Respuesta al tratamiento con Interferón beta-1a en pacientes con esclerosis múltiple remitente-recurrente / Response to treatment with Interferon beta-1a in patients with relapsing-remitting multiple sclerosis

RESUMEN Fundamento: los fármacos modificadores, en la esclerosis múltiple, tienen la finalidad de reducir la frecuencia de recaídas, retardar la progresión de la discapacidad, así como la aparición de nuevas lesiones en el Sistema Nervioso Central. Objetivo determinar los indicadores precoces de respuesta al tratamiento con IFNb-1ª en pacientes con esclerosis múltiple remitente-recurrente. Métodos: estudio observacional, analítico de cohorte con prospectiva longitudinal en los pacientes con diagnóstico de esclerosis múltiple. Se conformaron dos cohortes de estudio, cada una con 39 pacientes. Resultados: la media y desviación estándar de la escala ampliada del estado de discapacidad a los 36 meses fue de 2.37 ± 1.86 en el grupo estudio y en el control de 3.15 ± 2.1. En los brotes de .13 ± .33 en el grupo estudio y en el grupo control de .41 ± .59. Las lesiones nuevas en T2 tras los 12 primeros meses de tratamiento fue de 0.90 ± 1.16 para el grupo estudio y para el control de 1 ± 1.10. La progresión por escala ampliada del estado de discapacidad, la tasa anualizada de brotes antes del tratamiento, la edad de inicio de la enfermedad, tiempo de evolución de la enfermedad y lesiones que realzan gadolinio se asociaron de forma significativa con la razón de ventaja de mayor probabilidad de no progresión para el grupo estudio con respecto al grupo control por la variable combinada progresión por escala ampliada del estado de discapacidad y brotes. Conclusiones: se identificaron indicadores precoces de respuesta al tratamiento con el interferón beta-1a, que ayudan a valorar la respuesta al tratamiento de forma precoz, lo que repercute de forma positiva en la evolución de la enfermedad.

ABSTRACT Background: multiple sclerosis modifying drugs are intended to reduce the frequency of relapses, delay the progression of disability, as well as the appearance of new lesions in the Central Nervous System. Objective: to determine the early indicators of response to treatment with IFNb-1a. Methods: Observational, analytical longitudinal prospective cohort study in patients diagnosed with multiple sclerosis. Two study cohorts were formed, each with 39 patients. Results the mean and standard deviation of the expanded disability status scale at 36 months was 2.37 ± 1.86 in the study group and 3.15 ± 2.1 in the control group. In the outbreaks of .13 ± .33 in the study group and in the control group of .41 ± .59. New lesions in T2 after the first 12 months of treatment was 0.90 ± 1.16 for the study group and 1 ± 1.10 for the control. Extended-scale progression of disability status, pretreatment annualized relapse rate, age of disease onset, time since disease progression, and gadolinium-enhancing lesions were significantly associated with the odds ratio of older Probability of non-progression for the study group with respect to the control group for the combined variable progression by extended disability status scale and relapses. Conclusions: early indicators of response to treatment with interferon beta-1a were identified; that help assess the response to treatment early, which has a positive impact on the evolution of the disease.

Evolución clínica de pacientes con esclerosis múltiple remitente- recurrente tratados con interferón beta-1a / Clinical evolution of patients with relapsing-remitting multiple sclerosis treated with interferon beta-1a

RESUMEN Introducción: El inicio de la terapia con interferón ha sido y es el primer paso en el tratamiento de muchos pacientes con esclerosis múltiple, con el propósito de retrasar la progresión de la enfermedad. Objetivo: Identificar los marcadores clínicos de respuesta al tratamiento con interferón beta-1a de pacientes con esclerosis múltiple remitente-recurrente. Métodos: Se realizó un estudio observacional, descriptivo, longitudinal, prospectivo, de una serie de casos de pacientes con diagnóstico de esclerosis múltiple remitente-recurrente, que recibían tratamiento con interferón beta-1a, en el periodo comprendido entre enero del 2014 a diciembre del 2020. Se incluyeron los 39 pacientes. Resultados: La media de edad fue de 34,54 años. La media del nivel de discapacidad en la línea base, 12, 24 y a los 36 meses fue de 1,76; 1,91; 2,1 y 2,37 respectivamente. La media de los brotes en la línea base, 12, 24 y a los 36 meses fue de 1,13; 0,26; 0,38 y 0,13 respectivamente. Se muestra la cifra de progresiones inferior en un 51 % a los 36 meses. La razón de ventajas (odds ratio) para la no presencia de brotes se muestra entre 2 y 4 veces en estos pacientes. Conclusiones: Se identifican marcadores clínicos de respuesta al tratamiento con interferón beta-1a que ayudan a valorar la respuesta al tratamiento, lo cual repercute de forma positiva en la evolución de la enfermedad.

