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1.
Am J Physiol Regul Integr Comp Physiol ; 321(2): R152-R161, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34160288

RESUMO

Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (n = 39) were randomly assigned to 20 IU·kg body wt-1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P < 0.05) and hepcidin levels (P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P < 0.05) and ERFE (P ≤ 0.001) parallel with increases in hematocrit (P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.


Assuntos
Doença da Altitude/sangue , Altitude , Epoetina alfa/administração & dosagem , Eritropoese/efeitos dos fármacos , Hematínicos/administração & dosagem , Hepcidinas/sangue , Ferro/sangue , Hormônios Peptídicos/sangue , Doença da Altitude/diagnóstico , Biomarcadores/sangue , Dinamarca , Método Duplo-Cego , Feminino , Homeostase , Humanos , Injeções Intravenosas , Masculino , Proteínas Recombinantes/administração & dosagem , Espanha , Fatores de Tempo
2.
Drug Dev Ind Pharm ; 47(5): 820-824, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34056986

RESUMO

OBJECTIVE: This study aims at emphasizing the significant impact of the incentives to promote the United States (US) pharmaceutical innovation. METHODS: We carried out a retrospective single-case study. We analyzed the innovation process of Epogen: basic research, applied research, regulatory, and marketing. RESULTS: Incentives and policies of pharmaceutical innovation significantly facilitates the entire life cycle of Epogen. The transfer of patent presented by the Bayh-Dole Act allowed Amgen to purchase the research results of Epogen. Relying on the intellectual property mechanisms and financing incentives, Amgen raised the funds needed for Epogen in applied research. Special review shortened the regulatory of Epogen. Epogen obtained orphan drug designation twice and 8 years of market exclusivity. Tax deduction and research funding provided direct economic compensation. The patent system enabled Epogen to obtain 32 years of patent protection (1983-2015). Monopoly pricing was a significant determinant to increase the sales of Epogen through pricing strategies. CONCLUSION: We pointed out that Amgen has developed the successful innovation of Epogen taking advantages of the incentives. Effective and flexible incentives and policies are essential to support the entire life cycle of new drugs, ultimately forming a sustainable driver for the long-run pharmaceutical innovation.


Assuntos
Indústria Farmacêutica , Preparações Farmacêuticas , Pesquisa Empírica , Epoetina alfa , Motivação , Estudos Retrospectivos , Estados Unidos
3.
Clin Lab ; 67(4)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33865269

RESUMO

BACKGROUND: Erythropoiesis stimulating agents are exogenous erythropoietin medications that are used to stimulate the bone marrow red blood cells' production for the management of anemia of chronic kidney disease, some anticancer drugs, myelodysplastic syndrome, and others. Currently, there are different erythropoiesis stimulating agents accessible in the market. The objective of this narrative literature review is to summarize the role of some erythropoiesis stimulating agents in the treatment of anemia. METHODS: The following method was used to prepare this narrative literature review. The comprehensive computerized search of literatures was carried out using PubMed, Cochrane library, Google scholar, and Science direct. Keywords such as recombinant human erythropoietin, epoetin, darbepoetin, continuous erythropoietin receptor agonist, pegzyrepoetin alfa, erythropoiesis stimulating agents in combination with anemia/anaemia were used. The pertinent original and review full articles which are written in the English language were included in this narrative review. RESULTS: From the discussions of the literature, erythropoiesis stimulating agents that are produced by different biosimilar manufacturers have different clinical characteristics and stabilities as a result of their chemical modifications. The chemical modifications of erythropoiesis stimulating agents like glycosylation and polyethylene glycosylation determine the half-life, affinity to erythropoietin receptor, and immune response of the agents. Erythro-poiesis stimulating agents are categorized as short-acting and long-acting agents due to their chemical structures that influence the clinical efficacy and safety of the agents. CONCLUSIONS: The effectiveness of the agents is different in different patients depending on the individual characteristics and etiologies of anemia. The agents not only have the benefits but also, they have the risks for the patients. Hence, the risks and benefits of erythropoiesis stimulating agents must be given special consideration in the managements of anemia to get maximum efficacy for anemic patients. The treatment is dependent on hemoglobin levels of individual patients. The physician must follow the patients during and after therapy using erythropoiesis stimulating agents.


