Effects Of Darbepoetin-alpha Research Articles

Darbepoetin Alpha Ameliorates Neuronal Damage in a Rat Model of Acute Ethanol Intoxication

ABSTRACTObjective: Acute ethanol intoxication has been shown to cause oxidative damage in many organ systems including the brain. Erythropoietin has antioxidant effects and prevents neuronal damage in the animal model of ischemic brain injury. In this study, we aimed to investigate the effects of darbepoetin alpha, an analog of erythropoietin with a longer half-life and higher in vivo activity, on ethanol-induced acute brain injury. Methods: Forty-eight Wistar albino rats were allocated to four groups. The first group received ethanol treatment (E), the second group was treated with ethanol and darbepoetin (ED), the third group received only saline treatment (S), and the fourth group received both saline and darbepoetin treatment (SD). Plasma S100-β and neuron-specific enolase (NSE) levels were measured. Histopathological evaluation of the brains was performed. Results: The plasma S100-β and NSE levels were significantly lower in group ED compared with group E. In group E, we have observed focal red-neuron formation at the granular layer of the dentate gyrus. We did not observe any histopathological changes in the other groups (ED, S, and SD). Conclusion: Our findings suggest that darbepoetin alpha has neuroprotective effect in acute ethanol intoxication, possibly through its antioxidant effect.

Effects of darbepoetin-alpha in spinal cord ischemia-reperfusion injury in the rabbit

Darbepoetin-alpha (DA) is a novel erythropoiesis-stimulating agent developed for treating anemia. In animal models, recombinant human erythropoietin has been reported to be beneficial for neuroprotection. In this study, we determined whether DA would protect the spinal cord against ischemia-reperfusion injury in a rabbit model. Forty rabbits were randomized into five groups of eight animals each: group 1 (sham), group 2 (ischemia), group 3 (vehicle), group 4 (30 mg/kg methylprednisolone), group 5 (30 μg/kg DA). Only laparotomy was performed in the sham group. In all the other groups, the spinal cord ischemia model was created by a 20-min occlusion of the aorta just caudal to renal artery with an aneurysm clip. The drugs were administered immediately after the clamp was removed. The animals were killed 24 h later. Spinal cord segments between L2 and L5 were harvested for analysis. Neurological evaluation was performed with the Tarlov scoring system just before the animals were killed. Level of tissue malondialdehyde was analyzed as a marker of lipid peroxidation and tissue caspase-3 activity as a marker of apoptosis. Also, histopathological evaluation of the tissues was performed. Both malondialdehyde and caspase-3 levels were significantly decreased by DA administration. Histopathological evaluation of the tissues also demonstrated decrease in neuronal degeneration and infiltration parameters after DA administration. In the DA group, neurological outcome scores were statistically significantly better compared with the ischemia and the vehicle groups. Although further studies considering different dose regimens and time intervals are required, DA was shown to be at least as effective as methylprednisolone in spinal cord ischemia/reperfusion model.

Abstract 4373: Effects of Darbepoetin-Alpha on Plasma Markers of Oxidative and Nitrosative Stress in Anemic Patients with Chronic Heart Failure

Increased oxidative and nitrosative stress may be important pathophysiologic mechanisms that mediate cardiac and vascular dysfunction in chronic heart failure (CHF). This study investigate the effects of recombinant human erythropoietin analogue darbepoetin-alpha(α) on plasma markers of oxidative and nitrosative stress along with cardiac function and exercise capacity in patients with CHF and anemia. Thirty CHF patients [Hew York Heart Association class, II-III; LV ejection fraction (EF) <40%; hemoglobin <12.5 g/dl; serum creatinine <2.5 mg/dl] were randomized (1:1) to receive either a 3-month darbepoetin-α regimen at 1.5 μg/Kg every 20 days plus oral iron or placebo plus oral iron. Echocardiographic indices of LV function, plasma B-type natriuretic peptide (BNP) and plasma markers of oxidative [oxidative: malondyaldheyde (MDA), carbonyl proteins; anti-oxidative: glutathione) and nitrosative (nitrotyrosine) stress, and 6-min walked distance were assessed at baseline and post-treatment. A significant improvement of LV ejection fraction (p<0.01) and six min walked distance (p<0.001) was observed only in darbepoetin-treated patients. Moreover, plasma BNP (661±858 from 1102±1200 pg/ml, p<0.001), MDA (2.1±0.9 from 2.5±0.8 ng/ml, p<0.01), protein carbonyl (1.7±0.6 from 2.1±0.7 ng/ml, p<0.01) were significantly reduced, while plasma anti-oxidative enzyme glutathione (124±11 from 116±10 ng/ml, p<0.05) was increased after darbepoetin treatment. These factors remained unaffected in placebo-treated patients. Darbepoetin-induced percent changes in carbonyl protein was significantly correlated with respective changes in BNP (r=0.55, p<0.05) and LV ejection fraction (r=−0.46, p<0.05). Finally, a drug-induced percent reduction in nitrotyrosine was significantly correlated with the respective improvement in 6 min walked distance (r=−0.63 p<0.05). Darbepoetin seems to attenuate deleterious effects of oxidative and nitrosative stress into cardiovascular system of anemic patients with CHF. This beneficial action may be related with the drug-induced improvement of cardiac function and exercise capacity of these patients.

