Evaluación de la relación exposición-respuestade cetuximab en pacientes con cáncer colorrectal metastásico y cáncer de cabeza y cuello / Assessment of exposure-response relationship for cetuximab in patients with metastatic colorectal cancer and head and neck cancer

Objetivo: Evaluar, en condiciones de vida real, la relación entre lasconcentraciones valle en estado estacionario de cetuximab y el control dela enfermedad, así como buscar la relación entre estas concentraciones y lasupervivencia. Además, estudiar si existe una concentración límite que sepueda asociar con la probabilidad de beneficio clínico.Método: Estudio observacional prospectivo llevado a cabo en pacientescon cáncer colorrectal metastásico o cáncer de cabeza y cuello entratamiento con cetuximab. Se realizó un análisis de regresión de ecuacionesde estimación generalizadas para evaluar la asociación entre laconcentración valle en estado estacionario de cetuximab y la respuesta altratamiento (progresión o beneficio clínico). Mediante modelos de riesgosproporcionales de Cox, se evaluó la asociación entre la mediana de concentracionesvalle en estado estacionario de cetuximab en cada pacienteo la última medida con la supervivencia global y la supervivencia librede progresión, en cada una de las patologías. Asimismo, se buscó unpunto de corte óptimo a través del área bajo la curva de característicasoperativas del receptor. Resultados: Se analizaron 30 muestras de 16 pacientes. La concentraciónvalle en estado estacionario mediana fue 26,86 mg/l y se encontróuna gran variabilidad inter e intraindividual (desviación estándar de 32,4 y16,9 mg/l, respectivamente). Se observó una asociación positiva entre laconcentración valle en estado estacionario y el beneficio clínico (odds ratio1,24; intervalo de confianza del 95%: 0,95-1,63; p = 0,113), aunque noalcanzó significación estadística debido a la baja potencia.

Objective: There is limited scientific evidence on the cetuximab exposure-response relationship and no concentration threshold has been associatedwith optimal disease control. The aims were to assess, in a real-lifesetting, the relationship between steady state cetuximab concentrations(Ctrough, SS) and disease control.Method: A prospective observational study in patients with metastaticcolorectal cancer or head and neck cancer treated with cetuximab. Steadystate trough concentrations were compared with the results of radiologicalassessment of response (progression or clinical benefit). Generalizedestimating equations analysis was performed. To test the association betweensteady state concentrations and overall survival and progression-freesurvival, Cox proportional hazard models were developed. An optimalcut-off point was searched using the area under the receiver operatingcharacteristic curve.Results: A total of 30 steady state cetuximab concentrations from16 patients were analysed. Median Ctrough, SS was 26.86 mg/L andthere was marked inter- and intraindividual variability (standard deviation 32.4 mg/L and 16.9 mg/L, respectively). A positive associationwas found between cetuximab Ctrough, SS and clinical benefit (odds ratio1.24, 95% confidence interval: 0.95-1.63, p = 0.113), although withoutreaching statistical significance. The area under the receiver operatingcharacteristic curve (n = 30) had moderate discrimination power (0.71;95% confidence interval 0.49‑0.93), and the empirical optimal cutoffpoint was 19.12 mg/L. However, no association was observed betweencetuximab Ctrough, SS and survival in metastatic colorectal cancer or neckcancer patients.

Análisis de la relación dosis-respuesta de la actividad física recreativa con los eventos cardiovasculares y la mortalidad por todas las causas: el estudio REGICOR / Analysis of the dose-response relationship of leisure-time physical activity to cardiovascular disease and all-cause mortality: the REGICOR study

Introducción y objetivos La práctica de actividad física (AF) es un factor protector contra las enfermedades cardiovasculares y la mortalidad. Sin embargo, el patrón de esta relación aún no está claro. El objetivo de este estudio es evaluar la relación de la AF recreativa con los eventos cardiovasculares y la mortalidad total en una población española. Métodos Cohorte prospectiva de 11.158 individuos de la población general. La AF recreativa se evaluó mediante un cuestionario validado y se identificaron los casos mortales y los eventos cardiovasculares en el seguimiento (mediana, 7,24 años). La asociación entre la AF recreativa y los eventos de interés se analizó mediante modelos aditivos generalizados multivariados. Resultados Se observó una relación no lineal entre la AF recreativa y la mortalidad total y los eventos cardiovasculares. La AF moderada-vigorosa se asoció con estos efectos beneficiosos, pero no la AF ligera. Se identificó un umbral en 400 MET-min/día; por debajo de este, cada aumento de 100 MET-min/día se asociaba con una reducción del riesgo de mortalidad total del 16% (HR=0,84; IC95%, 0,77-0,91), del riesgo de mortalidad cardiovascular del 27% (HR=0,73; IC95%, 0,61-0,87) y del de eventos cardiovasculares del 12% (HR=0,88; IC95%, 0,79-0,99). Por encima de 400 MET-min/día no se observó un beneficio adicional. Conclusiones Existe una relación inversa y no lineal de la AF recreativa de intensidad moderada-vigorosa con la enfermedad cardiovascular y la mortalidad. Los beneficios ya se observan a bajos niveles de AF, con un beneficio máximo a niveles que corresponden a 3-5 veces las recomendaciones actuales. (AU)

