Use Of rhEPO Research Articles

Age and genotype dependent erythropoietin protection in COVID-19.

Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a “bait” for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.

Survey on clinical use and non-use of recombinant human erythropoietin in European neonatal units.

Objectives Recombinant human erythropoietin (rhEPO) has been shown to effectively and safely prevent the anemia of prematurity and to reduce the transfusion need in very low birth weight (VLBW) infants and has been licensed for this indication in Europe in 1997. The objective of the study was to obtain information on the use or non-use of rhEPO in neonatal units in Germany and other European countries. Methods Anonymized 14-questions web-based questionnaire. Results Seventy-nine questionnaires from Germany and 63 questionnaires from other 15 European countries were completed. Of the responders, 39% indicated to use rhEPO routinely or occasionally in VLBW infants, whereas 61% responded to never use rhEPO in this population. The major reasons given for non-use were lack of recommendation in national guidelines (69%) and/or doubt about efficacy of rhEPO to reduce transfusion need (53%). Twenty-seven percent of the responders indicated to use rhEPO for neonates with birth weights above 1,500g. Neuroprotection in VLBW infants (26%) and hypoxic ischemic encephalopathy in term neonates (27%) were given as indications for off label use of rhEPO. Conclusions This survey indicates that rhEPO is used for the anemia of prematurity as licensed in less than half of neonatal units in Germany and other European countries. On the other hand it seems to be used off label in neonates for neuroprotection in a considerable number of units although there is no final evidence on its neuroprotective effects.

Clinical Indications of Recombinant Human Erythropoietin in a Single Center: A 10-Year Retrospective Study.

In the 1980s, recombinant human erythropoietin (rhEPO) began to be used in clinical practice. In this study, the clinical application of rhEPO from single-center in recent ten years was reviewed, and the scope of indications and clinical efficacy were evaluated. The medical records of 35829 in-patients who were treated with rhEPO in the first Medical Center of the Chinese PLA General Hospital from 2009 to 2018 were collected. According to the scope of indications approved by CFDA (China Food and Drug Administration), curative effect and off-label of rhEPO were analyzed. Of the 35829 patients, 19013 (53.1%) were male and 16816 (46.9%) were female, with an average age of (52.1 ± 18.6) years. The usage of rhEPO is increasing year by year. The overall effective rate was 53.1%. The number of patients who met the indications accounted for 67.2%, and the effective rate patients with indications and Off-label were 48.8% and 50.7%. Among the patients with irregular use of rhEPO perioperative imperfect laboratory examination patients accounted for the highest proportion (7.1%). The volume of RBC(s) (red blood cell(s)) transfusion in patients with rhEPO was significantly less than that in patients without rhEPO (p<0.05). The use of rhEPO Off-label is very common and has a certain curative effect. It can be used as evidence support for the update of the scope of indications. In addition, There are still irregular use of rhEPO and transfusion in clinic. The unreasonable use of rhEPO and transfusion should be further standardized to ensure the safety and effectiveness.

Recombinant Human Erythropoietin: Manfaat dalam Bidang Kedokteran

Recombinant human erythropoietin (rhEPO) is one of the biotechnology-based drugs that are needed by the human medicine and has also been used in the veterinary medicine. Currently RhEPO has been widely used in the world of human medicine for the treatment of anaemia caused by renal failure, cancer, chronic inflammation and AIDS. In veterinary medicine, although there is still not much data on its achievements, rhEPO has also been used for cases of chronic renal failure in dogs and cats. However, since rhEPO is not identical to feline EPO and canine EPO, some patients eventually produce antibodies against the drug. The antibodies not only prevent EPO therapy from being effective, but also may lead to severe and life-threatening anemia. This paper provides a review of the use of RhEPO, rfEPO and rcEPO in veterinary medicine, especially for the purpose of non-regenerative anemia therapy in cases of chronic renal failure in dogs and cats.

Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis.

Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent for neuroprotection in neonates. To investigate whether prophylactic rhEPO administration in very preterm infants improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials (RCTs). Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched in December 2016 and complemented by other sources. RCTs investigating the use of rhEPO in preterm infants versus a control group were selected if they were published in a peer-reviewed journal and reported neurodevelopmental outcomes at 18 to 24 months' corrected age. Data extraction and analysis followed the standard methods of the Cochrane Neonatal Review Group. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary outcomes included a Psychomotor Development Index <70, cerebral palsy, visual impairment, and hearing impairment. Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio (95% confidence interval) of 0.51 (0.31-0.81), P < .005. The number needed to treat was 14. There was no statistically significant effect on any secondary outcome. Prophylactic rhEPO improved the cognitive development of very preterm infants, as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up.

