment of these infections are discussed. Concerning fungal infections especially the new azoles and new approaches of amphotericin B administration are of interest.

Anti-Infective Agents↗
PubMed1994

Busulfan pharmacokinetics in bone marrow transplant patients: is drug monitoring warranted?

Pharmacokinetics were studied in relation to hepatic side-effects in 20 patients (19 adults aged 18-53 years and one child of 11 years) undergoing BMT after conditioning with 1 mg/kg busulfan (every 6 hours for 16 doses). Busulfan was quantitated in plasma samples at 10 time points within the 6 h dosing interval using HPLC before and after dose numbers 1, 2, 5, 13 and 14. For 13 patients data on all five doses are available; for the remaining seven patients three to four doses were studied. Mean maximum concentrations were 1512 ng/ml; mean trough levels for second and subsequent doses were 615 ng/ml. Maxima (Cmax) tended to be lower and times of maxima (Tmax) were later when busulfan was taken with a meal. Correlation of the area under the concentration versus time curve (AUC0-6h) between different doses was low within patients. In several patients problems with compartmental fitting of concentration data were observed mainly caused by the short dosing interval, which made estimates of T1/2 and model derived AUCs unstable. Three patients experienced hepatic veno-occlusive disease; kinetic parameters were not helpful in describing a particulate risk constellation for this subgroup. In our experience, the role of drug monitoring in this setting needs to be defined more clearly.

Adolescent↗
PubMed1993

Cytochrome P-450-induced cytotoxicity of mitoxantrone by formation of electrophilic intermediates.

Recent studies of our group have shown that the oxidation of the substituted anthraquinone skeleton is involved in the biotransformation of mitoxantrone. In this report the importance of this process with regard to the mode of action of the drug is investigated. This communication describes a new high performance liquid chromatography separation for mitoxantrone and its metabolites allowing the direct coupling of high performance liquid chromatography to mass spectrometry. Application of this technique to bile of mitoxantrone-treated pigs reveals the formation of several metabolites in addition to the drug-derived compounds found in urine. Seven biliary metabolites are identified as thioether derivatives of mitoxantrone and its side chain oxidation products. Independent synthesis and structural elucidation of 3 thioether conjugates of the drug provides unequivocal evidence that the hydroquinone moiety of mitoxantrone is the site of reaction with glutathione. Furthermore, the formation of the thioether conjugates in HepG2 hepatoma cells and in rat hepatocytes during cell incubations is demonstrated. Inhibition of cytochrome P-450 with metyrapone prevents the formation of the thioether conjugates and leads to a complete loss of the cytotoxicity of mitoxantrone in HepG2 cells and rat hepatocytes up to concentrations of 200 to 400 microM thereby indicating that mitoxantrone has a negligible effect by itself. Rat hepatocytes were found to be more susceptible for the oxidation-induced cytotoxicity than HepG2 cells. These results demonstrate that the acute cytotoxicity of mitoxantrone depends on prior oxidation of its 1,4-dihydroxy-5,8-diaminoanthraquinone moiety.

Animals↗
PubMed1993

Lymphocytopenia as an unfavorable prognostic factor in patients with cytomegalovirus infection after bone marrow transplantation.

Sixty-three recipients of an allogeneic marrow transplant were screened for the occurrence of cytomegalovirus (CMV) infection and clinical parameters possibly predicting the development of CMV disease in a retrospective study. Blood and urine samples obtained from these patients were screened weekly after bone marrow transplantation (BMT) for the presence of CMV by polymerase chain reaction (PCR) and virus culture technique. Forty-six of the 63 patients studied were found to be CMV-positive by PCR technique in blood and urine samples at a median of 29 days after BMT. In 33 of these 46 patients, CMV could be cultured from urine samples and 16 of the 46 had culture-positive viremia. Twenty-eight of these 46 PCR-positive patients developed CMV disease. Whereas PCR assays showed an optimal negative predictive value and sensitivity for the development of CMV disease, their positive predictive value was 61% and could not be remarkably increased when culture-proven viruria (64%) and viremia (69%) were considered. Acute graft-versus-host disease (GVHD) grade 2 to 4 (P < .05), but not underlying disease, conditioning therapy, or GVHD prophylaxis, was associated with CMV infection. On day +49, a remarkable decrease (P < .001) in the lymphocyte count, as well as in the absolute number of CD4+, CD8+, and CD56+ lymphocytes, occurred only among the patients who later developed CMV disease. The decrease of all of these cell counts, but predominantly the CD4+ T cells, to less than 100/microL on day +49 after BMT showed a very high positive predictive value (100%) for the development of CMV disease in patients with PCR-proven viremia. Persisting CD4 lymphopenia after antiviral therapy was only observed in patients who finally died of CMV disease. Thus, immunophenotyping of the patients after BMT in addition to a highly sensitive virus detection assay might help to identify patients at high risk to develop CMV disease and indicate the need for additional adoptive immunotherapy.

Adolescent↗
PubMed1993

Leukemic red bone marrow changes assessed by magnetic resonance imaging and localized 1H spectroscopy.

