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Pimentel, Marcos Antônio, Maria Cristina Vasconcellos, Rafaela de Oliveira Penha, Edson Perez Guerra, and André Luís Lopes Da Silva. "Ação de diferentes enzimas na germinação de sementes de alface (Lactuca sativa L.) - Asteraceae." Journal of Biotechnology and Biodiversity 3, no. 3 (August 1, 2012): 1–4. http://dx.doi.org/10.20873/jbb.uft.cemaf.v3n3.pimentel.
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A germinação de sementes envolve o uso de diferentes enzimas no metabolismo. O objetivo deste estudo foi avaliar o efeito de diferentes enzimas comerciais na germinação de sementes de alface. As sementes de alface foram imersas em uma solução de 300 mL de água destilada e 5,0 mL de solução enzimática durante uma hora. Os tratamentos consistiram nas soluções comerciais de enzimas: (1) Alcalase® e Celluclean® (catalisam a hidrólise de ligações peptídicas e ligações de beta 1,3 e 1,4 glucana presentes na celulose, respectivamente), (2) Pectinex® ( dilui a pectina de propósito, liberando açúcares), (3) Alcalase® (objetivo de catalisar ligações peptídicas), (4) Pectinex® e Alcalase® (objetivo de catalisar ligações peptídicas e liberar açúcares), (5) Alcalase® e Ban® ( objetivo de catalisar ligações peptídicas e hidrólise de ligações alfa 1,4 - dextrina formadora glucosídica, de preferência como produto), (6) Spirizyme® (enzima glucoamilase: glucana 1,4 alfa-glucosidase) e (7) controle (água destilada livre de enzimas ) Após o tratamento com as soluções enzimáticas, as sementes foram semeadas em placas de Petri contendo papel de filtro ou solo como substrato, ambos saturados com água destilada. As sementes de todos os tratamentos germinaram em quatro dias após a semeadura. A porcentagem de germinação das sementes em papel de filtro não mostrou diferenças significativas entre os tratamentos, mas a porcentagem de germinação mostrou diferenças estatísticas quando germinadas no solo. As maiores porcentagens de germinação no solo foram no tratamento controle (96,6%) e no tratamento com Pectinex® e Alcalase® (81,6%). A aplicação de enzimas industriais em sementes de alface não aumenta a velocidade e a porcentagem de germinação das sementes.
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González-Núñez, Dossnay Hermes, Raúl Piad Barreras, and Nadir Reyes-Sánchez. "COMPORTAMIENTO PRODUCTIVO DE POLLOS DE ENGORDE SUPLEMENTADOS CON UN PCL-GLUCANO DE PRODUCCIÓN NACIONAL." La Calera 13, no. 21 (December 4, 2014): 82–87. http://dx.doi.org/10.5377/calera.v13i21.1650.
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Se realizó un experimento para evaluar un prebiótico de producción nacional, derivado de paredes celulares de levadura Saccharomyces cerevisiae (PCL-Glucano) en el comportamiento productivo de pollos de engorde (Cobb 500). Se utilizaron 210 pollitos mixtos Cobb 500 de un día de edad, que fueron distribuidos en un diseño completamente al azar en tres tratamientos, con siete repeticiones y 10 aves por repetición. Los tratamientos evaluados fueron: T1: concentrado comercial (CC), T2: CC + 0.05% PCL-Glucano (0.5 kg ton-1 de alimento) y T3: CC + 0.10% PCL-Glucano. Las variables evaluadas fueron peso vivo, consumo de alimento y conversión alimenticia, realizando mediciones a los 21, 35 y 42 días. Los resultado muestran que el consumo de alimento (3 812 g), peso vivo (2 017 g) e índice de conversión alimenticia (1.89) que se obtienen en los pollos alimentados con la dieta CC + 0.10% PCL-Glucano, a los 42 días de edad, fueron significativamente (P<0.05%) mejores a los de T1 (3 751 g, 1 617 g y 2.32) y T2 (3 642 g, 1 648 g y 2.21), los cuales no difieren estadísticamente entre sí. En conclusión la utilización de PCL-Glucano a razón de 0.10% en el concentrado iniciador y finalizador para pollos de engorde es una alternativa viable biológicamente ya que manifestó su actividad prebiótica mediante una mejora progresiva y significativa de los indicadores productivos. DOI: http://dx.doi.org/10.5377/calera.v13i21.1650
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Luna, U. V., J. G. Caramori Júnior, G. S. S. Corrêa, C. Kiefer, M. A. Souza, F. M. Vieites, R. A. S. Cruz, and S. D. Assis. "Mananoligossacarídeo e ß-glucano em dietas de leitões desmamados." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 67, no. 2 (April 2015): 591–99. http://dx.doi.org/10.1590/1678-7146.
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Avaliou-se o efeito da suplementação de mananoligossacarídeo, ß-glucano e antibiótico em dietas de leitões machos castrados, durante a fase de creche (21 aos 54 dias de idade), sobre o desempenho, características morfo-histológicas da mucosa intestinal e ocorrência de diarreia. Foram utilizados 368 leitões de mesma linhagem, distribuídos em delineamento inteiramente ao acaso, com quatro tratamentos (1: 330g de mananoligossacarídeo t/ração (oriundos do núcleo), 2: 1.830g de mananoligossacarídeo t/ração (330g oriundos do núcleo + 1.550g da suplementação), 3: 330g de mananoligossacarídeo (oriundos do núcleo) + 500g de ß-glucano t/ração e 4: 330g de mananoligossacarídeo (oriundos do núcleo) + 250g de Colistina t/ração) e quatro repetições com 23 animais por unidade experimental. O desempenho foi avaliado pelo ganho de peso, consumo de ração e conversão alimentar. As características morfo-histológicas da mucosa intestinal estudadas foram altura de vilosidade, profundidade das criptas intestinais, perímetro de vilosidade e a relação altura de vilosidade:profundidade de cripta do duodeno, jejuno e íleo. A ocorrência de diarreia foi observada diariamente pela avaliação de escore fecal. A suplementação de mananoligossacarídeo, β-glucano e antibiótico na dieta de leitões machos castrados, na fase de creche, não influenciaram o desempenho e a ocorrência de diarreia. Maior altura de vilosidade e maior profundidade de criptas no duodeno e íleo foram verificadas nos animais suplementados com ß-glucano. No jejuno foi observado maior perímetro de vilosidade nos animais suplementados com ß-glucano e nos animais que não receberam suplemento adicional na dieta.
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Pérez-Llano, Yordanis, Eya Caridad Rodríguez-Pupo, Irina S. Druzhinina, Komal Chenthamara, Feng Cai, Nina Gunde-Cimerman, Polona Zalar, et al. "Stress Reshapes the Physiological Response of Halophile Fungi to Salinity." Cells 9, no. 3 (February 25, 2020): 525. http://dx.doi.org/10.3390/cells9030525.
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(1) Background: Mechanisms of cellular and molecular adaptation of fungi to salinity have been commonly drawn from halotolerant strains and few studies in basidiomycete fungi. These studies have been conducted in settings where cells are subjected to stress, either hypo- or hyperosmotic, which can be a confounding factor in describing physiological mechanisms related to salinity. (2) Methods: We have studied transcriptomic changes in Aspergillus sydowii, a halophilic species, when growing in three different salinity conditions (No NaCl, 0.5 M, and 2.0 M NaCl). (3) Results: In this fungus, major physiological modifications occur under high salinity (2.0 M NaCl) and not when cultured under optimal conditions (0.5 M NaCl), suggesting that most of the mechanisms described for halophilic growth are a consequence of saline stress response and not an adaptation to saline conditions. Cell wall modifications occur exclusively at extreme salinity, with an increase in cell wall thickness and lamellar structure, which seem to involve a decrease in chitin content and an augmented content of alfa and beta-glucans. Additionally, three hydrophobin genes were differentially expressed under hypo- or hyperosmotic stress but not when the fungus grows optimally. Regarding compatible solutes, glycerol is the main compound accumulated in salt stress conditions, whereas trehalose is accumulated in the absence of salt. (4) Conclusions: Physiological responses to salinity vary greatly between optimal and high salt concentrations and are not a simple graded effect as the salt concentration increases. Our results highlight the influence of stress in reshaping the response of extremophiles to environmental challenges.
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Souza, Fabiano Inácio de, Arnaldo Valdir Zumiotti, and Ciro Ferreira da Silva. "Neuregulinas 1-alfa e 1-beta na regeneração de nervos periféricos." Acta Ortopédica Brasileira 18, no. 5 (2010): 250–54. http://dx.doi.org/10.1590/s1413-78522010000500003.
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OBJETIVO: Avaliar o efeito das neuregulinas 1-alfa e 1-beta na regeneração de nervos ciáticos de camundongos C57BL/6J, adultos, machos, através da técnica de tubulização. MÉTODOS: Utilizaram-se 18 animais, divididos em 3 grupos, implantando-se prótese de polietileno em falhas de 4,0 mm no nervo ciático esquerdo: grupo 1 contendo apenas colágeno purificado (Vitrogen®); grupo 2, colágeno associado a neuregulina 1-alfa; grupo 3 com colágeno e neuregulina 1-beta. O grupo controle foi formado por 6 segmentos de nervos ciáticos direitos. Após 4 semanas, os animais foram sacrificados; extraiu-se segmento do ponto médio do nervo regenerado no interior das próteses, padronizaram-se cortes histológicos e confecção das lâminas para análise histomorfométrica. Confrontaram-se os resultados estatisticamente. RESULTADOS: Os animais tratados com neuregulinas tiveram maior número de axônios mielinizados, com diferença estatisticamente significante quando comparados ao grupo colágeno. Não houve diferença estatística entre os grupos de neuregulinas 1-alfa e 1-beta. CONCLUSÃO: a adição de neuregulinas proporcionou aumento significativo do número de fibras mielinizadas.
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Tolcher, Anthony W., Michael Gordon, Kathleen M. Mahoney, Anna Seto, Marianna Zavodovskaya, Chia-Hsiang Hsueh, Shuyan Zhai, et al. "Phase 1 first-in-human study of dalutrafusp alfa, an anti–CD73-TGF-β-trap bifunctional antibody, in patients with advanced solid tumors." Journal for ImmunoTherapy of Cancer 11, no. 2 (February 2023): e005267. http://dx.doi.org/10.1136/jitc-2022-005267.
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BackgroundCluster of differentiation (CD)73-adenosine and transforming growth factor (TGF)-β pathways are involved in abrogated antitumor immune responses and can lead to protumor conditions. This Phase 1 study (NCT03954704) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of dalutrafusp alfa (also known as GS-1423 and AGEN1423), a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-β signaling in patients with advanced solid tumors.MethodsDose escalation started with an accelerated titration followed by a 3+3 design. Patients received dalutrafusp alfa (0.3, 1, 3, 10, 20, 30, or 45 mg/kg) intravenously every 2 weeks (Q2W) up to 1 year or until progressive disease (PD) or unacceptable toxicity.ResultsIn total, 21/22 patients received at least one dose of dalutrafusp alfa. The median number of dalutrafusp alfa doses administered was 3 (range 1–14). All patients had at least one adverse event (AE), most commonly fatigue (47.6%), nausea (33.3%), diarrhea (28.6%), and vomiting (28.6%). Nine (42.9%) patients had a Grade 3 or 4 AE; two had Grade 5 AEs of pulmonary embolism and PD, both unrelated to dalutrafusp alfa. Target-mediated drug disposition appears to be saturated at dalutrafusp alfa doses above 20 mg/kg. Complete CD73 target occupancy on B cells and CD8+ T cells was observed, and TGF-β 1/2/3 levels were undetectable at dalutrafusp alfa doses of 20 mg/kg and higher. Free soluble (s)CD73 levels and sCD73 activity increased with dalutrafusp alfa treatment. Seventeen patients reached the first response assessment, with complete response, partial response, stable disease, and PD in 0, 1 (4.8%), 7 (33.3%), and 9 (42.9%) patients, respectively.ConclusionsDalutrafusp alfa doses up to 45 mg/kg Q2W were well tolerated in patients with advanced solid tumors. Additional evaluation of dalutrafusp alfa could further elucidate the clinical utility of targeting CD73-adenosine and TGF-β pathways in oncology.
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Neto, Luiza Érika Schmid Melo, Cyro Teixeira da Silva, Gilberto Perez Cardoso, Ângela Santos Ferreira, Guilherme da Costa Marino, and Nicolau Pedro Monteiro. "Aspectos pulmonares na deficiência de alfa-1-antitripsina." Revista Portuguesa de Pneumologia 10, no. 2 (March 2004): 145–54. http://dx.doi.org/10.1016/s0873-2159(15)30566-3.
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Solms, Alexander, Anita Shah, Erik Berntorp, Andreas Tiede, Alfonso Iorio, Camila Linardi, Maurice Ahsman, Maria Elisa Mancuso, Tihomir Zhivkov, and Toshko Lissitchkov. "Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A." Annals of Hematology 99, no. 11 (September 24, 2020): 2689–98. http://dx.doi.org/10.1007/s00277-020-04280-3.
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Abstract An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0–tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 (ClinicalTrials.gov identifier). Date of registration: July 9, 2019
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Lissitchkov, Toshko, Annemieke Willemze, Suresh Katragadda, Kara Rice, Stacey Poloskey, and Craig Benson. "Efanesoctocog alfa for hemophilia A: results from a phase 1 repeat-dose study." Blood Advances 6, no. 4 (February 11, 2022): 1089–94. http://dx.doi.org/10.1182/bloodadvances.2021006119.
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Abstract Efanesoctocog alfa (rFVIIIFc-VWF-XTEN; BIVV001) is a new class of factor VIII (FVIII) replacement that breaks the von Willebrand factor–imposed FVIII half-life ceiling. In a phase 1/2a study, single-dose efanesoctocog alfa was well tolerated, and no safety concerns were identified. We evaluated the safety, tolerability, and pharmacokinetics of repeat-dose efanesoctocog alfa in a phase 1 study in previously treated adults (≥150 exposure days) with severe hemophilia A. Participants received 4 once weekly doses of efanesoctocog alfa (cohort 1, 50 IU/kg; cohort 2, 65 IU/kg). All enrolled participants (cohort 1, n = 10; cohort 2, n = 14) completed the study. Inhibitor development to FVIII was not detected. After the last dose of efanesoctocog alfa, geometric mean (range) FVIII activity half-life, area under the activity-time curve, and steady-state maximum concentration for cohort 1 and cohort 2 were 41.3 (34.2-50.1) and 37.3 (28.9-43.8) hours, 8290 (5810-10 300) and 11 200 (7040-15 800) hours × IU/dL, and 131 (96-191) and 171 (118-211) IU/dL, respectively. There was minimal accumulation after 4 doses. Mean FVIII activity for cohort 1 and cohort 2, respectively, was 46% and 69% on day 3 postdose and 10% and 12% on day 7 postdose. Overall, 4 once-weekly doses of efanesoctocog alfa were well tolerated, no safety concerns were identified, and no bleeds were reported during the treatment period. Once-weekly efanesoctocog alfa provided high sustained FVIII activity within the normal to near-normal range for 3 to 4 days postdose and may improve protection against bleeds in patients with hemophilia A. The trial is study 2018-001535-51 in the EU Clinical Trials Register.