ABSTRACT Introduction: The initiation of interferon therapy has been and is the first step in the treatment of many patients with multiple sclerosis, with the aim of delaying the progression of the disease. Objective: To identify the clinical markers of response to treatment with Interferon beta-1a in patients with relapsing-remitting multiple sclerosis. Methods: An observational, descriptive, longitudinal, prospective study was carried out of a series of cases of patients diagnosed with relapsing-remitting multiple sclerosis, who received treatment with interferon beta-1a, in the period between January 2014 and December 2020. All 39 patients were included. Results: The mean age was 34.54 years. The mean disability level at baseline, 12, 24, and 36 months was 1.76; 1.91; 2.1 and 2.37 respectively. The mean number of flares at baseline, 12, 24, and 36 months was 1.13; 0.26; 0.38 and 0.13 respectively. The number of progressions lower by 51% at 36 months is shown. The odds ratio for the absence of relapses is between 2 and 4 times in these patients. Conclusions: Clinical markers of response to treatment with Interferon beta-1a are identified that help assess the response to treatment, which has a positive impact on the evolution of the disease.

Esclerosis múltiple: reacciones adversas a medicamentos en pacientes bajo ley 20850, Hospital Regional de Talca / Multiple sclerosis: adverse drug reactions in patients under law 20850, Hospital Regional de Talca

INTRODUCTION: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, which occurs in up to 85% of cases as relapsing remitting (RR), with episodes of neurological dysfunction partially forwarded. Its treatment in Chile is financially protected by the Explicit Health Guarantees (GES) and Law 20,850 on high-cost diseases. The Regional Hospital of Talca (HRT) has 25 patients benefiting from Law 20,850 in treatment with second-line biologic therapy. Adverse reactions (RAM) to the use of these drugs have been described and to date there are no case reports or studies of significant adverse events in Chile. Objectives: To present the experience of the use of biologic therapy in EMRR in HRT, in relation to adverse events. METHODS: A review of the current guidelines in Chile for the treatment of relapsing-remitting multiple sclerosis and the protocol of law 20,850 was carried out, the clinical records of 25 patients benefiting from the law in the HRT were reviewed, with emphasis on the adverse events presented before First and second line therapies and the con sequences of these events on the continuity of therapy. RESULTS: Half of the patients who started their treatment with first-line drugs had adverse effects, of which 28% involved a change in therapy, the remaining changed from therapy due to failure to treatment. Of the 26 patients included in the sample, 24 are currently using second-line drugs. The profile of adverse effects should be a variable to consider when indicating a therapy for MS.

Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter

Polycomb chromobox (CBX) proteins regulate gene transcription by maintaining chromatin states, which guide a variety of biological processes. Now, epigenetic regulation of innate immune response is an emerging field. However, the role of CBX proteins in innate immunity remains unclear. We confirmed that the expression of CBX family proteins, especially Cbx2, was decreased in macrophages upon viral infection, and then we investigated the role of Cbx2 in the antiviral immune response. Silencing or knockdown of Cbx2 in macrophages inhibited virus-induced production of IFN-β. Furthermore, heterozygous Cbx2 knockout were susceptible to VSV challenge. Mechanistically, Cbx2 binds to and recruits Jmjd3 to the Ifnb promoter, leading to demethylation of H3K27me3 and increased transcription of IFN-β. Together, our study reveals a non-traditional function of a Cbx protein and adds new insight into the epigenetic regulation of antiviral innate immunity.

Evaluation of recombinant human interferon beta 1b by liquid chromatography methods and bioassay

Recombinant human interferon beta 1b (rhIFNß-1b) is clinically used to treat multiple sclerosis. A reversed-phase liquid chromatography (RP-LC) method was carried out on a Jupiter C4 column (250 mm × 4.6 mm i.d.). The mobile phase A consisted of 0.1% trifluoroacetic acid (TFA) in water, and the mobile phase B was acetonitrile with 0.1% TFA run at a flow rate of 1.0 mL/min. A size exclusion liquid chromatography (SE-LC) method was carried out on a BioSep-SEC-S 2000 column (300 mm × 7.8 mm i.d.). The mobile phase consisted of 1 mM monobasic potassium phosphate, 8 mM sodium phosphate dibasic and 200 mM sodium chloride buffer pH 7.4, run isocratically at a flow rate of 0.8 mL/min. Retention times were 31.87 and 17.78 min, and calibration curves were linear over the concentration range of 1-200 µg/mL (r2 = 0.9998) and 0.50-200 µg/mL (r2 = 0.9999), respectively, for RP-LC and SE-LC, with detection at 214 nm. Liquid chromatography (LC) methods were validated and employed in conjunction with the in vitro bioassay to assess the content/potency of rhIFNß-1b, contributing to improve the quality control and to ensure the efficacy of the biotherapeutic

