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阿替白介素α

药物名称   阿替白介素α
药物别名   阿替白介素α
英文名称   Atexakin alfa
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日期:2009年1月18日 - 来自[其它调节免疫功能药]栏目
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促黄体素α

药物名称   促黄体素α
药物别名   促黄体素α
英文名称   Lutropin alfa
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日期:2009年1月18日 - 来自[其它激素及调节内分泌]栏目

绒促性素α

药物名称   绒促性素α
药物别名   绒促性素α
英文名称   Choriogonadotropin alfa
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日期:2009年1月18日 - 来自[肾上腺皮质激素及促肾]栏目
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Aranesp对于非化学治疗引起的贫血无效

  January 29, 2007 — 一项大型、随机分派、安慰剂控制试验已经显示,darbepoetin alfa(Aranesp)使用于癌症病患并不能治疗非因化学治疗引起的贫血,该试验结果也显示,接受该药物治疗的病患死亡率较高;Amgen公司全球发展资深副总裁与医疗事务法人主席Sean Harper医师在一项发给健康照护专业人员的信件中强调,Aranesp并未核准使用于这种情况,而是核准使用于接受化学疗法治疗癌症所造成的贫血,并非癌症本身造成的贫血。
  
  Harper医师表示,在这个被设计扩展该药物新适应症的研究中,有时候是非核准适应症,结果并无法减少降低输血的试验终点;该试验并未设计以检验该药物对于存活率的影响,而是要检验安全性终点;然而,相较于接受安慰剂病患,使用Aranesp的病患死亡人数更多。
  
  美国食品药物管理局的回覆已经张贴在MedWatch上,该官方组织的安全性资讯与不良反应通报系统网站,该产品的警示为该药物无法降低红血球输注需求,也不能减少疲倦的情况。
  
  Darbepoetin alfa被核准使用于非骨髓恶性癌症接受化学疗法引起的贫血,以及使用于慢性肾衰竭的贫血病患,该药物于2001年先被核准使用于肾衰竭病患,接着在2002年被核准使用于癌症病患,该产品是一种红血球生成素,一种由肾脏制造且透过血液循环至骨髓的醣蛋白,在骨髓可以刺激红血球生成。
  
  在这一项最新的研究中,darbepoetin alfa相较于使用安慰剂,针对活性癌症不论其是否接受化学治疗或放射线治疗病患;Amgen公司赞助该试验,为一项双盲第三期临床试验,收纳989位血红素低于11 g/dl且罹患癌症病患,由独立的安全性检验委员会监视,将近60%病患罹患活性疾病,使用darbepoetin alfa的目标血红素值为12 g/dl。
  
  【增加死亡率且无法减少红血球输注需求与改善疲倦】
  在最后分析起初16周的结果后,发现该药物对于主要试验终点并无显著影响,使用安慰剂组接受红血球输注的比例为24%,相较于使用治疗组则是18%(P=.15;危险比例为0.89;95% CI为0.65-1.22)。
  
  Darbepoetin alfa治疗组的死亡率比安慰剂组高(26%相较于20%),平均存活追踪时间为4.3个月;使用darbepoetin alfa治疗组实际的死亡数目较高(49%相较于46%;危险比例为1.25;95% CI为1.04-1.51),后续追踪存活时间至少需2年以上。
  
  这封给健康照护相关人员的信件中表示,darbepoetin alfa仅供使用于该产品被核准的项目,该公司被要求必须提供相关谘询,请联络Amgen,电话为1-800-77AMGEN(美国)或上网站http://www.amgenmedinfo.com。

Aranesp Ineffective in Anemia Not Caused by Chemotherapy

By Allison Gandey
Medscape Medical News

January 29, 2007 ??A large, multicenter, randomized, placebo-controlled study has shown that darbepoetin alfa, marketed as Aranesp, failed in cancer patients who have anemia not caused by chemotherapy. The study also showed higher mortality in patients who received the product. "Aranesp is not approved for use in this population," Sean Harper, MD, senior vice president of global development and corporate chief medical officer at Amgen, emphasized in a letter to healthcare professionals. "Aranesp is approved for the treatment of patients with anemia that is caused by chemotherapy treatment of their malignant disease, rather than the underlying malignant disease itself."