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Tanvetyanon, Tawee, Edward A. Stadtmauer, and Lawrence A. Kerson. "Concurrent Administration of Interferon Alfa-2b and Beta-1a." Annals of Pharmacotherapy 37, no. 1 (January 2003): 77–79. http://dx.doi.org/10.1345/aph.1c120.
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OBJECTIVE To describe the concurrent use of interferon (IFN) alfa and beta in a patient with multiple sclerosis (MS) and chronic myeloid leukemia (CML). CASE SUMMARY A 60-year-old white man developed CML while receiving IFN beta-1a treatment for MS. The patient was started on IFN alfa-2b 1 million units 3 times weekly with IFN beta-1a 30 μg weekly. The dosage of IFN alfa was increased to 3 million units/d 1 month later. He achieved complete hematologic remission in 3 months. The observed adverse effects were mild and included fatigue, somnolence, weight loss, and difficulty with memory. At 19 months after treatment, the patient remained in hematologic remission and his expanded disability status scale score remained unchanged. DISCUSSION Concomitant treatment with interferon alfa and beta by a gradual increase in the dosage of IFN alfa was well tolerated. Although imatinib mesylate may be a preferred treatment for patients with CML and MS at this time, our experience with safe concurrent use of IFN alfa and beta may benefit other patients who require this combined treatment. CONCLUSIONS Concurrent administration of interferon alfa-2b and beta-1a was well tolerated by our patient with CML and MS.
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BRITO, Vitor Hugo dos Santos, Erica Caroline da SILVA, and Marney Pascoli CEREDA. "Digestibilidade do amido in vitro e valor calórico dos grupos de farinhas de mandioca brasileiras." Brazilian Journal of Food Technology 18, no. 3 (September 2015): 185–91. http://dx.doi.org/10.1590/1981-6723.2714.
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Resumo A preferência cultural do brasileiro originou grupos e subclassificações da farinha de mandioca em função dos processos adotados. Diferenças de processamento das farinhas de mandioca podem afetar a digestibilidade do amido, assim seu teor calórico foi investigado. Foram selecionadas cinco amostras dos três grupos de farinha de mandioca: Seca, Bijusada e D’água. O teste de digestibilidade do amido foi realizado in vitro, incubando a suspensão de farinha com amilase (alfa-1,4-glucano-4-glucanohidrolase) em condições de temperatura e pH que simulam a digestão humana. Alíquotas foram coletadas a cada 15 minutos, durante 1 hora e o teor de glicose liberado foi expresso em calorias rapidamente disponíveis. Os resultados mostraram que o valor calórico de todas as amostras de farinha de mandioca permaneceu ao redor de 300 kcal. 100 g–1. Considerando a cinética de liberação em função do tempo e do grupo, as amostras de farinha de mandioca diferiram. As farinhas de mandioca com menor granulometria, Biju Fina e Furnas (Grupo Bijusada e Seca), apresentaram rápida liberação de açúcares aos 15 minutos, variando de 110 a 215 kcal. 100 g–1, respectivamente. A farinha de mandioca Fina (Grupo Seca) teve liberação uniforme de glicose durante a avaliação. O açúcar liberado pelas farinhas de mandioca com maior granulometria, Biju Grossa e D’água (Grupo Bijusada e D’água), apresentaram dois picos de liberação: o primeiro aos 15 minutos de incubação (liberando 84,2 e 120,48 kcal. 100 g–1, respectivamente); enquanto o segundo pico para a amostra Biju Grossa ocorreu aos 45 minutos (112 kcal. 100 g–1), para a farinha D’água foi após 60 minutos (67,88 kcal. 100 g–1). Pela avaliação microscópica foi observada a presença de grânulos de amido residuais não hidrolisados, variando de 2,42 a 17,85%. Os resultados mostraram que o valor calórico das farinhas de mandioca variou em função do processamento, que afetou a granulometria da farinha, que por sua vez influenciou a gelatinização do amido, fatores esses que determinaram a intensidade da ação das enzimas na liberação de glicose.
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Lohner, Szimonetta, Tamás Marosvölgyi, István Burus, János Schmidt, Dénes Molnár, and Tamás Decsi. "Dietary supplementation of obese children with 1000 mg alpha-linolenic acid per day: a placebo-controlled double blind study." Orvosi Hetilap 148, no. 32 (August 1, 2007): 1499–503. http://dx.doi.org/10.1556/oh.2007.28015.
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Az omega-3 zsírsav fogyasztásának növelése kedvező hatású lehet a fokozott cardiovascularis kockázatú személyek, köztük az elhízottak számára. A kedvező hatások létrejöttének feltétele az omega-3 zsírsavaknak a szervezet plazmalipideibe történő beépülése, azonban a gyermekkorban ehhez szükséges szupplementációs dózisra vonatkozóan igen kevés adat áll rendelkezésre. A jelen vizsgálatunk célja napi 1000 mg alfa-linolénsavval kiegészített étrend a plazmalipidek zsírsavösszetételére kifejtett hatásának vizsgálata volt elhízott gyermekekben. Személyek és módszerek: Ebben a placebóval kontrollált, keresztező önkontrollos, 2 × 6 hétig tartó vizsgálatban a részt vevő 9 elhízott gyermek (életkor: 13,1 [±2,5] év, testtömegindex: 31,2 [±6,2] kg/m 2 , medián [IQR]) étrendjébe speciális takarmánnyal etetett tyúkoktól származó napi 1 tojást és 50 g csirkehúst építettünk be, amivel napi 1000 mg alfa-linolénsav bevitelét tudtuk biztosítani. A plazmalipidek zsírsavösszetételét nagy felbontóképességű kapilláris gáz-folyadék kromatográfiával határoztuk meg. Eredmények: Az alfa-linolénsav-értékek emelkedő tendenciája volt megfigyelhető az alfa-linolénsavval történő szupplementációt követően a foszfolipid-, a triacil-glicerin- és a szterol-észter-frakcióban egyaránt, azonban egyik frakcióban sem volt a változás szignifikáns. A nem észterifikált zsírsavfrakcióban az alfa-linolénsav értékei szignifikánsan emelkedtek (0,11 [0,08] szemben 0,14 [0,20], tömeg%, p < 0,05), jelezve az alfa-linolénsav plazmalipidekben történő feldúsulásának a kezdetét. Következtetés: Az elhízott gyermekekben az étrend 6 héten keresztül napi 1000 mg alfa-linolénsavval történő kiegészítése csak a plazma nem észterifikált zsírsavaiban növelte szignifikánsan az omega-3 zsírsavak arányát, az észterifikált frakciókban nem volt szignifikáns hatás. Elhízott gyermekekben az omega-3-zsírsavellátottság befolyásolásához az alfa-linolénsav-szupplementáció dózisának 1 g/nap fölé történő növelése tűnik szükségesnek.
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Averyanov, A. V., and A. E. Polivanova. "Alfa-1-antitripsin deficiency and chronic obstrictive pulmonary disease." PULMONOLOGIYA, no. 3 (June 28, 2007): 103–9. http://dx.doi.org/10.18093/0869-0189-2007-0-3-103-109.
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Steensma, David P., Shaker R. Dakhil, Paul J. Novotny, Jeff A. Sloan, David B. Johnson, Daniel M. Anderson, Bassam I. Mattar, Dennis F. Moore, Daniel Nikcevich, and Charles L. Loprinzi. "A Randomized Comparison of Standard Weekly Epoetin Alfa to Every-3-Week Epoetin Alfa and Every-3-Week Darbepoetin Alfa: A Study of the Mayo Clinic Cancer Research Consortium (MCCRC)." Blood 114, no. 22 (November 20, 2009): 3008. http://dx.doi.org/10.1182/blood.v114.22.3008.3008.
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Abstract Abstract 3008 Poster Board II-984 Introduction: The erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients (pts) with cancer chemotherapy-associated anemia (CAA). Extended-interval ESA dosing (i.e., administration less than once weekly) is a common practice with DA, which is FDA approved for dosing once every 3 weeks (q3wks); a previous study of the North Central Cancer Treatment Group suggested that EA can also be given less often than the FDA-approved once weekly schedule (Steensma DP et al, J Clin Onc 2006; 24:1079). The present study compared 2 different q3wks extended-interval EA regimens with weekly fixed-dose EA and with q3wks DA in pts with CAA. Patients and Methods: Eligible pts were receiving chemotherapy for a non-myeloid malignancy and had Hb <10.5 g/dL, ferritin >20 ng/mL, weight >40 kg and <150 kg, and ECOG performance score £2. Pts were randomized 1:1:1:1 to receive EA 40,000 Units subcutaneously (SC) once weekly (40K arm), EA 80,000 Units SC q3wks (80K arm), EA 120,000 Units SC q3wks (120K arm), or DA 500 mcg SC q3wks (DA arm), for 15 weeks. EA and DA were held for Hb >12 g/dL and restarted at a lower dose when Hb fell to '11.5 g/dL. All pts received ferrous sulfate 325 mg orally once daily, if tolerated. Quality of life (QOL) was measured using the Symptom Distress Scale (SDS), Brief Fatigue Inventory (BFI), FACT-An, and Linear Analogue Self Assessment (LASA) tools. The primary endpoint was the proportion of pts achieving Hb≥11.5 g/dL or increment of Hb>2.0 g/dL from baseline. Secondary endpoints included RBC transfusion requirements, adverse events (AEs), and QOL. Results: 239 pts (236 evaluable) enrolled at 10 MCCRC sites between Feb. 2007 and Dec. 2008; 62% of pts completed all study interventions. The median age of enrolled pts was 66 years; 42.4% were men, 91.5% had solid tumors, 26.7% had severe anemia (Hb <9.5 g/dL), and 44.9% were receiving platinum-containing regimens. Baseline characteristics were balanced between study arms, with the exception of gender (39% female for 40K, 60% for 80K, 43% for 120K, 26% for DA). There were no significant differences between treatment arms in the proportion of pts achieving a Hb response (68.9% for 40K, 61.7% for 80K, 65.5% for 120K, and 66.7% for DA; p>0.41 for all comparisons), but the median Hb increment from baseline was higher in the 40K and DA arms compared to the 2 extended dosing EA arms (40K-2.8 g/dL, 80K-2.0 g/dL, 120K-2.1 g/dL, DA-2.6 g/dL; p=0.005 for 40K vs 80K). Hb response was achieved more quickly in the weekly EA arm, but the difference was not significant (40K-32 days, 80K-50 days, 120K-49 days, DA-49 days; p>0.13). The proportion of patients transfused was similar between arms (40K-27.9%, 80K-33.3%, 120K-22.4%, DA-29.8%; p>0.49). There were no significant differences in QOL changes. Deaths were also similar between arms (40K-5 pts, 80K-7 pts, 120K-7 pts, DA-1 pt, p>0.10) and were primarily due to disease progression. AEs and serious AEs were comparable between study groups; grade 3/4 AEs were observed in 22% of pts in the 40K arm, 22% on 80K, 17% on 120K, and 13% on DA; p>0.56. The median total dose of EA used was highest in the 120K arm (40K-265,000 U; 80K-240,000 U; 120K-360,000 U; p=0.0009 for 40K vs 120K), while pts on the 40K arm were more likely to omit a dose due to a high Hb (40K-63.9% of pts omitted at least one dose; 80K-30.0%; 120K-34.5%; DA-43.6%, p<0.0001 for 40K vs 80K). Conclusion: Although there was no significant difference in the proportion of responding pts (the primary endpoint), Hb increments from baseline were moderately higher with the 2 FDA-approved regimens – weekly EA 40,000 Units, and q3wk DA 500 mcg – than with the extended dosing regimens. This study was supported by a grant from Centocor Ortho Biotech, Inc. to the MCCRC. Disclosures: No relevant conflicts of interest to declare.
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Kudchadkar, Ragini Reiney, Geoffrey Thomas Gibney, Jeffrey Weber, Ann Chen, Kim Smith, and Stephanie Merek. "A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9079. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9079.
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9079 Background: Peginterferon alfa-2b (Sylatron) as adjuvant therapy has been shown to benefit patients with high-risk resected melanoma and some interferon studies have shown that the induction of autoantibodies may correlate with benefit. Ipilimumab (IPI, Yervoy) is a fully human anti-CTLA-4 antibody that induces autoimmune toxicity that in some cases appears to correlate with clinical benefit. This study was performed to assess whether ipilimumab can be safely administered with peginterferon alfa-2b. Methods: This study combined IPI at 3mg/kg every 3 weeks for 4 doses along with concurrent peginterferon alfa-2b at 3 mcg/kg weekly for up to 156 weeks or until disease progression, unacceptable toxicity or patient decision to discontinue. The study was designed to obtain toxicity, tolerability and autoimmune antibody data and to define a well-tolerated dose of the combination. Results: Median age was 61 with 9 female and 8 male subjects. There were 3 patients (pts) with partial responses, 1 stable disease, and 6 with progressive disease in 10 pts evaluable for response thus far. Six pts have not yet completed cycle 1 and therefore are not evaluable for response at the time of this publication but will be presented. One pt withdrew consent prior to finishing cycle 1. Toxicities from peginterferon alfa-2b 3mcg/kg were dose-limiting with 7 pts requiring dose reduction in peginterferon alfa-2b secondary to toxicity. The Grade 3 events leading to dose reductions were nausea and vomiting, leucopenia, dehydration, and hyponatremia. peginterferon alfa-2b was dose reduced to 2 mcg/kg weekly in future pts after these toxicities were noted. No Grade 3 or 4 toxicities attributable to ipilimumab have occurred thus far. No Grade 3 or 4 events have been noted to date in the10 pts initiated at 2 mcg/kg of peginterferon alfa-2b. There was no significant change in the presence autoantibodies (ANA, anti-double stranded DNA, antithyroglobulin, antimicrosomal antibodies, and anticardiolipin antibodies) between responders and non-responders in the evaluable pts. Conclusions: Peginterferon alfa-2b added to IPI results in an excellent response rate in this small population. Peginterferon alpha-2b at 2 mcg/kg weekly with IPI at 3 mg/kg every 3 weeks appears well-tolerated and the combination warrants further exploration. Clinical trial information: NCT01496807.
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Zimran, Ari, Gheona Altarescu, Mici Philips, Drorit Attias, Marina Jmoudiak, Maher Deeb, Nan Wang, Kiran Bhirangi, Gabriel M. Cohn, and Deborah Elstein. "Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience." Blood 115, no. 23 (June 10, 2010): 4651–56. http://dx.doi.org/10.1182/blood-2010-02-268649.
