PubMed Health⌕ Search

Biomedical subjects

I C Macdougall

Publications and source records attributed to I C Macdougall.

At least 37 records · Page 2Linked to original sources
PubMed1999

Strategies for iron supplementation: oral versus intravenous.

Iron supplementation has become an integral part of the management of patients receiving epoetin therapy, and clinicians have found it necessary to learn how and when to use it to the best advantage. Three routes of administration for iron are available: oral, intramuscular, and intravenous. Oral iron has the advantage of being simple and cheap, but it is limited by side-effects, poor compliance, poor absorption, and low efficacy. Intravenous iron is the best means of guaranteeing delivery of readily available iron to the bone marrow, but it requires greater clinical supervision. The i.v. iron preparations vary widely in their degradation kinetics, bioavailability, side-effect profiles, and maximum dose for single administration. Iron dextran is hampered by a small but significant risk of anaphylaxis, whereas all i.v. iron preparations can induce "free iron" reactions if the circulating plasma transferrin is overloaded. Intravenous iron may be given in advance of epoetin therapy, as concomitant treatment to prevent the development of iron deficiency, as treatment of absolute or functional iron deficiency, or as adjuvant therapy to enhance the response to epoetin in iron-replete patients. Markers of iron status that may indicate a need for i.v. iron include a serum ferritin of less than 100 microg/liter, a transferrin saturation of less than 20%, and a percentage of hypochromic red cells more than 10%. Various regimens are available for giving i.v. iron: low-dose administration of 20 to 60 mg every dialysis session in hemodialysis patients, medium-dose administration of 100 to 400 mg, and high-dose administration of 500 to 1000 mg. Iron sodium gluconate can only be given as a low-dose regimen because of toxicity, whereas the only preparation suitable for high-dose administration is iron dextran. Although concerns have been raised regarding iron overload and long-term toxicity with i.v. iron therapy in terms of increased risk of infections, cardiovascular disease, and malignancy, there is little evidence to substantiate this in patients receiving epoetin. Care should be taken, however, to prevent the serum ferritin rising above 800 to 1000 microg/liter and the transferrin saturation above 50%. Provided this is done, the benefits of i.v. iron almost certainly outweigh the risks in terms of optimizing the response to epoetin therapy.

Administration, Oral↗
PubMed1999

Optimizing erythropoietin therapy.

Much attention has been focused in recent years on ways of optimizing the use and cost-effectiveness of erythropoietin therapy. The balance of evidence suggests that the subcutaneous route allows lower doses to be used compared with the intravenous route, and dosing should be two to three times weekly. Concomitant use of intravenous iron potently enhances the response to erythropoietin, and more recently other adjuvant therapies such as ascorbic acid, L-carnitine, folic acid, vitamin D, androgens, and other cytokines and growth factors have been investigated. Many factors can affect the response to erythropoietin, and underdialysis and co-administration of angiotensin converting enzyme inhibitors have attracted much recent interest. Controversy regarding the optimum target hemoglobin concentration in patients with renal failure remains, but three multicenter studies are providing useful data on this issue.

Costs and Cost Analysis↗
PubMed1999

Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients.

Novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of recombinant human erythropoietin (Epoetin) which has an increased terminal half-life in animal models. The aim of this study was to extend these observations to humans. Using a double-blind, randomized, cross-over design, the single-dose pharmacokinetics of Epoetin alfa (100 U/kg) and an equivalent peptide mass of NESP were compared following intravenous bolus in 11 stable peritoneal dialysis patients. This was followed by an open-label study to determine the single-dose pharmacokinetics of an equivalent peptide mass of NESP by subcutaneous injection in six of these patients. The mean terminal half-life for intravenous NESP was threefold longer than for intravenous Epoetin (25.3 versus 8.5 h), a difference of 16.8 h (95% confidence interval, 9.4 to 24.2 h, P = 0.0008). The area under the serum concentration-time curve was significantly greater for NESP (291.0 +/- 7.6 ng x h per ml versus 131.9 +/- 8.3 ng x h per ml; mean +/- SEM; P < 0.0005), and clearance was significantly lower (1.6 +/- 0.3 ml/h per kg versus 4.0 +/- 0.3 ml/h per kg; mean +/- SEM; P < 0.0005). The volume of distribution was similar for NESP and Epoetin (52.4 +/- 2.0 ml/kg versus 48.7 +/-2.1 ml/kg; mean +/-SEM). The mean terminal half-life for subcutaneous NESP was 48.8 h. The peak concentration of subcutaneous NESP was approximately 10% of that following intravenous administration, and bioavailability was approximately 37% by the subcutaneous route. The longer half-life of NESP is likely to confer a clinical advantage over Epoetin by allowing less frequent dosing in patients treated for anemia.

