Nitazoxanide: A Drug Repositioning Compound with Potential Use in Chagas Disease in a Murine Model.

Chagas disease (ChD), caused by Trypanosoma cruzi, is the most serious parasitosis in the western hemisphere. Benznidazole and nifurtimox, the only two trypanocidal drugs, are expensive, difficult to obtain, and have severe side effects. Nitazoxanide has shown to be effective against protozoa, bacteria, and viruses. This study aimed to evaluate the nitazoxanide efficacy against the Mexican T. cruzi Ninoa strain in mice. Infected animals were orally treated for 30 days with nitazoxanide (100 mg/kg) or benznidazole (10 mg/kg). The clinical, immunological, and histopathological conditions of the mice were evaluated. Nitazoxanide- or benznidazole-treated mice had longer survival and less parasitemia than those without treatment. Antibody production in the nitazoxanide-treated mice was of the IgG1-type and not of the IgG2-type as in the benznidazole-treated mice. Nitazoxanide-treated mice had significantly high IFN-γ levels compared to the other infected groups. Serious histological damage could be prevented with nitazoxanide treatment compared to without treatment. In conclusion, nitazoxanide decreased parasitemia levels, indirectly induced the production of IgG antibodies, and partially prevented histopathological damage; however, it did not show therapeutic superiority compared to benznidazole in any of the evaluated aspects. Therefore, the repositioning of nitazoxanide as an alternative treatment against ChD could be considered, since it did not trigger adverse effects that worsened the pathological condition of the infected mice.

Electrolyzed Oxidizing Water Modulates the Immune Response in BALB/c Mice Experimentally Infected with Trypanosoma cruzi.

Chagas disease is a major public health problem in Latin America. The mixed Th1/Th2 immune response is required against Trypanosoma cruzi. Electrolyzed oxidizing water (EOW) has been shown to have germicidal efficacy. The objective of this study was to evaluate the EOW effectiveness in T. cruzi-infected BALB/c mice clinically, immunologically, and histologically. The severity of the infection was assessed by parasitaemia, general health condition, mortality, mega syndromes, and histological lesions. IgG, TNF-alpha, IFN-gamma, and IL-1 beta levels were quantified. The EOW administration showed a beneficial effect on parasitaemia, general physical condition, and mortality. High levels of IgG1 at 50 days postinfection were observed. Prophylactic EOW treatment was able to induce a predominantly TH1 immune response based on an IgG2a levels increase at the late acute phase, and a 10-fold increase of INF-gamma in whole acute phase. EOW was able to control the acute phase infection as effectively as benznidazole. Splenomegaly was caused by EOW treatment and lymphadenopathy was stimulated by T. cruzi infection in all groups. Severe tissue damage was not prevented by EOW treatments. Moderate efficacy may be due to immunomodulatory properties and not to a direct toxic effect on the parasite.

Estudio piloto de monitorización terapéutica de nivolumab en la práctica clínica habitual / Therapeutic drug monitoring of nivolumab in routine clinical practice. A pilot study

OBJETIVO: Una revisión de la literatura sobre nivolumab permite verificar la existencia de diversos aspectos sin resolver sobre su intervalo de dosificación. El objetivo del presente estudio ha sido explorar las posibilidades de personalización del tratamiento con nivolumab mediante la monitorización terapéutica de sus concentraciones séricas para mejorar su efectividad y eficiencia. MÉTODO: Estudio observacional, prospectivo, realizado entre mayo de 2017 y junio de 2019 en pacientes tratados con nivolumab que estaban diagnosticados de diferentes tumores. Se obtuvieron muestras de sangre en la práctica clínica habitual, una vez alcanzado el estado de equilibrio de nivolumab. Las concentraciones séricas de nivolumab fueron determinadas mediante ELISA cuantitativo. La pauta posológica habitual de 3 mg/kg cada dos semanas tuvo que ser modificada en algunos pacientes debido a diferentes circunstancias, y las concentraciones séricas resultantes se compararon con las correspondientes a los pacientes en los que no se modificó y con datos publicados. RESULTADOS: Se analizaron muestras de 19 pacientes que recibieron inicialmente 3 mg/kg de nivolumab cada dos semanas. Se analizó un total de 39 muestras, entre los ciclos 6 y 27. La pauta habitual se modificó, una vez alcanzado el estado de equilibrio, en 12/19 (60%) pacientes, en los que se amplió el intervalo a 3, 4, 5, 6 o 7 semanas. No se encontraron diferencias estadísticamente significativas al comparar la administración cada dos semanas y cada cuatro semanas. Cuando los intervalos fueron de seis o siete semanas, la concentración sérica media mostró una diferencia estadísticamente significativa en comparación con la administración cada dos semanas. CONCLUSIONES: La información recogida parece confirmar la necesidad de explorar nuevos escenarios para personalizar la dosificación de nivolumab. Se necesitan estudios adicionales en series de mayor tamaño para confirmar esta información, correlacionarla con los resultados clínicos y definir mejor el papel de la monitorización terapéutica, no solo por motivos económicos, sino también para mejorar la calidad de vida de los pacientes y facilitar la administración clínica del tratamiento