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Abstract Enzyme replacement therapy is the standard of care for symptomatic Gaucher disease. Velaglucerase alfa is a human β-glucocerebrosidase produced in a well-characterized human cell line. A 9-month phase 1/2 open-label, single-center trial and ongoing extension study were conducted to evaluate safety and efficacy of velaglucerase alfa. Twelve symptomatic adult type 1 Gaucher patients (intact spleens) received velaglucerase alfa (60 U/kg per infusion) during phase 1/2. An extension study was offered to patients completing the trial; step-wise dose reduction (to 30 U/kg per infusion) was instituted. Eleven patients completed phase 1/2; 10 entered the extension; 9 patients reached 39 months of extension. No drug-related serious adverse events or withdrawals, and no antibodies were observed. Home therapy was successfully implemented during the extension. Statistically significant improvements (P < .004) were noted in mean percentage change from baseline to 9 months and baseline to 48 months for hemoglobin (+19.2%, +21.7%, respectively), platelet counts (+67.6%, +157.8%, respectively), normalized liver volume (−18.2%, −42.8%, respectively), and normalized spleen volume (−49.5%, −79.3%, respectively). These significant clinical changes and safety profile led to phase 3 trials and highlight the potential of velaglucerase alfa as alternative therapy for type 1 Gaucher disease. The extension trial is registered at http://www.clinicaltrials.gov as NCT00391625.
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Zorenko, Vladimir Yu, Georgy Mishin, Tatiana Severova, Alexandr Shuster, Dmitry Kudlay, Sergey Lukyanov, Anton Borozinets, Eugene Nikitin, and Ekaterina Klykova. "The Pharmacokinetic Properties, Safety and Tolerability of a New Nonacog Alfa (Innonafactor) in Patients with Hemophilia B." Blood 126, no. 23 (December 3, 2015): 4691. http://dx.doi.org/10.1182/blood.v126.23.4691.4691.
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Abstract Nonacog alfa is a recombinant factor IX (rFIX) product for hemophilia B, developed by CJSC «GENERIUM» (Russia). Nonacog alfa is safe with regard to transmitted infections because proteins of animal and human origin (including albumin) are not used in the process of rFIX production. Ðharmacokinetic parameters, safety and efficacy of Innonafactor has been studied in the phase I study in patients with severe and moderate hemophilia B. The primary aims of the study were to: 1. Determine the pharmacokinetic parameters of nonacog alfa in patients with severe and moderate hemophilia B. 2. Assess the safety and tolerability of different doses of nonacog alfa in patients with severe and moderate hemophilia B. The secondary aims of this study were to: 1. Set the maximum tolerated dose of nonacog alfa in practically possible range of doses. 2. Evaluate rFIX activity and the activated partial thromboplastin time (APTT) after nonacog alfa infusions in doses 50 IU kg-1 and 75 IU kg-1. During phase I clinical study the pharmacokinetic properties, safety and tolerability of the new nonacog alpha were evaluated. After screening and washout period lasting at least 4 days 12 men, aged from 23 to 50 years old with severe (n = 6) and moderate (n = 6) hemophilia B were included in the study. Patients consecutively were enrolled in 3 groups: in the 1st group (n = 3) nonacog alfa was injected slowly intravenously in a single dose of 25 IU kg-1, in the 2nd group (n = 6) - a single dose of 50 IU kg-1, then after 4 days of observation and laboratory monitoring - a second single dose of 75 IU kg-1 was administered, in the 3rd group (n = 3) - a single dose of 100 IU kg-1 (fig.1). The introduction of the nonacog alfa in doses of 50 and 75 IU kg-1 resulted in the normalization of FIX activity and activated partial thromboplastin time (APTT) within 15 min after injection. Normal FIX activity was maintained for at least 1 h after injection of the nonacog alfa at dose of 50 IU kg-1 and for 6 h after drug administration at a dose of 75 IU kg-1. Reduction of the FIX activity less than 5% was observed not earlier than 72 h after injection of the both drug doses. Significant increase of the APTT was observed only after 12 h after injection of the nonacog alfa at a dose of 50 IU kg-1 and after 24 h after administration of the nonacog alfa at a dose of 75 IU kg-1. The pharmacokinetics of nonacog alfa was studied at doses of 50 and 75 IU kg-1 (fig.1). A single dose injection of nonacog alfa led to a rapid accumulation of drug in the blood [median value of time to reach the maximum concentration (Cmax) - Tmax amounted to 0.33 ± 0,13 h] with the achievement of the average Cmax depending on the input dose (53,18 ± 9,79 IU DL-1 for doses of 50 IU kg-1 and 94,35 ± 18,47 IU DL-1 for doses of 75 IU kg-1) and the gradual elimination of the drug from the body [median value of area under the curve based on the concentration of FIX in plasma from the time of the study (AUC0-96 h) - 1069,9 ± 321,1 IU DL-1 × h for doses of 50 IU kg-1 and 1604,2 ± 389,41 IU DL-1 × h for the dose of 75 IU kg-1, the AUC0-∞ - 1125,49 ± to 300.36 and 1700,82 ± 369,95 IU DL-1 × h, the elimination half-life (T1/2) - is 24.05 ± 7,67 and 25,18 ± 6,16 h, respectively]. Nonacog alfa was well tolerated regardless of the administered dose. The maximum tolerated dose was not established because it exceeds the studied doses of the drug. A single application of the nonacog alfa in doses from 25 to 100 IU kg-1 was not accompanied by toxic, thrombogenic, immunogenic and allergic reactions. Figure 2. Average pharmacokinetic curve of the coagulation factor IX activity in the blood plasma during administration of two doses of the drug Figure 2. Average pharmacokinetic curve of the coagulation factor IX activity in the blood plasma during administration of two doses of the drug Disclosures No relevant conflicts of interest to declare.
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Hassan, M. A., and M. M. Sleem. "Phase II trial comparing darbepoetin alfa every 3-week versus weekly epoetin alfa for the treatment of chemotherapy-induced anemia." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e20724-e20724. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e20724.
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e20724 Background: Anemia is common in patients receiving chemotherapy and may adversely affect health-related quality of life. Erthyrpiotic factors darbepoetin alfa (DA) and epoetin alfa (EA) are currently approved for the treatment of anemia in patients with nonmyeloid malignancies who receive chemotherapy. Methods: Forty patients with a diagnosis of nonmyeloid malignancy with 8 weeks of planned chemotherapy, age 18 years, and anemia (hemoglobin 10 g/dL). 20 patients received DA 500 μg every three weeks (Q3W) and the others 20 patients received EA 40,000 units every week (QW) for up to 18 weeks. Treatment was hold at week 6 for nonresponse, which was defined as failure to achieve a hemoglobin increment of at least 2 g/dL above the baseline measurement. Efficacy was assessed by the incidence of RBC transfusion. Results: Forty patients with a diagnosis of nonmyeloid malignancy, the median age was 49 years and 52 years for DA and EA groups respectively, The majority of patients had solid tumors: Common cancer types for (DA - EA) groups were gastrointestinal (8 -5), breast (3–6), lung (3–3), soft tissue sarcoma (2–1), genitourinary (2–1), non-Hodgkin's lymphoma (1–1), multiple myeloma (1–1), Hodgkin's lymphoma (0–1), and metastatic with unknown primary in (1–0) respectively . 75% 0f the patients in both group achieved the target hemoglobin level. Transfusion incidence from week 6 to the end of the treatment phase (the primary end point) was required in 5 patients (25%) in both groups. The side effects reported in this study were thromboembolic in two patients in both groups 10%. Nausea, diarrhea and neutropnia were 25%, 15% and 10% for DA group respectively compare to 20%, 10%, and 15% in AE group respectively. Conclusions: This study demonstrates comparable efficacy and safety of DA 500 μg every three weeks (Q3W) and EA40, 000 units every week (QW). No significant financial relationships to disclose.
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Loaiza-Bonilla, Arturo, Andrew Artz, Francis Salerno, Sean X. Leng, Shing-Shing Yeh, Rex Biedenbender, Stefan Gravenstein, Jose Loera, Zeba Shaheen Geloo, and William B. Ershler. "Correction of Anemia in the Frail Elderly (CAFÉ): Results of a Randomized, Double-Blind, Placebo-Controlled Study with Darbepoetin Alfa in Elderly Patients with Chronic Unexplained Anemia." Blood 120, no. 21 (November 16, 2012): 5153. http://dx.doi.org/10.1182/blood.v120.21.5153.5153.
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Abstract Abstract 5153 Objectives: To evaluate the effect of darbepoetin alfa treatment on hemoglobin (Hb) levels in frail, community dwelling elderly patients with chronic unexplained anemia and its correlation with the presence of comorbidities, serum baseline erythropoietin concentrations and renal function. Design: A 24 weeks, prospective, randomized (1:1), double-blind, placebo-controlled clinical trial. Participants: Eighty community-dwelling, consenting pre-frail or frail (Hopkins Frailty Index score 1 to 3) patients 70 years or older with chronic anemia (Hb <11. 5 g/dL). Intervention: Subcutaneous darbepoetin alfa or placebo weekly for 24 weeks with a 22 week open-label extension. Initial dose 60 μg every other week (bi-weekly). Measurements: Hemoglobin, Erythropoietin serum levels, estimated glomerular filtration rate, Charlson Comorbidity Index and Age Adjusted Comorbidity Index scores. Results: 80 subjects were enrolled, and complete data was analyzed. Of those enrolled, most were White (86. 25%) and male (58. 75%) and had a low comorbidity score, and a mean age ± standard deviation 81. 34 ± 6. 34. Mean baseline Hb was 10. 93 ± 0. 57 g/dL (9. 1–11. 9). Erythropoietin baseline levels (mU/mL) for placebo arm were 21. 4 ± 15 and 17. 6 ± 12. 4 for treatment arm. Estimated Glomerular filtration rates at baseline, mL/min per 1. 73m2 were 58. 7 ± 22. 4 and 50. 5 ± 17. 7 for placebo and treatment arms, respectively. During the observation period, there was a significantly greater hematopoietic response (mean 1. 13 ± 0. 59 g/dL) in the participants treated with darbepoetin alfa than in those receiving placebo (0. 3 ± 0. 18 g/dL). All participants (100%) responded to darbepoetin alfa treatment by week 8, attaining the target Hb level of 12 g/dL and maintaining those levels throughout the observation period. The average bi-weekly dose of darbepoetin alfa required to achieve the hemoglobin goal of 12 g/dL by week 8 was 63. 1 ± 3. 5 μg. After the eight week, 77% required less than 40. 46 ± 5. 4/week, and 23 patients (58. 9%) were maintained on weekly average dosages of less than 35 μg/week. The mean bi-weekly dose of darbepoetin alfa during the 24-week observation period was 74. 7 ± 12. 4 μg subcutaneously. The calculated average weekly dose of darbepoetin alfa needed to increase the hemoglobin levels by 1 g/dL was 40. 63μg/Hb/wk. Among the participants receiving placebo, only 3 out of 41 (7. 31%) patients had levels of Hb 12 g/dL or greater at end of the study (week 24) (P 0. 00006). This response was maintained and more significant among patients with lower age-adjusted comorbidity scores (<9) irrespective of gender, renal function and baseline erythropoietin levels. No significant differences were found between treatment and placebo on high comorbidity scores (≥9). Darbepoetin alfa was well tolerated and no major adverse events were reported in this group of patients with Hb target level of 12 g/dL. Conclusion: In this trial involving predominantly older white community dwelling patients with anemia, a direct relationship existed between increases in Hb during darbepoetin alfa therapy, this finding being more evident in the groups with lower age-adjusted comorbidity scores. Relatively lower dosages of darbepoetin alfa were required to attain a durable Hb response, with a good safety profile. Disclosures: Off Label Use: To evaluate the effect of darbepoetin alfa treatment on hemoglobin (Hb) levels in frail, community dwelling elderly patients with chronic unexplained anemia and its correlation with the presence of comorbidities, serum baseline erythropoietin concentrations and renal function.
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Fishbane, Steven, Carol A. Pollock, Mohamed El-Shahawy, Elizabeth T. Escudero, Anjay Rastogi, Bui Pham Van, Lars Frison, et al. "Roxadustat Versus Epoetin Alfa for Treating Anemia in Patients with Chronic Kidney Disease on Dialysis: Results from the Randomized Phase 3 ROCKIES Study." Journal of the American Society of Nephrology 33, no. 4 (March 31, 2022): 850–66. http://dx.doi.org/10.1681/asn.2020111638.
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BackgroundConcerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis by increasing endogenous erythropoietin and iron availability.MethodsIn this open-label phase 3 study, patients with DD-CKD and anemia were randomized 1:1 to oral roxadustat three times weekly or parenteral epoetin alfa per local clinic practice. Initial roxadustat dose depended on erythropoiesis-stimulating agent dose at screening for patients already on them and was weight-based for those not on them. The primary efficacy end point was mean hemoglobin change from baseline averaged over weeks 28‒52 for roxadustat versus epoetin alfa, regardless of rescue therapy use, tested for noninferiority (margin, −0.75 g/dl). Adverse events (AEs) were assessed.ResultsAmong 2133 patients randomized (n=1068 roxadustat, n=1065 epoetin alfa), mean age was 54.0 years, and 89.1% and 10.8% were on hemodialysis and peritoneal dialysis, respectively. Mean (95% confidence interval) hemoglobin change from baseline was 0.77 (0.69 to 0.85) g/dl with roxadustat and 0.68 (0.60 to 0.76) g/dl with epoetin alfa, demonstrating noninferiority (least squares mean difference [95% CI], 0.09 [0.01 to 0.18]; P<0.001). The proportion of patients experiencing ≥1 AE and ≥1 serious AE was 85.0% and 57.6% with roxadustat and 84.5% and 57.5% with epoetin alfa, respectively.ConclusionsRoxadustat effectively increased hemoglobin in patients with DD-CKD, with an AE profile comparable to epoetin alfa.Clinical Trial registry name and registration number:Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis. ClinicalTrials.gov Identifier: NCT02174731.
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Beguin, Yves, Johan Maertens, Bernard De Prijck, Rik Schots, Pascale Frere, Christophe Bonnet, Kaoutar Hafraoui, et al. "Darbepoetin-Alfa and I.V. Iron Administration after Autologous Hematopoietic Stem Cell Transplantation: A Prospective Randomized Multicenter Trial." Blood 112, no. 11 (November 16, 2008): 54. http://dx.doi.org/10.1182/blood.v112.11.54.54.