Introduction and objectives Regular leisure-time physical activity (LTPA) has been consistently recognized as a protective factor for cardiovascular diseases (CVD) and all-cause mortality. However, the pattern of this relationship is still not clear. The aim of this study was to assess the relationship of LTPA with incident CVD and mortality in a Spanish population. Methods A prospective population-based cohort of 11 158 randomly selected inhabitants from the general population. LTPA was assessed by a validated questionnaire. Mortality and CVD outcomes were registered during the follow-up (median: 7.24 years). The association between LTPA and outcomes of interest (all-cause mortality and cardiovascular disease) was explored using a generalized additive model with penalized smoothing splines and multivariate Cox proportional hazard models. Results We observed a significant nonlinear association between LTPA and all-cause and CVD mortality, and fatal and nonfatal CVD. Moderate-vigorous intensity LTPA, but not light-intensity LTPA, were associated with beneficial effects. The smoothing splines identified a cutoff at 400 MET-min/d. Below this threshold, each increase of 100 MET-min/d in moderate-vigorous LTPA contributed with a 16% risk reduction in all-cause mortality (HR, 0.84; 95%CI, 0.77-0.91), a 27% risk reduction in CVD mortality (HR, 0.73; 95%CI, 0.61-0.87), and a 12% risk reduction in incident CVD (HR, 0.88; 95%CI, 0.79-0.99). No further benefits were observed beyond 400 MET-min/d. Conclusions Our results support a nonlinear inverse relationship between moderate-vigorous LTPA and CVD and mortality. Benefits of PA are already observed with low levels of activity, with a maximum benefit around 3 to 5 times the current recommendations. (AU)

Analysis of the dose-response relationship of leisure-time physical activity to cardiovascular disease and all-cause mortality: the REGICOR study.

INTRODUCTION AND OBJECTIVES: Regular leisure-time physical activity (LTPA) has been consistently recognized as a protective factor for cardiovascular diseases (CVD) and all-cause mortality. However, the pattern of this relationship is still not clear. The aim of this study was to assess the relationship of LTPA with incident CVD and mortality in a Spanish population. METHODS: A prospective population-based cohort of 11 158 randomly selected inhabitants from the general population. LTPA was assessed by a validated questionnaire. Mortality and CVD outcomes were registered during the follow-up (median: 7.24 years). The association between LTPA and outcomes of interest (all-cause mortality and cardiovascular disease) was explored using a generalized additive model with penalized smoothing splines and multivariate Cox proportional hazard models. RESULTS: We observed a significant nonlinear association between LTPA and all-cause and CVD mortality, and fatal and nonfatal CVD. Moderate-vigorous intensity LTPA, but not light-intensity LTPA, were associated with beneficial effects. The smoothing splines identified a cutoff at 400 MET-min/d. Below this threshold, each increase of 100 MET-min/d in moderate-vigorous LTPA contributed with a 16% risk reduction in all-cause mortality (HR, 0.84; 95%CI, 0.77-0.91), a 27% risk reduction in CVD mortality (HR, 0.73; 95%CI, 0.61-0.87), and a 12% risk reduction in incident CVD (HR, 0.88; 95%CI, 0.79-0.99). No further benefits were observed beyond 400 MET-min/d. CONCLUSIONS: Our results support a nonlinear inverse relationship between moderate-vigorous LTPA and CVD and mortality. Benefits of PA are already observed with low levels of activity, with a maximum benefit around 3 to 5 times the current recommendations.

Relación entre las concentraciones séricas devedolizumab en fase de inducción y respuesta temprana y mantenida en el primer año de tratamiento en pacientes con colitis ulcerosa / Relationship between vedolizumab serum concentrations in the induction phase and early and sustained response in the first year of treatment in patients with ulcerative colitis

