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1.
Mult Scler ; 28(3): 480-486, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34498507

RESUMO

During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks-5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan-Meier analysis; 95% confidence interval, 75.7-99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144.


Assuntos
Anticorpos Monoclonais Humanizados , Neuromielite Óptica , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Aquaporina 4 , Autoanticorpos , Humanos , Imunoglobulina G , Neuromielite Óptica/tratamento farmacológico
2.
Mult Scler Relat Disord ; 50: 102849, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33676197

RESUMO

Background Eculizumab, a terminal complement inhibitor, significantly reduced the risk of relapse compared with placebo in patients with anti-aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the PREVENT trial. We report efficacy and safety analyses in Asian patients in PREVENT and its open-label extension (OLE). Methods PREVENT was a double-blind, randomized, phase 3 trial. Patients with AQP4+ NMOSD were randomly assigned (2:1) to receive intravenous eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo. Patients who completed PREVENT could receive eculizumab in an OLE. Analyses were performed in a prespecified subgroup of Asian patients. Results Of 143 patients enrolled, 52 (36.4%) were included in the Asian subgroup (eculizumab, n = 37; placebo, n = 15); 45 Asian patients received eculizumab in the OLE. Most Asian patients (86.5%) received concomitant immunosuppressive therapy. During PREVENT, one adjudicated relapse occurred in patients receiving eculizumab and six occurred in patients receiving placebo in the Asian subgroup (hazard ratio, 0.05; 95% confidence interval: 0.01-0.35; p = 0.0002). An estimated 95.2% of Asian patients remained relapse-free after 144 weeks of eculizumab treatment. Upper respiratory tract infections, headache, and nasopharyngitis were the most common adverse events with eculizumab in the Asian subgroup. Conclusion Eculizumab reduces the risk of relapse in Asian patients with AQP4+ NMOSD, with a benefit-risk profile similar to the overall PREVENT population. The benefits of eculizumab were maintained during long-term therapy. Clinical trial registration ClinicalTrials.gov identifiers: NCT01892345 (PREVENT); NCT02003144 (open-label extension).


Assuntos
Neuromielite Óptica , Anticorpos Monoclonais Humanizados , Aquaporina 4 , Humanos , Imunoglobulina G , Neuromielite Óptica/tratamento farmacológico
3.
Ann Neurol ; 89(6): 1088-1098, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33586143

RESUMO

OBJECTIVE: During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy. METHODS: Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis. RESULTS: Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1-276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6-97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013-0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199-0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use. INTERPRETATION: This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088-1098.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Adulto , Idoso , Aquaporina 4/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Recidiva
4.
Mult Scler Relat Disord ; 47: 102641, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33310418

RESUMO

BACKGROUND: Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. METHODS: In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. RESULTS: The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. CONCLUSION: Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. TRIAL REGISTRATION: NCT01892345 (ClinicalTrials.gov).


Assuntos
Neuromielite Óptica , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Aquaporina 4 , Humanos , Neuromielite Óptica/tratamento farmacológico , Rituximab/uso terapêutico
5.
Curr Med Chem ; 24(18): 1930-1947, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28155602

RESUMO

BACKGROUND: Human serum albumin (HSA) is the most abundant protein in human serum. It has numerous functions, one of which is transport of small hydrophobic molecules, including drugs, toxins, nutrients, hormones and metabolites. HSA has the ability to interact with a wide variety of structurally different compounds. This promiscuous, nonspecific affinity can lead to sudden changes in concentrations caused by displacement, when two or more compounds compete for binding to the same molecular site. OBJECTIVE: It is important to consider drug combinations and their binding to HSA when defining dosing regimens, as this can directly influence drug's free, active concentration in blood. CONCLUSION: In present paper we review drug interactions with potential for displacement from HSA, situations in which they are likely to occur and their clinical significance. We also offer guidelines in designing drugs with decreased binding to HSA.


