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The efficacy and tolerance of intravenous and subcutaneous administrations of recombinant human erythropoietin (r-HuEPO) have been compared in 50 maintenance hemodialysis patients. A 2 month course of intravenous r-HuEPO given at stable dosage was followed by a 6 month course of subcutaneous r-Hu EPO. We reduced r-HuEPO dosage by 50% when starting subcutaneous administration and regularly adapted the dosage to achieve hematocrit levels between 30 and 35%. At the end of the study, mean r-HuEPO dosage was 82 +/- 8 (mean +/- SEM) IU/kg/week, which represented 70 +/- 7% of intravenous r-HuEPO dosage. Mean hematocrit value was 32.9 +/- 0.5% when starting subcutaneous administration and also at the end of this study. Arterial blood pressure remained stable over the whole trial period as did most biological blood tests which were not influenced by the route of administration. In 98% of cases, patients expressed either pain-free (50%) or slight to moderate pain (48%) at the injection site. This trial confirms a substantial dosage economy when using r-HuEPO by subcutaneous route rather than by intravenous route. Moreover, objective and subjective tolerance was excellent on r-HuEPO subcutaneous administration.
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PMID:[Comparison of the efficacy and tolerance of recombinant human erythropoietin between intravenous and subcutaneous administration in chronic hemodialysis. Prospective multicenter study]. 160 2

The effects of erythropoietin (EPO) on cytosolic free calcium concentration ([Ca2+]i) in platelets of 20 essential hypertensive patients (HT) and of 25 normotensive subjects (NT) were investigated using the fura2 technique. In resting platelets [Ca2+]i were not significantly higher in HT compared to NT (74.3 +/- 7.8 nM vs 59.8 +/- 7.0 nM, mean +/- SEM). Addition of EPO significantly increased [Ca2+]i in HT compared to NT (13.8 +/- 5.3 nM vs 0.9 +/- 1.9 nM, p less than 0.01). EPO increased the amount of calcium in intracellular stores. This was confirmed independently using thrombin-induced changes of [Ca2+]i in a calcium-free medium and using chlorotetracycline as a marker of stored calcium. After preincubation with EPO thrombin-induced changes of [Ca2+]i were significantly lower in HT compared to NT (306.1 +/- 30.0 nM vs 407.7 +/- 35.7 nM, p less than 0.05). In a calcium-free medium after preincubation with EPO thrombin-induced changes of [Ca2+]i were significantly lower in HT compared to NT (54.7 +/- 11.8 nM vs 100.9 +/- 10.5 nM, p less than 0.05) indicating lower storage capacity in HT. It is concluded that elevated response to EPO may provide a powerful tool to evaluate diagnosis and underlying pathophysiological mechanisms in essential hypertension.
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PMID:Erythropoietin induced transmembrane calcium influx in essential hypertension. 161 80

Infants of diabetic mothers frequently have polycythemia, elevated serum erythropoietin concentrations, and decreased serum iron and ferritin concentrations, likely representing a redistribution of fetal iron into erythrocytes to support augmented fetal hemoglobin synthesis. We hypothesized that fetal liver, heart, and brain iron concentrations are also reduced in these infants. After obtaining autopsy tissue from infants who had died before 7 days of age, we measured liver, heart, and brain iron concentrations using atomic absorption spectrophotometry. Seven infants of diabetic mothers and seven gestational age-matched control infants were studied. All infants of diabetic mothers had pancreatic islet cell hyperplasia, indicating fetal hyperglycemia and hyperinsulinemia. Liver iron concentrations in the infants of diabetic mothers were 6.6% of control values (489.0 +/- 154.4 vs 7379.7 +/- 1473.8 micrograms/gm dry tissue weight (mean +/- SEM); p less than 0.001), heart iron concentrations were 43.9% of control values (124.7 +/- 20.5 vs 284.1 +/- 34.8 micrograms/gm dry tissue weight; p less than 0.002), and brain iron concentrations were 60.6% of control values (106.1 +/- 13.7 vs 175.2 +/- 10.7 micrograms/gm dry tissue weight; p less than 0.003). Heart and brain iron concentrations were directly correlated with liver iron concentrations (r = 0.80 for both; p less than 0.001) and indicated that hepatic iron was greater than 75% depleted before heart and brain iron reduction. We conclude that severely affected infants of diabetic mothers have reduced liver, heart, and brain iron concentrations. The role of tissue iron deficiency in the genesis of the abnormal clinical findings in these infants deserves further consideration.
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PMID:Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers. 162 67