Effects of recombinant human interferon β1a on the chondrogenic differentiation of human bone marrow mesenchymal stem cell / 生物工程学报

Recombinant human interferon beta (rhIFN-β) is a glycoprotein produced by genetically engineered cells and has anti-virus, anti-tumor and immunoregulation functions. Although studies have shown that other subtypes of IFN such as IFN-γ affects cell proliferation and differentiation to some extent, the effect of rhIFN-β on chondrogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs) is less known. In this study we studied the effect of rhIFN-β on the chondrogenic differentiation of hMSCs by inducing hMSCs into cartilage pellet via adding IFN-β1a into regular TGF-β3 chondrogenic differentiation medium. We collected the induced pellets and then detected GAG content, assessed pellets size, observed agreecan using alcian blue staining, and analyzed the expression of Sox and CollangenⅡusing real-time PCR and Western blotting. Addition of 100 ng/mL IFN-β1a to regular TGF-β3 chondrogenic differentiation medium could improve the concentration of GAG, increase the size of pellets, promote the formation of aggrecan and up-regulate the expression of CollangenII and Sox9. IFN-β1a combined with TGF-β3 could promote chondrogenic differentiation of hMSCs.

Intervention effect discussion of recombinant human interferon beta-1b for injection in the treatment of relapsing remitting multiple sclerosis / 中国医师进修杂志

Objective To explore the clinical efficacy and safety of recombinant human interferon beta-1b for injection (rhINFβ-1b) in the treatment of relapsing remitting multiple sclerosis (RRMS). Methods Thirty patients with RRMS were selected. According to the condition of accepting rhINFβ-1b for treatment, they were divided into intensification treatment group (11 cases) and routine treatment group (19 cases). They were followed up for 24 months, all the patients′laboratory examination and imaging examination were performed. The scores of clinical extended disability scale (EDSS) and the number of recurrences were compared between the two groups before and after the treatment. In the initial admission (T0), at the end of treatment (T1), 6 months of follow-up (T2), 12 months of follow-up (T3) and 18 months of follow-up (T4), the sequence of MRI T2and the number of enhanced scan lesions were observed, and the adverse drug reactions and their severity were evaluated. The ROC curve of cystatin C level in cerebrospinal fluid(CSF) was drawn to comprehensively evaluate the efficacy of drug intervention. Results After treatment, the scores of EDSS in intensification treatment group were significantly decreased (P < 0.05). The scores of EDSS and the number of annual recurrence in intensification treatment group were significantly lower than those in conventional treatment group: (1.59 ± 0.75) scores vs. (4.07 ± 0.95) scores, (0.93 ± 0.38) times/year vs. (2.41 ± 0.54) times/year, there were significant differences (P＜0.01). The number of lesions at T0-T4time point in T2sequence and enhanced scan focus in intensification treatment group decreased. However, in conventional treatment group the number of lesions in T2sequences at T0-T4time point showed an upward trend, and the number of lesions at enhanced scan showed a broken line fluctuation. The results ROC curve showed that the area under the curve of intensification treatment group was 0.947 and the area under the conventional treatment group was 0.899. Conclusions rhINFβ-1b can effectively improve symptoms, significantly reduce the clinical relapse and MRI active lesions in patients with RRMS, slow down the progression of the disease, and have fewer adverse reactions.

Anti-proliferative Effect of Engineered Neural Stem Cells Expressing Cytosine Deaminase and Interferon-β against Lymph Node–Derived Metastatic Colorectal Adenocarcinoma in Cellular and Xenograft Mouse Models / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Genetically engineered stem cells may be advantageous for gene therapy against various human cancers due to their inherent tumor-tropic properties. In this study, genetically engineered human neural stem cells (HB1.F3) expressing Escherichia coli cytosine deaminase (CD) (HB1.F3.CD) and human interferon-β (IFN-β) (HB1.F3.CD.IFN-β) were employed against lymph node–derived metastatic colorectal adenocarcinoma. MATERIALS AND METHODS: CD can convert a prodrug, 5-fluorocytosine (5-FC), to active 5-fluorouracil, which inhibits tumor growth through the inhibition of DNA synthesis,while IFN-β also strongly inhibits tumor growth by inducing the apoptotic process. In reverse transcription polymerase chain reaction analysis, we confirmed that HB1.F3.CD cells expressed the CD gene and HB1.F3.CD.IFN-β cells expressed both CD and IFN-β genes. RESULTS: In results of a modified trans-well migration assay, HB1.F3.CD and HB1.F3.CD.IFN-β cells selectively migrated toward SW-620, human lymph node–derived metastatic colorectal adenocarcinoma cells. The viability of SW-620 cells was significantly reduced when co-cultured with HB1.F3.CD or HB1.F3.CD.IFN-β cells in the presence of 5-FC. In addition, it was found that the tumor-tropic properties of these engineered human neural stem cells (hNSCs) were attributed to chemoattractant molecules including stromal cell-derived factor 1, c-Kit, urokinase receptor, urokinase-type plasminogen activator, and C-C chemokine receptor type 2 secreted by SW-620 cells. In a xenograft mouse model, treatment with hNSC resulted in significantly inhibited growth of the tumor mass without virulent effects on the animals. CONCLUSION: The current results indicate that engineered hNSCs and a prodrug treatment inhibited the growth of SW-620 cells. Therefore, hNSC therapy may be a clinically effective tool for the treatment of lymph node metastatic colorectal cancer.

