[Who reports on the side effects of drugs?].
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Biomedical subjects
Publications and source records attributed to R Hast.
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In order to study the effect of oxymetholone therapy in advanced myelofibrosis, 11 patients (4 females, 7 males) were given, 3--5 mg per kg body weight, long-term oxymetholone treatment in a prospective multicenter study. Five cases had previously had a diagnosis of polycythemia vera. All patients had anemia initially, 4 leukocytopenia and 10 thrombocytopenia in addition. Hepato-splenomegaly was present in all cases but in varying degree. Five patients required regular blood transfusions before treatment. In 9 of the 15 courses given, there was normalization of the peripheral blood or substantial improvement (better than 3 g hemoglobin/dl or 50 X 10(9) platelets/1) after androgens. Significant effects were noted both on hemoglobin values and platelet counts. The need for blood transfusions ceased completely in all 5 cases. When oxymetholone treatment was reduced or interrupted 4 patients relapsed; 2 of them responded to a renewed course. The red cell counts returned to previous polycythemic values in one patient and another died from acute leukemia. The results of this study suggest that androgens might be of value in advanced cases of myelofibrosis with transfusion-requiring anemia or severe thrombocytopenia.
In four patients with chronic myelocytic leukemia, a solitary rise in serum alkaline phosphatase (S-ALP) was noted 2--12 months prior to death. All patients had received busulphan (Myleran) therapy for longer than 12 months (total dosage 1.0--2.4 g). It is suggested that the increase in S-alp was due to a cholestatic liver damage, possible secondary to the busulphan treatment.
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The prognostic significance of the bone marrow sideroblasts found in aregenerative anaemia with hypercellular bone marrow was evaluated particularly to see if the sideroblasts might be a preleukaemic sign. The study includes 32 patients with abnormal sideroblasts; 14 had mainly ringed sideroblasts while 18 had mainly the intermediate or ferritin type. Basic erythrokinetic data (59Fe erythrocyte incorporation and erythroblast labelling indices) were similar in the two groups. The colony forming capacity (CFUc) was abnormal in 2 of 5 patients with ringed sideroblasts compared to 12 of 13 in the intermediate sideroblast group. Patients with mainly ringed sideroblasts had significantly longer duration of disease state, higher platelet and leucocyte counts, no increase in the percentage of bone marrow myeloblasts and did less often develop acute leukaemia. Thus aregenerative anaemias can be divided according to the type of abnormal sideroblasts in two groups with different risk of development of acute leukaemia. The ringed sideroblastic anaemia seems not to be a preleukaemic stage in the prospective sense in contrast to aregenerative anaemia with mainly intermediate sideroblasts.
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In 34 patients with aregenerative anaemia and hypercellular bone marrow, a condition earlier suggested to be of a preleukaemic nature, erythroblast thymidine labelling indices (LI) were significantly decreased, as would be expected in preleukaemia. The 59Fe erythrocyte incorporation after 2 weeks was generally low. The 59Fe plasma clearance was fast in 22 of 31 patients, normal in 5 and moderately prolonged in 4. These 4 patients had a low relative number of erythroblasts in the marrow. A significant relationship between the marrow erythroblast number and the 59Fe plasma clearance could be demonstrated. Cases with an increased number of mueloblasts in the marrow did differ significantly from the rest in LI and iron incorporation.
This is a prospective multi-center study in which patients with aregenerative anaemia were treated with a standardized high dosage regime of an anabolic steroid (oxymetholone, Anasteron). 53 patients were included and divided into two groups according to bone marrow cellularity. Furthermore the hypocellular group was subdivided in order to make comparison with earlier studies possible. In the hypocellular group, the frequency of remission was 56% and the 2-year-survival from the onset of symptoms was 75%. This is longer than in some earlier studies, perhaps because of possible differences in etiology and/or because of the effect of systematic high dosage, long term androgen therapy. Patient selection was minimized and was not considered to be of major importance. Patients with hypercellular marrows, on the other hand, responded poorly to androgens. In this group 63% died of acute leukaemia, which confirms earlier suggestions that this form of aregenerative anaemia, frequently is of a preleukaemic nature.
