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RESUMEN Introducción: En Cuba se empezó la aplicación nasal de IFN alfa 2b recombinante humano (Nasalferon) en personal de riesgo para prevenir la infección por el SARS-CoV-2. Objetivo: caracterizar la seguridad de los expuestos al uso del Nasalferon en el Centro de Investigaciones Médico Quirúrgicas y explorar el efecto del uso profiláctico del fármaco contra cuadros respiratorios agudos causados preferentemente por el SARS-CoV-2. Material y Métodos: Estudio epidemiológico monocéntrico, prospectivo, abierto, de vigilancia temprana en trabajadores sanitarios, a los que se le administró nasalferon. Se realizó la vigilancia mediante el método de Vigilancia del Monitoreo de Eventos Adversos Ligados a la Prescripción. La variable principal fue la presencia de eventos adversos. Secundariamente se exploró el efecto del fármaco en la prevención de infección por el virus. Para el análisis de la variable principal se estimó la proporción de sujetos con cada uno de los eventos adversos que se presentaron. Se estimaron, además, la distribución de frecuencia del tipo de evento, intensidad, gravedad y la causalidad o imputabilidad. Resultados: Se incluyeron 86 sujetos, de ellos, 50 experimentaron 15 tipos de eventos adversos. No se reportaron eventos severos ni graves. Los catalogados como moderados fueron: cefalea, leucopenia, decaimiento e hipertensión arterial. Durante el tiempo que duró el tratamiento y hasta un mes después de este, ninguno de los sujetos incluidos presentó COVID-19 ni otros cuadros respiratorios agudos virales. Conclusiones: El Nasalferon resultó ser un fármaco seguro y tolerable y los sujetos incluidos no presentaron cuadros respiratorios agudos relacionados o no con la COVID-19.
ABSTRACT Introduction: In Cuba, the nasal application of recombinant human IFN-alpha- 2b (nasalferon) began in personnel at risk in order to prevent SARS-CoV-2 infection. Objective: To characterize the safety in those subjects exposed to the use of Nasalferon at the Surgical Medical Research Center and to explore the effect of the prophylactic use of the drug against acute respiratory symptoms mainly caused by SARS-CoV-2. Material and Methods: Monocentric, prospective, open, and early surveillance epidemiological study conducted in healthcare workers who were administered Nasalferon. Surveillance was performed using the Prescription-Related Adverse Event Monitoring Surveillance method. The main variable was the presence of adverse events. Secondarily, the effect of the drug in preventing virus infection was explored. For the analysis of the main variable, the proportion of subjects who experienced each of the adverse events was estimated. In addition, the frequency distribution of the type of event, intensity, severity, and causality or imputability were estimated. Results: A total of 86 subjects were included; 50 of them experienced 15 types of adverse events. No severe or serious events were reported. Headache, leukopenia, decay, and arterial hypertension were classified as moderate ones. During the whole duration of the treatment and until a month after it, none of the subjects included in the study presented COVID-19 or other viral acute respiratory symptoms. Conclusions: Nasalferon proved to be a safe and tolerable drug and the included subjects did not present acute respiratory symptoms related or unrelated to COVID-19.
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HumanosRESUMO
NTRODUCTION Diabetic foot ulcers are a chronic complication in patients with diabetes mellitus. They appear as a result of the combination of diabetic polyneuropathy and angiopathy, and in many cases require amputation of the affected extremity. Clinical trials have demonstrated that repeated local infiltration with Heberprot-P can improve healing of chronic diabetic foot ulcers. Although there is evidence of its effects as a granulation stimulator and on cell migration and proliferation, genetic control mechanisms explaining its anti-inflammatory and oxidative stress reduction properties are not yet thoroughly understood. OBJECTIVE Analyze changes in expression of genes involved in healing after treatment of diabetic foot ulcers with Heberprot-P. METHODS Biopsies were collected from diabetic foot ulcers of 10 responding patients before and after 2 weeks' treatment with Heberprot-P (75-µg applied intralesionally 3 times per week). Total RNA was obtained and quantitative PCR used to determine expression of 26 genes related to inflammation, oxidative stress, cell proliferation, ngiogenesis and extracellular matrix formation. Genetic expression was quantified before and after treatment using REST 2009 v2.0.13. RESULTS After treatment, there was a statistically significant increase in expression of genes related to cell proliferation, angiogenesis and formation of extracellular matrix (PDGFB, CDK4, P21, TP53, ANGPT1, COL1A1, MMP2 and TIMP2). A significant decrease was observed in gene expression related to inflammatory processes and oxidative stress (NFKB1, TNFA and IL-1A). CONCLUSIONS Our findings suggest that Heberprot-P's healing action on diabetic foot ulcers is mediated through changes in genetic expression that reduce hypoxia, inflammation and oxidative stress, and at the same time increase cell proliferation, collagen synthesis and extracellular matrix remodeling. The kinetics of expression of two genes related to extracellular matrix formation needs further exploration. KEYWORDS Epidermal growth factor, EGF, diabetic foot ulcer, wound healing, quantitative real-time PCR, gene expression, Cuba.
