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BACKGROUND: Several pieces of evidence have shown the neurotrophic effect of erythropoietin (EPO) and its introduction in the therapeutic practice of neurological diseases. However, its usefulness in the treatment of spinocerebellar ataxia type 2 (SCA2) has not been proven despite the fact that it is endogenously reduced in these patients. OBJECTIVE: The study aims to investigate the safety, tolerability, and clinical effects of a nasally administered recombinant EPO in SCA2 patients. METHODS: Thirty-four patients were enrolled in this double-blind, randomized, placebo-controlled, phase I-II clinical trial of the nasally administered human-recombinant EPO (NeuroEPO) for 6 months. The primary outcome was the change in the spinocerebellar ataxia functional index (SCAFI), while other motor, neuropsychological, and oculomotor measures were assessed. RESULTS: The 6-month changes in SCAFI score were slightly higher in the patients allocated to NeuroEPO treatment than placebo in spite of the important placebo effect observed for this parameter. However, saccade latency was significantly decreased in the NeuroEPO group but not in placebo. The frequency and severity of adverse events were similar between both groups, without evidences of hematopoietic activity of the drug. CONCLUSIONS: This study demonstrated the safety and tolerability of NeuroEPO in SCA2 patients after 6 months of treatments and suggested a small clinical effect of this drug on motor and cognitive abnormalities, but confirmatory studies are warranted. © 2022 International Parkinson and Movement Disorder Society.
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Eritropoetina , Ataxias Espinocerebelares , Método Duplo-Cego , Epoetina alfa , Eritropoetina/uso terapêutico , Estudos de Viabilidade , Humanos , Proteínas Recombinantes/uso terapêutico , Ataxias Espinocerebelares/tratamento farmacológicoRESUMO
Itolizumab is a humanized monoclonal antibody that selectively targets the CD6-ALCAM pathway. This article reports on the safety and efficacy of itolizumab in the treatment of moderate-to-severe plaque psoriasis in a clinical study conducted in Cuba in the setting of an expanded-access program (EAP). The study included 84 patients who had previously received conventional anti-psoriatic systemic therapies but were either intolerant, had an inadequate response, or had contraindications to these therapies. It consisted of multiple phases, including a 12-week induction phase, a 40-week maintenance phase, and a 24-week off-treatment follow-up phase, using either a 0.4 or 1.6 mg/Kg dose. The results showed that itolizumab monotherapy was safe and effective during 52 weeks of continuous treatment and the subsequent 24 follow-up weeks. Itolizumab treatment resulted in a significant improvement (PASI 75) in 80 % of patients at the end of the induction phase, and this effect was sustained till week 52 during the maintenance phase. Moreover, 24 weeks after treatment stopped nearly two-thirds of patients still showed a PASI ≥ 75. The observed effects were dose-dependent, with 1.6 mg/kg being the most convenient dose. This study further supports the strategy of targeting the CD6-ALCAM signaling pathway for the treatment of psoriasis and the use of itolizumab as a valuable asset in the armamentarium of anti-psoriasis drugs.
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Anticorpos Monoclonais Humanizados , Psoríase , Humanos , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Índice de Gravidade de Doença , Idoso , CubaRESUMO
We conducted a phase I-IIa, randomized, monocentric, double-blind, placebo-controlled clinical trial to evaluate the safety and impact of the combination treatment of Itolizumab and insulin on preserving beta cell function in adults with recent-onset type 1 diabetes. Twelve patients were randomly assigned to three treatment groups, each receiving a different Itolizumab dose (0.4/0.8/1.6 mg/kg body weight, respectively) and a placebo group. All patients received concomitant intensive multiple-dose insulin therapy. Endogenous insulin secretion was assessed by the measurement of C-peptide during the mixed-meal tolerance test. No serious adverse events were reported. No changes in the total daily insulin doses, glycated hemoglobin levels, and stimulated C-peptide were observed between the Itolizumab and placebo groups at 52 weeks. A significant decrease in stimulated C-peptide was observed during the follow-up period (p = 0.012). One subject treated with 1.6 mg of Itolizumab showed a marked increase in the levels of stimulated C-peptide three years after completion of the trial. Taken together, this is the first study to demonstrate that combination treatment with Itolizumab and insulin is safe in humans and does not affect the residual function of beta cells up to 52 weeks. The findings from our study show preliminary evidence that high doses of Itolizumab could potentially arrest the loss of beta cell function in the long term. Further studies with a longer follow-up and larger numbers of patients are envisaged to assess the effect with high dose Itolizumab.