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Abstract Background : We previously reported a retrospective study suggesting that erythropoietin therapy starting on day 28 after autologous HCT was highly effective to improve Hb levels and that i.v. iron might improve response in patients with low transferrin saturation (Baron et al., Clin Cancer Res 2003). This prompted us to conduct a multicenter prospective randomized study analyzing the impact of darbepoetin alfa with or without i.v. iron on erythroid recovery after autologous HCT. Patients and Methods : 127 autologous HCT recipients with lymphoid malignancies were randomized 1:2:2 between no treatment (group 1, n=25), darbepoetin alfa (Aranesp®) 300 μg QOW starting on day 28 after HCT for a total of 7 doses (group 2, n=52), or the same regimen of darbepoetin alfa plus i.v. iron sucrose (Venofer®) 200 mg on days 28, 42 and 56 after HCT (group 3, n=50). Once the target Hb (13 g/dL) was attained, the dose of darbepoetin alfa was reduced to 150 μg, while it was withheld when Hb was ≥ 14 g/dL. Primary endpoints included proportion of complete correctors (i.e. patients reaching Hb □ 13 g/dL) before day 126 post-transplant and median time to achieve Hb correction in each arm. Data were analyzed following the intention-to-treat principle. The proportion of complete correctors by day 126 in each group was compared using the Fisher’s exact test, and median times to reach 13 g/dL in each group were compared using the logrank test. Results : The proportion of complete correctors was 24% in group 1, 81% in group 2 (P<0.001 compared with group 1), and 92% in group 3 (P<0.001 compared to group 1, and P=0.099 compared to group 2). Median time to achieve Hb □ 13 g/dL was not reached in group 1, 42 days in group 2 (P<0.001 compared to group 1), and 32 days in group 3 (P<0.001 compared to group 1 and P=0.127 compared to group 2) (Fig 1A). Hb evolution in each group is shown in Fig 1B. Mean ± standard deviation total doses of darbepoetin-alfa administered were 1,445 ± 489 μg in group 2 vs 1,272 ± 443 μg in group 3 (P=0.06). Ferritin levels at the end of study were 477 ± 597, 393 ± 599 and 479 ± 488 in groups 1, 2 and 3, respectively (NS). Eight patients (2 in group 1, 4 in group 2, and 2 in group 3) required red blood cell transfusions on study, including 4 patients following early disease progression. There was no difference in rates of thrombo-embolic events or other complications among the groups. Quality-of-life data will be presented. Conclusions : This is the first prospective randomized trial demonstrating that darbepoetin alfa is safe and highly effective to ensure full erythroid reconstitution after autologous HCT when started on day 28 posttransplant. I.v. iron sucrose tended (not statistically significant) to further fasten erythroid recovery with a lower dose of darbepoetin alfa required. Future studies in this setting should aim at further investigating the impact i.v. iron might have on improving response in patients with low transferrin saturation. Figure 1. Figure 1.
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Fokina, D. S., O. V. Zhukova, A. L. Khokhlov, D. A. Kudlay, A. Yu Borozinets, and F. G. Pilyus. "The clinical use and cost-effectiveness of domestic blood coagulation factors VIII and IX." Pediatric Hematology/Oncology and Immunopathology 21, no. 1 (March 29, 2022): 72–82. http://dx.doi.org/10.24287/1726-1708-2022-21-1-72-82.
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According to the data from the Federal Center for Planning and Organization of Medicine Provision for Citizens of Ministry of Healthcare of Russia, as of 2021, a total of 11 151 people have been diagnosed with hemophilia, 35.9% of them being children. Here we aimed to analyze data on the use of domestic recombinant coagulation factors VIII and IX in real clinical practice and to evaluate their cost-effectiveness. For our analysis, we used data from an observational study and a comparative clinical study of moroctocog alfa (Octofactor) in patients with moderate and severe hemophilia A as well as data from a comparative clinical study of nonacog alfa (Innonafactor) in patients with moderate and severe hemophilia B. The observational study of moroctocog alfa (Octofactor) lasted 85 weeks (from 09 January 2016 to 01 September 2017) and included 30 Russian clinical centers with a total of 237 patients diagnosed with moderate or severe hemophilia A. All patients were male, aged between 19 and 78 years (the mean age was 35.2 ± 11.1 years). The comparative study of moroctocog alfa included 18 hemophilia patients receiving prophylactic treatment at 3 Russian clinical centers. The mean age in the study cohort was 38.2 ± 12.9 years. Similarly, the comparative study of nonacog alfa (Innonafactor) included 18 hemophilia patients receiving prophylactic treatment at 3 Russian clinical centers. The mean age in this study cohort was 34.1 ± 9.5 years. The clinical studies were approved by the Ethics Board of the Ministry of Healthcare of Russia. The observational study was approved by the Interuniversity Ethics Committee (Moscow) and local ethics committees. A health economic evaluation was conducted using the following methodologies: a cost-effectiveness analysis, a budget impact analysis, an opportunity cost analysis, and a sensitivity analysis. The main measure of moroctocog alfa (Octofactor) effectiveness was the frequency of spontaneous bleeding within 48–72 hours after the administration of a prophylactic drug. The frequency of bleeding episodes was reported to be 1.4 ± 2.9. The main measure of nonacog alfa (Innonafactor) effectiveness was the mean number of bleeding episodes in patients receiving prophylactic treatment. It was reported to be 0.22 ± 0.44 episodes. Our health economic evaluation showed that the cost-effectiveness ratio for moroctocog alfa (Octofactor) was 1.8 fold lower than that for the comparator (Octanate, a plasma-derived factor VIII product); the cost-effectiveness ratio for nonacog alfa (Innonafactor) was 2.1 fold lower than that for the comparator (Octanine F, a coagulation factor IX) meaning that domestic coagulation factor products allow patients to achieve better treatment results (i.e. fewer bleeding episodes) at lower cost. The budget impact and opportunity cost analyses in two model groups of patients (n = 100 each) revealed that the use of moroctocog alfa (Octofactor) would enable us to treat 36 more patients, while the use of nonacog alfa (Innonafactor) would allow 3 more patients to receive care. The sensitivity analysis showed that switching 50% of patients from the foreign comparator to moroctocog alfa (Octofactor) would save 5.32% of the budget, while switching 50% of patients from the foreign comparator (Octanine F) to nonacog alfa (Innonafactor) would save 0.98% of the budget meaning that more patients could receive treatment. It was also demonstrated that changes in the proportion of patients receiving Octofactor and Octanate within the range of ± 50% would result in cumulative costs ranging from ₽12 994 million to ₽15 233 million that correspond to a budget surplus of 5.32% and a budget deficit of 10.99%, respectively. Similarly, treatment costs for Innonafactor and Octanine F would vary from ₽2 473 million to ₽2 516 million that correspond to a budget surplus of 0.98% and a budget deficit of 0.74%, respectively.
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Cho, Seok-Goo, Sung-Won Kim, Kyung-Sin Park, Ji-Hyang Lim, Chang-Ki Min, Yong-Goo Kim, Jong-Wook Lee, and Woo-Sung Min. "Pilot Study of Peginterferon Alfa-2a (PEGASYS®) Concurrent Administration during Induction Chemoradiotherapy and Maintenance Therapy in Patients with EBV-Associated Extranodal NK/T Cell Lymphoma." Blood 112, no. 11 (November 16, 2008): 5005. http://dx.doi.org/10.1182/blood.v112.11.5005.5005.
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Abstract Extranodal NK/T-cell lymphoma, nasal type is common in Asians rather than in Western populations. This special subtype responds poorly to intensive chemotherapy regimens or has a significant relapse rate in spite of low IPI and loco-regional staging. The presence of the EBV genome within tumor cells raised the possibility of developing therapeutic strategies directed at viral targets. The primary objectives of this prospective, single center, nonrandomized phase II trial are the evaluation of efficacy by determination of progression-free survival after concurrent administration of peginterferon alfa-2a (PEGASYS®, provided by Roche Korea) and chemoradiotherapy in patients with extranodal NK/T cell lymphoma. In addition, we evaluated the efficacy of peginterferon alfa-2a maintenance therapy for 3 years. All seven patients with newly diagnosed CD56+ EBV+ extranodal NK/T-cell lymphoma were enrolled onto a prospective clinical trial. Step 1; PEGASYS® 180 mcg was administered once weekly on D1, D8 of ProMACE-CytaBOM. 1, 2 cycles. Step 2; PEGASYS® 180 mcg will be administered once weekly on D1, D8, D15, D22 of involved-filed irradiation 3600 cGy (180 cGy × 20, for 4 weeks). Step 3; PEGASYS® 180 mcg will be administered once weekly on D1, D8 of ProMACE-CytaBOM. 3, 4 cycles. Step 4; PEGASYS® 180 mcg will be administered every two weeks after hematologic recovery of high-dose therapy and autologous PBSCT for 3 years. In case of advanced stage and non-nasal lesion, Step 2 was omitted and ProMACE-CytaBOM was extended to 6 cycles. EBV DNA copy based on real-time PCR was monitored. Of all 7 patients, 6 patients achieved complete response and 1 patient was dead due to pneumonia during chemotherapy. With a median follow-up of 26 months (3–36 months), the 3-year PFS were 67%. Of 6 assessable patients, five patients extended to peginterferon alfa-2a maintenance therapy and four patients showed PFS. Among two relapsed patients, one patient refused a peginterferon alfa-2a maintenance therapy and eventually relapsed 3 months later. Titer of EBV DNA copy in whole blood was significantly decreased compared with the titer on initial diagnosis. The main toxicities of peginterferon alfa-2a were mild flu-like symptoms. This pilot study suggests that larger prospective randomized studies are needed to define the role of peginterferon alfa-2a concurrent administration during induction therapy and maintenance therapy in EBV-associated extranodal NK/T-cell lymphoma.
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Campos, Susana M., Mei Sheng Duh, Patrick Lefebvre, and James Rosberg. "Benefits Associated with an Early Hemoglobin Response to Epoetin Alfa Therapy in the Treatment of Chemotherapy-Related Anemia." Journal of the National Comprehensive Cancer Network 3, no. 6 (November 2005): 807–16. http://dx.doi.org/10.6004/jnccn.2005.0049.
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Although previous studies have recognized that timely correction of anemia is desirable, no published research quantifies the association between the timeliness of the hemoglobin rise and patients' outcomes. This study evaluates whether anemic patients with cancer who are receiving chemotherapy and who experienced an early response to epoetin alfa (≥ 1 g/dL hemoglobin increase at the end of 4 weeks of treatment) experienced better clinical and drug utilization outcomes compared with patients who did not experience an early response. Three large, open-label, community studies of epoetin alfa for the treatment of chemotherapy-related anemia were retrospectively analyzed to assess the association of early hemoglobin response to subsequent transfusion requirements, subsequent hemoglobin response, quality of life, and epoetin alfa dosage administered over the study. Two epoetin alfa dosing regimens were evaluated: 10,000 units 3 times weekly with potential escalation to 20,000 units, and 40,000 units once weekly with potential escalation to 60,000 units. In all studies, patients who experienced an early hemoglobin response had statistically lower subsequent transfusion requirements, higher rates of subsequent hemoglobin response, shorter time to hemoglobin response, better improvements in quality of life scores, and lower average weekly epoetin alfa dose than patients who did not experience an early hemoglobin response. Similar proportions of patients experienced early response in the 3-times weekly and once-weekly epoetin alfa regimens. This ad hoc analysis found that early hemoglobin response to epoetin alfa therapy was associated with improved clinical benefits and drug utilization. Early hemoglobin response may therefore be considered as a desired goal of epoetin alfa therapies.
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Cho, Byoung Chul, Amaury Daste, Alain Ravaud, Sébastien Salas, Nicolas Isambert, Edward Francis McClay, Ahmad Awada, et al. "Long-term follow-up of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck (SCCHN)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 6020. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.6020.
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6020 Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. A previous report of an expansion cohort from a phase 1 study (NCT02517398) suggested that bintrafusp alfa had a manageable safety profile and early signs of clinical activity in patients with heavily pretreated, advanced SCCHN after a median follow-up of 86.4 weeks. Here we report long-term efficacy and safety for this cohort. Methods: Patients with advanced SCCHN that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or < 6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg every 2 weeks until confirmed progressive disease, unacceptable toxicity, or trial withdrawal. The primary endpoint was confirmed best overall response assessed per RECIST 1.1 assessed by independent review committee (IRC); safety was a secondary endpoint. Results: As of May 15, 2020, 32 patients had received bintrafusp alfa for a median of 2.8 months (range, 0.5-29.9 months), no patient remained on treatment, and median follow-up to data cutoff was 41.7 months (range, 39.8-43.5 months). The objective response rate (ORR; 13%) was unchanged since the previous report; median duration of response (DOR) was increased at 21.4 months (95% CI, 5.5 months to not reached [NR]). While the clinical activity of bintrafusp alfa may be improved in patients with HPV-positive tumors (Table), outcomes were generally similar between PD-L1 subgroups (≥1% vs < 1% tumor cells). The overall safety profile was consistent with the previous report for this cohort, without grade 4 nor 5 treatment-related adverse events (TRAEs); no new TRAEs of grade 3 or that led to discontinuation of bintrafusp alfa were reported. Conclusions: With a median follow-up of over 3 years in patients with heavily pretreated advanced SCCHN, bintrafusp alfa showed sustained clinical activity and 3-year OS of 24.0%, which compares favorably to historical data. Clinical activity appeared to be greater in patients with HPV-positive tumors than those with HPV-negative tumors. The safety profile was manageable and consistent with earlier analysis. Further investigation of bintrafusp alfa in SCCHN and other HPV-associated cancers is ongoing. Clinical trial information: NCT02517398. [Table: see text]
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Prado, Gilmar Fernandes do, Luciane Bizari Coin de Carvalho, Ademir Baptista da Silva, and José Geraldo de Camargo Lima. "Classificação das Alterações Eletroencefalográficas na Aids." Revista Neurociências 2, no. 3 (October 31, 1999): 99–103. http://dx.doi.org/10.4181/rnc.1994.03.993.5p.