Red bone marrow of healthy persons has considerable contents of water and lipids. The cellularity and the corresponding fat-water ratio within the marrow show clear changes in hematological diseases. Magnetic resonance (MR) methods use the signals of the protons of water and lipids. This paper gives a comparison between different standard MR techniques and recently developed fat- and water-selective imaging methods, addressing their sensitivity to bone marrow changes in leukemia. Additionally, 1H results of spectroscopic methods are presented. The results and conclusions are based on the examination of 26 healthy volunteers and 106 patients with general or focal bone marrow alterations. Standard T1-weighted images did not distinguish bone marrow of young healthy volunteers with relatively high cellularity from acute leukemia. Using fat- and water-selective methods, patients with untreated leukemia showed only water proton signals and no lipid signals from red bone marrow of vertebral bodies and the pelvis. This phenomenon was never observed in healthy volunteers. Following chemotherapy, lipid and water contents normalize in successfully treated patients. Nonresponders did not show significant changes of the fat-water ratio after up to 3 weeks of therapy. Phase contrast imaging provides information about the difference between fat and water fractions within the bone marrow, but quantitative determination of the absolute fat and water fractions requires acquisition of several images and suffers from the susceptibility effects in trabecular bone marrow. The fat-water ratio and additional qualities of water and lipid protons (relaxation times) can be evaluated by volume-selective MR spectroscopy. Typical results of spectra from small-volume elements in hypercellular vertebral bone marrow of leukemic patients before cytotoxic treatment and of normocellular or hypocellular marrow after therapy are demonstrated.

Adolescent↗
PubMed1993

Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. Multicentre Study Group.

An open, randomized study was performed at 18 European centres to compare the efficacy, safety and tolerance of oral fluconazole with oral polyenes for the prophylaxis of fungal colonization and infection in adults at high risk of developing neutropenia. Five hundred and thirty-six hospitalized patients with malignant disease, about to receive chemotherapy, radiotherapy, or bone marrow transplantation, and who were already neutropenic or were expected to develop neutropenia were included in the study. Before therapy or transplantation, patients commenced either oral fluconazole therapy (50 mg/day as a single dose) or oral polyenes therapy (amphotericin B 2 g/day and/or nystatin 4 x 10(6) units/day in four or more divided doses), for a mean of 29.3 days and 31.3 days, respectively. After baseline clinical and mycological testing, patients were re-evaluated at least weekly during prophylaxis, at the end of prophylaxis and two to six weeks later to identify proven or suspected fungal infection and to determine rates of colonization with fungi. Fungal infection was diagnosed in 41 of 511 evaluable patients, 10 (3.9%) of 256 in the fluconazole group and 31 (12.2%) of 255 in the polyene group (P = 0.001). This total included four patients (1.6%) in the fluconazole group who developed oropharyngeal candidiasis compared with 22 (8.6%) in the polyene group (P < 0.001). Systemic infections comprised 6 (2.3%) in the fluconazole group and 9 (3.5%) in the polyene group (P = not significant), and included three Candida krusei infections in each group. Parenteral amphotericin B therapy was given empirically for persistent fevers in an additional 62 (24.2%) patients receiving fluconazole and 59 (23.1%) receiving polyenes (P = not significant). Colonization with fungi was generally similar in each treatment group, although an increased proportion of patients receiving fluconazole developed colonization of the faeces (P < 0.01). Adverse reactions, possibly related to treatment, were recorded in 15 (5.6%) of 269 patients in the fluconazole group and 14 (5.2%) of 267 in the polyene group; these necessitated discontinuation of therapy in seven patients in each group. Once-a-day fluconazole was therefore more effective than oral polyenes for the prevention of oropharyngeal fungal infection and as effective for the prevention of infections at other sites in patients with neutropenia.

Administration, Oral↗
PubMed1993

Secretion of IL-2, IL-3, IL-4, IL-6 and GM-CSF by CD4+ and CD8+ TCR alpha beta+ T-cell clones derived early after allogeneic bone marrow transplantation.

Secretion of different cytokines may be an important T-cell effector mechanism for bone marrow engraftment, graft versus host disease and graft versus leukaemia effects after allogeneic bone marrow transplantation (BMT). Cytokine secretion and autocrine proliferative capacity of T-cell clones derived from leukaemia patients 3-6 weeks after allogeneic bone marrow transplantation were investigated. Only a minority of post-transplant T-cell clones (23/120; 19%) was capable of undergoing autocrine proliferation. By contrast, 21/65 (32%) normal control clones from the marrow donors derived under the same conditions were autocrine proliferative. All clones were interleukin-2 (IL-2) responsive. A majority (12/17; 71%) of autocrine proliferating post-transplant clones secreted detectable IL-2. Compared with control clones, CD4+ T-cell clones derived early after BMT produced decreased levels of interleukin-4 (IL-4) and interleukin-6 (IL-6), whereas secretion of interleukin-3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) showed no significant difference. The small number (n = 8) of posttransplant CD8+ clones showed decreased production of IL-3, IL-4 and IL-6 compared with control clones, but normal secretion of GM-CSF. Neither CD4+ nor CD8+ T-cell clones secreted interleukin-7 (IL-7).

Adult↗
PubMed1993

IFN-gamma and TNF-alpha secretion by CD4+ and CD8+ TCR alpha beta + T-cell clones derived early after allogeneic bone marrow transplantation.

Secretion of the potentially antileukaemic cytokines IFN-gamma and TNF-alpha was investigated for CD4+ and CD8+ TCR alpha beta + T-cell clones derived from 4 leukaemia patients 3-6 weeks after allogeneic BMT. We investigated cytokine secretion in response to the activation signal accessory cells+phytohaemagglutinin+Interleukin 2. All clones derived after BMT were capable of IFN-gamma and TNF-alpha secretion, and both for CD4+ (n = 96) and CD8+ (n = 8) T cells quantities of IFN-gamma and TNF-alpha were significantly correlated with one another. When comparing the overall results for posttransplant and normal T-cell clones derived from 2 bone marrow donors (n = 65), both CD4+ and CD8+ TCR alpha beta + T-cell clones showed increased IFN-gamma production, and CD4+ but not CD8+ clones showed a decreased TNF-alpha secretion. The results suggest that noncytotoxic T cells derived after allogeneic BMT can produce IFN-gamma and TNF-alpha and may thus be capable of mediating antileukaemic effects.

Adult↗