Assuntos
Anemia , Eritropoetina , Hematínicos , Anemia/tratamento farmacológico , Darbepoetina alfa/farmacologia , Epoetina alfa/farmacologia , Eritropoese , Eritropoetina/farmacologia , Hematínicos/farmacologia , Hematínicos/uso terapêutico , Humanos , Proteínas Recombinantes/farmacologia
4.
Ann Hematol ; 100(6): 1451-1457, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33837816

RESUMO

Options for anemic lower-risk myelodysplastic syndromes (MDS) without del(5q) after failure of erythropoiesis-stimulating agents (ESAs) are very limited. The effectiveness of second-line treatments is uncertain. We retrospectively reviewed the clinical effectiveness and overall survival (OS) of lower-risk MDS without del(5q) patients exclusively treated with stanozolol (STZ) after failure of epoetin alfa. The response was defined according to the 2006 International Working Group (IWG) criteria. Fifty-six patients were included. The median follow-up time was 55 months (range: 5-156 months). Twenty-seven patients (48.2%) achieved hematologic improvement-erythroid response (HI-E). Higher response rates were observed in patients with lower IPSS-R scores (≤3.5, P = 0.008) and hypocellular bone marrow (P = 0.002). In univariate Cox analysis, HI-E was the strongest factor associated with better OS (P = 0.0003). In multivariate Cox, HI-E, age ≤ 50, and transfusion independence (TI) at the onset of STZ were factors associated with better OS. The estimated 5-year OS was 88.6% (68.7-96.2%) and 33.8% (14.9-54.0%) in responders and non-responders (P < 0.01), respectively. The most common side effects included masculinization and liver damage, but they were manageable with supportive measures and dose adjustments. STZ may be considered an alternative treatment in lower-risk MDS after failure of epoetin alfa.


Assuntos
Androgênios/uso terapêutico , Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Estanozolol/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Estudos Retrospectivos , Resultado do Tratamento
5.
Oncologist ; 26(8): e1418-e1426, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33586299

RESUMO

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.


Assuntos
Anemia , Antineoplásicos , Medicamentos Biossimilares , Neoplasias , Idoso , Anemia/induzido quimicamente , Anemia/tratamento farmacológico , Antineoplásicos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Epoetina alfa/uso terapêutico , Humanos , Medicare , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Estados Unidos
6.
Nephrol Dial Transplant ; 36(9): 1717-1730, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-33629100

RESUMO

BACKGROUND: We evaluated the efficacy and safety of roxadustat versus epoetin alfa for the treatment of chronic kidney disease-related anemia in patients new to dialysis. METHODS: HIMALAYAS was a Phase 3, open-label, epoetin alfa-controlled trial. Eligible adults were incident to hemodialysis/peritoneal dialysis for 2 weeks to ≤4 months prior to randomization and had mean hemoglobin (Hb) ≤10.0 g/dL. Primary endpoints were mean Hb (g/dL) change from baseline averaged over Weeks 28-52 regardless of rescue therapy [non-inferiority criterion: lower limit of 95% confidence interval (CI) for treatment difference >-0.75] and percentage of patients achieving an Hb response between Weeks 1 and 24 censored for rescue therapy (non-inferiority margin for between-group difference -15%). Adverse events were monitored. RESULTS: The intent-to-treat population included patients randomized to roxadustat (n = 522) or epoetin alfa (n = 521). Mean (standard deviation) Hb changes from baseline averaged over Weeks 28-52 were 2.57 (1.27) and 2.36 (1.21) in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior [least squares mean difference: 0.18 (95% CI 0.08, 0.29)] to epoetin alfa. Percentages of patients with an Hb response were 88.2% and 84.4% in the roxadustat and epoetin alfa groups, respectively. Roxadustat was non-inferior to epoetin alfa [treatment-group difference 3.5% (95% CI -0.7%, 7.7%)]. Adverse event rates were comparable between treatment groups. CONCLUSIONS: Roxadustat was efficacious for correcting and maintaining Hb levels compared with epoetin alfa. Roxadustat had an acceptable safety profile.