Erythropoietin and drug resistance in breast and ovarian cancers

Recombinant human erythropoietin (rhEPO) is used in breast and ovarian cancer patients to alleviate cancer- and chemotherapy-related anemia. Some clinical trials have reported that rhEPO may adversely impact survival and increase the risk of thrombovascular events in patients with breast cancer but not with ovarian cancer. The latter may potentially benefit the most from rhEPO treatment due to the nephrotoxic and myelosuppresive effects of standard platinum-based chemotherapy used in ovarian cancer disease. However, over the last decade the preclinical data have revealed that EPO is not only the principal growth factor and the hormone which regulates erythropoiesis, but also a cytokine with a pleiotropic activity which also can affect cancer cells. EPO can stimulate survival, ability to form metastases and drug resistance not only in continuous breast- and ovarian cancer cell lines but also in breast cancer stem-like cells. EPO receptor (EPOR) can also be constitutively active in both these cancers and, in breast cancer cells, may act in an interaction with estrogen receptor (ER) and epidermal growth factor receptor-2 (HER-2). EPOR, by an EPO-independent mechanism, promotes proliferation of breast cancer cells in cooperation with estrogen receptor, resulting in decreased effectiveness of tamoxifen treatment. In another interaction, as a result of the molecular antagonism between EPOR and HER2, rhEPO protects breast cancer cells against trastuzumab. Both clinical and preclinical evidence strongly suggest the urgent need to reevaluate the traditional use of rhEPO in the oncology setting.

Erythropoietin promotes retinal angiogenesis in a mouse model.

This study aimed to investigate the effect and potential mechanisms of exogenous administration of recombinant human erythropoietin (rhEPO) on retinal angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). Postnatal day 7 (P7) mice (n=132) were randomly assigned to one of six groups: Control group (n=22), OIR group (n=22), OIR + vehicle control group (n=22), OIR + rhEPO 10 IU group (n=22), OIR + rhEPO 50 IU group (n=22), and OIR + rhEPO 100 IU group (n=22). OIR was induced by exposing mice to 75±2% O2 for five days, followed by exposure to room air for a further five days. Animals in groups 3-6 (the OIR + vehicle control group and OIR + rhEPO 10 IU, 50 IU, and 100 IU groups) received an intraperitoneal injection of saline, or rhEPO 10 IU, 50 IU and 100 IU, respectively, which were administered daily from P7-P12. Immunofluorescent and hematoxylin-eosin staining were used to detect retinal neovascularization (RNV) in retinal whole mounts. Quantitative polymerase chain reaction and western blot analysis were used to detect the expression levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS). RNV occurred in the OIR groups and was accompanied by dilated, twisted and occluded blood vessels. rhEPO treatment resulted in an increase in the number of newly formed and severely dilated vessels. rhEPO increased RNV in a dose-dependent manner, which was accompanied by an increase in the messenger RNA and protein expression of VEGF, eNOS and nNOS. Thus, exogenous use of rhEPO promotes the RNV in a mouse model of OIR and is accompanied by increased expression levels of VEGF, eNOS and nNOS.

DI-042 Managing HCV treatment-related anaemia in patients on boceprevir treatment

BackgroundBoceprevir has been linked with high rates of anaemia in patients with HCV infection. Anaemia management strategies (AMS) are strongly recommended in order to achieve therapeutic success.PurposeTo describe AMS in...

A DNA-based method for detecting homologous blood doping

Homologous (or allogeneic) blood doping, in which blood is transferred from a donor into a recipient athlete, is the easiest, cheapest, and fastest way to increase red cell mass (hematocrit) and therefore the oxygen-carrying capacity of the blood. Although thought to have been rendered obsolete as a doping strategy by the increased use of rhEPO to increased hematocrits, there is evidence that athletes are still using this potentially dangerous method to improve endurance performance. Current testing for homologous blood doping is based on identification of mixed populations of red blood cells by flow cytometry. This paper proposes that homologous blood doping could also be tested for by high-resolution qPCR-based genotyping and demonstrates that assays could be developed that would detect second populations of cells even if the "donor" blood was depleted of 99% of the DNA-containing leukocytes. Issues of test specificity and sensitivity are discussed as well as some of the ethical considerations that would have to be addressed if athletes' genotypes were to be used by the anti-doping authorities to prevent, or detect, the use of prohibited ergogenic practices.

