PubMed Health⌕ Search

Biomedical subjects

M R Downing

Publications and source records attributed to M R Downing.

13 recordsLinked to original sources
PubMed1989

Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial.

STUDY OBJECTIVE: To determine the effectiveness and safety of recombinant human erythropoietin (rHuEpo). PATIENTS: Hemodialysis patients (333) with uncomplicated anemia (hematocrit less than 0.30). All received rHuEpo intravenously, three times per week at 300 or 150 U/kg body weight, which was then reduced to 75 U/kg and adjusted to maintain the hematocrit at 0.35 +/- 0.03 (SD). RESULTS: The baseline hematocrit (0.223 +/- 0.002) increased to 0.35, more than 0.06 over baseline within 12 weeks in 97.4% of patients. Erythrocyte transfusions (1030 within the 6 months before rHuEpo therapy) were eliminated in all patients within 2 months of therapy. Sixty-eight patients with iron overload had a 39% reduction in serum ferritin levels after 6 months of therapy. The median maintenance dose of rHuEpo was 75 U/kg, three times per week (range, 12.5 to 525 U/kg). Nonresponders had complicating causes for anemia, myelofibrosis, osteitis fibrosa, osteomyelitis, and acute or chronic blood loss. Adverse effects included myalgias, 5%; iron deficiency, 43%; increased blood pressure, 35%; and seizures, 5.4%. The creatinine, potassium, and phosphate levels increased slightly but significantly. The platelet count increased slightly but there was no increase in clotting of vascular accesses. CONCLUSIONS: The anemia of hemodialysis patients is corrected by rHuEpo resulting in the elimination of transfusions, reduction in iron overload, and improved quality of life. Iron stores and blood pressure must be monitored and treated to maintain the effectiveness of rHuEpo and to minimize the threat of hypertensive encephalopathy.

Adolescent↗
PubMed1989

Immunologic monitoring studies in advanced cancer patients treated with recombinant human gamma interferon (IFN-gamma 4A).

Thirty-nine patients with a variety of advanced malignancies were treated with recombinant IFN-gamma 4A (AMGen, specific activity 1 to 5 x 10(7) U/mg protein). IFN-gamma 4A was administered at a dose of 10-2,000 micrograms/m2/d. Following a 2-week rest, a maintenance phase was continued with injections 3 d/wk. Immunologic monitoring studies were performed on patients' peripheral blood cells before administration of IFN-gamma 4A, then on Days 15 and 90. Flow cytometric analysis was used to determine the absolute number of CD 3+, CD 4+, CD 8+, CD 19+, and CD 16+ cells using a panel of monoclonal antibodies. Natural killer (NK) cell function was assayed by monitoring lysis of the K562 cell line in the Cr51 release assay. Changes from baseline were observed on Days 15 and 90 in all parameters studied, although the ratio of helper to suppressor cells seemed to remain within the normal range. Whereas there were no substantial changes in CD 3+ and CD 4+ cells on Day 15, IFN-gamma 4A had an enhancing effect on CD 8+, CD 19+, and CD 16+ cells. This trend continued at Day 90 only for CD 19+ and CD 16+ cells at the higher dose levels. An increase in functional NK cell activity at Day 15 was less noted on Day 90. Comparison of intravenous (IV) to intramuscular-subcutaneous (IM-SC) administration showed differences in the effect on lymphocyte subpopulations at 450 and 1,000 micrograms. The effect of IFN-gamma 4A on the equilibrium among lymphocyte subpopulations and the possibility of its role in combination therapy with other biologic response modifiers are discussed.

Antigens, CD↗
PubMed1988

The use of recombinant human erythropoietin (EPO) to correct the anemia of end-stage renal disease: a progress report.

End-stage renal disease (ESRD) typically is associated with severe anemia. The major contributor to the anemia appears to be the absolute or relative deficiency of erythropoietin (EPO) production by the kidney. A series of clinical trials have been conducted in the United States using recombinant human EPO (rh EPO) to treat anemic patients with ESRD. The encouraging results of the Phase I-II clinical trials have been confirmed in a multicenter trial in which over 250 patients have been treated. The results indicate that rh EPO can effectively correct the anemia of ESRD and the rate of correction is dependent upon the initial dose given. The rHuEpo was well tolerated, produced few or no direct side effects, and was effective in greater than 95 percent of the patients. rh EPO should have a major role in the correction of the anemia of ESRD and contribute significantly to the rehabilitation of such patients.

Anemia↗
PubMed1988

A phase I trial of recombinant human gamma interferon (IFN-gamma 4A) in patients with advanced malignancy.

We report a Phase I study in 39 cancer patients of the tolerance and biologic activity of 47 intravenous (i.v.), intramuscular (i.m.), and subcutaneous (s.c.) treatments with recombinant methional gamma interferon (IFN-gamma 4A) which most closely resembles the natural material produced by T lymphocytes. Patients were treated with IFN-gamma 4A 5 days a week for 2 weeks. After a 2-week rest period, patients were placed on the same dose of drug three times a week. The most common side effects--fever, chills, malaise, myalgias, and nausea and vomiting--were seen with all routes of administration. Reversible increases in hepatic transaminase and decrease in granulocytes counts were seen. The dose-limiting toxicities observed were malaise and orthostatic hypotension. The maximum tolerated dose was 500-1,000 micrograms/M2/day. The t1/2 of IFN-gamma 4A in the circulation was 20 min after i.v. injection. No blood levels were detected after i.m. or s.c. injection. Antibody against IFN-gamma 4A increased in three patients. A complete response was observed in one patient with pulmonary metastases from renal cell carcinoma.

