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Fluid and solute fluctuations during the week are the main drawbacks of conventional hemodialysis (cHD) in patients' outcomes. The aim of our study was to evaluate the influence of every other day hemodialysis (eodHD) on clinical and laboratory parameters and to compare to that of cHD. Eighteen patients on cHD were included in the study. Nine patients (group I) were randomly switched to eodHD, while the rest (group II) remained on their regular cHD. By the end of the study (12 months) we observed a reduction in body weight followed by a parallel reduction in predialysis mean blood pressure by 7 mm Hg in group I (p

Purpose: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor. Experimental Design: 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity. Results: The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting. Conclusions: The schedule B daily cisplatin-topotecan × 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.

Several growth factors, such as growth hormone and insulin-like growth factor-1, have been used to reverse the high rate of catabolism observed either after an operation or during serious illness. We conducted a pilot study in Wistar rats in an attempt to assess whether regulatory peptides widely used in clinical practice, such as erythropoietin (EPO) and granulocyte macrophage colony-stimulating factor (GM-CSF), alone or in combination, might influence the metabolism after surgery. Forty animals were randomly allocated into four groups (one control group and three experimental groups; 10 animals per group). The rats in the control group received isotonic NaCl; the rats in one experimental group received recombinant human EPO (rHuEPO) at a dose of 500 IU/kg (EPO group) and those in another received recombinant GM-CSF at a dose of 20 microg/kg (GM-CSF group); in the fourth group, each animal received the two drugs in combination (EPO/GM-CSF group). In all groups, rats were given the drug(s) or NaCl daily for 15 days before the operation and for 7 days after the operation until they were killed. We estimated the body weight (g) and the hematocrit (%) on the first day of the experiment (baseline values) and on the seventh day after the operation, and we estimated the rate of healing and the breaking strength of the intestinal anastomosis on the day the rats were killed. At the end of the study we found that the body weight (median 250 g, minimum 230 g, maximum 270 g) and the levels of hematocrit (median 64%, minimum 60%, maximum 65%) were significantly increased in the EPO group (P < .001 and P < .005, respectively) as compared with the baseline values (median 217.5 g, minimum 200 g, maximum 250 g; median 51.5%, minimum 45%, maximum 55%, respectively). A similar significant increase in body weight (median 230 g; minimum 200 g; maximum 250 g) and hematocrit (median 64%; minimum 59%; maximum 67%) was found at the end of the study in the EPO/GM-CSF group (P = .01 and P < .005, respectively) as compared with the baseline values (median 210 g; minimum 200 g; maximum 250 g; median 50%, minimum 48%, maximum 54%, respectively). The breaking strength (in newtons (N)) statistically differed in the four groups (Kruskal-Wallis, P = .0008). A comparison between groups showed that the breaking strength had been significantly increased in the animals in the EPO group (median 2.18 N, minimum 1.98 N, maximum 2.44 N) as compared with those in the control group (median 1.66 N, minimum 1.33 N, maximum 1.87 N; P = .004), GM-CSF group (median 1.73 N, minimum 1.25 N, maximum 2.07 N; P < .005), and EPO/GM-CSF group (median 1.71 N, minimum 1.37 N, maximum 1.91 N; P = .0005). In conclusion, this study demonstrated that the administration of rHuEPO appears to have a beneficial positive effect on the body weight, hematocrit, and healing rate and the breaking strength of large bowel anastomoses in rats. These observations provide evidence of an as-yet-unknown anabolic effect of EPO, and they may expand its usual applications. However, more studies are needed to confirm our findings and furthermore to define the optimal dose and timing of EPO administration. J Lab Clin Med

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BACKGROUND: It is not clear whether the correction of anemia with erythropoietin (rhuEpo) in patients with chronic kidney disease (CKD) has any benefit on cardiac function and geometry. Most studies are based on indices of systolic function and left ventricular mass (LVM) and the results are conflicting. PATIENTS AND METHODS: We sought to investigate the effect of rhuEpo on LV systolic and diastolic performance using conventional and novel echocardiographic indices. Thirty one patients with CKD (stage 3 or 4) were included. Fifteen patients (group I) treated with rhuEpo targeting at Hb >or=13.0 g/dL, while the remaining (group II) were not treated. Clinical and laboratory parameters were recorded at baseline and 1 year later. Ejection fraction (EF) and LVM were carefully determined. Diastolic function was assessed by mitral inflow indices (E and A wave velocities, Edt deceleration time and E/A) and novel indices of mitral annulus motion using Tissue Doppler Imaging (Em, Am, and E/Em). An index of global cardiac function (Tei) was also calculated. RESULTS: At baseline, the 2 groups had comparable clinical and laboratory characteristics. After 1 year, a significant improvement in Hb levels (13.6 +/- 1.2 vs 10.3 +/- 1.2 g/dL, p < 0.05) as well as in systolic and diastolic function indexes was observed in group I compared to group II patients: EF (70.5 +/- 7.6 vs 63.4 +/- 9.3%, p < 0.05), LVM (116.5 +/- 34.9 vs 155.6 +/- 51.6 g/m(2), p < 0.05), Edt (233.9 +/- 98.6 vs 166.9 +/- 45.1 ms, p < 0.05), Tei index (0.35 +/- 0.12 vs 0.51 +/- 0.17, p < 0.01) and E/Em (9.7 +/- 2.4 vs 14.8 +/- 5.2, p < 0.05), respectively. Blood pressure and heart rate did not show significant changes. CONCLUSIONS: Correction of anemia with rhuEpo in patients with CKD seems to improve cardiac performance and geometry. Cardiovasc Drugs Ther

