Comparison of Epoetin Alfa and Darbepoetin Alfa Biological Activity under Different Administration Schedules in Normal Mice

Sasu, Barbra J.; Hartley, Cynthia; Schultz, Henry J.; McElroy, Patricia; Khaja, Raheemuddin; Elliott, Steven; Egrie, Joan C.; Browne, Jeffrey K.; Begley, C. Glenn; Molineux, Graham

doi:10.1159/000084446

Cited by 16 publications

(13 citation statements)

References 43 publications

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“…Nevertheless, the [Hb] measurements were repeatable between samples, and [Hb] was elevated in response to EPO. This elevation is consistent with previous EPO studies in mice (Egrie et al, 2003;Sasu et al, 2005; Imagawa et al, 2007) and humans (Connes et al, 2003;Smith et al, 2003;Wilkerson et al, 2005). However, a discrete dose-response relationship was not observed at the 300gkg -1 dose level.…”

Section: Erythropoietin Elevates V O 2 Max In Micesupporting

confidence: 92%

“…Every individual received an injection on day 15 and on day 17 of the experiment. Given that significant [Hb] elevation has been reported to start 5-6 days post-injection, with a maximal effect approximately 7-10 days post-injection, and multiple injections lengthen and increase the dose-response plateau of [Hb] (Breymann et al, 1996;Egrie et al, 2003;Sasu et al, 2005;Lundby et al, 2007), blood samples were obtained eight and 11 days following the second injection (day 25 and day 28, respectively). These two samples were used to verify E. M. Kolb and others the expected [Hb] plateau.…”

Section: Experimental Designmentioning

confidence: 99%

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Erythropoietin elevates but not voluntary wheel running in mice

Kolb

Kelly

Middleton

et al. 2010

Journal of Experimental Biology

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SUMMARYVoluntary activity is a complex trait, comprising both behavioral (motivation, reward) and anatomical/physiological (ability) elements. In the present study, oxygen transport was investigated as a possible limitation to further increases in running by four replicate lines of mice that have been selectively bred for high voluntary wheel running and have reached an apparent selection limit. To increase oxygen transport capacity, erythrocyte density was elevated by the administration of an erythropoietin (EPO) analogue. Mice were given two EPO injections, two days apart, at one of two dose levels (100 or 300gkg -1 and 300gkg -1 dose levels (overall mean of 4.5gdl -1 increase). EPO treatment significantly increased V O2,max by ~5% in both the HR and C lines, with no dose ϫ line type interaction. However, wheel running (revolutions per day) did not increase with EPO treatment in either the HR or C lines, and in fact significantly decreased at the higher dose in both line types. These results suggest that neither [Hb] per se nor V O2,max is limiting voluntary wheel running in the HR lines. Moreover, we hypothesize that the decrease in wheel running at the higher dose of EPO may reflect direct action on the reward pathway of the brain.Key words: artificial selection, central limitation, experimental evolution, maximum metabolic rate, oxygen transport, peripheral limitation, respiratory exchange ratio, selection limit, symmorphosis. THE JOURNAL OF EXPERIMENTAL BIOLOGY 511Erythropoietin elevates V O 2 ,max in mice aerobically supported exercise has also increased in the HR lines, as demonstrated by increased endurance (Meek et al., 2009) and increases maximum oxygen consumption [V O2,max (Swallow et al., 1998b;Rezende et al., 2005;Rezende et al., 2006a)] during forced treadmill exercise. However, the trait, or group of traits, that is limiting to even higher levels of wheel running in the HR lines remains an open question. Results to date indicate that glycogen depletion during nightly running is not responsible for the limitation (Gomes et al., 2009) nor are the HR mice limited by their ability to process enough energy to support the increased energy demands of running (Koteja et al., 1999;Koteja et al., 2001;Vaanholt et al., 2007a;Rezende et al., 2009).One of the main predictors of endurance-running ability is wholeorganism aerobic capacity (Wagner, 1996;Bassett and Howley, 2000;Lucia et al., 2001;Calbet et al., 2006;Noakes, 2007;Levine, 2008;Noakes, 2009). All else being equal, the higher the maximum aerobic capacity, the higher the maximum sustainable running speed. Maximum oxygen consumption defines the upper limits of the cardiovascular/respiratory system and of aerobic ability in general (for a review, see Levine, 2008). The ultimate determinant of organismal aerobic capacity occurs at the 'sink' of tissue oxygen consumption but all of the sequential steps of oxygen transport, from ventilatory convection in the lungs to oxygen diffusion in the peripheral tissues, contribute to V O2,max (Taylor an...