Objetivo: La evidencia sobre la utilidad de la monitorización proactiva delas concentraciones séricas de vedolizumab en la fase de inducción del tratamiento es limitada. El objetivo del estudio ha sido evaluar la capacidad delas concentraciones séricas de vedolizumab determinadas en esta fase parapredecir la respuesta al tratamiento en pacientes con colitis ulcerosa, con el finde establecer si los pacientes se beneficiarían clínicamente de una monitorización precoz.Método: Estudio descriptivo, prospectivo, realizado en tres hospitalesgenerales públicos. Incluyó a los pacientes adultos con colitis ulcerosa, queiniciaron tratamiento con vedolizumab en los centros participantes desdejunio de 2019 a junio de 2020. Se determinaron las concentraciones séricas de vedolizumab en las semanas 6 y 14 de tratamiento. La respuestabioquímica, clínica y endoscópica se evaluó en las semanas 6, 14 y 52.Se estudió la relación de las concentraciones séricas de vedolizumab determinadas en la semana 6 con la respuesta temprana al tratamiento, asícomo la relación de las concentraciones séricas de vedolizumab en lassemanas 6 y 14 con la persistencia de respuesta al año de tratamiento. (AU)

Objective: Evidence on the usefulness of proactive monitoring of vedolizumab serum concentrations during the induction phase of treatment islimited. The objective of our study was to evaluate the effectiveness ofmeasuring such concentrations during this phase in predicting responseto treatment in patients with ulcerative colitis with a view to determiningwhether patients would benefit from early monitoring of vedolizumabserum concentrations.Method: This was a prospective descriptive study carried out at threepublic general hospitals. It included adult patients with ulcerative colitiswho were initiated on vedolizumab at the participating hospitals from June2019 to June 2020. Vedolizumab serum concentrations were determined at weeks 6 and 14. Response to treatment was biologically, clinically,and endoscopically evaluated at weeks 6, 14, and 52. An analysis wasmade of the relationship between vedolizumab serum concentrations atweek 6 and early response to treatment, and of the relationship betweenthe vedolizumab serum concentrations at weeks 6 and 14 and persistentresponse at one year. (AU)

Loading dose of Dexdor® and optimal sedation during oral and maxillofacial ambulatory surgery procedures: An observational study. / Dosis de carga de Dexdor® y nivel óptimo de sedación durante procedimientos de cirugía oral y maxilofacial en régimen ambulatorio: un estudio observacional.

INTRODUCTION: Dexdor® do not include the possibility of loading dose, which could increase time to achieve adequate sedation for ambulatory procedures. The objective of this study was to evaluate the effect of several loading dose of dexmedetomidine in the time to achieve and maintain an optimal level of sedation and its clinical hemodynamic repercussion. MATERIAL AND METHODS: The IRB approved this observational study for patients that underwent oral and maxillofacial ambulatory surgery under dexmedetomidine at the University of Navarra Clinic from February 2013 to November 2014. According to the loading dose the patients were grouped into 3 categories:<0.5, 0.5, and>0.5µg/kg. Optimal level of sedation was defined as bispectral index<85. Data were analyzed using survival analysis techniques. Vasoactive drugs requirements was evaluated using exact logistic regression. RESULTS: Eighty-one patients were evaluated. Hazard ratios for patients in 0.5 and >0.5µg/kg loading dose categories for achieving a bispectral index<85 were 1.5 (95% CI 0.9, 2.6) and 1.8 (95% CI 0.8, 3.9), respectively, compared with the lowest category. Five patients (6.2%) required atropine for bradycardia. Patients in the group>0.5µg/kg showed greater risk of requiring atropine compared with the group<0.5µg/kg (odds ratio 2.2; 95% CI 0.03, 183). CONCLUSION: Loading dose of dexmedetomidine>0.5µg/kg appears minimize the time to achieve and maintain an optimal level of sedation during the first 60min of procedure. Further investigation to elucidate the association between loading dose of dexmedetomidine and subsequent atropine requirements may be warranted.

Eficiency of different doses of rituximab in rheumatoid arthritis. / Eficiencia de diferentes dosis de rituximab en la artritis reumatoide.

OBJECTIVE: Evaluate the effectiveness, cost and safety of rituximab in patients with rheumatoid arthritis (RA) depending on the dose used. MATERIAL AND METHODS: Retrospective observational study conducted on 52 patients with RA treated with at least one dose of rituximab for 135.3 patient-years were included. Three treatment groups were obtained: (G1) First course and following two 1g infusions separated by 15 days; (G2) First course 2 infusions of 1g followed by 2 infusions of 500mg; (G3) First course and followed by 2 infusions of 500mg separated by 15 days. Re-treatments were administered on-demand according to the clinical activity. The retention time (Log-Rank), retreats and adverse events rates (incidence rate ratio) and treatment costs per patient-month of rituximab were analysed by groups. RESULTS: Group 2 showed a better cost-effectiveness ratio than group 1, as it was associated with a longer retention of rituximab (mean [95% CI] 65.7 [60.8 to 70.7] months vs 33.5 [22.7 to 44.3]; P<.001) and a lower rate of severe adverse events with only a slight increase in the rate of retreatment (courses/patient-year [95% CI] 1.66 [1.39 to 1.93] vs. 1.01 [0.69 to 1.34]; P=.005), and in the costs (median/patient-month, €484.89 vs. €473.45). Although group 3 was €41.20/patient-month cheaper than group 2, it was associated with a higher rate of re-treatments and shorter retention of rituximab (P<.001). CONCLUSIONS: The use of full-dose rituximab at onset, followed by reduced doses in successive courses administered on-demand retreatment may be the most cost-effective option.