Assuntos
Anemia , Eritropoetina , Hematínicos , Falência Renal Crônica , Anemia/tratamento farmacológico , Anemia/etiologia , Epoetina alfa/uso terapêutico , Eritropoetina/uso terapêutico , Glicina/análogos & derivados , Hematínicos/uso terapêutico , Hemoglobinas , Humanos , Isoquinolinas , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Proteínas Recombinantes , Diálise Renal
7.
J Clin Oncol ; 39(9): 1001-1009, 2021 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-33439748

RESUMO

PURPOSE: Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin. METHODS: In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment. RESULTS: A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) (P = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively (P = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone. CONCLUSION: LEN restores sensitivity to recombinant erythropoietin in growth factor-insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Síndromes Mielodisplásicas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Recombinantes/farmacologia , Idoso , Idoso de 80 Anos ou mais , Epoetina alfa/administração & dosagem , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida
8.
AAPS J ; 23(2): 26, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33459871

RESUMO

Accurate assessment of antigen-specific immune responses is critical in the development of safe and efficacious biotherapeutics and vaccines. Endosomal processing of a protein antigen followed by presentation on major histocompatibility complex (MHC) class II constitute necessary steps in the induction of CD4+ T cell immune responses. Current preclinical methods for assessing immunogenicity risk consist of in vitro cell-based assays and computational prediction tools. Cell-based assays are time and labor-intensive while in silico methodologies have limitations. Here, we propose a novel cell-based assay capable of investigating an antigen's endosomal processing and MHC class II presentation capabilities. This novel assay relies on competition between epitopes for MHC class II binding and employs labeled soluble T cell receptors (sTCRs) as detectors of epitope presentation.


Assuntos
Apresentação do Antígeno , Bioensaio/métodos , Mapeamento de Epitopos/métodos , Antígenos de Histocompatibilidade Classe II/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células CHO , Simulação por Computador , Cricetulus , Células Dendríticas , Endossomos/metabolismo , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Epoetina alfa/isolamento & purificação , Epoetina alfa/metabolismo , Voluntários Saudáveis , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunoensaio/métodos , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T/isolamento & purificação
9.
BioDrugs ; 35(2): 239-254, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33439472

RESUMO

BACKGROUND: Since the approval and availability of the first biosimilar in 2015 in the United States (US), evidence regarding the post-marketing safety of cancer supportive care biosimilars remains limited. OBJECTIVE: The aim was to explore the adverse event (AE) reporting patterns and detect disproportionate reporting signals for cancer supportive care biosimilars in the US compared to their originator biologics. METHODS: The US Food and Drug Administration Adverse Event Reporting System database (January 1, 2004-March 31, 2020) was used to identify AE reports for filgrastim, pegfilgrastim, and epoetin alpha by type of product (originator biologics vs. biosimilars) and report characteristics. Plots of AE reports against years were used to reveal the reporting patterns. Disproportionality analyses using reporting odds ratios (RORs) were conducted to detect differences in serious and specific AEs between studied drugs and all other drugs. Breslow-Day tests were used to determine homogeneity between the originator biologic-biosimilar pair RORs for the same AE. RESULTS: Total numbers of AEs for all studied biosimilars increased after marketing. More AE reports were from female patients for all of the studied drugs. More AEs for originator biologics and filgrastim biosimilar were reported by health professionals, while the highest proportion of reports came from consumers for pegfilgrastim and epoetin alpha biosimilars (29% and 44.1%, respectively). Signals of disproportionate reporting in serious AEs were detected for a pegfilgrastim biosimilar (Fulphila®) compared to its originator biologic. CONCLUSION: Our findings support the similarity in the signals of disproportionate reporting between cancer supportive care originator biologics and biosimilars, except for Fulphila®.