The study, which was designed to establish the product in this new indication ??sometimes used off-label for this purpose ??failed to meet its primary end point of reducing red blood cell transfusions. "This study was not optimal in design to establish the effect on survival, a safety end point; however, more deaths occurred in the Aranesp treatment group when compared with the placebo group," Dr. Harper reported.

In response, the US Food and Drug Administration has posted an alert on MedWatch, its safety information and adverse-event reporting program. The alert flags the product's ineffectiveness in reducing red blood cell transfusions and adds that it failed to reduce fatigue as well.

Darbepoetin alfa is indicated for the treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies and for the treatment of anemia associated with chronic renal failure. First approved in 2001 for its renal indication and then in 2002 for cancer patients, the product is an erythropoietic protein. It is said to work in a similar fashion as the body? natural erythropoietin ??a glycoprotein produced by the kidneys that circulates through the bloodstream to bone marrow, where it stimulates red blood cell production.

In this latest study, darbepoetin alfa was compared with placebo in patients with active malignant disease not receiving or expected to receive chemotherapy or radiation therapy. The Amgen-sponsored study was a double-blind phase 3 trial involving a total of 989 patients with a hemoglobin < 11 g/dL with active cancer and was monitored by an independent data safety monitoring board. Approximately 60% of patients had advanced disease. The target hemoglobin in the darbepoetin alfa treatment group was 12 g/dL.

Increased Mortality Observed and Fails to Reduce Red Blood Cell Transfusions or Fatigue

The final analysis of the initial 16-week treatment period did not show a statistically significant effect on the primary efficacy end point, with an incidence of red blood cell transfusions of 24% in the placebo group vs 18% in the treatment group (P = .15; hazard ratio, 0.89; 95% CI, 0.65 ??1.22) .

More deaths were reported in the darbepoetin alfa treatment group than the placebo group (26% vs 20%), with median survival follow-up of 4.3 months. The absolute number of deaths was greater in the darbepoetin alfa treatment group (49% vs 46%; hazard ratio, 1.25; 95% CI, 1.04 ??1.51). Survival follow-up will continue for a minimum of 2 years.

The letter to healthcare professionals points out that darbepoetin alfa should be used only in accordance with its approved product labeling. The company is asking that any questions or requests for additional information be directed to Amgen at 1-800-77AMGEN or http://www.amgenmedinfo.com.

日期:2007年6月20日 - 来自[血液]栏目

Neuroprotective Effect of Darbepoetin Alfa, a Novel Recombinant Erythropoietic Protein, in Focal Cerebral Ischemia in Rats

    the Cerebral Vascular Disease Research Center (L.B., L.K., W.Z., A.V., A.B., R.B., M.D.G.), Department of Neurology, University of Miami School of Medicine Miami, Fla
    Amgen Inc (E.M.), Thousand Oaks, Calif.

    Abstract

    Background and Purpose— Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for treating anemia. In animal models, exogenous recombinant human erythropoietin has been reported to be beneficial in treating experimental cerebral ischemia. In this study, we determined whether darbepoetin alfa would protect in a rat model of transient focal cerebral ischemia.

    Methods— Rats received 2-hour middle cerebral artery suture-occlusion. The drug (darbepoetin alfa, 10 μg/kg) or vehicle was administered intraperitoneally 2 hours after onset of middle cerebral artery occlusion. Animals were allowed to survive for 3 or 14 days. Behavioral tests were performed sequentially. Infarct volumes and brain swelling were determined.

