Tumour necrosis factor, cholestatic jaundice, and chronic liver disease.
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Biomedical subjects
Publications and source records attributed to C Viner.
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50 previously untreated patients with multiple myeloma received two-phase treatment: repeated cycles of 4 day infusion with vincristine, doxorubicin, and methylprednisolone (VAMP) followed by high-dose melphalan (HDM), with autologous bone marrow transplantation where possible. The overall response rate was 74% (37/50), with 25 patients (50%) achieving complete haematological and biochemical remission. These remissions were associated with a good quality of life as measured by performance status, pain grade, and the reversal of humoral immunosuppression. 6 patients died during the VAMP phase and there was 1 death related to HDM. The achievement of complete remission, as defined here, in such a high proportion of patients is exceptional and may represent a useful advance in the management of myeloma.
In three studies we have attempted to increase the complete remission rate in a series of patients with multiple myeloma under the age of 69. A CR rate of 27% was seen in 63 patients treated with intravenous high-dose melphalan 140 m/m2 with or without the addition of high-dose methyl prednisolone 1 g/m2 for 5 days (in 22 patients). In a third study a CR rate of 50% was seen in 50 patients treated in a programme in which vincristine, adriamycin and methyl prednisolone was first given and patients then received high-dose melphalan 140-200 mg/m2 with an autologous bone marrow transplant where possible. Median remission duration in the first two studies was 19 months with a median survival of 5 years. A definition of complete remission in myeloma is proposed.
Fifty previously untreated patients with myeloma were entered into a 2-phase treatment programme: vincristine, adriamycin and methyl prednisolone (VAMP) followed by high dose intravenous melphalan (HDM) with autologous bone marrow transplantation where possible. The complete remission rate of 50% was associated with very good quality of life and the reversal of humoral immunosuppression. Complete remission is important in younger patients with myeloma as it represents a first step in achieving long, symptom- free survival.
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Forty-five patients with relapsed or refractory multiple myeloma received continuous infusions of vincristine (0.4 mg total dose daily for 4 days) and adriamycin (9 mg m-2 daily for 4 days) with a high dose of methylprednisolone (1 g m-2 i.v. or p.o. daily by 1 h infusion), the VAMP regimen. Sixteen (36%) responded, with a median duration of remission of 11 months and median survival of 20 months. Major toxicities encountered were infective and cardiovascular. Two smaller groups of myeloma patients were treated with high dose methylprednisolone (HDMP) alone, or VAMP plus weekly low dose cyclophosphamide (Cyclo-VAMP). HDMP produced short responses in 25% of patients with less toxicity than VAMP. Cyclo-VAMP was used in a highly selected group of patients who had previously responded to high dose melphalan. It was well tolerated and produced responses in 61% of this group.
Eighteen patients with advanced cancer have been treated intravenously with human recombinant tumour necrosis factor (rhTNF). The drug produced febrile reactions at all doses although these were preventable by steroids and indomethacin. Doses at or above 9 x 10(5) units (400 micrograms)m-2 were associated with hypotension, abnormal liver enzymes, leucopenia and mild renal impairment in a substantial proportion of patients. RhTNF was cleared from plasma with a half life of approximately 20 minutes but non-linear pharmacokinetics lymphoma, improvements in their tumours were recorded. RhTNF was noted to produce rapid increases in serum C-reactive protein concentrations. Endogenous TNF levels were not found to be elevated in 72 cancer patients. TNF deserves further therapeutic evaluation and these observations support its biological importance as an endogenous pyrogen, mediator of acute phase protein responses, and a mediator of endotoxic shock.
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A study of 32 patients receiving cyclophosphamide (CY) and verapamil (VER) in addition to the drug combination vincristine, adriamycin and methyl prednisolone (VAMP) was made in which the clinical response and growth of clonogenic myeloma cells (MY-CFUc) from bone marrow aspirates were compared. At presentation, MY-CFUc were grown from 72 per cent (23/32) of the patients. After treatment with CY-VAMP or VERCY-VAMP, MY-CFUc were grown from 25 per cent (8/32) of patients of whom only 50 per cent responded clinically. The overall clinical response rate for patients receiving CY-VAMP and VERCY-VAMP was 64 per cent (9/14) and 72 per cent (13/18) respectively of whom 14 per cent in each group achieved complete remission. There was no concomitant increase in normal tissue toxicity as measured by granulocyte-macrophage colony (GM-CFUc) formation. Comparison of these data with our previous study of patients receiving VAMP alone, suggests that the addition of CY to the regimen may increase the tumour cell kill. Further clinical studies will determine whether there is a significant increase in the complete remission rate.
The pharmacokinetics of oral and intravenous high dose methylprednisolone (Solu-medrone, Upjohn) were compared in patients with hematological malignancies. The aim of the study was to determine the oral bioavailability of high dose methylprednisolone and to establish whether this is a feasible and more convenient route of administration. The plasma pharmacokinetics were described by a one-compartment open model with peak plasma levels of 6.9 +/- 2.5 micrograms/ml. Total area under the plasma concentration versus time curve was similar by either route. Mean relative oral bioavailability was generally high (91 +/- 27 per cent). Retrospective analysis of 34 patients with chronic lymphocytic leukemia (CLL), non-Hodgkin's and Hodgkin's lymphoma treated with high dose methylprednisolone showed 11 responses including two complete remissions among nine patients with CLL. There was significant improvement in platelet counts in thrombocytopenic patients and treatment was well tolerated and toxicity was relatively low. High dose methylprednisolone may therefore be a useful palliative treatment for hematological malignancies, particularly where marrow suppression is a problem.
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