Patients' satisfaction with and views about treatment with disease-modifying drugs in multiple sclerosis / Satisfação e pontos de vista dos pacientes com esclerose múltipla em tratamento com drogas modificadoras da doença

ABSTRACT Objective The treatment of multiple sclerosis (MS) with disease-modifying-drugs (DMDs) is evolving and new drugs are reaching the market. Efficacy and safety aspects of the drugs are crucial, but the patients’ satisfaction with the treatment must be taken into consideration. Methods Individual interview with patients with MS regarding their satisfaction and points of view on the treatment with DMDs. Results One hundred and twenty eight patients attending specialized MS Units in five different cities were interviewed. Over 80% of patients were very satisfied with the drugs in use regarding convenience and perceived benefits. The only aspect scoring lesser values was tolerability. Conclusion Parameters for improving treatment in MS must include efficacy, safety, and patient satisfaction with the given DMD.

RESUMO Objetivo O tratamento da esclerose múltipla (EM) com drogas-modificadoras-da-doença (DMDs) está evoluindo e novas drogas estão sendo comercializadas. Eficácia e segurança são aspectos cruciais nas medicações, porém a satisfação do paciente com o tratamento deve ser levada em consideração. Métodos Entrevista individual com pacientes com EM investigando a satisfação e ponto de vista desta população em relação ao tratamento com DMDs. Resultados Cento e vinte e oito pacientes atendidos em unidades especializadas de EM de cinco cidades diferentes foram entrevistados. Mais de 80% dos pacientes estava bastante satisfeito com as medicações utilizadas, considerando aspectos de conveniência de uso e benefício das drogas. O único aspecto que pontuou menos foi tolerabilidade. Conclusão Parâmetros para melhor tratamento de EM devem incluir eficácia, segurança e satisfação dos pacientes com a DMD prescrita.

Effects of Systemic and Local Interferon Beta-1a on Epidural Fibrosis

STUDY DESIGN: Level 1 randomized controlled study. PURPOSE: To investigate the effects of systemic and local interferon-beta-1a (IFN-β-1a) on prevention of epidural fibrosis using histopathological parameters. OVERVIEW OF LITERATURE: Epidural fibrosis involves fibroblastic invasion of nerve roots into the epidural space. Formation of dense fibrous tissue causes lumbar and radicular pain. Many surgical techniques and several materials have been proposed in the literature, but no study has assessed the effect of IFN-β-1a on prevention of epidural fibrosis. METHODS: Forty-eight adult female Sprague-Dawley rats were divided into six groups of eight: sham group, control group, systemic 44 μg IFN-β-1a group and 22 μg IFN-β-1a group (after laminectomy and discectomy, 0.28 mL and 0.14 mL IFN-β-1a applied subcutaneously three times for a week, respectively), local 44 μg IFN-β-1a group (laminectomy and discectomy, followed by 0.28 mL IFN-β-1a on the surgical area), and local 22 μg IFN-β-1a group (laminectomy and discectomy, followed by 0.14 mL IFN-β-1a on the surgical area). All rats were sacrificed after 4 weeks and groups were evaluated histopathologically. RESULTS: Compared with sham and control groups, significantly less epidural fibrosis, dural adhesion, and fibroblast cell density were observed in the local and systemic 44 μg IFN-β-1a groups. No other differences were evident between the local and systemic groups. CONCLUSIONS: IFN-β-1a is effective in preventing epidural fibrosis with systemic and local application.