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RESUMEN Introducción: La prueba de tolerancia de comida mixta es considerada la prueba de oro para la medición de la producción de insulina endógena en pacientes con diabetes tipo 1. Objetivo: Determinar la utilidad de la prueba de tolerancia de comida mixta con Nutrial I para evaluar la función de las células ß en diabéticos tipo 1 de diagnóstico reciente y la relación de esa función con algunas características clínicas y bioquímicas. Métodos: Se estudiaron variables bioquímicas como la glucemia, hemoglobina glucosilada (HbA1c), péptido C y fracciones lipídicas. La prueba de tolerancia de comida mixta con Nutrial I se aplicó a 18 sujetos con diabetes tipo 1 de diagnóstico reciente y a 8 voluntarios con edades comprendidas entre 19 y 35 años. El consumo del suplemento Nutrial I se calculó según el peso del paciente. Se obtuvieron muestras para glucemia y péptido C a los -10, 0, 30, 60, 90 y 120 minutos. Resultados: Se observaron concentraciones elevadas de glucemia y disminuidas de péptido C durante la prueba de tolerancia de comida mixta en los diabéticos tipo 1 de diagnóstico reciente, en comparación con los voluntarios, así como, diferencias en las áreas bajo la curva de péptido C (AUC-pc) (p= 0,001). En los diabéticos tipo 1 de diagnóstico reciente se evidenció una correlación negativa entre el AUC-pc con los niveles de glucemia en ayunas (r= -0,747; p ( 0,0001) y la HbA1c (r= -0,535; p= 0,022). Por el contrario, se encontró una correlación positiva entre el AUC-pc y el péptido C en ayunas (r= 0,722; p= 0,001). El AUC-pc después de la prueba de tolerancia de comida mixta es mayor en los sujetos con glucemia en ayunas si GA < 7 mmol/L con respecto a los sujetos con glucemia en ayunas ( 7 mmol/L (p= 0,012). Conclusiones: El empleo del Nutrial I en la prueba de tolerancia de comida mixta fue útil en la evaluación de la función de las células β en diabéticos tipo 1 de diagnóstico reciente. Los valores bajos de glucemia en ayunas durante esta prueba son marcadores indirectos de una función residual de células ( más conservada en los diabéticos tipo 1 de diagnóstico reciente(AU)
ABSTRACT Introduction: The tolerance test of mixed food is considered the gold standard for the measurement of endogenous insulin production in patients with diabetes type 1. Objective: To determine the usefulness of the tolerance test of mixed food with Nutrial I to assess the ß-cells function in patients with diabetes type 1 of recent diagnosis and the relation of this function with some clinical and biochemical characteristics. Methods: There were studied biochemical variables as the blood glucose, glycosylated haemoglobin (HbA1c), C-peptide and lipid fractions. The tolerance test of mixed food with Nutrial I was applied to 18 individuals with diabetes type 1 of recent diagnosis and in 8 volunteers aged between 19 and 35 years old. The consumption of Nutrial I supplement was calculated according to the weight of the patient. Samples were obtained for blood glucose and C-peptide at -10, 0, 30, 60, 90 and 120 minutes. Results: There were observed high concentrations of glycemia and decreased amounts of C-peptide during the tolerance test of mixed food in recently diagnosed type 1 diabetics in comparison with the volunteers, as well as differences in areas under the curve of C-peptide (AUC-pc) (p= 0.001). In the recently diagnosed type 1 diabetics was evident a negative correlation between the AUC-pc with fasting plasma glucose levels (r= -0,747; p(0.0001) and HbA1c (r= -0,535; p= 0.022). On the contrary, it was found a positive correlation between the AUC-pc and fasting C-peptide (r = 0.722; p = 0.001). The AUC-pc after the tolerance test of mixed food was greater in subjects with fasting blood glucose < 7 mmol/L with respect to the subjects with fasting blood glucose ( 7 mmol/L (p= 0.012). Conclusions: The use of Nutrial I in the tolerance test of mixed food was useful in the assessment of the role of the β-cells in patients with recently diagnosed diabetes type 1. Low values of fasting blood glucose during this test are indirect markers of a residual function of (cells more preserved in type 1 diabetics of recent diagnosis(AU)
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Humanos , Glicemia/fisiologia , Diabetes Mellitus Tipo 1/diagnóstico , Secreção de Insulina/fisiologia , Epidemiologia Descritiva , Estudos TransversaisRESUMO
