• Biomolecules & Therapeutics
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• v.6 no.3
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• pp.317-327
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• 1998

The subchronic toxicity study of rHuEPO, a newly developed recombinant erythropoietin, was investigated for 13 weeks in Beagle dogs intravenously treated with doses of 100, 500 and 2,500 lU/kg/day. There were no significant changes in body weight, food intake, physical and opthalmic examination, urine analysis, etc. Any toxic response was not observed except for enlarged spleen and extramedullary hematopoiesis. These results indicate that the no-observed adverse effect level (NOAEL) of rHuEPO is 100 lU/kg in Beagle dogs.

• Toxicological Research
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• v.14 no.3
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• pp.415-425
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• 1998

A recombinant human erythropoietin (rHuEPO) was administered intravenously at dosage levels of 0, 100, 500, and 2500IU/kg/day for a period of 3 weeks. There were no observed clinical signs and deaths related to treatment in all groups tested. Decreases in body weight gain and food consumption were observed only in males of 2,5000IU/kg group after 2 weeks. In hematological parameters, erythrocyte content, hematocrit values and hemoglobin concentration were dose- dependently increased in rHuEPO treated groups. The ratio between kidney weight and whole body weight was significantly increased in females of 500 and 2,500IU/kg groups. The spleen weight was also increased in both sexes of 500 and 2,500IU/kg groups. However, the absolute weight change of other organs was not observed. In histopathological examinations, the renal tubular basophilia was observed only in males and females of 2,500IU/kg groups. From these results, it is concluded that the no-observed adverse effect level (NOAEL) of rHuEPO is 100 IU/kg in rats in the present study.

• Korean Journal of Clinical Pharmacy
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• v.19 no.2
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• pp.146-152
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• 2009

Purpose : 본 연구의 목적은 항암치료로 인한 빈혈환자의 치료에서 epoetin alpha (rHuEPO) 피하주사 시, 주일회 요법과 주삼회요법의 헤모글로빈(hemoglobin, Hb) 상승 효과를 비교하는 것이다. Methods : 본 연구는 1999년 3월부터 2005년 3월까지 국립암센터에서 항암치료로 인한 빈혈로 epoetin alpha를 투여 받은 환자를 대상으로 의무기록의 자료를 후향적으로 수집하여 분석하였다. 연구에 포함된 환자는 rHuEPO 10,000 IU 주삼회투여군(n = 127)과 20,000 IU 주일회투여군(n = 81)으로 구분되었으며, 이들은 필요에 따라 경구용 철분보조제를 섭취하였다. Epoetin alpha 치료 시작 후 최대 8주까지 2주 간격으로 Hb 수치변화를 분석하였다. Results : 치료 시작 시점의 rHuEPO 10,000 IU 주삼회투여군과 20,000 IU 주일회투여군의 평균 Hb수치는 유사하였 다 (9.4 g/dL vs. 9.7 g/dL). Epoetin alpha 치료 후 8주까지 두 그룹간의 헤모글로빈 수치의 상승 정도에는 유의한 차이가 없었다 ($1.57{\pm}1.39$ g/dL vs. $1.68{\pm}1.35$ g/dL, p=0.59). 또한 경구용 철분보조제 투여여부, cisplatin 포함 항암제 투여여부 및 성별에 따른 군의 분류에 있어서도 rHuEPO 10,000 IU 주삼회투여군과 20,000 IU 주일회투여군의 평균 Hb 상승수치는 유의한 차이를 보이지 않았다. Conclusion : 한국인에서 항암치료로 인한 빈혈의 치료 시에 rHuEPO 20,000 IU 주일회투여 용법은 10,000 IU 주 삼회투여 용법과 유사한 Hb 상승효과를 가진다.

• Molecules and Cells
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• v.38 no.6
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• pp.496-505
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• 2015

A variant peak was detected in the analysis of RP-HPLC of rHu-EPO, which has about 7% relative content. Fractions of the main and the variant peaks were pooled separately and further analyzed to identify the molecular structure of the variant peak. Total mass analysis for each peak fraction using ESI-TOF MS shows differences in molecular mass. The fraction of the main peak tends to result in higher molecular masses than the fraction of the variant. The detected masses for the variant are about 600-1000 Da smaller than those for the main peak. Peptide mapping analysis for each peak fraction using Asp-N and Glu-C shows differences in O-glycopeptide profiles at Ser126. The O-glycopeptides were not detected in the fraction of the variant. It is concluded that the variant peak is non-O-glycosylated rHu-EPO and the main peak is fully O-glycosylated rHu-EPO at Ser126.