    Results— Darbepoetin alfa-treated rats showed improved neuroscores relative to vehicle-treated animals beginning within 1 hour of treatment and persisting throughout the 14-day survival period. Darbepoetin alfa significantly reduced corrected total (cortical + subcortical) infarct volume (56.3±20.6 and 110.8±6.8 mm3, respectively) and total infarct areas at multiple levels compared with vehicle in the 14-day survival group. Brain swelling was not affected by treatment.

    Conclusion— Darbepoetin alfa confers behavioral and histological neuroprotection after focal ischemia in rats.

    Key Words: brain edema  cerebral ischemia  focal  middle cerebral artery occlusion  neuroprotection

    Introduction

    Erythropoetin (EPO) is a glycoprotein hormone that is the primary regulator of erythropoiesis.1 It binds to specific receptors on the cell surface of red blood cell precursors in the bone marrow, promoting their proliferation, differentiation, and survival, causing an increase in the circulating red blood cell mass.2 For more than a decade, recombinant human erythropoietin (rHuEpo) has been used to treat anemia associated with chronic renal failure, chemotherapy for cancer patients, and HIV infection, because of its ability to increase hemoglobin concentration, reduce the need for red blood cell transfusions, and improve symptoms associated with these conditions.3 EPO is neuroprotective in a variety of rodent models of hypoxic/ischemic central nervous system disorders when delivered directly into the brain4,5 or systemically.6 By contrast, 1 study showed increased cerebral infarct volumes in polycythemic mice overexpressing erythropoietin,7 suggesting that chronic overexpression of EPO might worsen outcome after stroke either because of the elevated hematocrit or other chronic effects.7

    Darbepoetin alfa is a novel erythropoiesis-stimulating agent with additional sialic acid-containing oligosaccharides compared with EPO, and an extended circulating half-life and increased in vivo biological activity.8 Darbepoetin alfa has 2 additional N-glycosylation sites and up to 22 sialic acid moieties, extending its half-life in the serum 3-fold longer than that of rHuEPO.9 Darbepoetin alfa is now being used extensively to treat anemia associated with chronic renal insufficiency and chemotherapy.10,11 Because darbepoetin alfa activates the EPO receptor, we hypothesized that it should also confer neuroprotection in stroke.

    Materials and Methods

    Animal Preparation

    Twenty-nine adult male Sprague–Dawley rats (277 to 339 grams; Charles River Laboratories, Wilmington, Mass) were fasted overnight but allowed free access to water. After atropine sulfate (0.5 mg/kg, intraperitoneally), anesthesia was induced with 3.5% halothane in a mixture of 70% nitrous oxide and 30% oxygen. Rats were orally intubated, immobilized with pancuronium bromide (0.6 mg/kg, intravenous), mechanically ventilated, and underwent insertion of femoral arterial and venous catheters. Rectal and cranial (left temporalis muscle) temperatures were separately monitored and held at normothermic levels. Arterial blood pressure was continuously monitored and blood gases, pH, glucose, and hematocrit were periodically measured as described previously.12

    Middle Cerebral Artery Occlusion

    The right middle cerebral artery (MCA) was occluded for 2 hours by the intraluminal-filament method using a poly-L-lysine–coated suture as previously reported.12 The suture was introduced retrogradely into the right external carotid artery and advanced into the internal carotid artery and MCA, a distance of 20 to 22 mm from the carotid bifurcation according to the animal’s weight. The incision was closed and rats were awakened and examined at 1 hour. Rats not having a right upper extremity deficit were excluded from further study (see Behavioral Testing). After 2 hours of MCA occlusion, rats were re-anesthetized and the intraluminal suture was carefully removed. The neck incision was closed with silk sutures, and the animals were allowed to survive for 3 or 14 days with free access to food and water.