OBJECTIVE: A review of the literature about the anti-programmed death 1 monoclonal antibody nivolumab permits to verify the existence of several issues still unresolved about their dosing schedule. The aim of the present work was to explore possibilities of nivolumab treatment perso-nalization through therapeutic drug monitoring, in order to improve their effectiveness and efficiency. METHOD: Observational, prospective study carried out from May 2017 through June 2019 in patients with different tumor diagnoses treated with nivolumab. Blood samples were obtained in the routine clinical practice, once nivolumab steady state was reached. Serum nivolumab levels were determined by means of quantitative ELISA. The standard schedule of 3 mg/kg every two weeks (Q2W) was modified in some patients due to different circumstances, and resulting serum concentrations were compared with those from the non-modified patients and the published data.RESULTS: Blood samples from 19 patients in treatment with nivolumab were analyzed. A total of 39 samples of nivolumab were analyzed bet-ween 6th and 27th cycles. The standard schedule of 3 mg/kg every two weeks was modified in 12/19 (60%) patients, with intervals of 3, 4, 5, 6 or 7 weeks, once the steady state was reached. No statistically significant differences were detected when comparing every two weeks and every four week intervals. When the intervals were six or seven weeks, mean plasma concentration showed a statistically significant difference compared with every two weeks.CONCLUSIONS: Current data contribute to confirm former suspects about the possibilities of exploring new scenarios to improve and personalize nivolumab dosage. Additional studies to confirm it in bigger series and correlate it with clinical results, and to better define the role of therapeutic drug monitoring in the treatment, are warranted, not only by financial concerns but also for improving quality of life of patients and clinical management aspects

Therapeutic drug monitoring of nivolumab in routine clinical practice. A pilot study.

OBJECTIVE: A review of the literature about the anti-programmed death 1 monoclonal antibody nivolumab permits to verify the existence  of several issues still unresolved about their dosing schedule. The aim of the present work was to explore possibilities of nivolumab treatment  personalization through therapeutic drug monitoring, in order to  improve their effectiveness and efficiency. METHOD: Observational, prospective study carried out from May 2017  through June 2019 in patients with different tumor diagnoses treated with nivolumab. Blood samples were obtained in the routine  clinical practice, once nivolumab steady state was reached. Serum  nivolumab levels were determined by means of quantitative ELISA. The  standard schedule of 3 mg/kg every two weeks (Q2W) was modified in  some patients due to different circumstances, and resulting serum  concentrations were compared with those from the non-modified  patients and the published data. RESULTS: Blood samples from 19 patients in treatment with nivolumab were analyzed. A total of 39 samples of nivolumab were  analyzed between 6th and 27th cycles. The standard schedule of 3  mg/kg every two weeks was modified in 12/19 (60%) patients, with  intervals of 3, 4, 5, 6 or 7 weeks, once the steady state was reached.  No statistically significant differences were detected when comparing  every two weeks and every four week intervals. When the intervals  were six or seven weeks, mean plasma concentration showed a  statistically significant difference compared with every two weeks. CONCLUSIONS: Current data contribute to confirm former suspects about the possibilities of exploring new scenarios to improve and  personalize nivolumab dosage. Additional studies to confirm it in bigger  series and correlate it with clinical results, and to better define the role  of therapeutic drug monitoring in the treatment, are warranted, not only by financial concerns but also for improving quality of life of patients  and clinical management aspects.