Introducción: el uso de anticuerpos monoclonales transformó el tratamiento de los linfomas no hodgkinianos. El Centro de Inmunología Molecular generó un anticuerpo anti-CD20 (CIMABior®) biosimilar del rituximab, que se ha caracterizado desde el punto de vista biológico, pero la seguridad y eficacia aún están en estudio. Objetivo: evaluar la seguridad y la respuesta al tratamiento con CIMABior ®, en pacientes con síndromes linfoproliferativos de células B tratados con intención compasiva. Métodos: estudio multicéntrico, exploratorio, con dos grupos de tratamiento (monoterapia o combinado con quimioterapia) no controlado, ni aleatorizado. Se incluyeron adultos con linfomas no hodgkinianos y leucemia linfocítica crónica, no elegibles para el ensayo clínico en ejecución con este producto. Se determinó la frecuencia de eventos adversos y se caracterizaron. La respuesta al tratamiento se definió como: remisión completa, remisión parcial, enfermedad estable o en progresión. Se calculó la tasa de respuesta objetiva (remisión completa más remisión parcial) con el intervalo de confianza al 95 por ciento, se evaluó la relación de algunas variables con la respuesta y se estimó la razón de Odss. Como medida de balance beneficio-riesgo se estimó el factor de Bayes. Resultados: los eventos adversos más frecuentes fueron: temblor (12,8 por ciento) y fiebre (10,3 por ciento). Los relacionados con el producto (43,4 por ciento) fueron leves o moderados y evolucionaron hacia la recuperación. No se informó muerte asociada directamente al tratamiento. Se constató respuesta objetiva global de 71,2 por ciento (59,6 por ciento de remisiones completas y 11,5 por ciento, parciales). La respuesta objetiva en el grupo de monoterapia fue de 66,7 por ciento y de 73,0 por ciento en el grupo de CIMABior® más quimioterapia, con remisiones completas de 46,7 por ciento y 64,9 por ciento, respectivamente. Conclusiones: el AcM CIMABior® es seguro, bien tolerado y se demostraron evidencias de efecto. El tratamiento aportó un beneficio clínico superior al riesgo de desarrollar algún evento adverso grave(AU)
Introduction : The use of monoclonal antibodies transformed the treatment of non-Hodgkin lymphomas. The Center of Molecular Immunology created an anti-CD20 monoclonal antibody (CIMABior®), biosimilar of rituximab, which has been characterized from a biological point of view, but the safety and effectiveness are still being studied. Objective: Evaluate the safety and response to treatment, in patients with B-cell malignancies with compassionate use of CIMABior®. Methods : A multicenter, exploratory, non-controlled, non-randomized study was conducted with two variants of treatments (monotherapy or combined with chemotherapy). Adults with non-Hodgkin lymphomas and chronic lymphocytic leukemia not eligible for clinical trial with this product were included. Frequency of adverse events was calculated and those were characterized. The response to treatment was defined as: complete response, partial response, stable disease or progressive disease. Overall response rate (complete plus partial remission) was calculated with 95 percent confidence interval. The relation of some variables with response was estimated per Odss ratio. As a measure of the benefit-risk balance, the Bayes factor was estimated. Results : The more frequent adverse events were: tremors (12.8 percent) and fever (10.3 percent). Those related to the product (43.4 percent) were minor and evolved to recovery. There were no deaths in reference to the treatment. An overall response of 71.2 percent was confirmed (59.6 percent complete remissions and 11.5 percent partial remission). The monotherapy group objective response was 66.7 percent and 73.0 percent in the CIMABior® plus chemotherapy group, with complete remissions of 46.7 percent and 64.9 percent respectively. Conclusions: The monoclonal antibodies CIMABor® is safe, well tolerated and evidences of its effectiveness was demonstrated. The treatment provided a superior clinical benefit to the risk of developing a severe adverse event(AU)
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Humanos , Masculino , Feminino , Linfoma não Hodgkin/terapia , Leucemia de Células B/terapia , Resultado do Tratamento , Cuba , Ensaios de Uso Compassivo/ética , Citometria de Fluxo/métodos , Antineoplásicos Imunológicos/uso terapêutico , Anticorpos/uso terapêuticoRESUMO