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Os autores fazem um estudo das alterações eletroencefalograficas da AIDS (Acquired Immunodeficiency Syndrome), classificando-as segundo o ritmo de base e a presença ou não de atividades paroxisticas. Foram estudados 73 pacientes HIV (Human Immunodeficiency virus) positivos (4), com ou sem complicações secundarias, sendo que um pertencia ao grupo II do CDC (Center for Disease Control), quatro ao grupo Ill e 68 ao grupo IV. Classificamos as alterações EEG (Eletroencef alograma) encontradas conforme se segue: Grau .0 (presença de ritmo de base constituido por alfa posterior maior que 9Hz), Grau Oa (grau 0 com assimetria da atividade elétrica cerebral - AAEC), Grau 1 (ritmo alfa 8-9Hz; ou ritmo alfa maior que 9Hz, porém com EEG anterior evidenciando alfa pelo menos 1Hz acima da freqüência atual; ou ritmo de base - alfa posterior - maior que 9Hz associado a ondas teta difíceis de serem distinguidas daquelas relacionadas á sonolência), Grau la (grau 1 com AAEC), Grau 2 ( ritmo de base alfa associado a breves surtos de teta e ou delta difusos de predomínio anterior não relacionados a sonolência; ou presença de ondas teta mescladas ao alfa; ou ritmo de base beta com EEG de baixa voltagem), Grau 2a (grau 2 com AAEC), Grau 3 (ritmo de base teta associado ou não a breves surtos de delta (predomínio anterior); ou ritmo de base beta com EEG de baixa voltagem associado a ritmos lentos (teta e delta não relacionados a sonolência), Grau 3a (grau 3 com AAEC), Grau 4 (ritmo de base delta), Grau 4a (grau 4 com AAEC). Grau 5 (ritmo de base delta associado a breves períodos de supressão da atividade elétrica cerebral - AEC), Grau 5a (grau 5 com AAEC), Grau 6 (supressão da AEC associado a breves surtos de delta), Grau 6a (grau 6 com AAEC), Grau 7 (EEG isoelétrico).
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Thompson, John A., D. Gary Gilliland, Josef T. Prchal, John M. Bennett, Kay Larholt, Richard A. Nelson, Esther H. Rose, and Margaret H. Dugan. "Effect of recombinant human erythropoietin combined with granulocyte/ macrophage colony-stimulating factor in the treatment of patients with myelodysplastic syndrome." Blood 95, no. 4 (February 15, 2000): 1175–79. http://dx.doi.org/10.1182/blood.v95.4.1175.004k51_1175_1179.
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This randomized, placebo-controlled trial was designed to assess the efficacy and safety of therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (epoetin alfa) in anemic, neutropenic patients with myelodysplastic syndrome. Sixty-six patients were enrolled according to the following French–American–British classification: refractory anemia (20), refractory anemia with excess blasts (35), refractory anemia with ringed sideroblasts (9), and refractory anemia with excess blasts in transformation (2). Patients were stratified by their serum erythropoietin levels (less than or equal to 500 mU/mL, n = 37; greater than 500 mU/mL, n = 29) and randomized, in a 2:1 ratio, to either GM-CSF (0.3-5.0 μg/kg·d) + epoetin alfa (150 IU/kg 3 times/wk) or GM-CSF (0.3-5.0 μg/kg·d) + placebo (3 times/wk). The mean neutrophil count rose from 948 to 3831 during treatment with GM-CSF ± epoetin alfa. Hemoglobin response (increase greater than or equal to 2 g/dL, unrelated to transfusion) occurred in 4 of 45 (9%) patients in the GM-CSF + epoetin alfa group compared with 1 of 21 (5%) patients with GM-CSF + placebo group (P = NS). Percentages of patients in the epoetin alfa and the placebo groups requiring transfusions of red blood cells were 60% and 92%, respectively, for the low-endogenous erythropoietin patients and 95% and 89% for the high-endogenous erythropoietin patients (P = NS). Similarly, the average numbers of units of red blood cells transfused during the 12-week study in the epoetin alfa and the placebo groups were 5.9 and 9.5, respectively, in the low-endogenous erythropoietin patients and 9.7 and 8.6 in the high-endogenous erythropoietin patients (P = NS). GM-CSF ± epoetin alfa had no effect on mean platelet count. Treatment was well tolerated in most patients, though 10 withdrew from the study for reasons related predominantly to GM-CSF toxicity.
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Toney, Nicole, Yo-Ting Tsai, Claire Rumfield, Samuel Pellom, Caroline Jochems, Julius Strauss, James Gulley, Jeffrey Schlom, and Renee Donahue. "375 Expansion of HPV-16 specific T cells in patients with HPV-related cancers treated with bintrafusp alfa." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A400. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0375.
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BackgroundThe safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking PD-L1, have been demonstrated in patients with human papillomavirus (HPV)-related cancers in an open label, multicenter phase 1 trial (NCT02517398), and an open-label, single center phase 2 trial (NCT03427411). The current study aimed to investigate whether HPV-16-specific T cells are expanded with therapy and associate with the clinical response of patients in these trials. We also present pre-clinical evidence from a mouse model of HPV-associated cancer supporting the combination of bintrafusp alfa with an HPV-16 targeted therapeutic vaccine and an immunostimulatory cytokine.MethodsPeripheral blood mononuclear cells (PBMC) were obtained from 33 patients prior to and 2 weeks after 1 and/or 3 cycles of bintrafusp alfa and evaluated for HPV-16 specific CD4+ and CD8+ T cells. PBMCs were stimulated with 15-mer peptide pools of the HPV-16 E6 and E7 oncoproteins, and T cell responses were assessed for the production of cytokines (TNFa, IFNg, IL-2) and positivity for the degranulation marker CD107a. Multifunctional T cells, positive for >2 measures, were also enumerated. For pre-clinical studies, a syngeneic mouse model of TC-1 carcinoma was treated with bintrafusp alfa alone or in combination with a liposomal-based HPV-16 therapeutic vaccine (PDS 0101) and a tumor targeting immunocytokine (NHS-muIL12) and evaluated for anti-tumor activity and immune responses.ResultsHPV-16 specific T cells were increased after 1 cycle of bintrafusp alfa in a greater proportion of responders (9/14) than non-responders (4/17) (p=0.03). In addition, the magnitude of HPV-16 specific T cells was greater after 1 (p=0.04) and 3 (p<0.0001) cycles of bintrafusp alfa in responders than non-responders. Multifunctional HPV-16-specific T cells were also increased to a greater extent in responders than non-responders. Preclinical studies demonstrated that the combination of bintrafusp alfa with an HPV-16-targeted therapeutic vaccine along with an immunocytokine resulted in maximal anti-tumor activity and T cell responses.ConclusionsAn early increase in HPV-16 specific T cells (after a single administration of bintrafusp alfa, prior to restaging) was associated with clinical activity in patients with HPV-related cancers undergoing bintrafusp alfa therapy. This evidence, and the pre-clinical finding of enhanced antitumor activity observed when combining bintrafusp alfa with an HPV-16 targeted vaccine and an immunostimulatory cytokine have provided the rational for an ongoing study evaluating this combination in patients with advanced HPV-associated malignancies (NCT04287868).Ethics ApprovalAll patients provided written informed consent for participation in a clinical trial that was approved by the Institutional Review Board at the National Cancer Institute (NCT02517398, NCT03427411)
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Rolfo, Christian, Laurent Greillier, Remi Veillon, Firas Badin, Francois Ghiringhelli, Nicolas Isambert, Astrid Paulus, et al. "465 Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety and pharmacokinetic results of the INTR@PID LUNG 024 study." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A494. http://dx.doi.org/10.1136/jitc-2021-sitc2021.465.
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BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ”trap”) fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site’s independent ethics committee.
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Vogl, Dan T., Jonathan L. Kaufman, Sarah A. Holstein, Shebli Atrash, Omar Nadeem, Murali Janakiram, Kaveri Suryanarayan, et al. "Modakafusp Alfa (TAK-573), an Immunocytokine, Shows Clinical Activity in Patients with Relapsed/Refractory Multiple Myeloma; Updated Results from a First-in-Human Phase 1 Study." Blood 138, Supplement 1 (November 5, 2021): 898. http://dx.doi.org/10.1182/blood-2021-148463.
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Abstract Background: Modakafusp alfa (previously known as TAK-573) is a first-in-class immunocytokine designed to deliver interferon alpha-2b (IFNα2b) to CD38+ cells. It consists of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody (mAb). The specificity for CD38 and reduced IFN receptor binding affinity of the attenuated IFNα2b molecules significantly reduces the potential for off-target binding and toxicity. Furthermore, modakafusp alfa binds to a different epitope on CD38 than the currently approved anti-CD38 therapeutic mAbs, daratumumab and isatuximab. Preclinical evaluation of modakafusp alfa supports activation of type I IFN signaling in CD38+ cells, inducing direct anti-proliferative effects on myeloma cells, as well as direct and indirect immune cell activation. We have previously reported preliminary results from the first 59 patients (pts) in our first-in-human phase 1 trial of modakafusp alfa in pts with relapsed/refractory multiple myeloma (RRMM; NCT03215030), showing responses to single-agent therapy with doses starting at 0.1 mg/kg weekly; thrombocytopenia and neutropenia were dose-limiting toxicities when modakafusp alfa was administered weekly (QW), every 2 weeks (Q2W), and every 3 weeks (Q3W) (Vogl, Blood 2020). Here we report updated results from this trial, focusing on results from an expansion cohort with dosing every 4 weeks (Q4W). Methods: Eligible pts with RRMM who had received at least three previous lines of treatment received modakafusp alfa as a 1- to 4-hour intravenous infusion at 11 dose levels from 0.001 to 6 mg/kg following a 3+3 dose-escalation design. The initial dosing schedule was QW for 8 doses, then Q2W for 8 doses, and then monthly; subsequent cohorts evaluated dosing Q2W, Q3W or Q4W. Expansion cohorts were planned using modakafusp alfa at protocol-defined, biologically active doses that did not exceed the maximum tolerated dose (MTD). Results: As of May 2021, 83 pts had been treated across all planned dosing schedules. With Q4W dosing, the MTD was exceeded at the 6 mg/kg dose due to DLTs: a grade 3 infusion reaction and prolonged thrombocytopenia and neutropenia, which delayed the start of cycle 2 by >14 days. In total, 24 pts were treated with 1.5 mg/kg modakafusp alfa Q4W (5 pts during dose escalation and 19 pts in an expansion cohort). Analyses include data from all 24 pts. The median number of prior lines of therapy received was 6 (range 4-16); 21 pts (88%) were refractory to an anti-CD38 mAb, and 20 (83%) were triple class-refractory (to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb). Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 18 pts (75%). The most frequent grade 3-4 TEAEs were neutropenia in 12 pts (50%; grade 4 in 6 [25%]), leukopenia in 9 (38%), decreased lymphocyte count in 9 (38%), anemia in 8 (33%), and thrombocytopenia in 8 (33%; grade 4 in 3 [13%]). One pt (4%) had a grade 3 bleeding event and continues on study treatment; 3 pts (13%) had infections (grade 3 in 2 [8%]); and 8 (33%) had infusion reactions (grade 3 in 1 [4%]). The overall response rate (ORR, ≥partial response [PR]) was 42% (complete response [CR], n=2; very good partial response [VGPR], n=5; PR, n=3), and the clinical benefit rate (ORR + minimal response [MR]) was 54% (MR, n=3). Median progression-free survival was 5.7 months (95% confidence interval [CI], 1.9-not reached [NR]), median time to response was 1.9 months (95% CI, 0.95-NR), and median duration of response was 7.4 months (95% CI, 2.3-NR). Among the 21 anti-CD38 mAb-refractory pts, the ORR was 43%, while among the 4 pts who received an anti-CD38 mAb in their most recent line of therapy prior to enrollment, the ORR was 75% (CR, n=1; VGPR, n=2). Correlative studies show evidence of T-cell and natural killer-cell activation, as well as activation of IFN signaling in CD38+ cells, including upregulation of CD38 expression. Conclusion: Modakafusp alfa (TAK-573) is a novel candidate for the treatment of RRMM, which has shown promising anti-myeloma activity in heavily pretreated pts, including anti-CD38 mAb-refractory pts and those who have received an anti-CD38 mAb in their most recent line of treatment. A Q4W dosing schedule of modakafusp alfa is feasible and the optimal dose and potential combinations are being explored. Disclosures Vogl: Takeda: Consultancy, Research Funding; Karyopharm: Consultancy; GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; CSL Behring: Consultancy; Active Biotech: Research Funding. Kaufman: Genentech, AbbVie, Janssen: Consultancy, Research Funding; Amgen: Research Funding; Janssen: Honoraria; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Fortis Therapeutics: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Sutro, Takeda: Research Funding; Tecnofarma SAS, AbbVie: Honoraria; BMS: Consultancy, Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding. Holstein: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Atrash: AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau; GSK: Research Funding. Nadeem: Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Janakiram: Kyowa Kirin Therapeutics: Honoraria; Takeda Pharmaceuticals: Research Funding; FATE Therapeutics: Research Funding; ADC Therapeutics: Research Funding. Suryanarayan: Takeda: Current Employment. Liu: Takeda: Current Employment. Parot: Takeda Pharmaceuticals: Current Employment. OffLabel Disclosure: Modakafusp alfa (TAK-573) is a first-in-class immunocytokine consisting of 2 attenuated interferon alpha-2b molecules genetically fused to an anti-CD38, IgG4 monoclonal antibody. This abstract contains information about investigational use of modakafusp alfa in patients with relapsed/refractory multiple myeloma. Safety and efficacy have not been determined.
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Widiyastuti, Novi, Aan Juhana Senjaya, and Wiwit Damayanti Lestari. "PERBEDAAN KEMAMPUAN KONEKSI MATEMATIS PADA MATERI SEGITIGA BERDASARKAN JENIS APERSEPSI ALFA ZONE DAN MATHEMATICAL HABITS OF MIND LEVEL PADA MODEL PEMBELAJARAN KOOPERATIF TIPE STAD." M A T H L I N E : Jurnal Matematika dan Pendidikan Matematika 4, no. 1 (February 20, 2019): 41–48. http://dx.doi.org/10.31943/mathline.v4i1.106.
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Tujuan penelitian ini untuk mengetahui perbedaan kemampuan koneksi matematis pada materi segitiga berdasarkan jenis apersepsi Alfa Zone, Mathematical Habits of Mind Level dan interaksi antara jenis apersepsi Alfa Zone dan Mathematical Habits of Mind Level pada model pembelajaran kooperatif tipe STAD. Penelitian ini adalah penelitian eksperimen dengan populasi kemampuan koneksi matematis seluruh siswa kelas VII SMP Negeri 3 Jatibarang tahun pelajaran 2017/2018. Sampel kelas diambil sebanyak dua kelas dengan menggunakan teknik cluster random samppling dengan cara diundi. Penelitian ini menggunakan analisis data ANAVA 2x2 by Level. Berdasarkan analisis data, diperoleh kesimpulan sebagai berikut: (1) Terdapat perbedaan rata-rata kemampuan koneksi matematis pada materi segitiga berdasarkan pemberian jenis apersepsi Alfa Zone pada model pembelajaran kooperatif tipe STAD; (2) Tidak terdapat perbedaan rata-rata kemampuan koneksi matematis pada materi segitiga berdasarkan Mathematical Habits of Mind Level Zone pada model pembelajaran kooperatif tipe STAD; (3) Tidak terdapat perbedaan interaksi kemampuan koneksi matematis pada materi segitiga berdasarkan pemberian jenis apersepsi Alfa Zone dan Mathematical Habits of Mind Level Zone pada model pembelajaran kooperatif tipe STAD.