Effects of Systemic and Local Interferon Beta-1a on Epidural Fibrosis

STUDY DESIGN: Level 1 randomized controlled study. PURPOSE: To investigate the effects of systemic and local interferon-beta-1a (IFN-β-1a) on prevention of epidural fibrosis using histopathological parameters. OVERVIEW OF LITERATURE: Epidural fibrosis involves fibroblastic invasion of nerve roots into the epidural space. Formation of dense fibrous tissue causes lumbar and radicular pain. Many surgical techniques and several materials have been proposed in the literature, but no study has assessed the effect of IFN-β-1a on prevention of epidural fibrosis. METHODS: Forty-eight adult female Sprague-Dawley rats were divided into six groups of eight: sham group, control group, systemic 44 μg IFN-β-1a group and 22 μg IFN-β-1a group (after laminectomy and discectomy, 0.28 mL and 0.14 mL IFN-β-1a applied subcutaneously three times for a week, respectively), local 44 μg IFN-β-1a group (laminectomy and discectomy, followed by 0.28 mL IFN-β-1a on the surgical area), and local 22 μg IFN-β-1a group (laminectomy and discectomy, followed by 0.14 mL IFN-β-1a on the surgical area). All rats were sacrificed after 4 weeks and groups were evaluated histopathologically. RESULTS: Compared with sham and control groups, significantly less epidural fibrosis, dural adhesion, and fibroblast cell density were observed in the local and systemic 44 μg IFN-β-1a groups. No other differences were evident between the local and systemic groups. CONCLUSIONS: IFN-β-1a is effective in preventing epidural fibrosis with systemic and local application.

Human Rhinovirus-induced Proinflammatory Cytokine and Interferon-beta Responses in Nasal Epithelial Cells From Chronic Rhinosinusitis Patients

PURPOSE: Asthma exacerbation from human rhinovirus (HRV) infection is associated with deficient antiviral interferon (IFN) secretion. Although chronic rhinosinusitis (CRS), an inflammatory upper airway disease, is closely linked to asthma, IFN-beta responses to HRV infections in human nasal epithelial cells (HNECs) from CRS patients remain to be studied. We evaluated inflammatory and antiviral responses to HRV infection in HNECs from CRS patients. METHODS: HNECs, isolated from turbinate tissue of 13 patients with CRS and 14 non-CRS controls, were infected with HRV16 for 4 hours. The HRV titer, LDH activity, production of proinflammatory cytokines and IFN-beta proteins, and expression levels of RIG-I and MDA5 mRNA were assessed at 8, 24, and 48 hours after HRV16 infection. RESULTS: The reduction in viral titer was slightly delayed in the CRS group compared to the non-CRS control group. IL-6 and IL-8 were significantly increased to a similar extent in both groups after HRV infection. In the control group, IFN-beta production and MDA5 mRNA expression were significantly increased at 8 and 24 hours after HRV16 infection, respectively. By contrast, in the CRS group, IFN-beta was not induced by HRV infection; however, HRV-induced MDA5 mRNA expression was increased, but the increase was slightly delayed compared to the non-CRS control group. The RIG-I mRNA level was not significantly increased by HRV16 infection in either group. CONCLUSIONS: HRV-induced secretion of proinflammatory cytokines in CRS patients was not different from that in the non-CRS controls. However, reductions in viral titer, IFN-beta secretion, and MDA5 mRNA expression in response to HRV infection in CRS patients were slightly impaired compared to those in the controls, suggesting that HRV clearance in CRS patients might be slightly deficient.

Combination Therapy for Gliomas Using Temozolomide and Interferon-Beta Secreting Human Bone Marrow Derived Mesenchymal Stem Cells

OBJECTIVE: Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-beta) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-beta on gliomas. METHODS: We engineered human MSCs to secret mouse IFN-beta (MSC-IFN-beta) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-beta treatment. RESULTS: In vitro, the combination of MSC-IFN-beta and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-beta and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. CONCLUSION: These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-beta and TMZ could be considered as a new option for the treatment of malignant gliomas.

Interferon beta11a treatment in htlv-1-associatd myelopathy/tropical spastic pparaparesis: a case report / Tratamento com interferon beta-1a em mielopatia associada ao HTLV-1/paraparesia espástica tropical: relato de caso

Here a young patient (< 21 years of age) with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF). Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved.

Descreve-se caso de mielopatia associada ao HTLV-1/paraparesia espástica tropical tratada com interferon beta-1a em paciente jovem de 21 anos e com história de dermatite infecciosa na infância. Foi estabelecida clinicamente paraparesia espástica tropical (HAM/TSP), confirmada laboratorialmente pela presença de anticorpos para HTLV-1 no LCR e excluídas caxumba, citomegalovirus, Epstein-Barr, esquistossomose, herpes virus 1 e 2, rubéola, sarampo, toxoplasmose varicela-zoster, hepatite, HIV e sífilis por sorologias. Foi diagnosticada bexiga neurogênica, com quadro clínico de nictúria, urgência urinária, parestesia no membro inferior esquerdo e discreta redução de força muscular nos membros superiores, mais acentuada nos membros inferiores. Na 4a semana de tratamento com interferon beta-1a houve desaparecimento da urgência urinária e da parestesia e melhora da clínica motora.