Many patients with anemia fail to respond to treatment with erythropoietin (Epo), a commonly used hormone that stimulates erythroid progenitor production and maturation by human BM or by murine spleen. The protein product of growth arrest–specific gene 6 (Gas6) is important for cell survival across several cell types, but its precise physiological role remains largely enigmatic. Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. In the absence of Gas6, erythroid progenitors and erythroblasts were hyporesponsive to the survival activity of Epo and failed to restore hematocrit levels in response to anemia. In addition, Gas6 may influence erythropoiesis via paracrine erythroblast-independent mechanisms involving macrophages. When mice with acute anemia were treated with Gas6, the protein normalized hematocrit levels without causing undesired erythrocytosis. In a transgenic mouse model of chronic anemia caused by insufficient Epo production, Gas6 synergized with Epo in restoring hematocrit levels. These findings may have implications for the treatment of patients with anemia who fail to adequately respond to Epo.

Anaemia is considered a common problem in many cancers secondary to the disease itself or related to chemo- and/or radiotherapy. Several clinical trials have advocated the prognostic value of anaemia and hypoxia in the outcome of many cancers. Erythropoietin is recognised as an effective treatment for anaemia, which also improves the quality of life in patients with malignant disease. External radiotherapy plays an important role in the treatment of loco-regional cancer but its efficacy can be compromised by many factors. Tumor hypoxia is considered by many authors as an important factor contributing to radioresistance. We report in this article the radiobiological rationale in favour of combining radiotherapy and erythropoietin, and review relevant clinical papers published in this field.

BACKGROUND: Women carrying triplets are at greater risk for both anemia, due to the increased demands of the developingfetuses, and peripartum hemorrhage. Jehovah's witnesses are a unique obstetric population since women of this faith refuse blood transfusion. CASE: A Jehovah's Witness with a triplet pregnancy was successfully administered recombinant human erythropoietin (rHuEpo), 200 IU/kg 3 times per week subcutaneously, in order to correct her peripartum anemia. No side effects were observed during rHuEpo therapy, and the patient delivered healthy triplets. CONCLUSION: rHuEpo can be safely administered, with a beneficial effect in pregnancy, and seems to be an effective option in preventing transfusions as demonstrated in this case in a Jehovah's Witness. J Reprod Med

Objectives: Platinum compounds are commonly associated with significant anemia. Erythropoietin administration has been found effective in correcting anemia in patients with solid tumors receiving chemotherapy. We conducted a randomized, open label study to assess the efficacy of erythropoietin in preventing transfusions and significant anemia (hemoglobin Methods: One hundred forty-four patients with hemoglobin Results: All patients were evaluable for efficacy. Transfusions were reduced by the administration of rHuEPO (15.3 vs. 33.3%, p = 0.019), and fewer patients developed significant anemia (16.6 vs. 45.8%, p < 0.0001). Subgroup analysis showed that patients with observed to predicted (O/P) serum erythropoietin levels ≤0.9 and responders to chemotherapy benefited from erythropoietin administration in contrast to patients with O/P >0.9 or non-responders. Conclusions: rHuEPO at a dose of 10,000 U thrice weekly prevents transfusions and development of significant anemia in patients with solid tumors receiving platinum-based chemotherapy.

Amifostine is a cytoprotective agent mainly used in cancer therapies, in order to ameliorate the toxic effects of anticancer chemotherapy and radiotherapy. In the past years an intriguing number of applications of amifostine have been identified; one of these is bone marrow cells protection and stimulation. Amifostine was administered in seven patients with myelodysplastic syndromes, four males and 3 females aged between 67 and 78 years old, in order to estimate its efficacy in reducing the need for red blood cells transfusions. Two patients had RAEB, four RA and one RARS. The drug was administered in an outpatient basis in a dose of 300 mgr/m2, three times weekly for at least four weeks. We administered at the same time erythropoietin 10.000 U subcutaneously. All patients received daily supplementation of oral ferrum sulfate and folic acid. Three patients, a woman with RA and two men, one with RA and another with RAEB improved the levels of Hb beyond 12,0 gr/dl and did not receive blood transfusions after the second week of treatment. The drug was well tollerated without any side effects in all of the patients. J Exp Clin Cancer Res

