RESUMO
INTRODUCTION: Management and care of individuals with hemophilia A advanced immensely with the introduction of recombinant factor VIII (rFVIII) replacement products. This review provides a historical overview of rFVIII development with a focus on Bayer's rFVIII (with albumin) and sucrose-formulated rFVIII (rFVIII-FS), the only rFVIII products cloned in baby hamster kidney (BHK) cells with >25 years of proven safety and efficacy. Areas covered: We review the advances in rFVIII technology and the efficacy and safety data for BHK-derived rFVIII/rFVIII-FS from clinical trials, investigator-initiated studies, and observational studies. Innovative products with new treatment potentials (eg, BAY 81-8973 and BAY 94-9027) built on this established safety and efficacy profile are also briefly discussed. The literature search strategy included targeted searches (PubMed) with manual article selection and other product-specific searches. Expert commentary: Development of rFVIII products and related improvements in viral safety and manufacturing efficiency have guaranteed an adequate supply of factor products worldwide and increased prophylaxis use. The net effects have been joint health preservation, reduction in morbidity and mortality, and quality-of-life enhancements. Current treatment challenges include lack of adherence to prophylaxis and inhibitor development; extended-half-life rFVIII products and non-FVIII replacement therapies in development may help overcome these challenges.
Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Animais , Anticorpos/imunologia , Inibidores dos Fatores de Coagulação Sanguínea , Testes de Coagulação Sanguínea , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Fator VIII/farmacologia , Hemofilia A/sangue , Humanos , Engenharia de Proteínas , Processamento de Proteína Pós-Traducional , Proteínas Recombinantes/farmacologia , Resultado do TratamentoRESUMO
The use of intravenous immune globulin (IVIg) has increased significantly in the past decade, benefiting a wide variety of immune diseases. Seven different formulations of IVIg are now licensed in the United States. Although all contain pooled IgG, there are differences in their production and composition that affect their efficacy, tolerability, and side-effect profile. Important variables include concentration, volume, osmolality, sodium, and sugar content. This article reviews what is known about the composition and properties of the various IVIg formulations that might affect the therapeutic outcome.
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Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Imunoglobulinas Intravenosas/administração & dosagem , Preparações Farmacêuticas/administração & dosagem , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Tolerância a Medicamentos/fisiologia , Humanos , Resultado do TratamentoRESUMO
A novel method of large-scale chromatography has been developed to improve recovery and purity of immunoglobulin G (IgG) from pooled plasma. The current study compares safety, toxicity and efficacy of two intravenous immunoglobulin products: a novel formulation, IGIV caprylate/chromatography (IGIV-C; Gamunex, 10%) and a licensed solvent/detergent-treated product, Gamimune N, 10% (IGIV-SD). The study, a randomized, double-blind, parallel group, therapeutic equivalence trial, was conducted at 25 treatment centers in Canada and the United States. Patients (n=172) having confirmed chronic primary immunodeficiency (PID), aged 1-75 years, and receiving IGIV therapy were enrolled. For 9 months, patients were treated with IGIV-C or IGIV-SD in accordance with the patient's individualized treatment regimen utilized before study entry. The primary endpoint was the proportion of patients with >or=1 validated acute sinopulmonary infection during the treatment period. Secondary endpoints included the proportion of patients with all infections, time to first infection, annual infection rates, lung function parameters, infusion-related safety and viral safety. The annual validated infection rate in the IGIV-C group was 0.18 compared to 0.43 in the IGIV-SD group (p=0.023). Nine patients receiving IGIV-C experienced validated infections, compared to 17 patients in IGIV-SD group (p=0.06). Acute sinusitis (validated plus clinically defined) was less frequent in the IGIV-C group (p=0.012). Presence of bronchiectasis did not affect efficacy. Adverse reactions were similar in frequency and severity in both groups. No evidence of viral transmission was observed. IGIV-C appears to be superior to IGIV-SD in preventing validated sinopulmonary infections, especially acute sinusitis, in patients with PID.
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Caprilatos/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/terapia , Adolescente , Adulto , Idoso , Caprilatos/efeitos adversos , Caprilatos/isolamento & purificação , Criança , Pré-Escolar , Cromatografia por Troca Iônica/métodos , Detergentes , Suscetibilidade a Doenças , Método Duplo-Cego , Feminino , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/isolamento & purificação , Síndromes de Imunodeficiência/complicações , Incidência , Lactente , Controle de Infecções , Infecções/epidemiologia , Infecções/imunologia , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Pneumonia/imunologia , Pneumonia/prevenção & controle , Sinusite/epidemiologia , Sinusite/imunologia , Sinusite/prevenção & controle , Solventes , Resultado do TratamentoRESUMO
The World Federation of Hemophilia (WFH) 2010 World Congress held in Buenos Aires, Argentina, in July 2010, attracted more than 4,300 participants from 106 countries. This report summarizes two symposia held during the congress. The first, titled "Emerging Co-Morbidities in the Aging Hemophilia Population: Healthcare Challenges and Treatment Opportunities," chaired by Gerry Dolan, MD, and Jussara Almeida Cruz, MD, examined the co-morbidities experienced by the aging hemophilic patient population, such as cardiovascular disease, cancer, arthritis, osteoporosis, hypertension, and obesity. In addition, Bayer's products in preclinical and clinical development were reviewed, including a novel factor VIIa variant and a long-acting factor VIII molecule, i.e., one that has undergone site-specific PEGylation (attachment of polyethylene glycol [PEG] polymer chains to another molecule). The other symposium, titled "Practical Steps to Making Better Care for Hemophilia Patients a Reality," chaired by Carmen Altisent, MD, and Cesar Guerrero, RN, reviewed the steps that hemophilia caregivers can take to improve the care of their patients. Issues such as the treatment of hemarthroses, the role of the research nurse, and the management of pediatric patients transitioning to adulthood were discussed.
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Hemofilia A/terapia , Adolescente , Idoso , Fatores de Coagulação Sanguínea/química , Fatores de Coagulação Sanguínea/farmacologia , Fatores de Coagulação Sanguínea/uso terapêutico , Comorbidade , Descoberta de Drogas , Avaliação Geriátrica , Saúde Global , Hemartrose/terapia , Hemofilia A/tratamento farmacológico , Hemofilia A/epidemiologia , Humanos , Expectativa de Vida , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transição para Assistência do AdultoRESUMO
Aprotinin (GAS 9087-70-1) is known as a potent inhibitor of serine proteases such as trypsin, plasmin, tissue and plasma kallikrein. In this study, an aprotinin variant was designed by means of rationale mutagenesis that differs from aprotinin by two amino acids in the active site and by seven amino acids in the backbone. The recombinant protein is expressed in a secretory yeast system enabling large scale production. A purification procedure was developed to yield high amounts of pure and correctly processed aprotinin variant. The changes in the active site of the aprotinin variant increase the potency towards inhibition of plasma kallikrein whereas the inhibition of plasmin is only marginally reduced. The net charge of the molecule is reduced from the basic (IP 10.5) to the neutral range (IP 5.6). The recombinant aprotinin variant shows a decrease of immunogenicity in several models. No cross-reactivity with human and rabbit antibodies directed against aprotinin was observed both in in vivo and in ex vivo studies. In addition, the variant is more potent in a rat brain edema model of acute subdural hematoma compared to aprotinin.