Assuntos
Preparações Farmacêuticas/metabolismo , Albumina Sérica/metabolismo , Animais , Sítios de Ligação , Interações Medicamentosas , Humanos , Cinética , Simulação de Acoplamento Molecular , Preparações Farmacêuticas/química , Ligação Proteica , Albumina Sérica/química
6.
Biochem Med (Zagreb) ; 25(1): 36-48, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25672465

RESUMO

Interleukin 10 (IL-10) is important pleiotropic immunoregulatory cytokine which gene is located on chromosome 1 at 1q31-32. There are many genetic variants of IL-10 gene. However, the most studied are two dinucleotide repeats (microsatellites), IL10.G and IL10.R, located 1.2 kb and 4 kb upstream of the transcription start site and three single nucleotide polymorphisms (SNPs) -1082(G/A), -819(C/T) and -592(C/A). A large number of studies have shown that IL-10 gene polymorphisms are associated with different diseases and play an important role in pathophysiology and clinical course of these diseases. This review summarizes published literature knowledge about the association of IL-10 polymorphisms and expression patterns with asthma, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, rheumatoid arthritis, tuberculosis and some neoplasms.


Assuntos
Repetições de Dinucleotídeos , Regulação da Expressão Gênica/genética , Inflamação , Interleucina-10 , Polimorfismo de Nucleotídeo Único , Animais , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/biossíntese , Interleucina-10/genética
7.
J Clin Pharmacol ; 52(6): 798-808, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21680782

RESUMO

This study clinically evaluated a novel PEGylated form of interferon beta-1a (PEG-IFN beta-1a), a potential first-line treatment for relapsing multiple sclerosis, in healthy volunteers. Two randomized, blinded phase I studies were conducted: a single-dose study (n = 60) comparing subcutaneous or intramuscular PEG-IFN beta-1a (63, 125, or 188 µg) with intramuscular unmodified IFN beta-1a 30 µg and a multiple-dose study (n = 69) comparing subcutaneous PEG-IFN beta-1a dosed once every 2 or 4 weeks with placebo. Assessments included pharmacokinetic and pharmacodynamic (serum neopterin and 2',5'-OAS) measures, exploratory immune assessments, safety, and tolerability. A dose-proportional increase in PEG-IFN beta-1a exposure was observed, with a 4-fold greater exposure at 63 µg (6 million international units [MIU]) of PEG-IFN beta-1a than with 30 µg (6 MIU) intramuscular unmodified IFN beta-1a. Increases in neopterin and 2',5'-OAS levels and changes in T helper cell pathway gene expression and lymphocyte subsets were greater and more sustained with PEG-IFN beta-1a than with unmodified IFN beta-1a. PEG-IFN beta-1a was well tolerated, with only transient reductions in absolute neutrophils and some lymphocytes. Flu-like symptoms were a commonly reported adverse event. These data support the continued clinical development of PEG-IFN beta-1a as a potentially effective treatment for patients with relapsing multiple sclerosis.


Assuntos
Imunossupressores/efeitos adversos , Interferon beta/química , Interferons/efeitos adversos , Polietilenoglicóis/efeitos adversos , 2',5'-Oligoadenilato Sintetase/sangue , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Adolescente , Adulto , Biotransformação , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Imunossupressores/farmacologia , Injeções Intramusculares , Injeções Subcutâneas , Interferon beta/administração & dosagem , Interferon beta/efeitos adversos , Interferon beta/farmacologia , Interferons/administração & dosagem , Interferons/sangue , Interferons/farmacologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Neopterina/sangue , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacologia , RNA Mensageiro/sangue , RNA Mensageiro/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Adulto Jovem
8.
J Interferon Cytokine Res ; 30(10): 777-85, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20836711

RESUMO

Multiple sclerosis is a chronic autoimmune disease of the central nervous system for which a number of disease-modifying therapies are available, including interferon beta (Avonex®, Rebif®, and Betaseron/Betaferon®), glatiramer acetate (Copaxone®), and an anti-VLA4 monoclonal antibody (Tysabri®). Despite the availability and efficacy of these protein and peptide drugs, there remains a significant number of patients who are untreated, including those with relatively mild disease who choose not to initiate therapy, those wary of injections or potential adverse events associated with therapy, and those who have stopped therapy due to perceived lack of efficacy. Since these drugs have side effects that may affect a patient's decision to initiate and to remain on treatment, there is a need to provide a therapy that is safe and efficacious but that requires a reduced dosing frequency and hence a concomitant reduction in the frequency of side effects. Here we describe the development of a PEGylated form of interferon beta-1a that is currently being tested in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study in relapsing multiple sclerosis patients, with the aim of determining the safety and efficacy of 125 microg administered via the subcutaneous route every 2 or 4 weeks.


Assuntos
Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Polietilenoglicóis/química , Humanos , Interferon beta-1a , Interferon beta/efeitos adversos , Interferon beta/imunologia , Esclerose Múltipla/imunologia , Polietilenoglicóis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva
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