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M J Pippard

Publications and source records attributed to M J Pippard.

At least 37 records · Page 2Linked to original sources
PubMed1989

Desferrioxamine-induced iron excretion in humans.

Iron excretion in response to DF in humans is dependent upon the degree of iron overload, particularly of parenchymal liver cells. However, a number of variables, including ascorbate status, erythroid activity and liver disease, affect both the amount of iron mobilized and the route by which it is excreted. Faecal iron, derived from the bile, appears to arise from intracellular chelation of a transit iron pool related to hepatocyte iron stores, whereas urine iron may be derived from iron capable of exchanging with plasma transferrin at cell membranes of both hepatocytes and macrophages. Faecal iron predominates as iron stores return towards normal on regular chelation therapy. An understanding of the variables which influence iron excretion allows rational planning of long-term therapy with DF in patients with iron-loading anaemias. In young children a dose of 40-50 mg/kg given on five or six nights a week from the age of about 3 years is appropriate for prevention of serious iron loading. In older children the dose must be carefully tailored (by means of an individual urinary iron excretion dose-response curve) to achieve maximum safe chelation of pre-existing iron stores. In patients with slower rates of iron loading from excessive gastrointestinal iron absorption, intermittent use of DF infusions may be sufficient to maintain normal iron stores.

Deferoxamine↗
PubMed1989

Characterization of the anaemia of chronic renal failure and the mode of its correction by a preparation of human erythropoietin (r-HuEPO). An investigation of the pharmacokinetics of intravenous erythropoietin and its effects on erythrokinetics.

Studies were directed to characterization of the anaemia of renal failure of 11 patients on haemodialysis and determination of the way in which it is corrected by human erythropoietin derived from recombinant DNA expressed in Chinese hamster ovary cells (r-HuEPO) administered intravenously. Erythrokinetics before treatment showed that total red cell mass was below normal and that both erythron transferrin uptake and red cell survival were modestly reduced; treatment increased both total red cell mass and erythron transferrin uptake but did not change red cell survival in previously untransfused patients. When BFU-e and CFU-e from patient bone marrow were cultured in autologous serum we found no evidence for inhibitors of erythroid progenitor maturation in patient serum compared with normal. Erythroid expansion in response to r-HuEPO was not limited by the availability of iron, iron requirements for new red cell formation being met from stores (if adequate) or from oral iron supplements. In pharmacokinetic studies the plasma clearance of r-HuEPO could be expressed by a three-parameter exponential curve with T1/2 range of 2.3 to 7.3 h. T1/2 after the first dose of r-HuEPO was not significantly different from that after 14 to 54 weeks treatment when the erythron had expanded to a new steady state. Erythron transferrin uptake before treatment was related to endogenous production of erythropoietin estimated from the plasma clearance of the first dose of r-HuEPO administered intravenously. This finding suggested that the availability of erythropoietin was the main factor limiting expansion of the erythron. This conclusion was supported by the continuity of the relationship during the response to treatment.

Adult↗
PubMed1988

Erythroid progenitor cell kinetics in chronic haemodialysis patients responding to treatment with recombinant human erythropoietin.

The response of bone marrow and peripheral blood erythroid progenitors to human recombinant erythropoietin (rHuEPO) was studied in nine haemodialysed renal failure patients receiving this hormone for the correction of their anaemia. The haematocrit rose in all patients in response to thrice weekly injections of escalating rHuEPO doses (12-192 IU/kg). Both the numbers of CUF-e and BFU-e and their proliferative state in the bone marrow as well as BFU-e numbers in the peripheral blood were estimated before treatment and again after correction of the anaemia, at 16 h following an intravenous dose of rHuEPO. Following treatment bone marrow BFU-e numbers fell to a mean of 24.5% (P less than 0.01) of the pre-treatment values although there was no significant change in CFU-e or circulating BFU-e numbers. The mitotic rate (percentage S-phase cells) estimated by tritiated thymidine suicide rose from 45.2% to 68.4% (P less than 0.05) in the case of CFU-e and from 16.4% to 45.1% (P less than 0.05) for BFU-e following treatment with rHuEPO thus indicating in-vivo sensitivity of both the primitive as well as the mature erythroid progenitors to the hormone. The fall in BFU-e numbers in the bone marrow after several months of treatment may be due to a loss of cells from this progenitor pool by maturation that is uncompensated by replacement from the pluripotential stem cell compartment.

Adult↗
PubMed1988

In vivo studies on the relationship between intestinal iron (Fe3+) absorption, hypoxia and erythropoiesis in the mouse.

