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Biomedical subjects

G Ehninger

Publications and source records attributed to G Ehninger.

At least 235 records · Page 13Linked to original sources

Immunohistology of the human spleen after bone marrow transplantation for leukemia with special reference to the early post-transplantation period.

Immunohistochemical investigations were undertaken on paraffin-embedded tissue from the spleens of seven patients who had died after bone marrow transplantation (BMT) for leukemia. Parallel investigations were undertaken on three surgically resected traumatically ruptured (but otherwise normal) spleens and three spleens removed at autopsy from accident victims. 1) Up to ten weeks after BMT, the splenic lymphoid tissue was extremely atrophic. Lymphoid follicles (LFs) and periarteriolar lymphatic sheaths (PALS) were completely absent. A considerable increase in lymphoid cells in the red pulp and formation of small LFs and PALS occurred only in the longest surviving patient, who had died 50 weeks after BMT. 2) B cells (L26+, 4KB5+, Ki-B3+) were almost completely absent in the early post-transplantation period and thus T cells (UCHL1+) represented the major constituent of the hypoplastic splenic lymphoid tissue. Considerable numbers of T cells were already found two weeks after BMT. T-immune-accessory reticulum cells (S-100 protein+) were found in the PALS of the controls, but were absent in three of the BMT recipients. The findings clearly reflect the marked immunodeficiency in the early post-transplantation period, during which many patients (4/7 in this study) die of opportunistic infections, and are in line with the fact that the earliest signs of reconstitution of the immune system have been found to occur at three months post-transplantation. Since six of our BMT recipients had suffered from graft-versus-host disease our findings probably do not fully correspond to those when the immune system undergoes undisturbed reconstitution.

Adolescent↗

Plasma vitamin E and beta-carotene concentrations during radiochemotherapy preceding bone marrow transplantation.

Blood from 19 patients was examined for the essential antioxidants alpha-tocopherol and beta-carotene before, during, and after bone marrow transplantation (BMT). Marrow ablation and immunosuppression for BMT conditioning was achieved by treatment with high-dose chemotherapy, mostly combined with total body irradiation. All patients required total parenteral nutrition beginning 1 wk before BMT. After conditioning therapy the concentration of absolute and lipid-standardized alpha-tocopherol and beta-carotene in plasma decreased significantly, presumably as a result of an enhanced breakdown of these antioxidants. The loss of these lipid-soluble antioxidants has to be considered as a possible cause for early posttransplant organ toxicity.

Adolescent↗

8-Methoxypsoralen and ultraviolet A therapy for cutaneous manifestations of graft-versus-host disease.

The potentially beneficial effect of 8-methoxypsoralen and ultraviolet A (PUVA) irradiation for treatment of drug-resistant cutaneous manifestations of graft-versus-host disease led us to investigate the effect of this therapy in a larger series of patients with GvHD. To date, 11 patients with histologically demonstrated cutaneous GvHD (acute GvHD grade III-IV in 4 patients, extensive lichenoid chronic GvHD in 6 patients, sclerodermatous chronic GvHD in 1 patient) have received PUVA treatment for 2-24 weeks. All patients have been on CsA for GvH prophylaxis; 5 with mismatched grafts had additionally received methotrexate or monoclonal antibody campath-1 after bone marrow transplantation. Seven patients were on CsA and prednisolone; 2 patients on CsA, prednisolone, and azathioprine; 1 patient on azathioprine and prednisolone; and 1 patient had no immunosuppressive treatment for the duration of PUVA treatment. The 8-methoxypsoralen (0.6 mg/kg bw) was given as photosensitizer before each ultraviolet A irradiation (0.3-8.5 joules/cm2). The only observed adverse reaction was mild nausea. In all patients improvement of cutaneous lesions could be observed with complete response in 5 patients and partial response in 6 patients. Immunosuppressive drugs could be withdrawn in 2 patients and reduced in 8 patients after initiation of PUVA treatment. These findings suggest that PUVA therapy may be a useful adjunct to conventional therapy for cutaneous GvHD.

Adolescent↗

Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients.

The effect of the 4-quinolone antimicrobial agent ciprofloxacin on the concentration in plasma and the pharmacokinetics of the immunosuppressive agent cyclosporine was studied in 10 bone marrow transplant recipients. There were no statistically or clinically significant changes in cyclosporine trough concentrations or areas under the concentration-time curve following oral doses of 500 mg of ciprofloxacin every 12 h for 4 days. The data suggest a lack of relevant pharmacokinetic interaction of ciprofloxacin with cyclosporine. There was no indication of an enhanced nephrotoxicity for this drug combination.