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Pé Diabético/tratamento farmacológico , Fator de Crescimento Epidérmico/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Biópsia , Pé Diabético/metabolismo , Pé Diabético/patologia , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes , TranscriptomaRESUMO
BACKGROUND: More potent antitumor activity is desired in Interferon (IFN)-treated cancer patients. This could be achieved by combining IFN alpha and IFN gamma. The aim of this work was to characterize the pharmacokinetics and pharmacodynamics of a novel formulation containing a co-formulated combination of IFNs alpha-2b and gamma (CIGB-128-A). METHODS: A group of nine healthy male subjects received intramuscularly 24.5 × 106 IU of CIGB-128-A. IFN concentrations were evaluated for 48 h. Serum neopterin, beta2-microglobulin (ß2M) and 2'-5' oligoadenylate synthetase (2'-5' OAS), classical IFN-inducible serum markers, were measured during 192 h by enzyme immunoassay and body temperature was used as pharmacodynamic variable as well. RESULTS: Concerning pharmacokinetics, serum IFNs' profiles were better fitted to a mono-compartmental model with consecutive zero order and first order absorption, one bioavailability value. No interferences by simultaneous administered IFNs were observed in their typical similar systemic profiles. Neopterin and ß2M time profiles showed a delay that was efficiently linked to pharmacokinetics by means of a zero order absorption rate constant. Neopterin level was nine-fold higher than initial values, 48 h post-administration, an increment not described before. At this time, mean serum ß2M peaked around the double from baseline. Serum concentrations of the enzyme 2'-5' OAS was still elevated on the 8 day post-injection. The formulation was well tolerated. Most frequent adverse reactions were fever, headache, arthralgia and lymphopenia, mostly mild. CONCLUSIONS: The administration of co-formulated IFN alpha-2b and IFN gamma likely provides improved pharmacodynamic properties that may be beneficial to treat several malignancies. TRIAL REGISTRATION: Cuban Public Registry of Clinical Trials RPCEC00000118 , May 24, 2011.
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Composição de Medicamentos/métodos , Interferon-alfa/administração & dosagem , Interferon-alfa/farmacocinética , Interferon gama/administração & dosagem , Interferon gama/farmacocinética , Adulto , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Injeções Intramusculares , Interferon alfa-2 , Masculino , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Adulto JovemRESUMO
BACKGROUND: After several exploratory and confirmatory clinical trials, the intralesional administration of human recombinant epidermal growth factor (hrEGF) has been approved for the treatment of advanced diabetic foot ulcers (DFU). The aim of this work was to evaluate the effectiveness and safety of this procedure in medical practice. METHODS: A prospective, post-marketing active pharmacosurveillance was conducted in 41 hospitals and 19 primary care polyclinics. Patients with DFU received hrEGF, 25 or 75 µg, intralesionally 3 times per week until complete granulation of the ulcer or 8 weeks maximum, adjuvant to standard wound care. Outcomes measured were complete granulation, amputations, and adverse events (AE) during treatment; complete lesion re-epithelization and relapses in follow-up (median: 1.2; maximum 4.2 years). RESULTS: The study included 1788 patients with 1835 DFU (81% Wagner's grades 3 or 4; 43% ischemic) treated from May 2007 to April 2010. Complete granulation was observed in 76% of the ulcers in 5 weeks (median). Ulcer non-ischemic etiology (OR: 3.6; 95% CI: 2.8-4.7) and age (1.02; 1.01-1.03, for each younger year) were the main variables with influence on this outcome. During treatment, 220 (12%) amputations (171 major) were required in 214 patients, mostly in ischemic or Wagner's grade 3 to 5 ulcers. Re-epithelization was documented in 61% of the 1659 followed-up cases; 5% relapsed per year. AE (4171) were reported in 47% of the subjects. Mild or moderate local pain and burning sensation, shivering and chills, were 87% of the events. Serious events, not related to treatment, occurred in 1.7% of the patients. CONCLUSIONS: The favorable benefit/risk balance, confirms the beneficial clinical profile of intralesional hrEGF in the treatment of DFUs.