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ANGHINAH, RENATO, PAULO AFONSO DE MEDEIROS KANDA, MÁRIO SILVA JORGE, and ANTONIO CARLOS DE PAIVA MELO. "Eletrencefalograma quantitativo e topográfico (mapeamento cerebral): estudo do padrão normal para uma população adulta." Arquivos de Neuro-Psiquiatria 56, no. 1 (March 1998): 59–63. http://dx.doi.org/10.1590/s0004-282x1998000100009.
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Realizamos estudo com o intuito de normatizar a atividade elétrica cerebral de base de indivíduos adultos e normais, com EEG quantitativo e topográfico. Foram avaliados 20 pacientes que apresentaram exames clínico, laboratoriais e de análise visual do EEG normais, além do mini-exame do estado mental com escores superiores a 27 pontos. Após a aplicação da transformada rápida de Fourier (FFT) encontramos distribuição do espectro com padrão monomodal no histograma de barras às custas de maiores potenciais em regiões posteriores na faixa de frequência alfa. Ao analisarmos a média dos espectros nas diferentes bandas de frequência (delta, teta, alfa, beta 1, beta 2, beta 3) encontramos alguns padrões que diferem dos achados tradicionalmente descritos na eletrencefalografia com análise visual, tais como a presença de atividade alfa em regiões anteriores e atividade delta difusa durante a vigília. Os comportamentos das bandas beta 2, e beta 3, também com distribuição difusa, não são os classicamente encontrados. Por outro lado, outros achados são congruentes à análise visual, como o predomínio alfa posterior e a maior presença de atividade teta em regiões centrais.
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Cole, Christopher Browning, and Christina M. Annunziata. "First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant or refractory ovarian cancer." Journal of Clinical Oncology 38, no. 5_suppl (February 10, 2020): 1. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.1.
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1 Background: This phase I study evaluated the safety and tolerability of autologous intraperitoneal monocytes treated with SYLATRON (Peginterferon alfa-2b) and ACTIMMUNE (Interferon gamma-1b). Methods: For the dose escalation portion, 3-6 patients with platinum-resistant or refractory ovarian cancer were enrolled into 4 cohorts and treated intraperitoneally (IP) with Peginterferon alfa-2b (25-250 mcg) and Interferon gamma-1b (5-50 mcg), with or without autologous monocytes (75-750 x 106 cells), in order to determine the recommended phase II dose (RP2D). A total of six patients were treated at the RP2D. Patients received the combination of interferons+/- monocytes via IP catheter once every 28 days. Results: 18 patients were enrolled (median age, 61 years; median 5 prior therapies). 1 of 3 patients at the second dose level experienced a dose-limiting toxicity (DLT, grade 3 anemia) and so this cohort was expanded to 6 patients; no subsequent DLTs were observed. The RP2D was defined as 250 mcg/50/mcg/750 x 106 cells on the basis of overall safety and tolerability. The only treatment–related grade 3 or higher adverse events occurring in more than one patient were lymphocyte decrease (33.3%) and abdominal pain (11.1%). Preliminary assessment of efficacy is ongoing. The best response observed has been partial response (PR) in 2/11 evaluable patients, with one patient having a 61% reduction in target lesion size. An additional 4/11 patients had stable disease, and 3 patients remained on treatment for >6 cycles. Exploratory biomarker analyses are ongoing to to further elucidate changes in the immune cell population and correlate with response. An expansion cohort of 10 patients at the RP2D is currently enrolling. Conclusions: This is the first-in-human study of the combination of IP peginterferon alfa-2b, interferon gamma-1b, and autologous monocytes, and the combination displays good tolerability and antitumor activity in a heavily pretreated population, supporting further investigation. Clinical trial information: NCT02948426.
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Andreeva, Tatiana, Vladimir Yu Zorenko, Igor Davydkin, Valeria Konstantinova, Olga Zalepukhina, Nina Klimova, Georgy Mishin, et al. "Safety and Efficacy of New Nonacog Alfa Drug (Innonafactor) in Prophylactic Treatment in Patients with Severe and Moderate Hemophilia B." Blood 126, no. 23 (December 3, 2015): 3532. http://dx.doi.org/10.1182/blood.v126.23.3532.3532.
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Abstract During a controlled, randomized, open, prospective, multicenter clinical trial the efficacy and safety of a new domestically produced recombinant factor IX (FIX, nonacog alfa, CJSC "GENERIUM", Russia) were investigated in comparison with plasma drug Octanine® F (filtered) ("Octapharma pharmazeutika produktionsges mbH", Austria) for the prophylactic treatment of bleedings in patients with severe and moderate hemophilia B. After screening and a 4-day washout period 18 patients with moderate (n=8) and severe (n=10) hemophilia B were divided into 2 groups according to randomization: the 1st group patients (n=9) received the nonacog alfa, the 2nd group (n=9) Octanine F (fig. 1). In the 1st group there were 4 patients with severe hemophilia B (activity of FIX was less than 1%) and 5 patients with the moderate form of the disease (activity of FIX was 1-3%). In the 2nd group 6 patients had severe and 3 moderate hemophilia B (activity of FIX was 1-2,6%). In order to prevent bleeding nonacog alfa was injected slowly intravenously at a dose of 50±5 IU kg-1. Octanine F was infused at a dose of 30±5 IU kg-1. Drugs were injected 2-3 times per a week during 26±1 weeks (6 months). The main criterion of drug efficacy was the average number of bleedings within 6 months of prophylactic treatment. Anticipated average number of bleedings was determined based on the effectiveness of the original drug Benefix® (Pfizer, USA) and was 9±3 cases. Additional criteria of efficacy were severity of bleeding, activated partial thromboplastin time (APTT) and FIX activity before and 30 min after drug administration compared with normal values. In the 1st group 2 moderate bleeding episodes occurred in 2 patients, while in the 2nd group 10 hemorrhagic episodes occurred in 4 patients (1 episode was severe, 1 - moderate, and 8 were low grade). There were no significant differences in frequency of bleeding events. The average number of bleedings during the analyzed period in patients of the 1st group was 0,22±0,44. In patients of the 2nd group it was 1,11±1,97; the differences were statistically insignificant (p=0,24). In patients of both groups, the average number of bleeding was within planned range (fig. 2). Pharmacokinetics was evaluated by K-value (incremental recovery) and in vivo recovery (IVR). After carrying out of prophylactic therapy during 6 months, Incremental recovery of nonacog alfa was 1,24 ± 0,32 IU/DL per IU/kg. The Incremental recovery (K-value) of Octanine F was analogous and amounted to 1,14 ±0,29 IU/DL per IU/kg. During 6 months IVR of nonacog alfa was 47,56 ±13,56% and the IVR of Octanine F was not different and amounted to 49,05 ±15,68%. Prophylactic therapy was accompanied by normalization of coagulation activity of blood. On the 26th week of therapy APTT values taken 30 minutes after drug administration were 38,04 ±3,63 sec. in 1st group and 41,49 ± 3,44 sec. in the 2nd group. Safety assessment was performed in 18 patients. There were 6 adverse events in the 1st group and 12 in the 2nd group. All adverse events were not associated with drugs administration. Thus, the study shows that nonacog alfa (Innonafactor) is effective in prophylaxis of bleeding in patients with severe and moderate hemophilia B. The results are comparable with the results of the use of Octanine F. The study demonstrated that nonacog alfa (Innonafactor) with its pharmacodynamic and pharmacokinetic characteristics is comparable to Octanine F. Administration of nonacog alfa (Innonafactor)to patients with severe and moderate hemophilia B was accompanied by normalization of APTT and FIX activity and rising activity of FIX and its degree of recovery. Treatment with nonacog alfa (Innonafactor) was safe and without side effects, infection transmission, de novo inhibitor incident. Disclosures No relevant conflicts of interest to declare.
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Faiss, Siegbert, Ulrich-Frank Pape, Michael Böhmig, Yvonne Dörffel, Ulrich Mansmann, Werner Golder, Ernst Otto Riecken, and Bertram Wiedenmann. "Prospective, Randomized, Multicenter Trial on the Antiproliferative Effect of Lanreotide, Interferon Alfa, and Their Combination for Therapy of Metastatic Neuroendocrine Gastroenteropancreatic Tumors—The International Lanreotide and Interferon Alfa Study Group." Journal of Clinical Oncology 21, no. 14 (July 15, 2003): 2689–96. http://dx.doi.org/10.1200/jco.2003.12.142.
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Purpose: Somatostatin analogs and interferon alfa control hormone-active/functional neuroendocrine gastroenteropancreatic tumors. In addition to hormonal control, variable degrees of antiproliferative effects for both agents have been reported. Until now, however, no prospective, randomized studies in therapy-naive patients have compared somatostatin analogs or interferon alfa alone with a combination of the two.Methods: Eighty therapy-naive patients with histologically verified neuroendocrine tumor disease (primary localization: foregut, n = 36; midgut, n = 30; hindgut, n = 3; unknown, n = 11; functional, n = 29; nonfunctional, n = 51) were randomly treated either with lanreotide (1 mg three times a day administered subcutaneously [SC]) or interferon alfa (5 × 106U three times a week SC) or both. All patients had disease progression in the 3 months before study entry, verified with imaging procedures.Results: Twenty-five patients were treated with lanreotide, 27 patients were treated with interferon alfa, and 28 patients were treated with the combination. Partial tumor remission was seen in four patients (one patient who received lanreotide, one patient who received interferon alfa, and two patients who received the combination). During the 12 months of therapy, stable disease was observed in 19 patients (seven patients who received lanreotide, seven patients who received interferon alfa, and five patients who received the combination), whereas tumor progression occurred in 14 of 25 patients (lanreotide), 15 of 27 patients (interferon alfa), and 14 of 28 patients (combination). Side effects leading to an interruption of therapy were more frequent in the combination group than in the monotherapy arms.Conclusion: This prospective, randomized, multicenter study shows for the first time that somatostatin analogs, interferon alfa, or the combination of the two had comparable antiproliferative effects in the treatment of metastatic neuroendocrine gastroenteropancreatic tumors. Response rates were lower compared with those published in previous, nonrandomized studies. The antiproliferative effect of the tested substances was similar for functional and nonfunctional neuroendocrine tumors.
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Blanco Blanco, I., H. Canto Argiz, and F. Carro del Camino. "Bronquiectasias en pacientes con déficit severo de alfa-1-antitripsina: ¿una asociación frecuente?" Archivos de Bronconeumología 30, no. 9 (November 1994): 473. http://dx.doi.org/10.1016/s0300-2896(15)31024-3.
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Tsai, Yo-Ting, Julius Strauss, Nicole J. Toney, Caroline Jochems, David J. Venzon, James L. Gulley, Jeffrey Schlom, and Renee N. Donahue. "Immune correlates of clinical parameters in patients with HPV-associated malignancies treated with bintrafusp alfa." Journal for ImmunoTherapy of Cancer 10, no. 4 (April 2022): e004601. http://dx.doi.org/10.1136/jitc-2022-004601.
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PurposeBintrafusp alfa is a bifunctional agent consisting of an anti-human PD-L1 antibody linked to two TGFβRII. It is designed to act both as a checkpoint inhibitor and to ‘trap’ TGFβ in the tumor microenvironment. Phase I and II clinical studies demonstrated clinical activity in patients with a range of human papillomavirus (HPV)-associated cancers. The purpose of the studies reported here was the interrogation of various aspects of the peripheral immunome in patients with HPV-associated cancers, both prior to and early in the treatment regimen of bintrafusp alfa to better understand the mode of action of the agent and to help define which patients are more likely to benefit from bintrafusp alfa treatment.Patients and methodsThe peripheral immunome of patients (n=65) with HPV+ malignancies was analyzed both prior to treatment with bintrafusp alfa and day 14 post-treatment for levels and changes in (1) 158 different immune cell subsets, (2) multiple plasma soluble factors including analytes reflecting immune stimulatory and inhibitory status, (3) complete blood counts, and in a subset of patients (4) TCR diversity and (5) HPV-specific T-cell responses.ResultsInterrogation of the peripheral immunome prior to bintrafusp alfa treatment revealed several factors that associated with clinical response, including (1) higher levels of sCD27:sCD40L ratios, (2) lower levels of TGFβ1 and 12 additional factors associated with tumor mesenchymalization, and (3) higher CD8+ T cell:MDSC ratios. Analysis at 2 weeks post bintrafusp alfa revealed that eventual clinical responders had fewer increases in IL-8 levels and the neutrophil to lymphocyte ratio, and higher levels of HPV-16 specific CD8+ T cells. This study also provided information concerning differences in the peripheral immunome for patients who were naïve versus refractory to prior checkpoint inhibition therapy. While preliminary, two multivariate models developed predicted clinical benefit with 76%–91% accuracy.ConclusionsThese studies add insight into the mechanism of action of bintrafusp alfa and provide evidence that the interrogation of both cellular and soluble components of the peripheral immunome of patients with HPV-associated malignancies, either prior to or early in the therapeutic regimen, can provide information as to which patients are more likely to benefit with bintrafusp alfa therapy.
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Johnson, Curtis A., Maureen Wakeen, Claude A. Taylor, Stephen W. Zimmerman, John Burkart, Abhik Bhattacharya, and Michael R. Kosorok. "Comparison of Intraperitoneal and Subcutaneous Epoetin Alfa in Peritoneal Dialysis Patients." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 19, no. 6 (November 1999): 578–82. http://dx.doi.org/10.1177/089686089901900613.
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Objective To compare the efficacy of intraperitoneal (IP) and subcutaneous (SC) administration of epoetin alfa in patients receiving peritoneal dialysis (PD). Design A 32-week prospective, randomized, cross-over experimental design. Setting Two university-based outpatient PD centers. Patients Twenty adult PD patients receiving stable doses of SC epoetin alfa enrolled in the study. Thirteen patients completed 32 weeks of follow-up. Intervention Patients were randomly assigned to receive either SC or IP epoetin alfa at the start of the study. Dose adjustments were made to maintain baseline hematocrit ± 3 percentage points. Following 16 weeks of treatment, patients crossed over to the other route of administration for an additional 16 weeks. Intraperitoneal epoetin alfa was administered into an empty peritoneal cavity for approximately 8 hours before resuming dialysis. End-of-study IP epoetin alfa doses required to maintain target hematocrit were given twice weekly ( n = 1), once weekly ( n = 11), or once every other week ( n = 1). All patients received iron supplements to maintain or exceed prestudy iron parameters. Main Outcome Measure Prior to the study, the primary outcome measure was defined as the difference in epoetin alfa dose between IP and SC administration. Results Thirteen patients completed the study. The area under the dosing-requirement curve for IP epoetin alfa was larger than for SC administration ( p = 0.0029), and the slope of the 16-week dose-requirement curve was greater for IP administration ( p = 0.017), suggesting greater dose stability for SC administration. Paired analysis indicated greater IP intrapatient dose requirements ( p < 0.0001). The mean difference in SC versus IP doses was 5000 ± 1510 units per week. Some patients required escalating IP doses to maintain target hematocrit values. Iron administration and iron stores were similar in both groups. Conclusion Intraperitoneal epoetin alfa may be a suitable alternative for some patients for whom SC dosing is undesirable. Large IP versus SC dosing differences noted in a few patients are unexplained, but may result from interpatient variability in IP epoetin alfa absorption. Intraperitoneal dosing into an empty peritoneum can be done safely and effectively.