Adult↗

[Continuous infusion of natural interleukin 2 (n IL-2) in treatment of malignant diseases: phase I study].

This is the first report of a phase I study with n-IL 2. N-IL 2 shows a higher biological activity and different immunomodulatory effects compared to recombinant IL 2. 14 patients (9 male, 5 female) entered our phase I study with continuous i.v. n-IL 2 with a median age of 40 years (range 4-65), including 4 children. The study design was a dose rising continuous iv infusion over 5 days with a starting dose of 1 x 10(6) U n-IL 2 up to 6 x 10(6) n-IL 2 over 24 h. In 2 of 16 regimen with n IL-2 there was a dose reduction and in 6 there was an interruption necessary. In 2 patients there was only a dose reduction necessary because of thrombocytopenia and hypotension. In 6 patients n-IL 2 had to break the continuous infusion. Reasons were an increasing BUN, respiratory insufficiency, thrombocytopenia, neurological symptoms and increasing liver enzymes. The 4 children developed an other side effect profile with edema of the face, abdominal cramps and thrombocytopenia. During the study no intensive care was necessary. The most common side effects were erythema, fever, nausea, dyspnea and hypotension. There was no complete remission, 21.5% of the patients had a partial remission, 7% showed no change and 71.5% had a progression. There were no significant differences in toxicity and response was comparable to studies using continuous r IL-2.

Adolescent↗

Pharmacokinetics and metabolism of mitoxantrone. A review.

Mitoxantrone, a cytotoxic anthracenedione derivative, has given clinical evidence of beneficial activity in breast cancer, lymphoma and leukaemia. Several different mechanisms of action have been suggested to account for this. In addition to intercalation, biological effects such as electrostatic interactions with DNA, DNA-protein cross-links, immunosuppressive activities, inhibition of topoisomerase II, prostaglandin biosynthesis and calcium release have been described. Various methods of drug monitoring in biological fluids and tissues are available: the highest sensitivity has been achieved with high performance liquid chromatography with electrochemical detection, radioimmunoassay and enzyme linked immunosorbent assay. Early pharmacokinetic studies of mitoxantrone in experimental animals using radioactive material showed an extensive tissue distribution and a long terminal plasma half-life. The best fit for the plasma concentration-time curve in humans is achieved in a 3-compartment model. All studies reported a short absorption half-life of between 4.1 and 10.7 minutes, with the distribution phase being between 0.3 and 3.1 hours. In contrast, the values of the terminal half-life are quite variable, ranging from 8.9 hours to 9 days. Differences might be attributed to assay sensitivity, number and weighting of data points beyond 24 hours and coadministration drugs. Many studies showed a very large volume of distribution with sequestration of mitoxantrone in a deep tissue compartment. In autopsy studies, relatively high tissue concentrations have been measured in liver, bone marrow, heart, lung, spleen and kidney. Bile is the major route for the elimination of mitoxantrone, with lesser amounts excreted in the urine. Several metabolites have been separated, 2 of which were identified as the monocarboxylic and dicarboxylic acid derivatives. Mitoxantrone is usually administered by rapid intravenous infusion at 3-weekly intervals; other regimens include continuous infusion, daily repeated doses or weekly administration. In peritoneal carcinosis, the pharmacological advantage of intraperitoneal administration is clear. The optimal regimen for different disease categories with respect to efficacy and side-effects remains to be determined in future clinical trials.

Animals↗

Lymphokine release, suppressor cell generation, cell surface markers, and cytotoxic activity in cancer patients receiving natural interleukin-2.

We monitored patients treated for 5 days with continuous infusion of increasing doses (3 to 6 x 10(6) U/d) of natural interleukin-2 (IL-2). CD16+, CD25+, and CD56+ cells increased after treatment. Plasma tumor necrosis factor-alpha (TNF-alpha) levels, but not interferon-gamma (IFN-gamma) levels, increased during IL-2 treatment, but spontaneous and IL-2-stimulated TNF-alpha secretion in vitro remained abnormally low. However, mitogen-stimulated TNF-alpha release was normal. Mitogen-stimulated, but not IL-2-stimulated, IFN-gamma release was strongly depressed. Low spontaneous and IL-2-stimulated cytotoxicity on K562 or Daudi increased after treatment. Low suppressor cell generation also normalized after treatment. This appears to be the first reported study of immunologic monitoring of cancer patients treated with natural rather than recombinant IL-2.