The anemia of pregnancy in presence of beta-thalassemia intermedia usually aggravates pregnancy procedure. In the present study we investigated whether the administration of recombinant human erythropoietin (rHuEpo) recombinant human erythropoietin in combination with iron and folic acid may ameliorate blood indices as an alternative choice to blood transfusion. Minerva Ginecol

Twenty-five premature infants (mean gestational age+/-SD, 31.4+/-1.9 weeks) were administered subcutaneously recombinant human erythropoietin (rHuEpo) at a dose of 300 u/kg of body weight three times a week beginning on the third day of life and continuing for 6 weeks. The controls (n=23) were premature infants with a mean gestational age of 32.2+/-2.3 weeks who did not receive rHuEpo. Haematological indices, haemoglobin and serum phosphate (Pi), and red blood cell (RBC) phosphate metabolites (ATP, 2,3-DPG, RBCPi) were tested monthly until the 6th month and thereafter at the 9th and 12th months of life. The level of serum soluble transferrin receptors (sTfR) correlated significantly with rHuEpo (p

OBJECTIVES: The aim of this study was to investigate the efficacy of recombinant human erythropoietin (rHuEpo) in postpartum anemia. STUDY DESIGN: At the University Hospital of Ioannina, rHuEpo was administrated subcutaneously to twenty anemic women (hemoglobin [Hb]2 g/dl in the group undergoing rHuEpo therapy as compared to 0.7 g/dl in the control group on day 5 (P

Eur J Haematol

The single-dose pharmacokinetics of recombinant human erythropoietin (rHuEPO) given SC was investigated in 20 patients aged 7-20 years at different stages of chronic renal failure. In a pilot study we confirmed the lower bioavailability of the drug in 2 children when given SC compared with the IV route (24% and 43%, respectively). Following administration of 4,000 units/m2, rHuEPO SC effective serum erythropoietin concentrations increased from a mean baseline level (+/- SD) of 23 +/- 13 units/l to a mean peak concentration of 265 +/- 123 units/l, which was reached after 14.3 +/- 9.4 h, followed by a slow decline until baseline values were attained at 72 h. Mean residence time was 30 +/- 9 h and mean elimination half-time 14.3 +/- 7 h. The single-dose kinetics of SC rHuEPO in children with different degrees of renal failure are comparable to those in adult patients. Possibly, the higher efficacy of SC rHuEPO in patients with renal anaemia compared with IV rHuEPO is related to its prolonged action.

We have evaluated the therapeutic activity of recombinant erythropoietin (rEpo), in comparison with recombinant interleukin-3 (rIL-3) and granulocyte-macrophage colony-stimulating factor (rGM-CSF), on a lethal form of acute anemia resulting from Fc gamma receptor-mediated erythrophagocytosis after a single injection (500 micrograms) of a monoclonal anti-mouse red blood cell (MRBC) autoantibody. Continuous perfusion of rEpo before the administration of anti-MRBC monoclonal antibody completely protected animals from death due to anemia with a rapid recovery, while no protection was obtained by rIL-3 perfusion. In contrast, rGM-CSF perfusion markedly accelerated the progression of anemia and the mortality rate. This was found to result from an enhancement of erythrophagocytosis by Kupffer cells and by polymorphonuclear leukocytes that massively infiltrated the livers. Even after the injection of a sublethal dose (100 micrograms) of anti-MRBC monoclonal antibody, rGM-CSF-perfused mice died of a severe form of acute anemia. Furthermore, we have shown that rEpo was able to treat efficiently a spontaneous form of autoimmune hemolytic anemia in a majority of anemic NZB mice, whereas rGM-CSF markedly aggravated anemia. This may be of clinical importance, because GM-CSF administration could exhibit an adverse effect in some autoimmune diseases that involve autoimmune anemia.

We have evaluated the therapeutic activity of rIL-3, in comparison with recombinant granulocyte-macrophage CSF (rGM-CSF) and recombinant erythropoietin (rEpo), on a lethal form of acute anemia induced by a single injection of a monoclonal IgG1 anti-mouse RBC (MRBC) autoantibody. Continuous perfusion of rIL-3 before the administration of anti-MRBC mAb prevented animals from the death due to anemia with a rapid recovery in greater than 90% of the cases, while only partial protection (one third of the cases) was obtained by rEpo perfusion, and no protection by rGM-CSF. Since the anti-MRBC mAb induced a marked agglutination of RBC in spleens and livers, and subsequent hemodynamic failure may be an additional contributing factor to the animals' death, the activation of Fc gamma receptor-dependent phagocytosis by rIL-3, as well as the increased number of monocytes/macrophages resulting from rIL-3 perfusion, may also facilitate rapid elimination of these agglutinated RBC, resulting in the further amelioration of the animals' survival. Our results suggest that the therapeutic effect of rIL-3 on anti-MRBC autoantibody-induced anemia is achieved by: (a) its activity to promote the growth and differentiation of erythroid progenitors responsive to Epo and of monocyte/macrophage lineage; and (b) its activity to enhance the phagocytic activity of macrophages to efficiently eliminate agglutinated RBC in spleens and livers.

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.