The effect of a six months therapy with human recombinant erythropoietin (rHu-EPO) on blood pressure and on several parameters of sympathetic nervous activity was studied in chronic haemodialysis patients in a controlled and randomized trial in order to gain further insight into the mechanism of rHu-EPO-induced blood pressure elevation. Treatment was started at a dose of 3 X 80 IE/kg/week in eleven patients aiming to increase the initial hemoglobin concentration (7.0 +/- 0.3 [SEM] g%) to 10.0 g% by dose adjustments, while another untreated eleven patients served as a control group. Diastolic arterial pressure measured before and after haemodialysis increased on rHu-EPO treatment by 7 and 8 mm Hg respectively (p less than 0.05). Plasma noradrenaline concentration was increased (p less than 0.05) after the six months treatment period in the presence of unchanged dry weights. Conversely platelet alpha 2-adrenoceptor density (3H-yohimbine binding) and the fraction of high affinity binding sites for alpha 2-agonists (3H-UK 14.304) decreased (p less than 0.01) along with a decrease in reactivity to exogenous noradrenaline (p less than 0.05). None of these parameters changed in the control group compared to pretreatment values. The results obtained demonstrate that increased plasma noradrenaline concentrations may participate in rHu-EPO induced blood pressure increases. The decrease in platelet alpha 2-adrenoceptor densities and the decrease in noradrenaline reactivity in the presence of increased plasma noradrenaline concentrations suggest an intact regulation of alpha 2-adrenoceptors in chronic haemodialysis patients on chronic rHu-EPO therapy.
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PMID:[Effect of erythropoietin therapy on alpha receptor density in chronic dialysis patients]. 165 81

The use of recombinant human erythropoietin (rhuEPO) has revolutionized the treatment of renal anemia, but the dose regimens have not been established. We studied the effects of subcutaneous rhuEPO given 4,000U (1 vial) every 5-10 days in 9 patients on continuous ambulatory peritoneal dialysis (CAPD). Ten stable CAPD patients (6 females and 4 males; mean age +/- SEM, 54.4 +/- 5.6 years; mean baseline hemoglobin concentration 7.3 +/- 1.2g/dL) were commenced on s.c. rhuEPO. None of the patients had a history of gastrointestinal bleeding, aluminum overload, sepsis nor receiving androgens. Seven patients were receiving 4,000 U rhuEPO weekly, one patient each was receiving 4,000 U every 5 and 10 days (range, 66.7-89.3 U/kg/week). The dose was adjusted every 4 weeks according to response by altering the dose interval. The mean hemoglobin concentration increased from 7.3 +/- 1.2 g/dL to 10.3 +/- 1.1 g/dL over 8 weeks. There was no significant changes in the serum ferritin, urea, creatinine and potassium levels. One patient required an increase in antihypertensive therapy. We feel that s.c. rhuEPO 4,000 U given on an intermittent basis is effective in the treatment of anemia in CAPD patients. The administration of a single vial each time is convenient and cost sparing. The gradual rise in hematocrit avoids complications.
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PMID:Subcutaneous recombinant human erythropoietin in patients on CAPD. 168 Apr 47