Assuntos
Medicamentos Biossimilares , Neoplasias , Medicamentos Biossimilares/efeitos adversos , Bases de Dados Factuais , Epoetina alfa , Feminino , Humanos , Neoplasias/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration
12.
Acta Haematol ; 144(3): 252-258, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32662775

RESUMO

BACKGROUND: Erythroid stimulating agents (ESAs) have pleiotropic effects, and in animal and human studies those exposed to high erythropoietin had lower blood glucose. OBJECTIVE: To determine the association between ESA and glucose in anemia-treated patients with myelodysplastic syndromes (MDS) or multiple myeloma (MM). PATIENTS AND METHODS: Patients' glucose levels were compared while on to while off ESA, and all served as their own controls. To test the association between ESA and blood glucose, we employed a linear mixed model, accounting for variability in the number of measurements for each patient. RESULTS: Charts of 20 patients were reviewed. Mean age was 77 ± 9.8 years (range 50-91). Thirteen patients had MDS, and 8 had MM (1 with both). Glucose (mean ± standard error of the mean) was 116.38 ± 5.21 mg/dL without ESA, as opposed to 105.64 ± 5.11 mg/dL with ESA (p < 0.0001). The 3 diabetic and 5 steroid-treated patients also demonstrated reduced glucose by approximately 19 mg/dL with ESA (p = 0.003 and p = 0.0001, respectively). There was no difference in collective hemoglobin levels between the 2 groups. CONCLUSION: ESA treatment for anemia is associated with lower blood glucose in hematologic patients. In those who also have diabetes mellitus, ESA might contribute to glucose control, and even to hypoglycemia. Glucose monitoring is thus advised. Further studies with both diabetic and nondiabetic patients are needed to clarify this association and underlying mechanisms.


Assuntos
Anemia/tratamento farmacológico , Glicemia/análise , Darbepoetina alfa/uso terapêutico , Epoetina alfa/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/patologia
13.
J Pharm Biomed Anal ; 194: 113750, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33234415

RESUMO

Recombinant human erythropoietin (rEPO) biosimilars are copies of epoetin drugs developed after the first patents ended. However differences in the process of production can result in small structural differences when compared to the reference product. Differences in N-glycosylation profiles are of particular importance for rEPOs, because they can drastically impact the half-life in circulation and activity. Changes of structure can also impact electrophoretic profiles that are used to reveal the presence of a rEPO in a doping control sample. In this study three not well characterized biosimilars were evaluated (Jimaixin™ authorized in China, and Hemax® and Epotin™ authorized in Algeria). As these products could be used for doping, first their EPO profiles were determined using the antidoping methods (electrophoretic separation by the charge (isolectric focusing, IEF-PAGE) or the molecular weight (SDS-PAGE) and specific EPO immunodetection). Compared to the original epoetin alfa Eprex®, it revealed more basic isoforms for Epotin™ and Jimaixin™ after IEF-PAGE and a slightly lower molecular weight after SDS-PAGE in particular for Hemax®. To better understand the reason for these differences, EPO specific N-glycans were evaluated using two complementary approaches: MALDI-TOF mass spectrometry (MS) and hydrophilic interaction liquid chromatography (HILIC) with fluorescence detection. All three biosimilars presented a significant decrease in the major glycan forms of Eprex® along with an increase in less complex forms. Jimaixin™ and Epotin™ presented also a lower amount of fully sialylated forms. HILIC method also showed that O-acetylation level of sialic acid residues might vary from one rEPO to the other.