Ten patients with the myelodysplastic syndrome (eight with anemia, two with granulocytopenia, four with thrombocytopenia) were given etretinate (ER) and retinoid acid (RA). No correlation was seen between the RA effect in vitro and its clinical effect. No effect was seen of the ER-treatment or of the RA-treatment on anemia, thrombocytopenia or the abnormal karyotype seen in three patients. In three of eight patients given RA a decreased blast cell percentage in the bone marrow was seen, and in two of these there was also a normalization of the in vitro bone marrow cell colony formation. We found no clinical effect of ER and only a minimal one of RA.
Recombinant human granulocyte/macrophage colony-stimulating factor (rhGM-CSF) was administered to a patient with multiple myeloma (IgA, stage IIA) who had a chemotherapy-induced bone marrow aplasia with granulocytopenia complicated by severe pneumonia and septicemia. The rhGM-CSF was given as i.v. infusions, 300-400 micrograms daily, for three weeks. The patient responded both hematologically and clinically with improved granulocyte counts and clearance of massive pulmonary infiltrates. We also observed a partial remission of the myeloma with decreasing s-IgA levels and reduced plasma cell infiltration of the bone marrow during a period of up to four months after the rhGM-CSF treatment. Immunological studies performed during and after cytokine administration showed an increase in serum interleukin-2 (IL-2) levels and HLA-DR positive T-lymphocytes indicating an activation of the immune system. It is suggested that rhGM-CSF induced immunological changes which may have contributed to the partial regression of the myeloma.
The levels of TNF-alpha and IFN-gamma were examined in serum from 32 patients with multiple myeloma and 33 healthy controls using sensitive enzyme-linked immunosorbent assays (ELISA). The detection limits for TNF-alpha and IFN-gamma were 80 pg/ml and 200 pg/ml, respectively. All samples were obtained at the time of diagnosis, before treatment. In sera from 8 of the myeloma patients the TNF-alpha concentrations were above the detection limit with a maximum value of 1.0 ng/ml. Overall, the TNF-alpha levels of the myeloma patients did not differ from the levels of the control group. Detectable amounts of IFN-gamma were found in 17 of the patient sera with 10.7 ng/ml as the top value. In contrast, the control group showed significantly lower s-IFN-gamma levels without detectable amounts in any of the samples (p less than 0.01). High IFN-alpha levels in 4 patients coincided with intercurrent infections but were not accompanied by a parallel increase of the TNF-alpha levels. The TNF-alpha and IFN-gamma values were compared with the serum levels of beta 2-microglobulin, calcium and creatinine, the M-component, the erythrocyte sedimentation rate, the degree of plasma cell infiltration of the bone marrow, the degree of skeletal destructions and with patients survival. No significant correlations could be observed between TNF-alpha or IFN-gamma and these variables of myeloma activity. We conclude that detection of serum TNF-alpha and IFN-gamma levels in multiple myeloma appears to be without any clinical value.
Survival, causes of death and hospitalization have been studied in 99 patients with the myelodysplastic syndrome. The median survival of the patients was 702 days, and the 10 year actuarial survival only 10 per cent, which is not significantly better than the corresponding figures in the remission stage of AML. Although MDS-patients who developed acute leukemia had significantly (p less than 0.05) more platelets, they also had significantly (p less than 0.05) more major bleeding as a contributory cause of death than patients who did not develop leukemia. Bleeding seems to be diagnosed only in 12 per cent in vivo, whereas major bleeding is found at autopsy in 38 per cent of the patients. The patients who did not develop leukemia died significantly (p = 0.018) more often of cardiovascular causes. MDS patients spend one sixth of their remaining life in hospital, on an average. This is true both for those who develop leukemia and for those who do not. The terminal hospital stay lasts an average of 24 days, which is comparable to the figure for myeloma.