    Treatment

    The drug (darbepoetin alfa, 10 μg/kg,) or vehicle (human serum albumin [0.25%], NaCl [140 mmol/L], and sodium phosphate [20 mmol/L], pH 6.0) was administered intraperitoneally at time of reperfusion, ie, 2 hours after onset of MCA occlusion. Four treatment groups were studied: 3-day survival (vehicle, n=7; darbepoetin alfa-treated, n=8) and 14-day survival (vehicle, n=6; darbepoetin alfa-treated, n=8). Rats were allocated to treatment groups in a randomized manner.

    Behavioral Testing

    Behavioral tests were performed in all 29 rats. In the 3-day survival groups, repeat testing was performed before MCA occlusion, during occlusion (at 60 minutes), and after treatment at 1 hour and 1, 2, and 3 days. In the 2-week survival groups, additional testing was performed at 7, 10, and 14 days. Examinations were performed by an observer blinded to the experimental condition. The battery, consisting of postural-reflex and forelimb-placing tests, yielded a scale of 0 to 12 (normal score=0, maximal score=12) as previously described.12 Four rats with convulsions or sustained disturbances of consciousness were excluded from the study; most of these animals proved to have subarachnoid hemorrhage secondary to suture-induced arterial rupture.

    Infarct Assessment

    Animals were allowed to survive for 3 or 14 days. Brains were then perfusion-fixed, paraffin-embedded, coronally sectioned at 10 μm, and sections stained with hematoxylin and eosin as previously described.12 Sections were digitized at 9 standardized coronal levels (MCID image-analysis system; Imaging Research Corp, St. Catherines, Canada). An investigator blinded to the experimental groups used software developed by us to quantify infarct size and brain swelling.13 We performed 3 histopathological analyses of infarction: (1) measurement of cortical and subcortical areas of infarction on a section-by-section basis in individual animals;12 (2) traditional total infarct volume estimation by integrating infarct areas from selected coronal levels; and (3) depiction of infarct frequency distribution by computer-assisted image mapping for the 4 groups, which were compared statistically at 9 corresponding anatomic levels by Fisher exact test.13 Infarct volume within a volume of interest was corrected for swelling by a scaling factor that was defined as the ratio between the contralateral and the ipsilateral volume of interest. Infarct volume was then scaled to the contralateral equivalent unit so that the effect of brain edema was corrected. The degree of brain edema was determined as the difference in brain volume between the 2 hemispheres.

    Statistical Analysis

    Data are presented as mean values±SEM. Neurobehavioral scores and infarction size data were compared among treatment groups by repeated-measures analysis of variance (ANOVA) followed by Bonferroni tests. Physiological variables were compared by Student t tests. Differences at P<0.05 were considered statistically significant.

    Results

    Physiological Variables

    There were no significant differences with respect to rectal temperature, cranial temperature, arterial blood gases, arterial blood pressure, or arterial blood glucose (Table). Darbepoetin alfa therapy led to moderate increases in hematocrit (by 5% to 16%) compared with vehicle-treated animals during the first 7 days, but this tended to normalize between 7 and 14 days (Table).

    Physiological Variables

    Neurological Assessment

    Neurological score was normal (0) in all animals before MCA occlusion. High-grade contralateral deficits (score, 11±0) were present at 60 minutes of MCA occlusion in all rats (Figure 1); thus, no animals required exclusion based on inadequate ischemia. A significant improvement in neurological score was evident in darbepoetin alfa-treated animals compared with vehicle-treated rats within 1 hour of treatment and was sustained at every observational point throughout the 3-day and 14-day survival periods (Figure 1). By repeated-measures ANOVA, the overall between-group treatment effect was highly significant (P<0.0001).