Adult↗
PubMed1986

Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis.

Ten patients with end-stage renal failure and anaemia (mean haemoglobin 6.1 g/dl, range 4.6-8.8 g/dl) on thrice-weekly haemodialysis were treated with human erythropoietin derived from recombinant DNA (rHuEPO). This was given as an intravenous bolus after each dialysis in rising doses within the range 3-192 IU/kg. All patients showed increases in reticulocyte numbers and haemoglobin concentration and after the first week of treatment none of the four previously transfusion-dependent patients needed further transfusions. In nine patients treated for 12 weeks haemoglobin rose to a mean of 10.3 g/dl, range 9.5 to 12.8 g/dl. Thereafter the dose of erythropoietin was adjusted to avoid a further rise in haemoglobin. During treatment one patient had an episode of hypertensive encephalopathy and two had clotting in their arteriovenous fistulas (complete in one). rHuEPO is an effective treatment for the anaemia of end-stage renal failure but longer-term observations are needed on the consequences of increasing the haematocrit.

Adult↗
PubMed1978

Comparison of the inhibition of thrombin by three plasma protease inhibitors.

Human alpha-thrombin is inhibited by the circulating protease inhibitors alpha1-antitrypsin, antithrombin III, and alpha2-macroglobulin. Kinetic analyses of the inhibitor thrombin interactions were carried out utilizing either fibrinogen or the synthetic substrate Bz-Phe-Val-Arg-p-nitroanilide as substrates to determine residual thrombin activity. These studies demonstrated that the inhibition of thrombin by alpha1-antitrypsin, antithrombin III, and alpha2-macroglobulin followed second-order kinetics. The rate constants for the inhibition of thrombin by alpha1-antitrypsin, antithrombin III, and alpha2-macroglobulin are 6.51 +/- 0.38 x 10(3), 3.36 +/- 0.34 x 10(5), and 2.93 +/- 0.02 x 10(4) M-1 min-1, respectively. Comparison of the second-order rate constants and the normal plasma levels of the three inhibitors demonstrates that, under the in vitro conditions utilized, antithrombin III is five times and alpha2-macroglobulin is one-third as effective as alpha1-antitrypsin in the inhibition of thrombin.

Antithrombin III↗
PubMed1977

Thrombin: structural features related to specificity.

A comparison of the primary structure of human thrombin with the structures of chymotrypsin, trypsin, elastase and factor Xabeta reveals several structural features which may be involved in the specificity of thrombin toward macromolecular substrates. Among the major structural differences noted in such a comparison are the insertions of five extended peptide regions in the primary structure of alpha-thrombin when compared to chymotrypsin. These insertions, which we refer to as "loops", have been designated A, B, C, D, and E. The A, B and C "loops" in human thrombin appear to be large enough to interact at or near the active active site if an alpha-thrombin-chymotrypsin three-dimensional structural homology is assumed. In beta-thrombin, the configuration of the A and B "loops" may be perturbed by proteolysis, and the ability of beta-thrombin to clot fibrinogen is thus reduced. Perturbation of the configuration of the C "loops" by proteolysis in the formation of gamma-thrombin may further reduce the ability of thrombin to bind fibrinogen.

Amino Acid Sequence↗
PubMed1975

Human prothrombin activation.

Human prothrombin has been purified from American Red Cross Factor IX concentrates. Studies of the activation of the human prothrombin with the use of sodium dodecyl sulfate electrophoretic analysis of activation products indicated that human prothrombin activation is similar to bovine prothrombin activation. Molecular weight analysis of human prothrombin and intermediated by sodium dodecyl sulfate co-electrophoresis with bovine prothrombin and its intermediates resulted in molecular weights of 70,000 for prothrombin, 51,000 for intermediate 1, 41,000 for intermediate 2, 23,000 for intermediate 3, and 13,000 for intermediate 4. Amino acid compositions of human prothrombin and intermediates are similar to those for bovine prothrombin and intermediates. NH2-terminal sequence studies of human prothrombin, intermediates, and alpha-thrombin A and B chains placed the intermediates in the parent human prothrombin molecule as described for the bovine system. Intermediate 3 is the NH2-terminal of prothrombin, and intermediate 1 is the COOH-terminal segment of the zymogen. Intermediate 4 is the NH2-terminal of intermediate 1. Intermediate 2', the immediate precursor of alpha-thrombin, is the COOH-terminal segment of intermediate 1. In general, a high degree of homology in the primary structure of prothrombin and intermediates was observed between the human and bovine system. The NH2-terminal sequences of human intermediate 2' and alpha-thrombin A chain are identical. However, human intermediate 2' isolated in a manner identical with that used for the isolation of bovine intermediate 2 is homologous with bovine intermediate 2, beginning with residue 14.

Amino Acid Sequence↗