The single-dose pharmacokinetics of recombinant human erythropoietin (rHuEpo; 40 units/kg1) were investigated in children (9-16 years) with end-stage renal failure. After an intravenous (i.v.) dose, serum rHuEpo concentrations declined in a monoexponential manner with a mean half-life (t1/2) of 5.6 +/- 3 h (+/- SEM; n = 9). Serum clearance and the apparent volume of distribution were estimated to be 10.1 +/- 0.9 ml h-1 kg-1 and 79.5 +/- 5.0 ml kg-1 (n = 9) respectively. Subcutaneous (s.c.) delivery resulted in serum values that peaked at 10 h, and thereafter concentrations declined slowly with a t1/2 of 21.1 +/- 4.5 h (n = 9). Serum rHuEpo concentrations were maximal at 14 h after i.p. administration and the t1/2 was 9.5 +/- 1.0 h (n = 3). The mean fraction absorbed of SC rHuEpo was 0.40 whereas after i.p. administration this fraction was only 0.17. These results show that after both s.c. and i.p. delivery, disposition of the hormone is rate-limited by absorption, and bioavailability for these extravascular routes is poor. In addition, comparison of the results with those available for adults indicates that rHuEpo is better absorbed but more rapidly cleared in children.
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PMID:Pharmacokinetics of recombinant human erythropoietin in children with renal failure. 175 7

Primary as well as secondary hyperparathyroidism may be associated with anemia, and parathyroidectomy (PTx) may improve or even heal it. The precise link between the two conditions is still matter of discussion. The purpose of the present study was to investigate possible effects of PTx on serum immunoreactive erythropoietin (iEPO) in secondary (group I, n = 23), and primary (group II, n = 16) hyperparathyroidism patients, and in 3 patients undergoing cervicotomy for thyroid mass removal (group III). In group I patients, circulating iEPO levels rose from 23.1 +/- 4.8 mU/ml before PTx to 28.2 +/- 5.0 and 245 +/- 125 mU/ml (mean +/- SEM) at day 7 (p = NS) and 14 after PTx (p less than 0.003), respectively. Reticulocyte count increased 2 weeks after PTx: from 61,000 +/- 13,317 to 86,533 +/- 13,462/mm3 (p less than 0.05, n = 23). In 4 of these patients serum iEPO levels could be measured again 12-24 months after PTx. They were slightly higher than those determined before PTx: 37.0 +/- 8.4 versus 31.8 +/- 13.5 mU/ml. Their hematocrits were also higher than before PTx: 12.8 +/- 0.9 versus 11.0 +/- 0.9 g/dl. In group II patients, serum iEPO levels remained unchanged after PTx: 17.5 +/- 2.0 mU/ml before PTx and 20.0 +/- 3.0 mU/ml 14 days PTx. The reticulocyte count, however, increased significantly 2 weeks after PTx: from 25,103 +/- 3,000 to 40,827 +/- 4,080/mm3 (p less than 0.01). In group III patients, serum iEPO, reticulocyte count, and hemoglobin remained stable after surgery. Since all group I patients had received vitamin D supplementation after PTx, we studied an additional group of 14 chronic dialysis patients (group IV) who received either calcitriol (1 micrograms/day, n = 7) or placebo (n = 7) during 14 days. The patients on calcitriol treatment, but not those on placebo, had a significant decrease of serum iEPO: 18.6 +/- 4.9 versus 16.0 +/- 4.2 mU/ml (p less than 0.03). In conclusion, PTx led to a striking increase of serum iEPO and blood reticulocytes in uremic patients with secondary hyperparathyroidism, and an increase of reticulocyte count, but not of iEPO, in patients with primary hyperparathyroidism. Marked changes of circulating PTH, extra-or intracellular calcium and phosphorus concentrations as well as of tissue sensitivity to EPO after PTx could all be responsible. In contrast, the surgical procedure and the therapeutic increase in plasma calcitriol do not appear to be involved.
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PMID:Serum erythropoietin and erythropoiesis in primary and secondary hyperparathyroidism: effect of parathyroidectomy. 175 26