    Infarct Volume and Brain Swelling

    Cortical infarct areas were significantly reduced by treatment with darbepoetin alfa compared with vehicle at 4 coronal levels in the 14-day survival groups, but no intergroup differences were present in animals with 3-day survival (Figure 2A). Total cortical infarct volume was also significantly reduced by darbepoetin alfa compared with vehicle in the 14-day survival series (28.5±14.1 versus 68.0±4.5 mm3, respectively; P=0.04), but not in the 3-day series. Striatal (subcortical) infarct areas were by reduced by darbepoetin alfa-treated rats at 1 or 2 coronal levels in both the 3-day and 14-day series (Figure 2B). Total striatal infarct volume was significantly reduced by darbepoetin alfa compared with vehicle in the 3-day survival group (28.9±5.3 versus 46.4±5.3 mm3, respectively; P=0.04), and there was a nonsignificant trend at 14 days. Treatment with darbepoetin alfa significantly reduced corrected total (cortical plus subcortical) infarct volume by 49% (56.3±20.6 versus 110.8±6.8 mm3, respectively; P<0.05; Figure 3) and reduced total infarct areas compared with vehicle-treated animals at 3 coronal levels in the 14-day but not the 3-day survival series. Brain swelling was not affected by treatment with darbepoetin alfa (3-day survival: vehicle 11±2% and darbepoetin alfa 9±1%; 14-day survival groups: vehicle –7±2% and darbepoetin alfa –2±2%).

    Figure 4 displays pixel-based infarct frequency maps. Vehicle-treated animals showed a large cortical and subcortical infarct at multiple coronal levels. By contrast, the darbepoetin alfa-treated animals displayed marked reductions in the frequency of cortical and subcortical infarction in 14-day survival group.

    Seven animals died during the experiment in the 3-day survival groups: 5 in the vehicle group (3 on day 1 and 2 on day 2) and 2 in the darbepoetin alfa-treated group (on days 1 and 2). Eleven animals died in the 14-day survival groups: 9 in vehicle group (2 on days 1, 2, and 5, and 1 on days 6, 7, and 9) and 2 animals died in the darbepoetin alfa-treated group (on day 2). These animals were not included in the histological analysis. Autopsy revealed a large ipsilateral hemispheric infarct and extensive brain edema in all instances.

    Discussion

    The goal of our study was to determine whether the administration of darbepoetin alfa, a novel erythropoiesis-stimulating agent, was efficacious in protecting the brain after transient focal cerebral ischemia. Our results clearly demonstrate that this treatment improves outcome as measured by neurological score and by final pathological estimation of the size of infarction.

    The present results show a beneficial effect of darbepoetin alfa in a well-controlled animal model of MCA occlusion. Intraluminal occlusion of the MCA has become increasingly popular as a focal ischemia model because of its relative simplicity and minimally invasive nature. In the present study and in recently published observations, we have used a poly-L-lysine–coated suture and have found that this technique leads to reliable and highly consistent results.

    EPO is a glycoprotein that stimulates differentiation and proliferation of erythroid precursor cells, and hypoxic induction of EPO production increases numbers of red blood cells, leading to better oxygen supply to the tissues.1 In response to the systemic oxygen caused by decreased oxygen concentration after cerebral ischemia, EPO production is stimulated.4 It has recently been reported that both erythropoietin and its receptor (EPOR) are found in the human cerebral cortex and hippocampus and that in vitro, the cytokine is synthesized by astrocytes and neurons, has neuroprotective activity, and is upregulated after hypoxic stimuli.14 In animal models, rHuEpo has been reported to be beneficial in treating experimental global and focal cerebral ischemia and reducing nervous system inflammation. Sadamoto et al5 demonstrated that rHuEpo infused into the cerebral ventricles of stroke-prone spontaneously hypertensive rats with permanent MCA occlusion improved cognitive tests, reduced cortical infarction, and increased numbers of surviving thalamic neurons. In situ hybridization revealed that EPOR mRNA was upregulated at 24 hours in the ischemic penumbra after MCA occlusion.5 In addition, infusion of rhEPO into the lateral ventricles prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from global cerebral ischemic injury in gerbils.4