The effect of hypoxia and changes in erythropoiesis on the absorption of 59Fe3+ from in situ tied-off duodenal segments was studied in the mouse. Hypoxia led to an increase in mucosal uptake within 6 h, whilst mucosal transfer was unaffected for about 20 h, suggesting independent regulation of these two processes. Hypoxia (3 d) stimulated erythropoiesis and resulted in a 2-3-fold increase in the total mucosal uptake of 59Fe. Conversely, hyperoxia (100% O2) caused a decrease in reticulocyte counts and the total mucosal uptake. The changes in the transfer of 59Fe from the mucosa to the body were more marked than changes in uptake in both hypoxia and hyperoxia. Mice subjected to subtotal nephrectomy showed a normal increase in the total mucosal uptake of 59Fe3+ following hypoxic exposure, despite the absence of any changes in the reticulocyte count. Obliteration of the erythroid tissue of animals by splenectomy and 89Sr treatment was accompanied by a marked decrease in the transfer of 59Fe from mucosa to the carcass. However, exposure of splenectomized 89Sr-treated mice to hypoxia resulted in an increase in the total mucosal uptake and carcass transfer of 59Fe, without any change in erythropoiesis. These results indicate that hypoxia enhances mucosal iron uptake by a mechanism which is independent of stimulated erythropoiesis, but that changes in the rate of erythropoiesis have an additional effect, particularly on the transfer phase of iron absorption.

Animals↗
PubMed1988

The effect of erythroid hyperplasia on iron balance.

Measurements of erythropoiesis and iron balance were made in eight normal and 32 anemic subjects. The latter consisted of 12 individuals with ineffective erythropoiesis (beta-thalassemia/hemoglobin E), 13 subjects with ineffective erythropoiesis and hemolytic anemia (hemoglobin H), and seven subjects with hemolytic anemia (hereditary spherocytosis). A consistent relationship within each group existed between the degree of erythropoiesis and radioiron absorption. Although the effect of erythropoiesis on iron absorption was of similar magnitude in the two thalassemia groups, the effect in hereditary spherocytosis was much less. There was agreement between absorption and ferritin or magnetic susceptibility (SQUID) measurements of iron stores in thalassemia, but in hereditary spherocytosis a discrepancy existed between absorption and ferritin. It is concluded that, although increased erythropoiesis is associated with increased iron absorption, some additional factor associated with red cell breakdown is more directly responsible for the positive iron balance in thalassemia.

Adolescent↗
PubMed1987

Iron chelation studies using desferrioxamine and the potential oral chelator, 1,2-dimethyl-3-hydroxypyrid-4-one, in normal and iron loaded rats.

A novel iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one, and desferrioxamine were compared for their ability to remove iron and for their site of action in iron release in rats. Repeated intraperitoneal injections of the chelators in rats with widespread tissue labelling by 59Fe derived from transferrin showed comparable 59Fe mobilisation by each chelator in normal and iron loaded rats. Specific labelling of a chelatable "cold" iron pool in hepatocytes by 59Fe derived from ferritin showed this pool to be equally accessible to parenteral doses of both chelators and also to oral 1,2-dimethyl-3-hydroxypyrid-4-one, which is an effective oral iron chelating agent that removes iron from parenchymal cells. This and other alpha-ketohydroxypyridines need further development as potential therapeutic agents in human iron overload.

Animals↗
PubMed1987

Microcytic anaemia in juvenile chronic arthritis.

The degrees of anaemia and microcytosis in 100 patients with juvenile chronic arthritis (JCA) were analysed according to the pattern of disease and its activity. Microcytosis was common (40% of patients had a mean corpuscular volume (MCV) of less than 75 fl), sometimes severe (MCV less than 65 fl in 14 patients), and closely correlated with the severity of the anaemia. The degrees of microcytosis and anaemia were both directly related to disease activity as measured by the ESR, and were most severe in cases with the systemic form of JCA. In 50 patients iron status was assessed. The serum iron concentration was directly related to the MCV, whereas the serum ferritin was inversely related to MCV and haemoglobin concentration and directly related to the ESR. Bone marrow iron stores were normal or increased in 6 patients with severe microcytic anaemia. These data suggest that the anaemia of JCA is typically microcytic, and that this microcytosis is associated with the disturbance of iron metabolism seen in the 'anaemia of chronic disorders' rather than overall depletion of body iron.

Adolescent↗
PubMed1987

Erythrokinetics and iron status in heterozygous beta thalassaemia, and the effect of interaction with alpha thalassaemia.

Ferrokinetic studies, alpha globin gene mapping, and assessment of iron status have been carried out in 16 healthy subjects with heterozygous beta thalassaemia. Six subjects had coinherited alpha thalassaemia and had more balanced alpha/beta globin chain synthesis ratios than the remaining 10 subjects with uncomplicated heterozygous beta thalassaemia. The overall efficiency of erythropoiesis was significantly reduced in the latter group (mean 76 +/- 17 (SD)% of normal), but was indistinguishable from normal in subjects with coexistent alpha thalassaemia. Red cell survival was unimpaired in both groups, indicating that the defect was one of mild ineffective erythropoiesis rather than peripheral haemolysis. Values for total plasma iron turnover were normal or only slightly increased. This suggests a lack of any additional stimulus to erythropoiesis, which might normally be expected to compensate easily for the mild degree of anaemia. Uncomplicated heterozygous beta thalassaemia produces an extremely mild disorder of erythropoiesis, which is dependent on the imbalance between alpha and beta globin chain synthesis, and is not associated with a risk of serious iron overload.

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↗