Human recombinant erythropoietin (r-HuEPO) improves quality of life in patients on maintenance haemodialysis, but the haemoglobin (Hb) level necessary to achieve this improvement is unknown. In this study, quality of life, functional capacity and symptoms of 28 haemodialysis patients with an initial Hb of 67 +/- 2 (mean +/- SEM) g/L were assessed after 0, 6 and 12 months of r-HuEPO, the dose of which was titrated to achieve a stable Hb of between 90 and 100 g/L. At six and 12 months Hb was 97 +/- 2 and 93 +/- 2 g/L, and mean r-HuEPO dose between three and six, and between nine and 12 months was 88 +/- 6 and 62 +/- 9 U/kg/week intravenously respectively. There was a significant improvement in level of activity and satisfaction with various aspects of life, and a reduction in fatigue, weakness, dyspnoea, angina and restless legs. Patients were able to walk 50% further in six minutes. The improvement in quality of life and function was similar to that reported from other centres whose target Hb was between 100 and 120 g/L, and where the r-HuEPO dose was 75% higher than in this study. Costs of r-HuEPO therapy were assessed. The drug itself costs +A3681/yr/patient, to which was added the estimated cost of additional dialyses and medications, bringing the total to +A5177/yr/patient. There was, however, a reduction in both hospitalisation by 8.3 days/yr/patient and medical consultation by 3.9 hours/yr/patient. Five patients commenced full-time work, one took up full-time study aimed at finding work, three transferred to home haemodialysis and six fewer patients drew social security benefits. The net cost saving from using low dose r-HuEPO was more than +A1,000/yr/patient.
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PMID:Low dose erythropoietin in maintenance haemodialysis: improvement in quality of life and reduction in true cost of haemodialysis. 175 17

Anaemia of chronic renal failure is multifactorial. Twenty-one patients with end-stage renal disease (ESRD) and 21 normal subjects were studied to determine the significance of serum erythropoietin levels and erythropoiesis inhibition in the aetiology of renal anaemia. Serum erythropoietin levels and erythropoiesis inhibition were measured by determining the incorporation of labelled-thymidine into the DNA of rabbit bone marrow cells. The mean haemoglobin concentration was 9.0 +/- 0.5 g/dl (mean +/- SEM) in ESRD and 14.4 +/- 0.4 g/dl in normal controls. Serum erythropoietin levels (99.9 +/- 17.9 mU/ml in ESRD vs 74.9 +/- 9.7 mU/ml in normal controls) and inhibition of erythropoiesis (252 +/- 28.9 in ESRD vs 186.2 +/- 19.4 in normal controls) were not significantly different in both groups. However, erythropoiesis inhibition had a significant correlation with the degree of anaemia (p less than 0.01). The results suggest that erythropoiesis inhibition play a significant role in the pathogenesis of renal anaemia.
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PMID:Erythropoietin levels and inhibition of erythropoiesis in end-stage renal failure. 180 63

The effect of recombinant human erythropoietin (rHuEPO) on the immune system of hemodialysis patients has been studied by evaluating their response to hepatitis B (HB) vaccination. Fifty hemodialysis patients were given four doses of 20 micrograms recombinant DNA hepatitis B vaccine (SKF) at an interval of 0, 1, 2 and 6 months. Thirty-seven patients could be evaluated at one year. Twelve of 15 (80%) of the rHuEPO treated patients and 12 of 22 (54%) of non-rHuEPO treated dialysis patients developed anti-HBs antibodies. At the time of maximum immune response (8 months), the geometric mean anti-HBs titers (mIU/ml +/- SEM) of responders and all patients were five times (224.0 +/- 5.9 vs. 41.7 +/- 1.5, P less than 0.001), and eight times (57.6 +/- 8.7 vs. 6.7 +/- 1.8, P less than 0.05), respectively, higher in rHuEPO treated patients than in patients not receiving the drug. High antibody response (greater than 100 mIU/ml) prevailed in the group of rHuEPO treated patients and was associated with a high helper/suppressor ratio. Discriminant multivariate analysis (P = 0.038) revealed the influence of treatment with rHuEPO (40%) and helper/suppressor ratio (31%) on antibody concentration, while age, gender, duration of dialysis and previous blood transfusions were similar in both patient groups. Although changes in lymphocyte subsets observed in rHuEPO treated patients may be the result of a reduced administration of blood transfusions, immune reactivity seems also to be directly affected by the drug.
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PMID:Treatment with recombinant human erythropoietin increases antibody titers after hepatitis B vaccination in dialysis patients. 192 Nov 47


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