Objetivo: Una revisión de la literatura sobre nivolumab permite  verificar la existencia de diversos aspectos sin resolver sobre su  intervalo de dosificación. El objetivo del presente estudio ha sido  explorar las posibilidades de personalización del tratamiento con  nivolumab mediante la monitorización terapéutica de sus  concentraciones séricas para mejorar su efectividad y eficiencia.Método: Estudio observacional, prospectivo, realizado entre mayo de 2017 y junio de 2019 en pacientes tratados con nivolumab que  estaban diagnosticados de diferentes tumores. Se obtuvieron muestras  de sangre en la práctica clínica habitual, una vez alcanzado el estado de  equilibrio de nivolumab. Las concentraciones séricas de nivolumab  fueron determinadas mediante ELISA cuantitativo. La pauta posológica  habitual de 3 mg/kg cada dos semanas tuvo que ser modificada en  algunos pacientes debido a diferentes circunstancias, y las  concentraciones séricas resultantes se compararon con las  correspondientes a los pacientes en los que no se modificó y con datos  publicados.Resultados: Se analizaron muestras de 19 pacientes que recibieron inicialmente 3 mg/kg de nivolumab cada dos semanas. Se  analizó un total de 39 muestras, entre los ciclos 6 y 27. La pauta  habitual se modificó, una vez alcanzado el estado de equilibrio, en  12/19 (60%) pacientes, en los que se amplió el intervalo a 3, 4, 5, 6 o 7 semanas. No se encontraron diferencias estadísticamente significativas  al comparar la administración cada dos semanas y cada cuatro  semanas. Cuando los intervalos fueron de seis o siete semanas, la  concentración sérica media mostró una diferencia estadísticamente  significativa en comparación con la administración cada dos semanas.Conclusiones: La información recogida parece confirmar la necesidad de explorar nuevos escenarios para personalizar la  dosificación de nivolumab. Se necesitan estudios adicionales en series  de mayor tamaño para confirmar esta información, correlacionarla con  los resultados clínicos y definir mejor el papel de la monitorización  terapéutica, no solo por motivos económicos, sino también para mejorar  la calidad de vida de los pacientes y facilitar la administración  clínica del tratamiento.

A simple flow-cytometry method to evaluate peripheral blood contamination of bone marrow aspirates.

Bone marrow (BM) aspirates used for flow-cytometry (FCM) studies are usually obtained from a second aspiration, as the primary aspirate is used for morphological assessment. For this reason, the FCM samples unavoidably contain some blood; although, good-quality samples contain only a small amount. It is of utmost importance to assess the quality of samples prior to FCM analysis; yet, contamination with peripheral blood (PB) is not evaluated in most laboratories, possibly because the methods available are either qualitative or too complex for daily practice. Here, we propose a simple FCM method to quantitatively evaluate PB contamination in BM aspirates, by analyzing the percentage of plasma cells and CD34+ cells - two cell populations nearly absent from PB - and CD10+ granulocytes, which comprise the majority of the PB granulocyte population. We analyzed these three populations in 122 BM aspirates from subjects without hematological disease, and identified samples with PB contamination by performing a hierarchical cluster analysis. A discriminant analysis yielded a function, which we named the PB contamination index (PBCI). This index value gives a quantitative indication about the degree of hemodilution of a given sample. A threshold was identified that discriminates low-quality samples. The method and the threshold proved to be useful in BM aspirates infiltrated with malignant cells, with the exception of cases where hematological disease altered two of the three parameters included in the index. We have easily implemented the PBCI calculation in our daily routine, and find it very helpful for an accurate interpretation of FCM results in a large proportion of BM specimens. Limitations of the technique are discussed.

Articulación productiva para la innovación en las pequeñas empresas acuícolas de la región occidente de México / Productive articulation for the Innovation of small aquaculture companies In the western region of Mexico

La realidad económica de nuestro país se ha orientado a encontrar nuevas formas de solucionar viejos problemas que atañen al sector primario, la acuicultura desarrollada desde las culturas primitivas de México ha crecido paulatinamente, mas como un esfuerzo constante por participar en actividades productivas de autoconsumo que con la intención de enfocar a las pequeñas empresas a formar proyectos conjuntos de articulación productiva y de desarrollo de Innovación. Este artículo de investigación, plantea tres aspectos esenciales: 1) las condiciones de las empresas rurales granjas acuícolas de la región occidente de México, en los estados de Colima, Jalisco, Michoacán y Nayarit, 2) Las modalidades de articulación productiva, redes o agrupamientos de organizaciones alrededor de las granjas acuícolas 3) Las características de los procesos de las granjas y su orientación a la innovación; la investigación analiza la manera en que las empresas, gobierno y la sociedad en su conjunto participan a través del trabajo común para la formalización de proyectos económicos que modifiquen a largo plazo las condiciones sociales de la población.

The economic reality of our country has been oriented to find new ways to solve old problems pertaining to the primary sector, aquaculture developed from the very primitive cultures in Mexico has grown gradually, more like a constant effort to participate in productive activities for self-consumption than intending to focus on small firms to form joint projects of productive articulation and development of innovation. This research article, poses Three essential aspects: 1) the conditions of rural enterprises aquaculture farms in the western region of Mexico, in the States of Colima, Jalisco, Michoacan and Nayarit, 2) modalities of productive articulation, networks or groupings of organizations around aquaculture farms 3) the characteristics of the processes on the farms and their orientation to innovation; this research analyzes the way in which businesses, the government and society, as a whole, participate through common work for the formalization of economic projects which modify, in the long run, the population’s social conditions.