Effects of Preoperative Intravenous Erythropoietin Plus Iron on Outcome in Anemic Patients After Cardiac Valve Replacement

Preoperative anemia is a risk factor for postoperative morbidity and in-hospital mortality in cardiac surgery. However, it is not known whether treatment of anemia before cardiac surgery by administering recombinant human erythropoietin (rhEPO) plus iron improves postoperative outcomes and decreases red blood cell transfusions in these patients. In 1998 a collection of consecutive data for patients who underwent valve replacement was initiated and the inclusion criterion was anemia. Treatment with rhEPO was given at a dose of 500 IU/kg/day every week for 4 weeks and the fifth dose 48 hours before valve replacement. During each rhEPO session, patients received intravenous iron sucrose supplementation. The intervention cohort (2006 to 2011) included 75 patients and the observation cohort was composed of 59 patients who did not receive any treatment (1998 to 2005). Multivariable logistic regression analysis showed that administration of combined therapy was independently associated with decreased postoperative morbidity (odds ratio [OR] 0.13, 95% confidence interval [CI] 0.03 to 0.59 p = 0.008) and in-hospital mortality (OR 0.16, 95% CI 0.28 to 0.95 p = 0.04) after adjusting for logistic European System for Cardiac Operative Risk Evaluation score, type of intervention, time of cardiopulmonary bypass, and year of surgery. Individually, this treatment also decreased postoperative renal failure (OR 0.23, 95% CI 0.06 to 0.88, p = 0.03). Rate of red blood cell transfusion decreased from 93% in the observation cohort to 67% in the intervention cohort as did days of hospitalization (median, 15 days, 10 to 27, versus 10 days, 8 to 14, respectively, p = 0.01 for all comparisons). In conclusion, administration of intravenous rhEPO plus iron in anemic patients before valve replacement improves postoperative survival, decreases blood transfusions, and shortens hospitalization.

Role of Pentoxifylline in Treatment of Anemic Patients Suffering Chronic Hemodialysis: a Randomized Clinical Trial

Anemia is a major problem in patients with end-stage renal disease on chronic hemodialysis. rh-EPO is used mostly to elevate serum hemoglobin level and improve complaints caused by anemia, although in some patients it may not be totally effective for treating the disease. In this study, we aimed to evaluate pentoxifylline as a drug for treating anemia. Fifty patients were enrolled in the study and divided into 2 groups. The case group took 400 mg of pentoxifylline daily for 6 months, while the control group took placebo for the same time. The levels of hemoglobin and serum albumin, TIBC, iron, ferritin, and PTH, and use of rh-EPO were estimated. The data were analyzed using SPSS-18 software. Of the 50 patients, 33 (66%) were male and 17 (34%) were female. Student paired t tests showed no significant difference in hemoglobin and serum albumin, TIBC, ferritin, and PTH levels, or use of rh-EPO between the case and control groups. However, iron level was significantly different in the 2 groups. In contrast to previous studies, our data do not support the concept that pentoxifylline elevates hemoglobin level and improves anemia, Further studies on a larger number of patients are required to assess whether or not pentoxifylline is useful in these patients.

The Use of Erythropoietin and its Derivatives to Treat Spinal Cord Injury

Spinal Cord Injury (SCI) is a complex process which leads to destruction of neuronal tissue and also vascular structure. After SCI many potentially toxic substances are activated and released into the injury site causing secondary degeneration. Erythropoietin (EPO) is a possible therapeutic strategy to treat SCI. Over the last decade attention has been focused on the molecular mechanisms underlying its neuroprotective effects. A major concern expressed by clinicians is that besides its protective effects, EPO also demonstrates hematopoietic activity and increases the risk for thrombosis after the administration of multiple doses of this glycoprotein. Recently, tissue protective functions of EPO have been separated from its hematopoietic actions leading to the development of EPO derivatives and mimetics. Neuroscientists are focusing on recombinant human EPO (rhEPO) and its non-erythropoietic derivatives, investigating their anti-apoptotic potential and anti-inflammatory function as well as their role in restoring vascular integrity. Carbamylated erythropoietin (CEPO) and asialo erythropoietin (AsialoEPO) are structural derivatives of EPO that have no effect on erythrocyte mass whereas they retained its neuroprotective effects. In this review article, we provide a short overview of the animal studies on rhEPO and its derivatives in experimental models of SCI. Both the efficacy and the safety profile of EPO-structural and functional variants are still to be demonstrated in patients. Further clinical studies should reveal whether derivatives and variants of erythropoietin provide any benefits over the use of rhEPO in the treatment of spinal cord injury observed in the experimental studies.