Antigens, Differentiation↗

Bone marrow transplantation in comparison with conventional therapy in children with adult type chronic myelogenous leukemia.

From 1983 to 1988 14 patients under 16 years of age with adult type chronic myelogenous leukemia (CML) in chronic or blastic phase were treated by allogeneic bone marrow transplantation (BMT) in our center. These comprise 54% of all patients under 16 years of age grafted for this disease in FRG. These BMT patients were compared with 24 similar patients treated conventionally with busulfan and/or hydroxyurea in various centers. The probability of an event-free survival 5 1/2 years after BMT was 0.61 (SD 0.16); the estimated probability of survival for 3-8 years after diagnosis in the group treated by GMT was 0.78 (SD 0.14) vs 0.55 (SD 0.12) for the non-BMT group. The difference is not significant. In the BMT group only two patients died of transplant-related complications. The non-BMT patient with the longest survival period died recently 10 years after diagnosis. For children with adult type CML, BMT is a safe and effective treatment, and should be recommended if there is an HLA compatible sibling donor or even a fully compatible unrelated donor. However, for a more conclusive comparison between bone marrow transplantation and conventional treatment a longer observation period and larger patient numbers are necessary.

Adolescent↗

[Severe hard tooth structure decay following full body radiotherapy prior to bone marrow transplantation].

A case of severe hard tooth structure decay in a patient aged 31 following bone marrow transplantation is presented. So far tooth decay of such severity was only found in connection with radiotherapies for oral and maxillofacial malignomas. Scanning electron micrographs of 4 extracted teeth reveal different degrees of enamel and dentine decay. Major areas of exposed dentine, particularly at the buccal and incisal surfaces where the enamel has broken off in splinters, show massive growth of bacteria. The dentinoenamel junction is also extensively involved. Implications for dental care of bone marrow transplant patients during and after treatment are being discussed.

Adult↗

[Initial experiences with pentamidine aerosol in prevention of Pneumocystis carinii pneumonia following bone marrow transplantation].

After bone marrow transplantation there is a risk of 10% to acquire a pneumonia caused by pneumocystis carinii, if no prophylaxis is used. So far cotrimoxazol is the treatment of choice from day -14 before to day +180 after bone marrow transplantation. This substance, however, may cause allergic reactions, may augment the risk of nephrotoxicity of other drugs, and may be myelosuppressive. The prophylaxis with pentamidine-inhalation was used in 26 patients after bone marrow transplantation so far. It could be shown, that after salbutamol-inhalation 60 to 300 mg of pentamidine can be given safely in 14 to 28 days intervals. The main side effects were cough and dyspnea in some patients. Only minimal amounts of the drug could be detected in serum and urine after application. No toxic side effects and no pneumocystis carinii pneumonia were observed.

Administration, Inhalation↗

Detection and separation of intracellular 1-beta-D-arabinofuranosylcytosine-5-triphosphate by ion-pair high-performance liquid chromatography.

An ion-pair high-performance liquid chromatographic method, using a reversed-phase C18 column, was developed to provide an isocratic, sensitive, fast and reproducible separation of intracellular 1-beta-D-arabinofuranosylcytosine-5-triphosphate and its measurement at a low limit of 5 pmol by ultraviolet absorbance at 280 nm with a coefficient of variation lower than 10%. A rapid separation is achieved by using a backflush procedure at 16 min and the retention time is 14 min.

Arabinofuranosylcytosine Triphosphate↗

[Transplantation of bone marrow from unrelated donors in chronic myeloid leukemia].

Bone marrow transplantations in four patients (aged 8-28 years, median 27 years) with chronic myeloid leukaemia (CML) were performed from unrelated donors who were HLA-identical and MLC-negative. One patient was in the stage of refractory blast crisis, one in a chronic phase, and two in the second chronic phase. Conditioning treatment consisted of fractionated radiation and administration of cyclophosphamide; in the patients with their second chronic phase additionally etoposide. Cyclosporin A and methotrexate were administered to prevent graft versus host reaction. The patient in the blast crisis died on day 12 after transplantation of Candida pneumonia. The other three patients are still alive 128, 306 and 530 days, respectively, after transplantation, only a mild form of graft versus host disease having occurred. It is suggested that for patients younger then 50 years with CML in the chronic phase an unrelated donor should be searched for in the absence of a familial donor.