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Pé Diabético/tratamento farmacológico , Fator de Crescimento Epidérmico/uso terapêutico , Vigilância de Produtos Comercializados , Cicatrização/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Amputação Cirúrgica/estatística & dados numéricos , Pé Diabético/epidemiologia , Pé Diabético/cirurgia , Relação Dose-Resposta a Droga , Fator de Crescimento Epidérmico/administração & dosagem , Fator de Crescimento Epidérmico/efeitos adversos , Feminino , Tecido de Granulação/efeitos dos fármacos , Humanos , Injeções Intralesionais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To determine if partial wound closure surrogate markers proposed for neuropathic, small diabetic foot ulcers (DFUs) can be extended to advanced lesions and if the development of granulation tissue can be used to predict complete healing. RESEARCH DESIGN AND METHODS: Data from two multicenter, double-blind, randomized clinical trials (one of them placebo controlled) that used intralesional recombinant human epidermal growth factor (rhEGF) to promote granulation and healing were used. For confirmation in a larger sample from common clinical practice, the results of an active postmarketing surveillance of rhEGF treatment of DFUs in 60 healthcare units was included. The surrogates evaluated were percent area change, log healing rate, ratio of log areas, and percent of granulation tissue covering the wound area. The tests used were surrogate final end point correlation, receiver operating characteristic curves to discriminate healers from nonhealers, validation tests using logistic regression models, and the proportion-mediated estimation. RESULTS: Two weeks >50% granulation, end of treatment >75% granulation, and 16.1% area change showed significant predictive value (>70% correct classification) for final wound closure. The granulation-based variables fulfilled the criterion that the effect of rhEGF treatment on wound closure was mediated by the surrogate. CONCLUSIONS: This work provides the first evidence for the use of granulation tissue development as a predictor of wound healing in advanced DFUs. These results can be useful for clinical trial design, particularly during the exploratory phase of new products.
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Pé Diabético/tratamento farmacológico , Fator de Crescimento Epidérmico/uso terapêutico , Cicatrização/efeitos dos fármacos , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: The synergistic combination of interferon (IFN) alpha-2b and IFN gamma results in more potent in vitro biological effects mediated by both IFNs. The aim of this investigation was to evaluate by first time the pharmacokinetics and pharmacodynamics of this combination in patients with mycosis fungoides. METHODS: An exploratory, prospective, open-label clinical trial was conducted. Twelve patients, both genders, 18 to 75 years-old, with mycosis fungoides at stages IB to III, were eligible for the study. All of them received intramuscularly a single high dose (23 × 10(6) IU) of a novel synergistic IFN mixture (HeberPAG) for pharmacokinetic and pharmacodynamic studies. Serum IFN alpha-2b and IFN gamma concentrations were measured during 96 hours by commercial enzyme immunoassays (EIA) specific for each IFN. Other blood IFN-inducible markers and laboratory variables were used as pharmacodynamics and safety criteria. RESULTS: The pharmacokinetic evaluation by EIA yielded a similar pattern for both IFNs that are also in agreement with the well-known described profiles for these molecules when these are administered separately. The average values for main parameters were: Cmax: 263 and 9.3 pg/mL; Tmax: 9.5 and 6.9 h; AUC: 4483 and 87.5 pg.h/mL, half-life (t(1/2)): 4.9 and 13.4 h; mean residence time (MRT): 13.9 and 13.5 h, for serum IFN alpha-2b and IFN gamma, respectively. The pharmacodynamic variables were strongly stimulated by simultaneous administration of both IFNs: serum neopterin and beta-2 microglobulin levels (ß2M), and stimulation of 2'-5' oligoadenylate synthetase (OAS1) mRNA expression. The most encouraging data was the high increment of serum neopterin, 8.0 ng/mL at 48 h, not been described before for any unmodified or pegylated IFN. Additionally, ß2M concentration doubled the pre-dose value at 24-48 hours. For both variables the values remained clearly upper baseline levels at 96 hours. CONCLUSIONS: HeberPAG possesses improved pharmacodynamic properties that may be very useful in the oncologic setting. Efficacy trials can be carried out to confirm these findings. TRIAL REGISTRATION: Registro Público Cubano de Ensayos Clínicos RPCEC00000130.