Erythropoietin Increases Survival and Attenuates Fulminant Hepatic Failure Injury Induced by d-Galactosamine/Lipopolysaccharide in Mice

Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), d-galactosamine (GalN)-induced FHF is a well-established model of liver injury in mice. Erythropoietin has a powerful tissue-protective effect in animal models. The aim of this study was to investigate the effect and mechanism of recombinant human erythropoietin (rhEPO) administration in FHF mice. C57BL/6 (n=42) mice were studied in vivo in a fulminant model induced by GalN/LPS. rhEPO was administered 30 min after the induction of FHF. Serum liver enzymes and hepatic tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were determined. Histologic analysis was performed, and apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor (NF)-κB and c-Jun-N-terminal kinase (JNK) activation were studied using Western blot analysis. After the induction of FHF, all control mice died within 12 hr of GalN/LPS administration. However, 83% of mice that were administered rhEPO were alive 2 weeks later, and overall survival improved (Kaplan-Meier, P<0.001). The serum liver enzymes, hepatic TNF-α and IL-1β levels, liver histologic injury, and apoptotic hepatocytes were significantly reduced in FHF mice that were administered rhEPO compared with untreated mice. A significant decrease in hepatic NF-κB and JNK activation was noted in FHF rhEPO-treated mice compared with FHF untreated mice. The administration of rhEPO brought about increased survival and attenuation of the hepatic injury. This was associated with decreased hepatic NF-κB and JNK activation and thus TNF-α and IL-1β levels. These findings have important implications for the potential use of rhEPO in FHF.

Synergistic benefits of erythropoietin and simvastatin after traumatic brain injury

Simvastatin and recombinant human erythropoietin (rhEpo) are implicated as potential therapeutic candidates for traumatic brain injury (TBI). Prominent effects of simvastatin include its anti-inflammatory, neurotrophic and neuroregenerative actions studied in various models of neuronal injury. On the other hand, rhEpo has been shown to promote cell survival mechanisms by producing anti-apoptotic and cell proliferative actions. Beneficial effects of rhEpo and statin monotherapies have been well studied. However, there are no reports showing combined use of rhEpo and statins after TBI. This investigation examined if combined efficacy of cell proliferative ability of rhEpo along with the neuroregenerative ability of simvastatin will render maximum recovery in a controlled cortical impact (CCI) mouse model of TBI. Results showed that compared to baseline TBI, rhEpo was more effective than simvastatin in promoting cell proliferation while simvastatin was more effective than rhEpo in restoring axonal damage following TBI. Combined treatment with simvastatin and rhEpo maximally restored axonal integrity while simultaneously inducing greater proliferation of newly formed cells resulting in better functional recovery after TBI than either alone. This is the first study showing the efficacy of erythropoietin–simvastatin combinational therapeutic approach in achieving greater structural and cognitive recovery after TBI.

The Effect of Recombinant Human Erythropoietin on the Development of Retinopathy of Prematurity

In addition to its hematopoietic effects, erythropoietin causes an increased release of endothelin-1 and the stimulation of angiogenesis and thereby it may have possible role in development of retinopathy of prematurity (ROP). Our objective was to determine if an association exists between recombinant human erythropoietin (rhEPO) treatment and the development of ROP. Our case-control study involved 85 very low birthweight infants with birthweights <1500 g born during 2003 and 2004. All the infants were divided into two groups on the basis of whether they got rhEPO or not. The rhEPO was given at the dose of 200 to 250 units/kg/dose three times a week for 10 doses. Further duration of rhEPO therapy was decided on the basis of the clinical response. Ophthalmological examinations were done at the age of 5 to 6 weeks and were repeated 1 to 4 weeks after the first examination according to the severity of the ROP disease during their in-hospital stay. Of 85 infants, 56 (66%) received rhEPO and 29 (34%) did not. In the rhEPO-treated group, 12 infants (21%) had ROP; in the non-rhEPO group, 11 infants (38%) developed ROP. This difference is not statistically significant (odds ratio = 2.63; P = 0.10). There was no correlation between the use of rhEPO and the stage of ROP (random sample = -0.01; P = 0.89). There was no significant difference in the incidence of plus, prethreshold, or threshold disease and the treatment required for ROP between the rhEPO-treated and the nontreated group. The study showed there is no significant difference in the incidence and severity of ROP between the rhEPO-treated and nontreated group.