Assuntos
Medicamentos Biossimilares , Eritropoetina , Preparações Farmacêuticas , Argélia , China , Epoetina alfa , Humanos , Polissacarídeos , Proteínas Recombinantes
14.
Stroke ; 52(1): 284-293, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33349013

RESUMO

BACKGROUND AND PURPOSE: Perinatal stroke is a common cause of life-long neurobehavioral compromise. Mesenchymal stromal cells (MSCs) and EPO (erythropoietin) have each demonstrated short-term benefit with delayed administration after stroke, and combination therapy may provide the most benefit. The purpose of this study is to determine the long-term histological and functional efficacy of enhanced, intranasal stem cell therapy (MSC preexposed to EPO) compared with standard MSC or multidose systemic EPO. METHODS: Transient middle cerebral artery occlusion or sham surgery was performed in postnatal day (P) 10 Sprague-Dawley rats, who were treated with single-dose intranasal MSC, MSC preexposed to EPO (MSC/EPO), multidose systemic EPO (EPO3; 1000 u/kg per dose×3 every 72 hours), or cell-conditioned media on P13 (day 3 [P13-P19] for EPO), or on P17 (day 7 [P17-P23] for EPO). At 2 months of age, animals underwent novel object recognition, cylinder rearing, and open field testing to assess recognition memory, sensorimotor function, and anxiety in adulthood. RESULTS: MSC, MSC/EPO, and EPO3 improved brain volume when administered at 3 or 7 days after middle cerebral artery occlusion. MSC/EPO also enhanced long-term recognition memory with either day 3 or day 7 treatment, but EPO3 had the most long-term benefit, improving recognition memory and exploratory behavior and reducing anxiety. CONCLUSIONS: These data suggest that single-dose MSC/EPO and multidose systemic EPO improve long-term neurobehavioral outcomes even when administration is delayed, although EPO was the most effective treatment overall. It is possible that EPO represents a final common pathway for improved long-term repair, although the specific mechanisms remain to be determined.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Acidente Vascular Cerebral/terapia , Administração Intranasal , Animais , Animais Recém-Nascidos , Ansiedade/psicologia , Comportamento Animal , Encéfalo/diagnóstico por imagem , Meios de Cultivo Condicionados , Epoetina alfa/uso terapêutico , Feminino , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/etiologia , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Gravidez , Desempenho Psicomotor , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/psicologia , Resultado do Tratamento
15.
Expert Rev Clin Pharmacol ; 14(1): 1-8, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33307871

RESUMO

Introduction: Erythropoietin stimulating agents (ESAs) have been established both to correct anemia and provide the clinical benefits of increased exercise capacity, reduced transfusion requirements, and improved quality of life. An increase in physician and patient adoption of biosimilars, as well as changes to healthcare reimbursement policies, have driven market competitors to innovate and expand the range of biosimilar products. While erythropoietin biosimilars have been approved by the EMA since 2007, the FDA's approval of epoetin alfa-epbx in 2018 marks the first erythropoietin biosimilar approved in the United States. Areas covered: In this article, we critically review the biology, clinical use, manufacturing, safety, and efficacy of ESAs and erythropoietin biosimilars. We then review the regulatory framework and potential impact on healthcare costs offered by erythropoietin biosimilars. Expert opinion: Due to the complex nature of manufacturing large-molecule biologics, it is important to recognize the challenges to quality assurance and overall safety posed by the introduction of biosimilars, which undergo much more limited clinical testing than their reference biologic product before coming to market. With many biologic therapies nearing patent expiration, biosimilars will become increasingly common in clinical practice. Ensuring patient safety with these products will require increased post-marketing surveillance and awareness from prescribers.


Assuntos
Medicamentos Biossimilares/administração & dosagem , Epoetina alfa/administração & dosagem , Hematínicos/administração & dosagem , Anemia/tratamento farmacológico , Medicamentos Biossimilares/efeitos adversos , Aprovação de Drogas , Epoetina alfa/efeitos adversos , Hematínicos/efeitos adversos , Humanos , Qualidade de Vida , Estados Unidos
16.
Expert Rev Hematol ; 13(11): 1175-1188, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33028115