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Stepin, A. D., M. N. Rysev, T. A. Ryseva, and T. D. Lisitskaya. "Evaluation of collection accessions of fiber flax according to flax fiber yield and adaptability parameters in the conditions of North-West of the Russian Federation." Agricultural Science Euro-North-East 23, no. 1 (February 25, 2022): 54–68. http://dx.doi.org/10.30766/2072-9081.2022.23.1.54-68.
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Studies on the evaluation of 20 accessions of fiber flax of domestic and foreign selection according to flax fiber yield and adaptability parameters were conducted in 2018-2020 in the conditions of the Pskov region on sod-weakly podzolic light loamy soil. The Dobrynya variety (Russia), the yield of which depending on the year of testing was 215...273 g/m2, was used as standard. The most favorable conditions for fiber flax were in 2018 (Ij = +24.3), and stressful conditions caused by hot and dry weather during the critical period of plant growth and development (GTK = 0.83) - in 2020 (Ij = -30.8). The samples from China V 51267, 97192-79, y 7S12-13, Vuan 2009, M0269-1, wsh2-5-4 were characterized by the highest average fiber yield over the years of testing (259...275 g/m2) and yield under contrasting conditions (254...279 g/m2), with an average varietal of 232 and 230 g/m2, respectively. The varieties Hon Jku 350, Honkei 28 (Japan), L-1 Soglasie х Alfa (Russia), V 51267 (China) showed the lowest yield variability (7.0...10.8 %). The same samples were distinguished by higher stress resistance. According to homeostaticity (Hom), Hon Jku 350 (Japan), L-1 Soglasie х Alfa (Russia), V 51267 (China) were distinguished: 106.9; 98.9 and 52.1, respectively. Highly responsive to growth conditions (bi>1) were samples 97192-79 (1.93), 97192-79-8 (1.88) from China and L-3 Orshansky-2 x Tvertsa (1.74), Nadezhda (1.56) from Russia; plastic - Heiya 8(1.06), 92199-6-5(1.08) (China) and st. Dobrynya (1.01) (Russia), weakly responsive (bi < 1) -L-1 Soglasie х Alfa (Russia), Hon Jku 350, Honkei 28 (Japan). The best in stability (Gd2) samples were Heiya 8 (13) – China; L-3 Orshansky-2 x Tvertsa (26), L-1 Soglasie х Alfa (179), L-2 Voskhod х Zaryanka (182) - Russia; Hon Jku 350 (186) – Japan. According to the yield of flax fiber and the complex of adaptability parameters, based on the ranking, the cultivars L-1 Soglasie х Alfa (Russia), V 51267, wsh2-5-4, 97192-79 (China) with the greatest adaptive potential were identified. They can be used as sources of adaptability when creating new varieties of flax.
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Marsh, Wallace, James Smeeding, John M. York, Rangasamy Ramanathan, and Krishnamurthy Sekar. "A Cost Minimization Comparison of Two Surfactants—Beractant and Poractant alfa—Based Upon Prospectively Designed, Comparative Clinical Trial Data." Journal of Pediatric Pharmacology and Therapeutics 9, no. 2 (April 1, 2004): 117–25. http://dx.doi.org/10.5863/1551-6776-9.2.117.
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OBJECTIVES To compare the pharmacoeconomic profiles of beractant (Survanta®, Ross Laboratories, Columbus, Ohio) and poractant alfa (Curosurf®, DEY LP, Napa, CA) via a cost-minimization analysis. METHODS This analysis was based upon clinical data from two previously published studies (Speer C, et al. Arch Dis Child 1995;72: F8-13; and Ramanathan R, et al. Am J Perinatol 2004; 21:109-19) where investigators found significant differences in the number of doses required to achieve a similar clinical response. Our analyses employed several models based upon single-use or multiple-use of single-use vial scenarios, average wholesale pricing, and costs computed on a per-patient basis. Model 1 involved single-dose vials and mean weight of the infants (both trials). Models 2 and 3, based on individual patient weights, assessed single-dose and multiple-use of single-dose vials cost scenarios, respectively. Individual patient weights allowed for statistical evaluation in Models 2 and 3. RESULTS Model 1 savings with poractant alfa treatment was $949.67 (53%) based upon Speer and $617.90 (46%) based upon Ramanathan. Models 2 and 3 reported savings for poractant alfa of $220.50 (20%) (P = 0.11) and $180 (20%) (P = 0.018), respectively over beractant. CONCLUSIONS These analyses would suggest poractant alfa may offer a less costly, clinically-equivalent option. Savings may vary with vial usage and mix, patient weight distribution, and how surfactants are used in practice. Institutions utilizing surfactants may wish to examine usage patterns, dosing protocols, and patient mix to determine what potential savings may exist.
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Castaigne, Sylvie, Cécile Pautas, Christine Terré, Aline Renneville, Claude Gardin, Felipe Suarez, Denis Caillot, et al. "Final Analysis of the ALFA 0701 Study." Blood 124, no. 21 (December 6, 2014): 376. http://dx.doi.org/10.1182/blood.v124.21.376.376.
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Abstract Aim: The first analysis of the ALFA-0701 study, testing the addition of gemtuzumab ozogamicin (GO) to standard treatment in de novo AML patients aged 50 to 70 years, was presented at ASH 2011 and showed a benefit in 2-year estimated EFS (primary endpoint of the study) (P=0.0018), RFS (P=0.0009) and OS (p=0.03). With a longer median follow up for alive patients of 43 months (reference date: 04/30/2013), we present here the final analysis of this study. Methods: Patients were randomized to receive induction therapy with daunorubicin (DNR) 60 mg/m2 for 3 days and cytarabine 200 mg/m2 for 7 days ± fractionated doses of GO (3mg/m2 on days 1, 4, 7). Patients in CR/CRi received 2 consolidations courses of intermediate doses of cytarabine ± one dose of GO (3mg/m2on day 1, maximum dose: 5mg), according to initial randomization. From March 2008 to November 2010, 278 patients were included. Results: CR+CRi was observed in 215/278 patients, 103/139 in control and 112/139 in GO arm (p=0.25). Primary resistant patients were 30/139 in control and 18/139 in GO arm (p=0.08). There were 6/139 (4%) induction deaths in control and 9/139 (6%) in GO arm (P=0.41). In this final analysis, with follow-up ranging from 30 up to 63.5 months in alive patients, the EFS and RFS benefits associated with GO were still observed, with estimated 3-year EFS at 19% in control versus 31% in GO arm (HR=0.66, 95%CI: 0.50-0.87; median: 9.7 vs. 15.6 months; p=0.0026) and 3-year RFS at 25% versus 38% (p=0.006). However, OS data did not confirm benefit with 3-year OS at 36% in control and 44% in GO arm (HR=0.82, 95%CI: 0.60-1.10; median: 20.8 vs 25.4 months; p=0.18). At the reference date, 132 patients had relapsed (69 control, 63 GO). After relapse, most patients received either intensive salvage with idarubicin and cytarabine (28 control, 42 GO) or GO as a single agent or in combination (20 control, 1 GO). A minority of patients received azacytidine (10 control, 8 GO) or supportive care (11 control, 12 GO). Second CR rate was 66% after intensive salvage, 47% after GO-containing salvage, and 5% after azacytidine. Cumulative incidence of second CR (42% in control and 51% in GO arm) did not differ according to the randomization group (p=0.38). Overall survival after relapse did not differ according to the randomization group. There was no evidence of difference in survival after relapse among those patients who received intensive or GO-containing salvage (2-year post-relapse OS, 31% and 37% respectively). Overall throughout the study, 47 patients in control and 33 in GO arm received an allogeneic stem cell transplant (SCT) either as primary resistant patients (6 and 3, respectively) or in CR1 (23 and 17, respectively) or after relapse (18 and 13, respectively). The cumulative incidence of SCT did not differ significantly between the two arms (p=0.29). Post-SCT survival did not differ between the two arms. Prognostic analyses were performed including age, gender, baseline WBC, ECOG, cytogenetics and the following gene mutations: NPM1, FLT3-ITD, IDH1, IDH2, RUNX1 and DNMT3A. Univariate prognostic analyses for EFS showed that besides treatment arm, cytogenetic and DNMT3Amutation were the only prognostic factors identified. After adjustment on these factors, GO arm remained significantly associated with longer EFS (p=0.013). The effect of treatment arm was then analyzed in the patient subsets: age (60-year cutoff), cytogenetics, FLT3-ITD, NPM1 and DNMT3Amutations. No significant heterogeneities were observed across these subsets for EFS or OS and the tests for interaction were negative, though the effect of GO was not observed in patients with unfavorable cytogenetics. In terms of safety, 68 and 101 SAEs were reported in 60 (43%) and 79 (57%) patients, in control and GO arm respectively. More patients from GO arm experienced more than one SAE (P= 0.031). Persistent thrombocytopenia (<50.10.9/L) by day 45 after induction or consolidation were reported in 21 patients (15%) in the GO arm compared to 4 patients (2%) in the control arm (P= 0.0001). Conclusion. Final analysis of the ALFA 0701 study with a longer follow up confirms the efficacy of adding GO to standard chemotherapy in AML treatment on primary endpoint EFS and on RFS. However, the gain in OS was no longer observed. After relapse, a similar number of patients reached second CR and were transplanted in second CR in the two arms. Of note, one third of patients from the control arm received GO at the time of relapse. Figure 1 Figure 1. Disclosures Castaigne: Pfizer Inc: Consultancy, Honoraria. Off Label Use: Gemtuzumab Ozogamicin is not authorized for previously untreated AML..
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Lerchenmueller, Christian, Faress Husseini, Bernd Gaede, Tony Mossman, Tamas Suto, and An Vanderbroek. "Intravenous (IV) Iron Supplementation in Patients with Chemotherapy-Induced Anemia (CIA) Receiving Darbepoetin alfa Every 3 Weeks (Q3W): Iron Parameters in a Randomized Controlled Trial." Blood 108, no. 11 (November 16, 2006): 1552. http://dx.doi.org/10.1182/blood.v108.11.1552.1552.
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Abstract Background and Aim: The role of IV iron supplementation during treatment with erythropoiesis-stimulating agents (ESAs) in patients with CIA is of increasing interest as a possible means of improving response. This randomized, open-label, multicenter study was designed to evaluate the safety and efficacy of IV iron vs standard practice in CIA patients receiving darbepoetin alfa. Interim efficacy analyses showed a higher response rate for darbepoetin alfa with IV iron compared to darbepoetin alfa with standard iron practice with no difference in the safety profile between the treatment arms (Vanderbroek et al, EHA 2006). Iron parameters are reported here. Methods: Eligible patients were diagnosed with a non-myeloid malignancy and had CIA with a baseline hemoglobin (Hb) value < 11g/dL. All patients received darbepoetin alfa 500 mcg administered Q3W with the SureClick™ prefilled autoinjector. Patients were randomized 1:1 to IV iron 200 mg (single dose Q3W at the same time as darbepoetin alfa or in 2 doses of 100 mg within 3 weeks) or standard practice (oral iron or no iron). Randomization was stratified by tumor type and baseline Hb category (< 10 or ≥10 g/dL). Results: A total of 400 patients were randomized. Mean (SD) age of the study population was 61.4 (11.5) years; range, 20–86. Sixty percent (n=241) of participants were women; 28% (n=114) had lung or gynecological tumors; and 52% (n=208) had a baseline Hb value ≥10 g/dL. In the interim analysis population (n=196), the mean (SD) weekly dose of IV iron was 64.8 (6.6) mg in the IV iron group (n=100). In the standard practice group, 28 of 96 patients (29%) received oral iron and 2 (2%) received IV iron (these patients were analyzed as randomized). Mean (standard error) serum ferritin concentrations and percent transferrin saturation (TSAT) in the 2 groups from baseline (BL) to end of study (EOS) are shown in the figure. Conclusions: The combination of darbepoetin alfa Q3W and IV iron appeared to be associated with a trend toward increased mean serum ferritin levels compared to the standard practice control arm. In contrast, mean TSAT surprisingly appeared to be similar in the 2 groups for most of the study period, perhaps suggesting that TSAT is influenced by other factors. Iron management appears to be an important factor in the response to ESAs and the findings presented here suggest the need for additional exploration into iron uptake and demand in cancer patients treated with darbepoetin alfa. Serum Ferritin Concentration Serum Ferritin Concentration Transferrin Saturation (%) Transferrin Saturation (%)
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Cheung, Wing K., Brian Danneman, Mary Wacholtz, Henry Lau, and Denis Miller. "Pharmacokinetics (PK) and Pharmacodynamics (PD) of Epoetin Alfa in Anemic Cancer Patients Receiving Cycling Chemotherapy." Blood 104, no. 11 (November 16, 2004): 4101. http://dx.doi.org/10.1182/blood.v104.11.4101.4101.