Characterization of a murine neuron-enriched model of primary trigeminal ganglia cultures to study the interferon-ß antiviral effect against Herpes Simplex Virus type 1 / Caracterización de un modelo murino de cultivos primarios de ganglio trigeminal enriquecido en neuronas para el estudio del efecto antiviral del interferón-ß frente al virus Herpes simple tipo 1

Objective: To characterize a neuron-enriched primary TG culture and evaluate interferon- β expression and activity after HSV-1 infection. Materials and methods: The percentage of neurons present in cultures was assessed by neurofilament immunocytochemistry. Cultures were treated with interferon- β and infected with HSV-1, then viral antigen positive cells were counted and interferon- βexpression was assessed by quantitative PCR. Results: The culture contained 15% neurons and 85% non-neuronal cells. A cytopathic effect was observed, associated with high viral spread (72.9% neurons and 48.3% non-neuronal cells were positive for viral antigen). Interferon- β treatment impaired the cytopathic effect and decreased the infected neurons to 16.7% and infected non-neuronal cells to 7.8%. Viral infection at 6 h postinfection significantly increased the interferon- β transcripts by 18.2 fold, while at 18 h postinfection Interferon pre-treatment in infected cultures increased interferon- β transcription by 3.7 fold. Discussion: This culture model contained 15% neurons, which is 10 times higher compared to other reported cultures, and non-neuronal cells comprised 85% of cells in this culture. All types of cells were found to be infected, which is similar to that reported during acute infections in vivo . Additionally, interferon- βdecreased the infected cells, avoiding the cytopathic effect, which is similar to that reported in swine TG cultures. Conclusions: A neuron-enriched primary TG model was characterized. Interferon- β treatment protected cells from cytopathic effects and viral spread, while viral infection up-regulated interferon- β expression. This result means that interferon- β exerts an important antiviral effect against HSV-1 in these cultures.

Objetivo: Caracterizar un cultivo primario de ganglio trigeminal (GT) enriquecido en neuronas y evaluar la expresión de interferón- y su actividad frente a la infección con Herpes simple tipo 1 (HSV-1). Materiales y métodos: El porcentaje de neuronas fue determinado por inmunocitoquímica para neurofilamento. Los cultivos fueron tratados con interferón- β e infectados con HSV-1, y se cuantificaron las células positivas para antígeno viral por inmunocitoquímica y la expresión de interferón- β por PCR cuantitativa. Resultados: El cultivo presentó un 15% de neuronas y 85% de células no neuronales. Se encontró efecto citopático, asociado a una alta diseminación de la infección (72,9% neuronas y 48,3% de células no neuronales positivas para antígeno viral). El interferón- β evitó la aparición de efecto citopático y disminuyó las células infectadas a 16,7% en neuronas y a 7,8% las células no neuronales. La infección viral incrementó la expresión de transcritos de interferón- β 18,2 veces a las 6 h de infección, mientras que a las 18 h post infección el tratamiento con interferón incrementó esta expresión 3,7 veces. Discusión: Los cultivos presentaron un 15% de neuronas, lo cual es 10 veces más que en otros cultivos reportados. Las células no neuronales representan el 85% de las células del cultivo, y se evidenció que todos los tipos de células se infectaron; similar a lo que ha sido reportado durante infecciones agudas in vivo . Adicionalmente, el interferón- β disminuyó el porcentaje de células infectadas y evitó la aparición de efecto citopático, similar a lo que ha sido reportado en cultivos de GT porcino. Conclusiones: Se caracterizó un modelo de cultivo primario de GT enriquecido en neuronas. Interferón- β protegió las células del efecto citopático y la diseminación viral mientras que la infección viral incrementó la expresión de interferón- β. Por lo tanto, el interferón- β ejerció un papel antiviral importante frente al HSV-1 en estos cultivos.

Costo-efectividad del tratamiento con interferón beta en pacientes con síndrome clínico aislado de alto riesgo en Colombia / The cost-effectiveness of interferon beta treatment in patients with a clinically isolated syndrome in Colombia

Introducción. En 85 % de los pacientes con esclerosis múltiple se presenta como manifestación inicial un primer evento desmielinizante o síndrome clínico aislado. En estos casos, el tratamiento con interferón beta retrasa hasta dos años la progresión a esclerosis múltiple. Sin embargo, en Colombia este medicamento es costoso. Objetivo. Determinar si el tratamiento del síndrome clínico aislado con interferón beta es costo-efectivo al retrasar la esclerosis múltiple en dos años. Materiales y métodos. Se realizó un análisis de costo-efectividad empleando un árbol de decisiones basado en la perspectiva del paciente y la sociedad. A partir de una revisión sistemática de la literatura y de conceptos de expertos se definieron las diversas probabilidades. Los costos de la enfermedad se calcularon por medio de la revisión de historias y la aplicación de encuestas a los pacientes atendidos en el Hospital Universitario San Ignacio. Para controlar la incertidumbre se realizó un análisis de sensibilidad mediante una simulación de Monte Carlo con mil pacientes. Resultados. El costo del tratamiento con interferón sobrepasa los Col$ 95´000.000 (US$ 50.000) por paciente durante los dos años. Aproximadamente, 80 % corresponde a los costos del medicamento. El costo de la recaída se acerca a Col$ 39´139.200 (US$ 21.744), y los costos indirectos corresponden a Col$ 10´958.400 (US$ 6.088). La tasa representativa del mercado fue de Col$ 1.800. Con el tratamiento se ganan sólo 0,06 años de vida ajustados por discapacidad (AVAD) adicionales. La razón de costo-efectividad ‘incremental´ (sic.) supera el umbral, incluso en el análisis de sensibilidad. Conclusión. La administración de interferón beta en pacientes con síndrome clínico aislado de alto riesgo en los primeros dos años no es costo-efectiva en Colombia.