RESUMO

INTRODUCTION: Anemia has and will continue to be a central theme in medicine particularly as clinicians are treating a burgeoning population of complex multi-organ system processes. As a result of multiple randomized controlled trials (RCTs), meta-analyses, and societal recommendations overly restrictive paradigms and under-administration of erythropoiesis stimulating agents (ESAs) have likely been followed by clinicians among all specialties. AREAS COVERED: A review of anemia in the context of chronic kidney disease, hematologic malignancies, and cancer is presented with focus on the establishment of ESAs as integral in the treatment of anemia. Multiple RCTs and meta-analyses studying the use of ESAs are presented with focus upon their application to clinical practice. A 'compendium' is proffered describing the evolution, establishment, and implications of ESA administration initially among those with CKD with rapid subsequent application to the Hematology-Oncology population of patients. Literature search methodologies have included MEDLINE (1985-2020), PubMed (1996-2020), Cochrane Central Trials (1985-2020), EMBASE (2000-2020), and ClinicalTrials.gov (2000-2020). EXPERT OPINION: Upon evaluation of risks and benefits of ESAs focused opinion and commentary is made supporting more liberal use of these agents and strongly suggesting that the current underlying treatment 'pendulum' has perhaps shifted too far to the 'under-treatment' side in many cases.


Assuntos
Anemia/terapia , Neoplasias/complicações , Insuficiência Renal Crônica/complicações , Anemia/tratamento farmacológico , Anemia/etiologia , Anemia/fisiopatologia , Transfusão de Sangue , COVID-19/epidemiologia , Terapia Combinada , Epoetina alfa/efeitos adversos , Epoetina alfa/uso terapêutico , Eritropoetina/fisiologia , Eritropoetina/uso terapêutico , Prova Pericial , Previsões , Fidelidade a Diretrizes , Hematínicos/administração & dosagem , Hematínicos/uso terapêutico , Neoplasias Hematológicas/complicações , Hematopoese , Humanos , Ferro/uso terapêutico , Medicina , Metanálise como Assunto , Estudos Multicêntricos como Assunto , Isquemia Miocárdica/complicações , Estudos Observacionais como Assunto , Pandemias , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores da Eritropoetina/efeitos dos fármacos , Diálise Renal , Insuficiência Renal Crônica/terapia , SARS-CoV-2 , Tromboembolia Venosa/induzido quimicamente
17.
Clin Breast Cancer ; 20(6): 439-447, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32800493

RESUMO

BACKGROUND: Hematologic toxicities are one of the greatest challenges in adjuvant chemotherapy for breast cancer. This analysis of the ADEBAR trial aims to evaluate application and effect of granulocyte colony-stimulating factor (G-CSF) and epoetin alfa (EPO) on hematologic parameters and fatigue in patients with breast cancer during chemotherapy. PATIENTS AND METHODS: In the ADEBAR trial, 1493 patients with node-positive primary breast cancer were randomized to either 6 × 5-fluorouracil, epirubicin, and cyclophosphamide (FEC120) or 4 × epirubicin and cyclophosphamide followed by 4 × docetaxel (EC-DOC). Co-medication with G-CSF or EPO was applied to treat chemotherapy-induced leukopenia or anemia. Fatigue was assessed at baseline and after one-half of the chemotherapy. RESULTS: In total, 899 patients could be included in the analysis. There was no evidence for an association between leucocyte or hemoglobin levels and application of G-CSF and EPO in the preceding cycle, respectively. Hemoglobin levels (B = -0.41; P < .001) were affected by treatment regimen. Fatigue during chemotherapy was mostly affected by the level of fatigue before the start of chemotherapy (B = 0.41; P < .001). Patients with G-CSF application in the preceding cycle showed an increased fatigue score (B = 5.43; P = .02). CONCLUSION: We showed that fatigue during adjuvant chemotherapy was mostly affected by the level of fatigue present before the start of chemotherapy. This result suggests that the level of fatigue before the start of treatment should be included as an important factor when deciding on type and toxicity of chemotherapy in early breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/terapia , Epoetina alfa/administração & dosagem , Fadiga/epidemiologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Adolescente , Adulto , Idoso , Anemia/induzido quimicamente , Anemia/diagnóstico , Anemia/epidemiologia , Anemia/prevenção & controle , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/diagnóstico , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Fadiga/induzido quimicamente , Fadiga/diagnóstico , Fadiga/prevenção & controle , Feminino , Hemoglobinas/análise , Humanos , Contagem de Leucócitos , Leucopenia/induzido quimicamente , Leucopenia/diagnóstico , Leucopenia/epidemiologia , Leucopenia/prevenção & controle , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Adulto Jovem
18.
J Perinat Med ; 48(7): 744-750, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32681780