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Section: Erythropoietin Elevates V O 2 Max In Micesupporting

confidence: 92%

Section: Experimental Designmentioning

confidence: 99%

Erythropoietin elevates but not voluntary wheel running in mice

Kolb

Kelly

Middleton

et al. 2010

Journal of Experimental Biology

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“…In a multicycle carboplatin chemotherapy/radiotherapy model in mice [54], a sixfold higher dose of rHuEPO was required to match the effect of the lower dose of darbepoetin alfa. In normal mice, in order to maintain or elicit a similar erythropoietic response, three times more rHuEPO was needed than darbepoetin alfa to provide the same response at three times per week administration in mice [47,55] (Fig. 6).…”

Section: Successful Development Of Darbepoetin Alfamentioning

confidence: 99%

“…5 Darbepoetin alfa serum concentration in stable peritoneal dialysis patients remains above the minimal effective concentration (MEC) for erythropoiesis longer than an equivalent dose of recombinant human erythropoietin (rHuEPO) (from [51], with permission) Fig. 6 In vivo activity of darbepoetin alfa increases compared with recombinant human erythropoietin (rHuEPO) as dose interval increases in mice [47,55] The apparent paradox, that rHuEPO glycosylation analogs with reduced receptor-binding-specific activity had increased in vivo specific activity, is explained by the counteracting effects of sialic-acid-containing carbohydrate on clearance. Slower clearance in vivo results in a slower decline in serum concentration over time when slow and faster clearing molecules are compared, and the relative concentration differences will increase with time.…”

Section: Successful Development Of Darbepoetin Alfamentioning

confidence: 99%

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Kiss¹,

Elliott

Jedynasty³

et al. 2010

Eur J Clin Pharmacol

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Cloning of the human erythropoietin (EPO) gene and development of the first recombinant human erythropoietin (rHuEPO) drug were truly breakthroughs. This allowed a deeper understanding of the structure and pharmacology of rHuEpo, which in turn inspired the discovery and development of additional erythropoiesisstimulating agents (ESAs). In vivo specific activity and serum half-life of rHuEPO are influenced by the amount and structure of the attached carbohydrate. Increased numbers of sialic acids on carbohydrate attached to rHuEPO correlated with a relative increase in in-vivospecific activity and increased serum half-life. The effect of increasing the number of sialic-acid-containing carbohydrates on in-vivo-specific activity was explored. Initial research focused on solving the problem of how the protein backbone could be engineered so a cell would add more carbohydrate to it. Additional work resulted in darbepoetin alfa, a longer-acting molecule with two additional carbohydrate chains.

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“…Darbepoetin-a (10 mg/kg body weight, Aranesp; Amgen Europe, Breda, The Netherlands) or the same volume of isotonic saline was injected intraperitoneally in a blinded manner every third day, beginning at the first day after BDL. This therapeutic schedule was adapted from the study of Sasu et al, 12 comparing the biological activity of epoetin-a and darbepoetin-a under different administration schedules in mice. To obtain blood and liver samples, mice (10 animals per group at each time point) were killed at days 2 and 5 as early time points for evaluation of hepatocellular necrosis and inflammation or at days 14 and 28 after BDL for evaluation of fibrosis.…”

Section: Surgical Procedures and Experimental Groupsmentioning

confidence: 99%

Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice

Sigal

Siebert

Zechner

et al. 2010

Laboratory Investigation

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Biliary obstruction and cholestasis result in hepatocellular necro-inflammation and lead to the development of liver fibrosis. The objective of this study was to analyze whether the multiple tissue-protective properties of erythropoietin are salutary in an experimental model of liver fibrosis. For this purpose, C57BL/6J mice underwent common bile duct ligation (BDL) and were treated with either darbepoetin-a (10 mg/kg i.p.) or physiological saline every third day, beginning 24 h after BDL. Mice were killed at 2, 5, 14, and 28 days after BDL. Beside hematological parameters, markers of inflammation and fibrosis were assessed histomorphometrically and immunohistochemically as well as by quantitative real-time PCR. In addition, a 7-week survival study was performed. BDL provoked cholestatic hepatitis characterized by biliary infarcts with accumulation of macrophages followed by marked collagen deposition and increased expression of profibrotic gene transcripts. Darbepoetin-a treatment significantly diminished the area of focal necrosis, reduced the infiltration of macrophages, decreased levels of profibrotic genes, and lowered collagen deposition. Moreover, darbepoetin-a significantly reduced systemic anemia caused by BDL. Finally, darbepoetin-a treatment significantly prolonged the survival time after BDL. This study suggests that darbepoetin-a, which is a clinically well-established substance, might be used as an efficient therapeutic option for patients with chronic cholestatic liver disease.

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Comparison of Epoetin Alfa and Darbepoetin Alfa Biological Activity under Different Administration Schedules in Normal Mice

Cited by 16 publications

References 43 publications

Erythropoietin elevates but not voluntary wheel running in mice

Erythropoietin elevates but not voluntary wheel running in mice

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice

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