    Darbepoetin alfa is a erythropoiesis-stimulating protein that produces a similar physiological response as rHuEpo. It was generated by site-directed mutagenesis of the erythropoietin gene, resulting in an increased number of glycosylation sites and greater carbohydrate content.8 In a recent report, darbepoetin alfa increased hematocrit levels, hemoglobin content, total red blood cells, reticulocytes, and platelet numbers, and also significantly reduced the degree of inflammation by as much as 80% in a model of experimental allergic encephalomyelitis in rats.15 Darbepoetin alfa was approved by the Food and Drug Administration for patients with chronic kidney disease in September 2001 and for chemotherapy-induced anemia in July 2002. In clinical trials of patients with renal failure, darbepoetin alfa was shown to have a 3-fold longer terminal half-life than rHuEpo (25.3 hours versus 8.5 hours).16 The longer half-life allows for less frequent dosing.17 In particular, in clinical studies this has translated into effectively maintaining the hemoglobin levels within the target range when administered monthly.18 Because rHuEPO treatment has been reported to improve stroke outcome in variety of animal models, we wanted to determine whether darbepoetin alfa would also confer protection in a rat model of transient focal cerebral ischemia. There are currently no publications demonstrating neuroprotective effects of darbepoetin alfa.

    Stroke in humans is commonly associated with impaired sensorimotor and cognitive function; 70% to 80% of all patients experience hemiparesis immediately after the insult. After MCA occlusion, rodents also exhibit a neurological deficit characterized by sensorimotor dysfunction.19 In the present study, administration of darbepoetin alfa significantly improved the neurological score compared with vehicle throughout the 3-day and 14-day survival periods. There were no adverse behavioral side effects observed with darbepoetin alfa administration.

    Histology in animals is a sensitive method of detecting neuroprotection. The present study shows that darbepoetin alfa confers histological neuroprotection when administered at 2 hours after the onset of MCA occlusion. Vehicle-treated animals showed a large cortical and subcortical infarct at multiple coronal levels. By contrast, darbepoetin alfa-treated animals showed significantly reduced cortical (by 58%) and total infarct volumes (by 50%) in the 14-day survival group. The 3-day survival group also showed reduction of subcortical infarction (by 27%). The protective effect of darbepoetin alfa in this study could not be explained by differences in body or brain temperatures, arterial pressure, or arterial blood gases because these variables were carefully controlled and did not differ among groups.

    This study focused on whether darbepoetin alfa was neuroprotective in an in vivo model of focal cerebral ischemia in rats, and not on the mechanism(s) of action by which darbepoetin alfa could be neuroprotective. The most profound effect of darbepoetin alfa in this study was found in the 14-day survival series. Several mechanisms by which erythropoietic therapy may confer neuroprotection can be considered. Ehrenreich20 has recently emphasized that rather than modulating disease-specific pathogenic mechanisms, EPO may have more general tissue-protective effects by targeting different neurodegenerative pathways, such as anti-apoptotic, antioxidant, glutamate-inhibitory, anti-inflammatory, neurotrophic, stem cell-modulatory, and angiogenic mechanisms. In the time frame of 14 days after the ischemic stroke in this study, long-term protective effects of EPO may be considered, such as angiogenesis and neurogenesis. It has been reported that EPO, similar to other growth factors such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, can stimulate endothelial proliferation and, in turn, new vessel formation both in vitro and in vivo.21 By driving the formation of new vessels, EPO might protect the ischemic brain by increasing the delivery of oxygen to brain tissue.22 Recently, Wang et al23 showed that treatment with rHuEpo significantly improved functional recovery, along with increases in density of cerebral microvessels, increased numbers of BrdUrd-positive cells in the ipsilateral subventricular zone, and neuroblasts in the ischemic boundary regions. Direct evidence for the ability of EPO to induce neurogenesis was reported both in vitro and in vivo.24

    In summary, our results demonstrate the neuroprotective efficacy of darbepoetin alfa, a novel erythropoiesis-stimulating agent, in an in vivo model of temporary focal cerebral ischemia as judged by neurological score and infarct size. A pharmacological agent such as darbepoetin alfa thus may have potential utility in treating focal ischemic stroke in the clinical setting. A beneficial outcome in stroke patients treated with EPO has been already reported by Ehrenreich et al.25 In Ehrenreich’s proof-of-concept trial in patients with MCA territory ischemic stroke, EPO (33 333 U/50 mL) or placebo was administered intravenously after enrollment and was repeated 24 and 48 hours later. Neurological follow-up, scoring, and outcome scales at 30 days showed significantly better results for the EPO-treated patients compared with placebo.