Introduction: Approximately 85% of patients with multiple sclerosis have an initial demyelinating event. Treatment with interferon beta delays the progression of multiple sclerosis for nearly two years in patients with a clinically isolated syndrome. In Colombia, interferon is very expensive when compared to other countries. Objective: We sought to determine the cost-effectiveness of a two-year interferon beta treatment within Colombia in patients with a clinically isolated syndrome. Materials and methods: Based on patient and society perspectives, a cost-effectiveness analysis was conducted using a decision tree. A variety of probabilities were defined after a systematic review of the available literature. The disease costs were calculated by reviewing medical charts at the Hospital San Ignacio University and surveys completed by multiple sclerosis patients. To control for uncertainty in these data, analysis of approximately one-thousand patients was performed using Monte Carlo methods. Results: The two-year treatment cost per patient exceeds Col$ 95,000,000 (US$ 50,000). Approximately 80 % of this cost corresponds to medications (US$ 40,500). The price of relapse and indirect costs totals Col$ 41,632,149 (US$ 21,744) and Col$ 11,656,389 (US$ 6,088), respectively. Treatment represents an increase of 0.06 quality-adjusted life years (QALY). The incremental cost-effectiveness ratio exceeds the threshold, regardless of the use of Monte Carlo methods for analysis. Conclusion: Administering interferon beta over the course of two years to high-risk patients with a clinically isolated syndrome is not cost-effective within Colombia.

Terapia gênica do câncer associando reparo da via p53 à imunoestimulação por IFNbeta / Cancer gene therapy associated repair via p53 immunostimulation by IFNbeta

Os avanços científicos das últimas décadas permitiram que a compreensão do câncer evoluísse de uma visão simplista, na qual o principal motor seria uma atividade celular hiperploriferativa, para uma visão mais complexa onde o estado fisiológico geral permite a gênese e progressão tumoral. Essa evolução permite o desenvolvimento de novas abordagens terapêuticas e traz novas esperanças para o tratamento de muitos tipos de cânceres ainda extremamente deletérios. Dentro desse novo panorama, terapias que estimulem a imunidade antitumoral têm se mostrado extremamente promissoras. Nesse trabalho, procuramos investigar os efeitos antitumorais desencadeados pela combinação da indução de morte celular e imunoestimulação. Para tanto, visamos à recuperação da via de p53 (pela transferência gênica do próprio p53 ou p19) associada à transferência gênica de IFNbeta. A transferência gênica foi mediada por vetores adenovirais do sorotipo 5. Nossas observações, em um modelo murino de carcinoma pulmonar, permitem concluir que esta linhagem é sensível a morte induzida pela transferência gênica de p19 e não p53. Porém, a transferência gênica intratumoral de IFNbeta se mostrou chave no controle do crescimento do tumor primário. Destacamos, entretanto, que a associação de IFNbeta com p19 produziu efeitos imunoprotetores superiores à transferência de IFNbeta ou p19 sozinhos. Tal efeito parece ser dependente da indução de fatores quimiotáxicos e conseqüente recrutamento de neutrófilos para o sítio tumoral. O efeito da transferência gênica combinada de ambos os genes IFNbeta e p19 se mostrou ainda mais promissor quando associado à cisplatina, induzindo uma notável redução no crescimento tumoral...

Scientific advances from the last decades enabled the evolution of our knowledge of cancer from a simplistic vision, in which the main motor was an excessive cell proliferation, to a more complex one, where the general physiologic state enables tumorigenesis and tumor progression. This evolution enabled the development of new therapies and brings new hopes for the treatment of several types of cancers. In this context, therapies that induce an antitumor immunity are very promising. In this work, we are investigating the antitumor effects triggered by the combination of cell death induction and immunostimulation. To this end, we aimed to restore p53 pathway (by p53 or p19 gene transfer) associated with immunostimulation by IFNbeta gene transfer. The gene transfer was mediated by Adenovectors Serotype 5. Our observations in a murine model of lung cancer showed that this cell line is sensitive to cell death induced by p19 gene transfer, but not p53. Nevertheless, intratumoral gene transfer of IFNbeta, was crucial in controlling tumor growth. Moreover, p19 and IFNbeta association induced higher immunoprotecting effects than p19 or IFNbeta alone. This effect seems to be depending on the induction of chemotactic factors, and the recruitment of neutrophils to the tumor site. The effect of combined gene transfer of p19 and IFNbeta was even more promising when associated with Cisplatine, inducing a remarkable reduction in tumor growth...