• Clinical and Experimental Pediatrics
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• v.53 no.10
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• pp.898-908
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• 2010

Purpose: The neuroprotective effects of erythropoietin (EPO) have been recently shown in many animal models of brain injury, including hypoxic-ischemic (HI) encephalopathy, trauma, and excitotoxicity; however, limited data are available for such effects during the neonatal periods. Therefore, we investigated whether recombinant human EPO (rHuEPO) can protect against perinatal HI brain injury via an antiapoptotic mechanism. Methods: The left carotid artery was ligated in 7-day-old Sprague-Dawley (SD) rat pups ($in$ $vivo$ model). The animals were divided into 6 groups: normoxia control (NC), normoxia sham-operated (NS), hypoxia only (H), hypoxia+vehicle (HV), hypoxia+rHuEPO before a hypoxic insult (HE-B), and hypoxia+rHuEPO after a hypoxic insult (HE-A). Embryonic cortical neuronal cell culture of SD rats at 18 days gestation ($in$ $vitro$ model) was performed. The cultured cells were divided into 5 groups: normoxia (N), hypoxia (H), and 1, 10, and 100 IU/mL rHuEPO-treated groups. Results: In the $in$ $vivo$ model, Bcl-2 expressions in the H and HV groups were lower than those in the NC and NS groups, whereas those in the HE-A and HE-B groups were greater than those of the H and HV groups. The expressions of Bax and caspase-3 and the ratio of Bax/Bcl-2 were in contrast to those of Bcl-2. In the $in$ $vitro$ model, the patterns of Bcl-2, Bax, and caspase-3 expression and Bax/Bcl-2 ratio were similar to the results obtained in the in vivo model. Conclusion: rHuEPO exerts neuroprotective effect against perinatal HI brain injury via an antiapoptotic mechanism.

• Clinical and Experimental Pediatrics
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• v.59 no.2
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• pp.100-103
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• 2016

Patients with hemolytic-uremic syndrome (HUS) can rapidly develop profound anemia as the disease progresses, as a consequence of red blood cell (RBC) hemolysis and inadequate erythropoietin synthesis. Therefore, RBC transfusion should be considered in HUS patients with severe anemia to avoid cardiac or pulmonary complications. Most patients who are Jehovah's Witnesses refuse blood transfusion, even in the face of life-threatening medical conditions due to their religious convictions. These patients require management alternatives to blood transfusions. Erythropoietin is a glycopeptide that enhances endogenous erythropoiesis in the bone marrow. With the availability of recombinant human erythropoietin (rHuEPO), several authors have reported its successful use in patients refusing blood transfusion. However, the optimal dose and duration of treatment with rHuEPO are not established. We report a case of a 2-year-old boy with diarrhea-associated HUS whose family members are Jehovah's Witnesses. He had severe anemia with acute kidney injury. His lowest hemoglobin level was 3.6 g/dL, but his parents refused treatment with packed RBC transfusion due to their religious beliefs. Therefore, we treated him with high-dose rHuEPO (300 IU/kg/day) as well as folic acid, vitamin B12, and intravenous iron. The hemoglobin level increased steadily to 7.4 g/dL after 10 days of treatment and his renal function improved without any complications. To our knowledge, this is the first case of successful rHuEPO treatment in a Jehovah's Witness child with severe anemia due to HUS.

• Clinical and Experimental Pediatrics
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• v.60 no.6
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• pp.181-188
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• 2017

Purpose: Hypoxic-ischemic encephalopathy is a significant cause of neonatal morbidity and mortality. Erythropoietin (EPO) is emerging as a therapeutic candidate for neuroprotection. Therefore, this study was designed to determine the neuroprotective role of recombinant human EPO (rHuEPO) and the possible mechanisms by which mitogen-activated protein kinase (MAPK) signaling pathway including extracellular signal-regulated kinase (ERK1/2), JNK, and p38 MAPK is modulated in cultured cortical neuronal cells and astrocytes. Methods: Primary neuronal cells and astrocytes were prepared from cortices of ICR mouse embryos and divided into the normoxic, hypoxia (H), and hypoxia-pretreated with EPO (H+EPO) groups. The phosphorylation of MAPK pathway was quantified using western blot, and the apoptosis was assessed by caspase-3 measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results: All MAPK pathway signals were activated by hypoxia in the neuronal cells and astrocytes (P<0.05). In the neuronal cells, phosphorylation of ERK-1/-2 and apoptosis were significantly decreased in the H+EPO group at 15 hours after hypoxia (P<0.05). In the astrocytes, phosphorylation of ERK-1/-2, p38 MAPK, and apoptosis was reduced in the H+EPO group at 15 hours after hypoxia (P<0.05). Conclusion: Pretreatment with rHuEPO exerts neuroprotective effects against hypoxic injury reducing apoptosis by caspase-dependent mechanisms. Pathologic, persistent ERK activation after hypoxic injury may be attenuateed by pretreatment with EPO supporting that EPO may regulate apoptosis by affecting ERK pathways.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.37 no.1
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• pp.9-14
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• 2011