Bone Marrow Transplantation↗

[Pharmacokinetics of cisplatin in long-term hemodialysis treatment].

A 66-year-old woman with ovarian cancer which had metastasized was receiving chemotherapy with cisplatin and cyclophosphamide while undergoing haemodialysis for chronic renal failure. Cisplatin concentration in plasma was measured by flameless atomic absorption spectroscopy. After infusion of 40 mg cisplatin/m2 body-surface peak levels of 2.06 micrograms/ml and 2.29 micrograms/ml were obtained after the second and third treatment cycles, respectively. Terminal half-life was 14 days. Clearance value during haemodialysis was 470 ml/min. Seven treatment cycles were administered, up to doses of 60 mg/m2 cisplatin and 600 mg/m2 cyclophosphamide. Complete remission occurred after five treatment cycles. But the patient died 22 months after onset of treatment from an acute non-A, non-B hepatitis.

Aged↗

Partial correction of defective generation of lymphokine-activated killer cells in patients with chronic myelogenous leukaemia after in vivo treatment with interferon-alpha (Wellferon).

Patients with chronic myelogenous leukaemia (CML) in untreated chronic phase are deficient in their ability to generate lymphokine-activated killer (LAK) cells from peripheral blood mononuclear cells although they possess essentially normal levels of CD16+ and Leu19+ lymphocytes, which do not seem to be actively suppressed by tumour cells. Attempts to enhance LAK cell generation in these patients are reported here. Combining the lymphokines interleukins-2, with -4 and -5 (IL-2, IL-4, IL-5), was not successful; in fact, IL-4 depressed LAK cell induction in both normal donors and CML patients. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate also failed to enhance cytotoxicity of normal donors or patients, and indomethacin was similarly without effect. The only agent found to enhance LAK cell induction by IL-2 in normal donors was interferon-gamma (but not IFN-alpha) and even this modest effect was not seen with the cells of CML patients. Increasing concentrations of IL-2 and/or culture duration also failed to improve LAK cell generation by patients. The only improvement in LAK cell generation was observed in CML patients treated for one or more months with IFN-alpha, where a steady increase of LAK activity with time after initiation of therapy was noted. These results show that the blockade of LAK cell induction in chronic-phase myelogenous leukemia patients is difficult to lift pharmacologically in vitro but possibly susceptible to biological response modifiers in vivo.

Cells, Cultured↗

Effect of etoposide (VP16-213) on lipid peroxidation and antioxidant status in a high-dose radiochemotherapy regimen.

A total of 13 patients receiving bone marrow transplants (BMT) for treatment of different haematological diseases were investigated. Conditioning therapy preceding BMT consisted of fractionated total-body irradiation (12 Gy) and high-dose chemotherapy with cyclophosphamide (2 +/- 60 mg/kg). Patients stratified to be at high risk for relapse (6/13) were additionally treated with etoposide (30 mg/kg). Plasma concentrations of absolute and lipid-standardized antioxidants (alpha-tocopherol and beta-carotene) decreased following conditioning therapy, presumably as the result of an enhanced breakdown of these antioxidants. Etoposide treatment did not amplify the loss of essential anti-oxidants but significantly increased lipid hydroperoxide concentrations in serum. We suggest that the abnormal generation of lipid hydroperoxides is the result of free radical formation.

Anemia, Aplastic↗

[131I]-metaiodobenzylguanidine in the treatment of metastatic neuroblastoma. Clinical, pharmacological and dosimetric aspects.

Ten children with stage III or IV neuroblastoma that had either relapsed or was refractory were treated with [131I]-metaiodobenzylguanidine (MIBG) from 1984 to 1986. The total dose ranged from 4,365 to 21,900 MBq and was given in one to five courses. Two patients achieved a complete remission (CR), two, a partial remission (PR), and three, an arrest of the disease. Pharmacological studies showed that 93% of detectable radioactivity was attributable to MIBG at the beginning of the infusion. However, by the end of the infusion this had decreased to 88%. The terminal half-life of MIBG was 37.0 h, whereas that of non-MIBG-bound iodine was 71.6 h. Therefore, the radioactivity-time product of non-MIBG-bound 131I was much higher than that of MIBG. Dosimetric studies showed a mean level of absorbed radiation for the total body of 160 microGy/MBq, a liver irradiation of 540 microGy/MBq and a mean tumour radiation of 10,500 microGy/MBq.

3-Iodobenzylguanidine↗