Antibodies to Interferon beta in Patients with Multiple Sclerosis Receiving CinnoVex, Rebif, and Betaferon

Treatment with interferon beta (IFN-beta) induces the production of binding antibodies (BAbs) and neutralizing antibodies (NAbs) in patients with multiple sclerosis (MS). NAbs against IFN-beta are associated with a loss of IFN-beta bioactivity and decreased clinical efficacy of the drug. The objective of this study was to evaluate the incidence and the prevalence of binding antibodies (BAbs) and neutralizing antibodies (NAbs) to IFN-beta in MS patients receiving CinnoVex, Rebif, or Betaferon. The presence of BAbs was studied in serum samples from 124 MS patients using one of these IFN-beta medications by ELISA. The NAbs against IFN-beta were measured in BAb-positive MS patients receiving IFN-beta using an MxA gene expression assay (real-time RT-PCR). Of the 124 patients, 36 (29.03%) had BAbs after at least 12 months of IFN-beta treatment. The proportion of BAb+ was 38.1% for Betaferon, 21.9% for Rebif, and 26.8% for CinnoVex. Five BAb-positive MS patients were lost to follow-up; thus 31 BAb-positive MS patients were studied for NAbs. NAbs were present in 25 (80.6%) of BAb-positive MS patients receiving IFN-beta. In conclusion, the three IFN-beta preparations have different degrees of immunogenicity.

Interferon beta-1b Treatment in a Korean Girl with Multiple Sclerosis / 대한소아신경학회지

Here we report a case of pediatric multiple sclerosis treated with interferon beta-1b. Interferon beta is widely used in adult patients with multiple sclerosis (MS). However, its effects and safety in pediatric patients have not been well established. Although supporting data are limited, the use of disease modifying therapies (DMTs) such as interferon beta-1b is recommended early in treatment of children with MS. Reports of interferon beta treatment in pediatric MS patients in Korea are rare. In this report, we describe a Korean girl who was effectively treated with interferon beta-1b for three years. There were no relapses or serious side effects. Therefore, this report provides evidence supporting the use of interferon beta in pediatric MS patients in Korea and other Asian countries. We also reviewed current medical treatment of MS, including some DMTs and second-line treatment options such as natalizumab and cyclophosphamide, and several new oral agents such as fingolimod.

Clinical response to interferon beta and glatiramer acetate in multiple sclerosis patients: a Brazilian cohort / Resposta terapêutica ao interferon beta e ao acetato de glatiramer em pacientes com esclerose múltipla: estudo de uma coorte brasileira

INTRODUCTION: Many patients with multiple sclerosis (MS) are currently receiving treatment with interferon beta (IFNb) and glatiramer acetate (GA). Identifying nonresponders patients is important to define therapy strategies. Several criteria for treatment response to IFNb and GA have been proposed. OBJECTIVE: It was to investigate the response to treatment with IFNb-1a, IFNb-1b and GA among relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: We analyzed treatment response to IFNb and GA in ninety-one RRMS patients followed for at least one year. Clinical response was established by clinical criteria based on relapses, disability progression or both. RESULTS: We observed a proportion of nonresponders, ranging from 3.3 to 42.9%, depending on the stringency of the criteria used. CONCLUSIONS: Our sample of Brazilian patients with MS has similarities when compared to other studies and there was no statistically significant difference regarding age, gender, ethnicity or disease duration between responders and nonresponders.

INTRODUÇÃO: Muitos pacientes com esclerose múltipla (EM) estão atualmente recebendo tratamento com interferon beta (IFNb) e acetato de glatiramer (AG). Identificar pacientes não respondedores é importante para definir estratégias terapêuticas. Foram propostos vários critérios para definir a resposta ao tratamento com IFNb e AG. OBJETIVO: Foi investigar a resposta ao tratamento com IFNb-1a, IFNb-1b e AG entre pacientes com esclerose múltipla remitente-recorrente (EMRR). MÉTODOS: Analisamos a resposta ao tratamento com IFNb e AG em 91 pacientes com EMRR acompanhados por um período de pelo menos um ano. A resposta clínica foi estabelecida por critérios baseados em surtos, progressão da incapacidade ou ambos. RESULTADOS: Observamos uma proporção de não respondedores que variou de 3,3 a 42,9%, dependendo do rigor do critério utilizado. CONCLUSÕES: Nossa amostra de pacientes brasileiros com EM tem semelhanças quando comparada a outros estudos e não apresentou diferença estatisticamente significativa entre respondedores e não respondedores com relação à idade, sexo, etnia ou duração da doença.