RESUMO

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 1,500 g. 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.


Assuntos
Anemia Neonatal , Revisão de Uso de Medicamentos , Epoetina alfa/administração & dosagem , Hipóxia-Isquemia Encefálica , Anemia Neonatal/etiologia , Anemia Neonatal/prevenção & controle , Revisão de Uso de Medicamentos/métodos , Revisão de Uso de Medicamentos/estatística & dados numéricos , Europa (Continente)/epidemiologia , Feminino , Pesquisas sobre Serviços de Saúde , Hematínicos/administração & dosagem , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/terapia , Saúde do Lactente/estatística & dados numéricos , Recém-Nascido , Recém-Nascido Prematuro/sangue , Recém-Nascido de muito Baixo Peso/sangue , Masculino , Fármacos Neuroprotetores/administração & dosagem
19.
Pharmacol Res ; 159: 105020, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32561478

RESUMO

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral medicines being developed for the treatment of anemia in chronic kidney disease (CKD) patients. This study aimed to compare the efficacy and safety of HIF-PHI vs epoetin and darbepoetin in CKD patients with anemia not undergoing dialysis. The PubMed, Embase, Cochrane Library, Web of Science, and clinicaltrials.gov databases were searched from inception to October 2019 for randomized controlled trials investigating different agents (six HIF-PHIs, epoetin, darbepoetin, and placebo) for treating CKD patients with anemia that did not undergo dialysis. The outcomes included a change in hemoglobin (Hb) levels and all-cause mortality. A total of 19 studies were included. Compared with the placebo, except for vadadustat (mean differences: 1.12, 95 % confidence interval [CI]: ‒0.11-2.35), the other drugs significantly increased Hb levels, with mean differences of 2.46 (95 % CI: 0.93-3.99) for desidustat, 1.81 (0.87-2.75) for enarodustat, 1.68 (0.64-2.72) for molidustat, 1.66 (0.89-2.44) for epoetin, 1.63 (0.69-2.56) for darbepoetin, 1.61 (0.99-2.22) for roxadustat, and 1.55 (0.74-2.36) for daprodustat. No differences were found in the Hb level elevations among these eight drugs. Compared with the placebo, there also was no significant association between the drugs and all-cause mortality (molidustat of RR, 0.39 [95 % CI, 0.06-2.59]; roxadustat, 0.40 (0.06-2.84); enarodustat, 0.33 (0.01-16.25); desidustat, 0.34 (0.01-17.00); epoetin, 0.50 (0.18-1.42); daprodustat, 0.54 (0.09-3.31); darbepoetin, 1.03 (0.65-1.65); and vadadustat, 1.43 (0.15-13.27)). No differences were observed in the all-cause mortality among the drugs. In conclusion, these HIF-PHIs are effective and relatively tolerant for treating anemia patients with CKD not undergoing dialysis. Further research should consider the limitations of our study to evaluate the value of these HIF-PHIs in clinical settings.


Assuntos
Anemia/tratamento farmacológico , Darbepoetina alfa/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Hemoglobinas/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Insuficiência Renal Crônica/complicações , Idoso , Idoso de 80 Anos ou mais , Anemia/enzimologia , Anemia/etiologia , Anemia/mortalidade , Biomarcadores/sangue , Darbepoetina alfa/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Epoetina alfa/efeitos adversos , Feminino , Hematínicos/efeitos adversos , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
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