Adult↗
PubMed1999

Inhibition of CFU-E colony formation in uremic patients with inflammatory disease: role of IFN-gamma and TNF-alpha.

BACKGROUND: There is evidence for the role of inflammatory cytokines in the inhibition of erythropoiesis in the anemia of chronic disease, but the extent to which they contribute to resistance to erythropoietin (EPO) in patients with chronic renal failure is not clear. The purpose of the present study was to assess the effect of sera from patients with end-stage renal failure with and without infection or inflammatory disease on CFU-E colony formation in vitro. METHODS: Bone marrow was obtained from uremic patients with inflammatory disease and from healthy controls. Standard colony assays were used to assess erythroid colony formation (CFU-E) in response to EPO in the presence or absence of 5% autologous serum. Normal bone marrow mononuclear cells were cultured with 5% v/v sera from three groups of patients: healthy volunteers, uremic controls, and uremic patients with inflammatory disease. RESULTS: There was no difference between normal and uremic bone marrow response to EPO. However, when uremic/inflammatory bone marrow was cultured with autologous serum the optimal response to EPO was significantly inhibited. Optimal CFU-E colony formation was suppressed significantly by sera from either uremic group when compared with cultures containing sera from controls. Treatment of parallel cultures with a combination of antibodies to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) almost completely restored the response to EPO. Additionally, bone marrow from healthy controls incubated with uremic sera showed an increased production of interleukin-1 alpha (IL-1 alpha) and IFN-gamma, and TNF-alpha was present in uremic sera. CONCLUSIONS: CFU-E colony formation is inhibited by soluble factors present in the sera of uremic patients with or without inflammatory disease. These soluble factors stimulate the production of IFN-gamma and TNF-alpha, which directly inhibit erythropoiesis at a local level in the bone marrow.

Adult↗
PubMed1998

Meeting the challenges of a new millennium: optimizing the use of recombinant human erythropoietin.

Optimizing the use of recombinant human erythropoietin (r-HuEPO) involves choosing an appropriate dose regimen and target haemoglobin level, addressing factors that inhibit response, and considering appropriate adjuvant therapy. Subcutaneous administration of r-HuEPO two or three times weekly is optimal for most patients. Early detection and treatment of iron deficiency is mandatory. Measurement of the percentage of hypochromic red blood cells is a reliable marker of functional iron deficiency, and the treatment of choice is intravenous iron. Other factors that can affect the response to r-HuEPO include blood loss (sometimes occult), infection, inflammation, hyperparathyroidism with marrow fibrosis, aluminium toxicity, vitamin B12/folate deficiency, haemolysis, bone marrow disorders, haemoglobinopathies, under-dialysis and possibly angiotensin-converting enzyme inhibitors. These factors should be identified and corrected where possible. Ascorbic acid, vitamin D, folic acid, carnitine, other cytokines and growth factors have all been shown to augment the response to r-HuEPO in some patients. Further research is required before any of these adjuvant therapies can be incorporated into routine clinical practice. With regard to target haemoglobin value, the current practice is to aim for a level of 10-12 g/dl, but it may be argued that a higher target would achieve greater benefits in terms of physical performance, quality of life, and possibly cardiac morbidity and mortality. International multicentre trials are currently in progress to address this issue, as are studies on other substances that may be able to stimulate erythropoiesis.

Anemia↗
PubMed1998

Quality of life and anemia: the nephrology experience.

Even with the reservations that exist regarding the accuracy of tools to measure quality of life, there is little doubt that epoetin has dramatically improved the quality of life in patients with the anemia of chronic renal failure. Patients feel better and have increased energy levels, greater capacity for physical exercise, fewer symptoms of lethargy and tiredness, improved memory and concentration, and less angina and breathlessness. Cardiac, sexual, and cognitive functions all improve, and quality of life assessments suggest enhancements in both physical and social aspects of well-being. Furthermore, circumstantial evidence suggests that treatment with epoetin is quite likely to reduce cardiovascular morbidity and mortality in patients with renal anemia. While chronic anemia has common characteristics irrespective of the etiology, the implications on quality of life in patients with chronic renal failure vary in a number of ways from those in patients with cancer.

Anemia↗