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Antineoplásicos/farmacocinética , Interferon-alfa/farmacocinética , Interferon gama/farmacocinética , Micose Fungoide/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Química Farmacêutica , Cuba , Combinação de Medicamentos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Feminino , Meia-Vida , Humanos , Injeções Intramusculares , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interferon-alfa/sangue , Interferon-alfa/uso terapêutico , Interferon gama/efeitos adversos , Interferon gama/sangue , Interferon gama/uso terapêutico , Masculino , Pessoa de Meia-Idade , Micose Fungoide/sangue , Micose Fungoide/metabolismo , Neopterina/agonistas , Neopterina/sangue , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/metabolismoRESUMO
Introducción: el índice HOMA-IR es un procedimiento simple, poco invasivo, y que permite, mediante una fórmula validada y bien establecida, precisar un valor numérico expresivo de resistencia insulínica. Calcular el índice HOMA-IR con un solo valor de insulinemia pudiera presentar una mayor variabilidad, lo cual se trata de solucionar con al menos la media de 3 insulinemias, de acuerdo con la fórmula original. En varios estudios es habitual que se realice con una sola determinación de insulinemia. Por esa razón se decidió hacer un estudio en pacientes con diabetes tipo 2 y comparar los resultados en cuanto a sensibilidad y especificidad con una sola determinación de sangre para la insulinemia y glucemia.Objetivo: evaluar la sensibilidad y especificidad de cada una de las determinaciones de insulinemia realizadas cada 5 min contra la media de estas durante la aplicación de la fórmula para el índice HOMA-IR.Métodos: se estudiaron 60 pacientes con diagnóstico de diabetes tipo 2, que acudieron a los servicios de consulta externa y de orientación en el Centro de Atención al Diabético de La Habana. Tenían un tiempo de evolución de la diabetes menor de 5 años como promedio, con predominio en el sobrepeso corporal, fueron captados en un período de 6 meses de forma consecutiva, y se les realizaron determinaciones de insulinemias y glucemias en ayunas mediante trocar y extracción de sangre venosa a los 0,5 y 10 min, para realizarles el cálculo del modelo homeostático de Matthews conocido como HOMA-IR.Resultados: un 88,3 por ciento tenía un HOMA-IR mayor de 3,2. La sensibilidad de una sola muestra de insulinemia, aunque elevada para confirmar el diagnóstico de resistencia insulínica, es variable, y la especificidad de una de las muestras resultó baja con un 14 por ciento. Se aprecia una adecuada concordancia entre los valores predictivos positivos con la sensibilidad y los valores predictivos negativos con la especificidad de la prueba. Conclusiones: una sola determinación de insulinemia para estudiar el HOMA-IR es de utilidad en la práctica diaria, aunque resulta de mucha mayor precisión aplicar la fórmula original para una mejor reproducibilidad(AU)
Introduction: HOMA-IR index is a simple and not much invasive procedure allowing by a validated and well established formula to specify exactly a value expression of insulin resistance. To estimate the HOMA-IR index with an only numerical value of insulinemia could to present a greater variability, something that could be solved with at least the mean of three insulinemias, according to original formula. En some studies it is habitual to perform it with a single insulinemia determination. Thus, we conducted a study in patients presenting type 2 diabetes and to compare the results as regards the sensitivity and specificity with a single blood determination for insulinemia and glycemia. Objectives: to assess the sensitivity and specificity of each of insulinemia determinations performed each 5 min versus the mean of these determinations during the application of formula for HOMA-IR index. Methods: sixty patients diagnosed with type 2 diabetes attended in the Center for Diabetic Care of La Habana were studied. They had a diabetes course time lower than 5 years as average with predominance of body excess weight recruited during 6 months in a consecutive way and the carrying out of fasting insulinemias and glycemias determinations by trocar and venous blood extraction at 0,5 and 10 min for a calculation of Mathews's hemostatic model known as HOMA-IR. Results: a 88,3 percent had a HOMA-IR greater than 3,2. The sensitivity of a single sample of insulinemia, although high to confirm the insulin resistance diagnosis, it is variable and specificity of one of samples was low with a 14%. There is an appropriate concordance among the positive predictor values with sensitivity and the negative predictive values with the test specificity. Conclusions: a single insulinemia determination to study HOMA-IR is useful in daily practice, although it is necessary much accuracy to apply the original formula for a better reproducibility(AU)