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Abstract Epoetin alfa is a recombinant human erythropoietin (EPO). The objective of this study was to compare the PK/PD of epoetin alfa after a fixed dose (40,000 IU) once weekly (QW) regimen to those after the weight based (150 IU/kg) 3 times per week (TIW) regimen for 4 weeks in healthy subjects and for 6 weeks in anemic cancer patients. In this randomized, open-label, parallel, multi-center study, PK profiles were determined during Week 1 and Week 3 in healthy subjects. For cancer patients, PK profiles were determined during Week 1 when patients were receiving chemotherapy and an optional one during Week 3 when patients were not receiving chemotherapy. Of the 33 enrolled cancer patients who received as least one dose of Epoetin alfa (safety population), 29 were evaluable for PK and 27 were evaluable for PD. Of the safety population (82% had solid tumors), ECOG scores were 0 (48%), 1 (42%), and 2 (9%). None of the patients had bone or kidney metastasis. Their ages and body weights ranged from 31–77 yrs (mean 59.2 yrs) and 50.9 –94.1 kg (mean 70.8 kg), respectively. Mean serum EPO concentrations in the cancer patients during Week 1 were higher than during Week 3. In general, the concentration-time profiles and PK parameters of anemic cancer subjects were different from those in healthy subjects during Week 1 but similar to healthy subjects during Week 3. Mean (SD) PK parameters are listed in following table. Epoetin alfa was safe and well tolerated after the two regimens in this study. The 40,000 IU QW regimen had a higher Cmax, higher exposure to epoetin alfa/erythropoietin in serum (in terms of AUC0-7days), and a lower clearance (CL/F) than the 150 IU/kg TIW regimen. Despite these PK differences, time-profiles of changes in PD parameters and their AUC (% reticulocytes, hemoglobin, and total RBCs) were similar. Mean (SD) PK parameters 150 IU/kg TIW 150 IU/kg TIW 40,000 IU QW 40,000 IU QW 1st Week 3rd Week 1st Week 3rd Week a n=3 for Week 1 and n=2 for Week 3; b n=11 for Week 1 and n=7 for Week 3. Cancer Patients (n=14) (n=4) (n=18) (n=7) Cmax, IU/mL 414 (312) 178 (58) 1077 (510) 897 (322) AUC0-7days, mIU.h/mL 43014(37270) 21082(6909) 84205(46999) 48254(17658) CL/F, mL/h/kg 20.2(15.9) 23.6(9.5) 9.16(4.69) 13.9(7.6) T1/2, h 43.7(3.9) 41.9(14.8)a 41.9(14.8)a 38.8(11.0)b Healthy Subjects (n=6) (n=6) (n=6) (n=6) Cmax, mIU/mL 163 (54) 125 (32) 1036 (238) 909 (398) AUC0-7days, mIU.h/mL 15708(4327) 12913(3249) 47469(13301) 32969(7945) CL/F, mL/h/kg 31.2 (11.5) 36.9 (10.0) 12.6 (3.1) 17.8 (3.7) T1/2, h 25.0 (7.1) 26.0 (8.9) 28.8 (8.1) 23.7 (8.5)
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Gane, Edward J., Régine Rouzier, Alicja Wiercinska-Drapalo, Dominique G. Larrey, Peter N. Morcos, Barbara J. Brennan, Sophie Le Pogam, et al. "Efficacy and Safety of Danoprevir-Ritonavir plus Peginterferon Alfa-2a–Ribavirin in Hepatitis C Virus Genotype 1 Prior Null Responders." Antimicrobial Agents and Chemotherapy 58, no. 2 (December 2, 2013): 1136–45. http://dx.doi.org/10.1128/aac.01515-13.
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ABSTRACTDanoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a–ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a–ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (<2-log10reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a–ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log10decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a–ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had anIL28Bnon-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a–ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered atClinicalTrials.govunder registration no. NCT01185860.)
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Diaz, George A., Simon A. Jones, Maurizio Scarpa, Karl Eugen Mengel, Roberto Giugliani, Nathalie Guffon, Isabela Batsu, et al. "One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency." Genetics in Medicine 23, no. 8 (April 19, 2021): 1543–50. http://dx.doi.org/10.1038/s41436-021-01156-3.
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Abstract Purpose To assess olipudase alfa enzyme replacement therapy for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. Methods This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52. Results Twenty patients were enrolled: four adolescents (12–17 years), nine children (6–11 years), and seven infants/early child (1–5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). Conclusion In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints.
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Patton, Jeffrey, Yong Mun, and Joel Wallace. "Darbepoetin alfa Maintains Hemoglobin Levels in Patients with Myelodysplastic Syndromes (MDS) after Therapeutic Interchange from Epoetin alfa: Results of a Retrospective Chart Review." Blood 104, no. 11 (November 16, 2004): 4708. http://dx.doi.org/10.1182/blood.v104.11.4708.4708.
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Abstract Patients with MDS often receive erythropoietic therapy for the treatment of anemia resulting from the disease. This retrospective chart review examined the impact of switching patients from their current dosing regimens of epoetin alfa (Procrit®) to darbepoetin alfa (Aranesp®) 200 mcg every two weeks (Q2W) following the implementation of therapeutic substitution guidelines in September 2003. Key eligibility criteria included: ≥ 18 years old with a diagnosis of MDS, and treatment with epoetin alfa therapy between May 2003 and January 2004. Patients receiving epoetin alfa therapy were either switched to darbepoetin alfa, or allowed to remain on epoetin alfa, depending on whether their treating physician had adopted therapeutic substitution guidelines. To ensure full characterization of the patient population, in the 16 weeks prior to the time of the therapeutic substitution, detailed demographic and disease characteristics were collected, in addition to dose requirements, transfusion status and hemoglobin profiles. To assess the impact on clinical outcomes, data were collected for 16 weeks after the therapeutic substitution guidelines were implemented (defined as the treatment period). Patients identified in the chart review who received at least one dose of study drug during both time periods were included in the analysis. Response was defined according to the international working group on MDS definitions (Cheson et al., Blood, 2000; 96(12):3671–4). Kaplan-Meier estimates (95% CL) for the percentage of patients with a major response (hemoglobin [Hb] change ≥ 2 g/dL over baseline or transfusion independence) or a minor response (Hb increase ≥ 1 g/dL to < 2 g/dL or a 50% reduction in transfusion requirements) during the treatment period were calculated. Data were abstracted from 142 patient charts, 112 (62 darbepoetin alfa; 50 epoetin alfa) of whom had confirmatory evidence of MDS available in their records (a documented bone marrow biopsy, French-American-British [FAB] classification, or karyotype [confirmed MDS population]). Baseline demographics for the confirmed MDS population were similar between the two cohorts. For those patients with data available, the majority had a FAB classification of refractory anemia with ≤ 5% bone marrow blasts. Mean baseline Hb was 11.0 g/dL for the darbepoetin alfa cohort (n=61) and 11.3 g/dL for the epoetin alfa cohort (n=48). The Kaplan-Meier percentage (95% CL) of patients with a major response was 27% (15, 39) for the darbepoetin alfa cohort and 19% (7, 30) for the epoetin alfa cohort; a minor response was noted for 46% (33, 59) and 47% (31, 63) of patients in the darbepoetin alfa and epoetin alfa cohorts, respectively. The Kaplan-Meier (95% CL) proportion of patients receiving red blood cell transfusions was similar between the groups: 8% (1, 15) for the darbepoetin alfa cohort and 12% (3, 22) for the epoetin alfa cohort. This study indicates that darbepoetin alfa achieved comparable clinical outcomes with epoetin alfa for the treatment of anemia in patients with confirmed MDS.
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Provenzano, Robert, Evgeny Shutov, Liubov Eremeeva, Svitlana Korneyeva, Lona Poole, Gopal Saha, Charles Bradley, et al. "Roxadustat for anemia in patients with end-stage renal disease incident to dialysis." Nephrology Dialysis Transplantation 36, no. 9 (February 25, 2021): 1717–30. http://dx.doi.org/10.1093/ndt/gfab051.
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Abstract 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.
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Shiller, Ekaterina, Vladimir Vdovin, Victor Petrov, Pavel Svirin, Tatiana Andreeva, Inna Lavrichenko, Artem Bullikh, et al. "Safety and Efficacy of New Moroctocog Alfa Drug (Octofactor) in Prophylactic Treatment in Adolescent Patients with Severe and Moderate Hemophilia a." Blood 126, no. 23 (December 3, 2015): 4703. http://dx.doi.org/10.1182/blood.v126.23.4703.4703.
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Abstract Efficacy and safety of a new domestically produced rFVIII-BDD (moroctocog alfa, Octofactor, CJSC "GENERIUM", Russia) was investigated in a controlled, open, prospective, multicenter clinical trial. After screening and a 4-days washout period 12 previously treated patients adolescents (age 12-18 years old) with severe hemophilia A (the activity of FVIII was less than 1%) were included in the clinical trial. The patients were given the moroctocog alfa as prophylactic treatment in a dose of 35±5 ME/kg 3 times per week during 21±1 weeks. Before participation in this clinical trial 2 pts had received treatment with another recombinant FVIII, 2 pts had therapy with pdFVIII and 8 pts had been treated with rFVIII and pdFVIII. The main criterion of drug efficacy was the incidence of spontaneous bleeding occurred within 48 hours after of the moroctocog alfa injection. The additional criteria were: · The severity of spontaneous bleeding occurred in 21 ± 1 week. · Number of injections needed for the one episode of bleeding according of its severity. · The total amount of drug administered over a period of prophylactic treatment and treatment "on demand". · The number of patients with severe hemophilia A with a residual activity of FVIII ≥1% in 48 hours after the injection on prophylactic therapy. During the follow up period (21±1 week) 17 bleeding episodes were registered, 2 of them (11,8%) were severe, 10 (58,8%) were moderate and 5 (29,4%) were mild (Tab.1). Number of bleeding episodes (spontaneous and traumatic) was 17 (1.55 in average). Number of spontaneous bleeding was 3 (17,6%), 1 of them was mild and 2 were moderate. The average number of injections that stop one bleeding episode was 1.7±0.8. The total amount of moroctocog alfa administered over a period was 1.502.000 ÌÅ for prophylactic treatment and 64.750 ÌÅ for "on demand" treatment. The number of patients with severe hemophilia A with a residual activity of FVIII ≥1% in 48 hours after injection on prophylactic therapy was 63,6% on visit 2, 90,09% on visit 3 and 81,1% on visit 4. The safety assessment was performed in 12 patients. There were 8 adverse events and 7 of them were not associated with drugs administration. There was one serious adverse effect, allergic reaction accompanied by arthralgia and cephalalgia. The patient was excluded from the trial without consequences for life and health. There were no infection transmissions and de novo inhibitor incident. The study showed that moroctocog alfa is effective and safe in prophylactic treatment and stopping of bleeding in adolescents with severe hemophilia A. Table 1. Efficacy evaluation Table 1. Efficacy evaluation Disclosures No relevant conflicts of interest to declare.
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Minkevičiūtė, Lina, Marius Šukys, Ričardas Kubilius, and Alvidas Keizeris. "STIMULIACIJOS ALFA MIKROSROVĖMIS REIKŠMĖ TRIŠAKIO NERVO NEURALGIJOS SKAUSMO GYDYMUI." Health Sciences 33, no. 1 (January 1, 2023): 51–55. http://dx.doi.org/10.35988/sm-hs.2023.012.
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Tikslas. Įvertinti ir apibendrinti alfa mikrosrovių poveikį trišakio nervo neuralgijos valdymui, taikant kompleksinį gydymą. Tyrimo medžiaga ir metodai. Lietuvos sveikatos mokslų universiteto ligoninės Kauno klinikų Veido ir žandikaulių chirurgijos klinikoje 2020-2021 m. atliktas prospektyvinis tyrimas. Pacientai atsitiktinai priskirti medikamentinio ar kompleksinio (medikamentinio gydymo su galvos smegenų stimuliacija mikrosrovėmis) gydymo grupei. Skausmo intensyvumas ir jo įtaka kasdieniam gyvenimui vertinta naudojant Penn veido skausmo skalę (PVSS). Pacientų būklė vertinta stacionarinio gydymo pirmą ir paskutinę dieną bei praėjus 1 ir 3 mėnesiams po gydymo. Rezultatai. Trišakio nervo neuralgija neigiamai veikė laisvalaikio, vaikščiojimo, darbinę veiklą, santykius ir bendravimą su aplinkiniais, miegą, gyvenimo kokybę, burnos higieną, kieto maisto kramtymą (teigiama koreliacija, R 0,26-0,37). Gydymo grupėse labiausiai po kiekvieno vertinimo skyrėsi intensyviausio skausmo praėjusią savaitę įverčiai, kompleksinio gydymo poveikis buvo ryškiausias po 1 ir 3 mėnesių (p<0,05). Lyginant skausmo vertinimo suminių vidurkių reikšmių skirtumus, skausmo balas kompleksinio gydymo grupėje sumažėjo 21,7 balo, o medikamentinio gydymo grupėje − 14,3 balo (p<0,05). Išvados. Skausmas darė reikšmingą neigiamą įtaką kasdieniam pacientų gyvenimui. Kompleksinio gydymo grupės pacientų skausmo įverčiai buvo reikšmingai mažesni ir jų gydymo efektyvumas buvo ilgalaikiškesnis.
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Straus, David J., Madeleine Duvic, Timothy Kuzel, Steven Horwitz, Marie-France Demierre, Patricia Myskowski, Kathleen Maignan, and Steven Steckel. "Results of a Phase II Trial of Oral Bexarotene Combined with Interferon Alfa-2b for Patients with Cutaneous T-Cell Lymphoma (CTCL)." Blood 104, no. 11 (November 16, 2004): 2644. http://dx.doi.org/10.1182/blood.v104.11.2644.2644.
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Abstract Bexarotene, a synthetic retinoid ligand for the retinoid X receptor (RXR), is a highly active agent in the treatment of relapsed or refractory CTCL with a response rate of ~45% (Arch Dermatol137: 581–93, 2001; J Clin Oncol19: 2456–71, 2001). Interferon alfa has a similar response rate although the doses and responses in the literature have varied. Promising results have been reported with combinations of retinoids and interferon alfa, including bexarotene (J Am Acad Dermatol50: 375–9, 2004). To explore this combination, a phase II trial was designed in which patients with CTCL were treated with bexarotene 300 mg/m2/day for at least 8 weeks. If less than a complete response was seen at this time, interferon alfa-2b at a dose of 3 million units escalated to 5 million units subcutaneously 3 times weekly was added for another 8 weeks. Responding patients could continue treatment beyond 16 weeks. Twenty-two patients with CTCL were enrolled in the trial: median age 58 years (22–79); 9 males, 13 females, TNM stages: IB (3), II (7), III (4), IV (8). One patient had no prior treatment; the rest had relapsed or refractory disease with a mean of 49 months from initial diagnosis to enrollment. Four patients had previously received bexarotene and 2 interferon alfa. Seventeen patients completed 16 weeks of treatment and are assessable for response, 1 has not completed 16 weeks and 4 received less than 16 weeks (1 early death, 1 non-compliant, 1 withdrawal of consent because of side effects, and 1 myocarditis, probably not treatment-related). Using reproducible objective criteria for response utilized in the single agent bexarotene trials cited above (Primary Endpoint Classification), 6 of 17 patients achieved a partial response and 1 a complete response (objective response rate 41%, 95% confidence intervals 18%–67%). Three of the 6 partial responses occurred with bexarotene alone at 8 weeks. Median duration of response was 2.7 months, range 1.1–7.6 months. Reversible grade 3 or 4 toxicities seen in more than 1 patient were hypercholesterolemia (2 pts.), hypertriglyceridemia (4 pts.), neutropenia (3 pts.), lymphopenia (2 pts.) and elevated AST in 2 patients. Lipid lowering agents were used in all patients. Six patients died, all of progressive disease from 1.6–29.9 months following initiation of treatment. The major response rate for the combination of bexarotene and interferon alfa is similar to that for bexarotene alone. Despite the wide confidence intervals that indicate that a small advantage might be missed by not increasing accrual, the clinical usefulness of this combination is limited by the inconvenience of interferon injections. Further trials in CTCL are planned combining bexarotene with other agents, including active cytotoxics.