Recently, the population of patients who refuse transfusion has increased for both religious and non-religious reasons, even in life threatening emergency situations. Their refusal has highlighted the need to develop nonblood transfusion surgery techniques to decrease the risk from blood transfusions. A 57-year woman with an ulcerative lesion on the gingiva of the right upper molar area visited the department of oral and maxillofacial surgery in Dankook University Dental Hospital. After a preliminary evaluation, the patient was diagnosed with squamous cell carcinoma. As she refused blood transfusion during surgery for religious reasons, surgery was planned using recombinant human erythropoietin (rHuEPO) without a blood transfusion. The patient underwent a partial maxillectomy, supraomohyoid neck dissection, free radial forearm flap and split thickness skin graft under general anesthesia. rHuEPO and iron were used before and after surgery. The hemoglobin/hematocrit (Hb/Hct) level, iron (Fe) and total iron-binding capacity (TIBC) were assessed. The patient recovered completely without any blood transfusions. rHuEPO is a viable alternative for patients with religious objections to receiving blood transfusions.

• Applied Microscopy
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• v.37 no.3
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• pp.167-174
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• 2007

Heat shock protein (HSP) 70 functions as a molecular chaperon and reduces stress-induced denaturation and aggregation of intracellular proteins. Erythropoietin (EPO) plays an important role during acute renal failure repair process by rapidly correcting anemia and enhancing renal tubular regeneration. The purpose of this study was to examine the effect of EPO treatment on renal HSP70 expression. Male Sprague-Dawley rats were injected rHUEPO. Kidney were preserved by in vivo perfusion with paraformaldehyde-lysine-periodate (PLP) and processed for immunohistochemistry and electron microscopy. In control kidney, HSP70 was expressed in the cortex, outer medulla and inner medulla. Especially, HSP immunoreactiviy was mainly founded in descending thin limb of outer medulla and inner medullary collecting duct. In EPO treated kidney, HSP70 expression markedly increased in the descending thin limb of outer medulla and newly detected in cortical collecting duct. Electron microscopy showed the presence of HSP immunoreactivity on the intracelluar vesicles and Golgi complex of descending thin limb and cortical collecting duct. These findings suggest that EPO treatment leads to new production of HSP70 in renal tubular cells, and induction of HSP70 by rHuEPO is causally related to protective function.

• Toxicological Research
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• v.18 no.1
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• pp.79-85
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• 2002

YHB216 is one of new recombinant human erythropoietins (rHu-EPO) developed by Yuhan Research Institute. The rHu-EPO products are widely being used for the treatment of various types of anemia. As a series of safety studies on YHB216, we performed the local irritation test (dermal & ocular application) in male New Zealand White rabbits and micronucleus test in male ICR mice. In the skin irritation test, 0.5 ml of YHB216 10,000 IU/ml solution was applied to the back skin of rabbits for 24 hours and sub-sequent observation was performed. There was no induced response after the treatment and the primary irritation index (P.I.I.) was‘0’. In the eye irritation test, 0.1 ml of YHB216 10,000 IU/mL solution was instilled into the conjunctiva of the eye. No treatment-related reaction was observed at the cornea, iris, and conjunctiva. In the micronucleus test, YHB216 was administered intravenously to male mice (6 mice per group) at dose levels of 0, 6,250, 12,500, and 25,000 IU/kg. Bone marrow cells were collected at 24 hours after the treatment. YHB216 treated groups showed no significant difference in the P/N (polychromatic erythrocyte/ normochromatic erythrocyte) ratio and in the number of micronucleated polychromatic erythrocyte com-pared with the control. In conclusion, YHB216 was found to be a non-irritating material up to 10,000 IU/ml in the local irritation test and to be a non-mutagen up to 25,000 IU/kg in the micronucleus test.