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Humanos , Resistência à Insulina/fisiologia , Diabetes Mellitus Tipo 2/diagnóstico , Teste de Tolerância a Glucose/métodos , Sensibilidade e Especificidade , Índice GlicêmicoRESUMO
Objetivos Describir la carga integral asociada a localizaciones ginecológicas de cáncer como son: mama, cuello de útero, endometrio y ovario, para Cuba, sus provincias y el Municipio Especial Isla de la Juventud, para los años 1990, 1995, 2000 y 2002. Métodos Se utilizó el indicador Años de Vida Ajustados por Discapacidad, obtenido como la suma de los Años de Vida Potencial Perdidos por mortalidad y los Años de Vida Potencial Perdidos por morbilidad. Los primeros se calcularon a partir de los estimados de Esperanza de Vida y los segundos, de las severidades, la incidencia y la duración promedio. Resultados El cáncer localizado en mama mostró la mayor carga por mortalidad y por morbilidad de manera consistente en los cuatro años para el país. La evolución de los Años de Vida Potencial Perdidos por mortalidad prematura por localización, fue ascendente en los años estudiados en las cuatro localizaciones ginecológicas. Las defunciones en edades más tempranas se debieron al cáncer de cuello. Excepto endometrio, el resto de las localizaciones incrementó su carga por morbilidad de 1990 al 2002. La carga integral aumentó en los años estudiados de 3,58 a 4,54, de 1,62 a 2,42, de 1,72 a 2,03 y de 0,86 a 0,88 por 1 000, para mama, cuello, endometrio y ovario, respectivamente. Se identificaron diferencias entre provincias, dentro de las que vale destacar la mayor carga integral por cáncer de mama en Ciudad de La Habana (6,72 por 1 000) y por cáncer de cuello en Camagüey y las provincias orientales. Conclusiones La evolución desfavorable de la carga del cáncer ginecológico en Cuba en los años estudiados fue a expensas tanto de la mortalidad como de la morbilidad.
Objectives To describe the comprehensive burden associated to gynecological cancer locations such as breast, uterine neck, endometrium and ovary for Cuba, its provinces and special municipality Isla de la Juventud during 1990,1995,2000 and 2002. Methods The disability-adjusted life year indicator, taken as the sum of potential years of life lost from mortality and the potential years of life lost from morbidity. The former was calculated on the basis of life expectancy estimates and the latter on the basis of severity, incidence and average duration of disease. Results The breast cancer consistently exhibited the highest burden caused by mortality and morbidity in the four studied years for the whole country. The potential years of life lost (PYLL) from premature death by location were on the rise in the four years for the four gynecological locations. Uterine cancer was responsible for deaths at younger ages. Except for endometrium, the rest of locations increased morbidity burden from 1990 to 2002. The comprehensive burden increased from 3.58 to 4.54; 1.62 to 2.42; 1.72 to 2.03 and 0.86 to 0.88 per 1 000 for breast, uterine neck, endometrium and ovary respectively. There were some differences among the provinces; it is worth to underline the highest comprehensive burden found in Ciudad de la Habana due to breast cancer (6.72 per 1000) and in Camagüey province and the rest of Eastern provinces due to uterine neck cancer. Conclusions Mortality and morbidity were both involved in the unfavorable development of the gynecological cancer burden in the studied years in Cuba.
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Anos de Vida Ajustados por Deficiência , Morbidade , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias dos Genitais Femininos/mortalidadeRESUMO
El presente trabajo tiene como objetivo identificar los factores biológicos y sociales que determinan la solicitud de ayuda médica en mujeres de edad mediana en un área urbana. Se realizó un estudio descriptivo transversal donde se seleccionaron, mediante el muestreo por conglomerados monoetápicos, 311 mujeres atendidas en 4 consultorios del médico de la familia del policlínico Área III, en Cienfuegos. A cada mujer se le realizó una entrevista para precisar sus características sociodemográficas, presencia de síntomas climatéricos y su intensidad, condicionamiento de género y sus conocimientos sobre climaterio y menopausia, así como los factores que se relacionaron con la solicitud de atención médica, la cual fue realizada por las mujeres con edades entre 45-54 años, con nivel escolar de preuniversitario, quienes presentaron síntomas climatéricos muy molestos y poseían un conocimiento adecuado sobre climaterio/menopausia. Entre las razones para no demandar ayuda médica se encontró que el 14,7 por ciento de las féminas refirió la falta de tiempo a pesar de tener síntomas molestos. La mayoría de las mujeres tuvo sobrecarga de género y conocimiento no adecuado sobre climaterio/menopausia. En conclusión, por primera vez en nuestro medio se reportan los factores sociales y biológicos que motivan o no atención médica durante el período del climaterio(AU)