Effectiveness of recombinant human erythropoietin, vitamin D3and iron therapy on long-term survival of patients with end-stage renal disease receiving haemodialysis: analysis of 702 patients after 10-year follow-up

Few studies have been conducted to investigate the influence of recombinant human erythropoietin (rhEPO) on the long-term prognosis of end-stage renal disease (ESRD). A retrospective cohort study. The largest regional hospital renowned for haemodialysis in northern Taiwan. A total of 702 ESRD patients undergoing haemodialysis between 1993 and 2002 were evaluated. The rate of overall use of rhEPO, vitamin D3 or Fe therapy was 62 %. The 10-year survival rate in patients with rhEPO supplementation was statistically more favourable than that in patients without rhEPO (hazard ratio (HR) = 0.38, 95 % CI 0.30, 0.47, P < 0.0001). Similar findings were noted for patients receiving vitamin D3 (HR = 0.36, 95 % CI 0.21, 0.64, P = 0.0004) and Fe (HR = 0.45, 95 % CI 0.33, 0.61, P < 0.0001). After adjusting for age, education and aetiology, the administration of rhEPO resulted in statistically significant improvements in long-term survival rate either with (HR = 0.30, 95 % CI 0.22, 0.42) or without (HR = 0.48, 95 % CI 0.38, 0.61) combined use of Fe or vitamin D3. We demonstrated a reduction in long-term mortality related to supplementation therapy with rhEPO, vitamin D3 and Fe. The findings provide a justification for the administration of combined supplement therapy in patients undergoing haemodialysis.

Erythropoietin Protects against Local Anesthetic Myotoxicity during Continuous Regional Analgesia

Local anesthetics offer the benefits of extended analgesia with greater patient satisfaction and faster rehabilitation compared with intravenous morphine. These benefits, however, can be offset by adverse iatrogenic muscle pain caused by bupivacaine. Here, the authors describe the mechanisms of local anesthetic-induced myotoxicity and a partial protective effect of recombinant human erythropoietin (rhEPO). The authors developed a rat analgesia model with femoral nerve catheter and a cell culture model of human skeletal muscle myoblasts to study local anesthetic effects. Rats were randomly assigned to four different groups: daily intraperitoneal injection with 5,000 U/kg rhEPO or saline coupled to a perineural catheter injection with 1 ml/kg bupivacaine, 0.25%, or saline. In psoas rat muscle, oxygen consumption rates were measured using a Clark-type electrode in saponin-skinned fibers. Mitochondrial adenosine triphosphate synthesis rates were determined by bioluminescence. Enzymatic activity of mitochondrial respiratory chain complexes was measured on tissue homogenates using spectrophotometric procedures, and mitochondrial morphology was analyzed by transmission electron microscopy. In addition, the interaction between bupivacaine and rhEPO was investigated on human skeletal muscle myoblasts by fluorescence microscopy using mitotracker green and using the lipophilic cation JC-1. Bupivacaine caused impairment of mitochondrial structure and bioenergetics in rats. Human myoblasts treated with bupivacaine showed a dose-dependent decrease in mitochondrial membrane potential associated with unusual morphologies. Impairment of mitochondrial bioenergetics was prevented partially by the use of rhEPO coadministered with bupivacaine. The authors demonstrated a dose- and time-dependent protective effect of rhEPO against bupivacaine-induced myotoxicity in regional analgesia.

A re-assessment of erythropoietin as a neuroprotective agent following rat spinal cord compression or contusion injury

This study was initiated due to an NIH “Facilities of Research — Spinal Cord Injury” contract to support independent replication of published studies that appear promising for eventual clinical testing. We repeated a study reporting the beneficial effects of recombinant human erythropoietin (rhEPO) treatment after spinal cord injury (SCI). Moderate thoracic SCI was produced by two methods: 1) compression due to placement of a modified aneurysm clip (20 g, 10 s) at the T3 spinal segment ( n=45) [followed by administration of rhEPO 1000 IU/kg/IP in 1 or 3 doses (treatment groups)] and 2) contusion by means of the MASCIS impactor ( n = 42) at spinal T9 (height 12.5 cm, weight 10 g) [followed by the administration of rhEPO 5000 IU/kg/IP for 7d or single dose (treatment groups)]. The use of rhEPO following moderate compressive or contusive injury of the thoracic spinal cord did not improve the locomotor behavior (BBB rating scale). Also, secondary changes (i.e. necrotic changes followed by cavitation) were not significantly improved with rhEPO therapy. With these results, although we cannot conclude that there will be no beneficial effect in different SCI models, we caution researchers that the use of rhEPO requires further investigation before implementing clinical trials.

