New Erythropoiesis-Stimulating Agents and New Iron Formulations

Locatelli, Francesco; Vecchio, Lucia Del

doi:10.1159/000327328

Cited by 10 publications

(3 citation statements)

References 22 publications

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“…droxide corestabilized byacarbohydrateligand (isomaltoside 1000,avery lowmolecularweightdextran) [15,16]. Currently,ferriccarboxymaltoseisavailable in numerous countries,while ferumoxytol islicensed onlyin the United Statesand IIM isr egistered in alimited numberof Europeanmarkets.IS similarpreparationshavealsobeen developed which,duetod ifferencesin theirphysicochemicalpropertiesthatarelikelytobecaused byvariationsin the manufacturing process,c annotberegarded asequivalenttothe originatorIS [17][18][19].I.v.iron compoundsvary in termsof molecularweight,kineticvariability (labile orr obust)and thermodynamicvariability (weako rs trong) [20].Largercomplexesareg enerally morestable thansmallercomplexes,withslowerdegradation rates in vitro [20].Less stable complexescontain moreweakly-bound iron and consequentlyexhibitgreaterr eactivity withthe transport protein transferrin.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of toxicity and oxidative stress induced by intravenous iron isomaltoside 1000 in a nonclinical model

Toblli

Cao

Oliveri

et al. 2012

Arzneimittelforschung

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The physicochemical characteristics of intravenous iron complexes affect the extent of weakly-bound iron and thus the degree of oxidative stress. The new preparation iron isomaltoside 1000 (IIM) was compared to iron sucrose (IS) and a control group in terms of biochemistry, oxidative stress, inflammatory markers and iron deposition in the liver, heart and kidneys of healthy rats. Renal function was significantly impaired in the IIM group versus both IS and controls. Liver enzymes were also significantly higher in IIM-treated animals versus the other groups, indicative of hepatic injury. Systolic blood pressure was significantly lower following IIM administration compared to IS or control animals. Oxidative stress in the liver, heart and kidneys was greater in the IIM group, as indicated by significantly increased levels of malondialdehyde and antioxidant enzyme activity, accompaniedby a significantly lower ratio of reduced to oxidized glutathione. Microscopy demonstrated more extensive positive staining for iron, and a smaller area of ferritin staining, in the liver, heart and kidneys of rats treated with IIM versus IS.Levels of the inflammatory markers TNF-alpha and IL6 were both significantly higher in the IIM group versus IS in all assessed tissues. These findings indicate that IIM has a less favorable safety profile than IS in healthy rats, adversely affecting iron deposition, oxidative stress and inflammatory responses, with impaired liver and renal function.

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Section: Introductionmentioning

confidence: 99%

Evaluation of toxicity and oxidative stress induced by intravenous iron isomaltoside 1000 in a nonclinical model

Toblli

Cao

Oliveri

et al. 2012

Arzneimittelforschung

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“…Nevertheless, older i.v. iron formulations have their limitations, including the potential for immunogenic reactions induced by dextran molecules (iron dextran) [113], dose limitations, a slow rate of administration (to prevent acute, labile iron-induced toxicity and vasoactive reactions) [70,113] [116]. Both of these compounds allow higher doses of intravenous iron to be administered rapidly as a bolus injection, without the need for a test dose.…”

Section: Iron Deficiencymentioning

confidence: 99%

Management of Anemia on Hemodialysis

Pantelias¹,

Grapsa²

2013

Hemodialysis

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patients on dialysis,, average Hb values have steadily increased during the past 15 years, following the advent of erythropoietin (EPO) and the development of clinical practice guidelines for anemia management [16, 17]. Anemia contributes to significant healthcare costs associated with CKD [20]. The average Hb value, however, varies considerably between countries, reflecting variability in practice patterns [21]. Before the availability of recombinant human erythropoietin (rhuEPO, or epoetin), patients on dialysis frequently required blood transfusions, exposing them to the risks of iron overload, transmission of viral hepatitis, and sensitization, which reduced the chances of successful transplantation. Anemia in CKD patients except from the lack of EPO [22, 23], is a multifactor process. Shorter lifespan of red blood cells, iron and vitamin deficiency due to dietary restrictions, and rarely bleeding that accompanies uremia seem to be other important factors [24, 25]. Adequate dialysis can contribute to anemia correction through many mechanisms, including the removal of molecules that may inhibit erythropoiesis using high-flux dialyzers [26-30]. It also seems that residual renal function is important in dialysis patients and its decline also contributes significantly to anemia, inflammation, and malnutrition in patients on dialysis [31, 32]. It is also affected by the underlying disease, co morbid conditions, malignancy, infection, heart failure, as mentioned above, the environment and several other factors (therapeutic treatment with angiotensin-converting enzyme(ACE) inhibitors, [33-37] increased PTH, [38-43] osteodystrophy [44, 45]) that differ among patients. Thus, anemia management in these patients needs an individualized approach. Each patient should be treated according to an Hb target with the lowest effective Erythropoiesis Stimulating Agents (ESA) dose, while avoiding large fluctuations in Hb levels or prolonged periods outside the target. This strategy may necessitate changes to the ESA dose, dosing frequency and iron supplementation over the course of a patient's treatment, and proactive management of conditions that can affect ESA responsiveness. While all ESAs effectively increase Hb levels, differences with respect to route of administration, pharmacokinetics, and dosing frequency and efficiency should be considered to maximize the benefits of ESA treatment for the individual patient [46]. Substitution of the subcutaneous route of administration for the intravenous route for epoetin-alfa can reduce drug acquisition and costs, the two largest components of healthcare costs in CKD patients [20]. Hence, treating anemia in CKD patients on HD seems to be very complex and has to be managed step by step correcting all the factors that affect this process. 2. Diagnostic approach of anemia in hemodialysis patients The diagnosis of anemia and the assessment of its severity are best made by measuring the Hb concentration rather than the hematocrit. Hb is a stable analyte measured directly in a standardized ...

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“…A randomized active controlled multicenter study has shown that ferric carboxymaltose in a dose 1000mg (high dose) is well tolerated and has shown comparable efficacy and safety with respect to other i.v. formulations [5][6][7][8][9]. Studies have shown that ferric carboxymaltose can be given without the test dose and single infusion can bring down cost, fewer hospital visits and patient inconvenience [10,11].…”

Section: Introductionmentioning

confidence: 99%