Introducción: la molécula CD6 es una glicoproteína de membrana considerada un antígeno de diferenciación leucocitario. El anticuerpo monoclonal humanizado itolizumab (anti-CD6) reconoce la molécula CD6 humana en las células mononucleares periféricas malignas de pacientes con leucemia linfocítica crónica- B y en los linfocitos de lesiones cutáneas de pacientes con linfoma T cutáneo. Objetivo: exponer los resultados preliminares de tres pacientes con leucemia linfocítica crónica-B tratados con el itolizumab, con dosis de 0.8 mg/kg/dosis semanal por 12 semanas. Métodos: la evaluación de la toxicidad asociada a la administración del itolizumab se realizó según Common Terminology Criteria for Adverse Events, versión 3.0, y la evaluación del beneficio clínico se definió según los criterios de respuesta, previamente establecidos por el National Cancer Institute Work Group, en remisión completa, remisión parcial, enfermedad estable, progresión y recaída. La evaluación de la respuesta se realizó después de haber recibido 6 administraciones del itolizumab (semana 7), después de haber recibido las 12 administraciones del itolizumab (semana 13), 6 semanas después de la última dosis (semana 18) y 12 semanas después de la última dosis (semana 24). Los datos de cada paciente se recogieron en las historias clínicas. Resultados: se evaluó la seguridad de la administración del producto en pacientes con síndromes linfoproliferativos CD6+ y se obtuvieron evidencias preliminares del efecto terapéutico de dicho fármaco. Conclusiones: en el 100 por ciento de los pacientes incluidos se reportó la aparición de fiebre y escalofríos relacionados con la primera infusión. No se observaron efectos adversos serios. Todos los pacientes evaluados tuvieron al menos alguna mejoría clínica o hematológica...
CD6 molecule is a membrane glycoprotein considered a leukocyte differentiation antigen. Itolizumab, humanized monoclonal antibody (anti-CD6) recognizes the human CD6 molecule in malignant peripheral mononuclear cells of patients with B-cell chronic lymphocytic leukemia and in lymphocytes of cutaneous lesions in patients with cutaneous T- cell lymphoma. We describe preliminary results of 3 patients with B-cell chronic lymphocytic leukemia treated with itolizumab at a weekly dose of 0.8mg/kg/dose for 12 weeks. Product administration safety was evaluated in patients with CD6+ lymphoproliferative disorders and preliminary evidence of therapeutic effect of the drug was obtained. In 100 percent of the patients the onset of fever and chills associated to the first infusion were reported. No serious adverse effects were observed. All patients evaluated had at least some clinical or hematological improvement...
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Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Avaliação de Medicamentos/métodos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Transtornos Linfoproliferativos/tratamento farmacológicoRESUMO
Los organismos con tejidos renovables tuvieron que evolucionar mecanismos que le permitieran prevenir el desarrollo de tumores. Entre esos mecanismos está la senescencia celular y la apoptosis o muerte celular programada. El primero impide de forma irreversible el crecimiento de células propensas a sufrir transformaciones neoplásicas; el segundo, mata células dañadas, que posean mutaciones y que puedan resultar peligrosas para el organismo. En trabajos recientes se ha demostrado cómo la pérdida de la apoptosis repercute en la iniciación del tumor, la progresión y el desarrollo de las metástasis. Por otra parte, se ha estudiado la complejidad del fenotipo senescente y su influencia sobre el organismo. Ambos mecanismos pudieran constituir ejemplos de pleiotropismo antagónico y la profundización en el balance que existe entre sus propiedades supresoras de tumores y sus aportes al fenotipo envejecido será esencial en el desarrollo de estrategias racionales para prevenir el cáncer y el proceso de envejecimiento.
Organisms with renewable tissues had to evolve mechanisms that would allow them to prevent the development of tunors. Cellular senescence and apoptosis or programmed cell death are among those mechanisms. The first irreversibly prevents the growth of cells prone to suffer neoplastic transformations. The second kills damaged cells that have mutations and that may be dangerous for the organism. In recent papers it has been proved how the loss of the apotopsis has a repercussion on the initiation of the tumor, the progression and the development of metastasis. On the other hand, the complexity of the senescent phenotype ant its influence on the organism has been studied. Both mechanisms could be examples of antagonistic pleiotropy and the deepening in the balance existing between its tumor- suppressing properties and its contributions to the aged phenotype will be esential in the development of rational strategies to prevent cancer and the aging process.