Effects of darbepoetin-alpha on quality of life and emotional stress in anemic patients with chronic heart failure

Anemia is a frequent comorbidity in chronic heart failure (CHF) adversely affecting patients' prognosis. Erythropoietin seems to improve exercise capacity in CHF patients. This study investigates the effects of recombinant human erythropoietin analog darbepoetin-alpha on quality of life and emotional stress, evaluated by relevant questionnaires in patients with CHF and anemia. Forty-one CHF patients [New York Heart Association class: II-III; left ventricular (LV) ejection fraction (EF)<40%; hemoglobin<12.5 g/dl; serum creatinine<2.5 mg/dl] were randomized (1:1) to receive either 3-month darbepoietin-alpha at 1.5 microg/Kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). Echocardiographic LVEF, questionnaires addressing quality of life (Kansas City Cardiomyopathy Questionnaire, functional and overall, Duke's Activity Status Index) and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory], as well as plasma b-type natriuretic peptide and 6-min walking distance (6MWT as a marker of exercise capacity) were assessed at baseline and posttreatment. A significant improvement in LVEF (32+/-6 from 26+/-6%, P<0.001), 6MWT (274+/-97 from 201+/-113 m, P<0.01), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, P<0.001) and plasma b-type natriuretic peptide (517+/-579 from 829+/-858 pg/ml, P=0.002) was observed posttreatment only in darbepoetin-treated group. Kansas City Cardiomyopathy Questionnaire functional (78+/-14 from 57+/-24%, P<0.01) and overall (68+/-20 from 47+/-22, P<0.001), Duke's Activity Status Index (19+/-11 from 14+/-9, P<0.05), Zung SDS (38+/-10 from 47+/-11, P<0.05) and Beck Depression Inventory (11+/-9 from 16+/-10, P<0.05) scores also improved in darbepoetin-treated patients, whereas they remain unchanged in the placebo group except for the Zung SDS which worsened (P<0.05). A significant correlation between drug-induced percent changes in 6MWT and Zung SDS (r=-0.627, P<0.05) was also observed. Darbepoetin-alpha improves quality of life and emotional stress in CHF patients with anemia, with a parallel increase in exercise capacity.

Effects of Darbepoetin-alpha on quality of life and emotional stress in anemic patients with chronic heart failure

Effects of Darbepoetin-alpha on quality of life and emotional stress in anemic patients with chronic heart failure

Effects of Darbepoetin-alpha on Plasma Pro-inflammatory Cytokines and Soluble Fas/Fas Ligand System in Anemic Patients with Chronic Heart Failure

Effects of Darbepoetin-alpha on Plasma Pro-inflammatory Cytokines and Soluble Fas/Fas Ligand System in Anemic Patients with Chronic Heart Failure

Effects of darbepoetin-alpha on plasma pro-inflammatory cytokines, anti-inflammatory cytokine interleukin-10 and soluble Fas/Fas ligand system in anemic patients with chronic heart failure

Pro-inflammatory cytokine over-expression may be implicated to the pathogenesis of anemia in chronic heart failure (CHF) through the suppression of bone marrow erythropoiesis. Erythropoietin administration has anti-inflammatory and anti-apoptotic properties in experimental CHF models and improves exercise capacity in anemic CHF patients. The present study investigates the effects of recombinant human erythropoietin analogue darbepoetin-α on circulating pro-inflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with CHF and anemia. Forty-one CHF patients (NYHA class: II–III; left ventricular (LV) ejection fraction (EF) <40%; hemoglobin <12.5 g/dl; serum creatinine <2.5 mg/dl) were randomized to receive either 3-month darbepoietin-α at 1.5 μg/kg every 20 days plus iron orally ( n = 21) or placebo plus iron orally ( n = 20). LV systolic function, plasma B-type natriuretic peptide (BNP), inflammatory markers (TNF-α, IL-6, CRP), anti-inflammatory cytokine IL-10, endothelial adhesion molecules (soluble ICAM-1 and VCAM-1) and soluble apoptosis mediators (soluble Fas, soluble Fas ligand), and 6-min walking distance were assessed at baseline and 3 months post-treatment. In darbepoetin-α treated patients, plasma BNP (451 (62-2770) from 802 (476-4440) pg/ml, p = 0.002), IL-6 (6.5 ± 4.7 from 10.5 ± 7.8 pg/ml, p = 0.013) and soluble Fas ligand (53.2 ± 16.6 from 59.2 ± 17.9 pg/ml, p = 0.023) decreased significantly, while LVEF (32 ± 6 from 26 ± 6%, p < 0.001), hemoglobin (12.8 ± 1.4 from 10.9 ± 1.0 g/dl, p < 0.001) and 6-min walked distance (274 ± 97 from 201 ± 113 m, p < 0.01) increased significantly. No significant changes were observed in the placebo arm, except for a worsening in 6-min walked distance ( p = 0.044). In conclusion, darbepoetin-α reduces circulating pro-inflammatory cytokine IL-6 and apoptotic mediator soluble Fas ligand in CHF patients with anemia, with a parallel improvement of cardiac performance and exercise capacity.