Recombinant human erythropoietin attenuates hepatic injury induced by ischemia/reperfusion in an isolated mouse liver model

Apoptosis is a central mechanism of cell death following reperfusion of the ischemic liver. Recombinant human erythropoietin (rhEPO) have an important role in the treatment of myocardial ischemia/reperfusion (I/R) injury, by preventing apoptosis. The aim of the study was to investigate the effect of different regimens of rhEPO in preventing apoptosis following I/R-induced hepatic injury. Isolated mouse livers were randomly divided into five groups: (1) control group, perfused for the whole study period (105 min); (2) 30-min perfusion followed by 90 min of ischemia and 15 min of reperfusion; (3), (4) and (5) like group 2, but with administration of rhEPO 5,000 units/kg i.p. at 30 min, 24 h, or both 30 min and 24 h respectively, before induction of ischemia. Perfusate liver enzyme levels and intrahepatic caspase-3 activity were measured, and apoptotic cells were identified by morphological criteria, TUNEL assay, and immunohistochemistry for caspase-3. Using immunoblot the expression of the proapoptotic JNK and inhibitor of NFkappaB (IkappaBalpha) were also evaluated. von Willebrand factor (vWF) immunohistochemistry was used as a marker of endothelial cells. Compared to the I/R livers, all 3 rhEPO pretreated groups showed: a significant reduction in liver enzyme levels (P < 0.05) and intrahepatic caspase-3 activity (P < 0.05), fewer apoptotic hepatocytes (P < 0.05) and positive vWF staining in numerous endothelial cells lining the sinusoids. EPO decreased JNK phosphorylation and the degradation of the inhibitor of NFkappaB (IkappaBalpha) during I/R. There was no added benefit of the multiple- over the single-dose rhEPO regimen. Pretreatment with one dose of rhEPO can attenuate post-I/R hepatocyte apoptotic liver damage. NFkappaB and JNK activation is likely to play a pivotal role in the pathophysiology of I/R hepatic injury and might have a key role in EPO-mediated protective effects. This effect is associated with the increase in sinusoidal vWF immunostaining suggests an additional effect of rhEPO in liver angiogenesis recovery. These findings have important implications for the potential use of rhEPO in I/R injury during liver transplantation.

Efficacy of Preoperative Erythropoietin Administration in Pediatric Neuromuscular Scoliosis Patients

This is a retrospective cohort study examining 61 patients with neurogenic scoliosis who underwent anterior and/or posterior spinal instrumentation at the age of 18 and younger. The purpose of this study is to investigate this finding further by analyzing the effect of recombinant human erythropoietin (rhEPO) on hematocrit, transfusion and complication rates, and the length of intensive care unit (ICU) days in patients with neurogenic scoliosis. The preoperative use of rhEPO has been shown to decrease perioperative transfusion requirements in many adult and pediatric patients. A recent study at our institution demonstrated the efficacy of rhEPO in pediatric idiopathic scoliosis patients, but suggested the possibility of an "erythropoietin resistance" in the pediatric neurogenic scoliosis population. The patients' age at the time of surgery, gender, Cobb angle, erythropoietin administration and dosage, hematocrit levels, type of surgery, intraoperative blood loss, duration of surgery, number of vertebrae fused, comorbidities, complications, transfusion status, and the length of ICU days were collected. Thirty-five (57.3%) children received preoperative rhEPO, whereas 26 patients (42.7%) did not receive rhEPO. The mean preoperative and discharge hematocrit levels in the patients treated with rhEPO were significantly higher than the non-rhEPO group (P = 0.05). There were no significant difference in likelihood of transfusion, complications, and the length of ICU days between the rhEPO and the non-rhEPO groups. A multivariate analysis demonstrated that the number of fused vertebral levels maintained its significance (P = 0.044) and surgical time had a trend toward significance (P = 0.051) in predicting likelihood of transfusion. The use of rhEPO effectively stimulated erythropoiesis in these patients and yet demonstrated no significant clinical benefit in reducing the likelihood of transfusion in neurogenic patients in this study. More research is necessary to design a transfusion risk reduction protocols that will minimize the exposure of neurogenic scoliosis patients to allogeneic blood products.