    Acknowledgments

    These studies were supported by a grant from Amgen Inc (Thousand Oaks, Calif), and by Program Project Grant NS 05820 of the National Institutes of Health (M.D.G.). The authors thank Guillermo Fernandez and Yolanda Loor for their expert technical assistance.

    References

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    Constantinescu SN, Ghaffari S, Lodish HF. The erythropoietin receptor: structure, activation and intracellular signal transduction. Trends Endocrinol Metab. 1999; 10: 18–23.

    Markham A, Bryson HM. Epoetin alfa. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in nonrenal applications. Drugs. 1995; 49: 232–254.

    Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A. 1998; 95: 4635–4640.

    Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S, Masuda S, Sasaki R. Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun. 1998; 253: 26–32.

    Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001; 98: 4044–4049.

    Wiessner C, Allegrini PR, Ekatodramis D, Jewell UR, Stallmach T, Gassmann M. Increased cerebral infarct volumes in polyglobulic mice overexpressing erythropoietin. J Cereb Blood Flow Metab. 2001; 21: 857–864.

    Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer. 2001; 84 (Suppl 1): 3–10.

    Egrie JC, Dwyer E, Browne JK, Hitz A, Lykos MA. Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol. 2003; 31: 290–299.

    Patton J, Reeves T, Wallace J. Effectiveness of darbepoetin alfa versus epoetin alfa in patients with chemotherapy-induced anemia treated in clinical practice. Oncologist. 2004; 9: 451–458.

    Schwartzberg L, Shiffman R, Tomita D, Stolshek B, Rossi G, Adamson R. A multicenter retrospective cohort study of practice patterns and clinical outcomes of the use of darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia. Clin Ther. 2003; 25: 2781–2796.

    Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD. Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke. 1996; 27: 1616–1622.

    Zhao W, Ginsberg MD, Prado R, Belayev L. Depiction of infarct frequency distribution by computer-assisted image mapping in rat brains with middle cerebral artery occlusion. Comparison of photothrombotic and intraluminal suture models. Stroke. 1996; 27: 1112–1117.

    Jumbe NL. Erythropoietic agents as neurotherapeutic agents: what barriers exist Oncology (Huntingt). 2002; 16: 91–107.

    Korach E, Miller G, Molineux G, Begley CG, Eliott S, Martin D. Modulation of immune responses in the brain by engaging the erythropoietin receptor. Blood. 2003; 102: 768a.

    Macdougall IC, Gray SJ, Elston O, Breen C, Jenkins B, Browne J, Egrie J. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999; 10: 2392–2395.

    Toto RD, Pichette V, Navarro J, Brenner R, Carroll W, Liu W, Roger S. Darbepoetin alfa effectively treats anemia in patients with chronic kidney disease with de novo every-other-week administration. Am J Nephrol. 2004; 24: 453–460.

    Agarwall, A., Ling, B., Walczyk, M., and et al. Aranesp (darbepoetin alfa) administered once monthly maintains hemoglobin levels in patients with chronic kidney disease (CKD). Natl Kidney Foundation Abstracts. 2000: 86.

    DeVries AC, Nelson RJ, Traystman RJ, Hurn PD. Cognitive and behavioral assessment in experimental stroke research: will it prove useful Neurosci Biobehav Rev. 2001; 25: 325–342.

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日期:2007年5月14日 - 来自[2005年第36卷第5期]栏目
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