Valoración dosis-respuesta del efecto diurético de un extracto acuoso de pericarpio de Cucumis melo var. reticulatus Ser. / Dose-response assessment of the diuretic effect in a pericarp aqueous extract of Cucumis melo L. var. reticulatus Ser.

Introducción: la investigación se realizó para determinar la relación dosis-respuesta del pericarpio de melón, validar su empleo en la medicina tradicional venezolana y promover su uso racional como planta medicinal, mediante el conocimiento científico. Objetivo: valorar la relación dosis-respuesta del efecto diurético de la concha del fruto de Cucumis melo var. reticulatus Ser. en ratas. Métodos: se licuó el pericarpio del fruto fresco y se colocó en solución fisiológica por 48 h para luego colarlo. Se administraron vía oral dosis de 1, 3 y 6 mL/300 g, se compararon con un grupo control respectivo y se midió el volumen de orina producido transcurrida 1 h. Resultados: la primera dosis no tuvo efecto diurético en ningún caso. La excreción urinaria de las 2 mayores dosis fue diferente de su respectivo grupo control. Los grupos tratados con extracto acuoso a 3 y 6 mL resultaron diferentes entre sí, igual que los grupos control a esos volúmenes. No se encontró diferencia en la acción diurética. Se halló una relación dosis-respuesta de regresión no-lineal. Conclusiones: se evidencia la relación dosis-respuesta basada en la excreción urinaria, tras administrar el extracto acuoso de la concha de melón, lo que sustenta su empleo como diurético en la medicina tradicional venezolana.

Introduction: research was conducted to determine the dose-response of melon pericarp, validate its use in traditional medicine in Venezuela and promote its rational use as a medicinal plant, through scientific knowledge. Objective: to assess the dose-response diuretic effect of the shell of the fruit of Cucumis melo var. reticulatus Ser. in rats. Methods: fresh fruit pericarp was liquefied and placed in saline solution for 48 hours to strain it later. Oral doses of 1, 3 and 6 mL/300g were administered, compared with a respective control group, and the volume of urine produced an hour later was measured. Results: the first dose had no diuretic effect in any case. Urinary excretion of the two higher doses differed from their respective control group. The groups treated with aqueous extract at 3 and 6 mL were different among them, as well as the control groups in those volumes. No difference was found in the diuretic action. The study found a dose-response of nonlinear regression. Conclusions: there is a clear dose-response relationship based on urinary excretion after administration of the aqueous extract of melon shell, which supports its use as a diuretic in traditional medicine in Venezuela.

Control del vector del dengue utilizando fracciones etéreas de dos plantas (Asteraceae) como larvicidas / Dengue vector control using ether fractions from two plants (Asteraceae) as larvicide

Objetivo Evaluar la actividad larvicida de dos fracciones etéreas de Heli opsisoppositifolia (L.) Drucey Jaegeria hirta (Lag.) Less en larvas de Aedes (Stegomyia) aegypti (L.) de 3-4 ínstar, en el municipio de Armenia, Quindio. Métodos Se realizó la colecta y análisis fitoquímico preliminar de dos especies vegetales, H. oppositifolia y J. hirta. Fueron preparadas fracciones etéreas de las dos especies. Con estas fracciones, fueron evaluadas 11 concentraciones para determinar las concentraciones letales CL50, CL90 y CL95 después de 24 y 48h. Con los resultados de las CL50,CL90 y CL95, se simuló y construyó un modelo que describe la dinámica población-concentración letal. Resultados La marcha fitoquímica preliminar permitió caracterizar en H. oppositifolia y J. hirta la presencia de: Taninos, flavonoides, quinonas, glicósidos cardiotónicos, esteroles, lactonas, terpenos, coumarinas y alcaloides. Las CL, 48 después para J. hirta (CL5024 CL9070 y CL9593 ppm) fueron menores que H. oppositifolia (CL5039, CL9077y CL9594 ppm). El ANOVA factorial confirmó esta tendencia, J. hirta (66 %, F=18.5, p<0.05) y H. oppositifolia (34 %, F=18.5, p<0.05). La simulación matemática sugiere que la aplicación cada 15 días de la CL50, y cada 30 días de las CL90 y CL95 de cualquiera de las dos especies, tienen la misma respuesta que la utilización de las CL90 y CL95 cada 30 días o la CL50 cada 15 días. Conclusión Ambas especies poseen efecto larvicida. Sin embargo, J. hirta se mostró más promisoria como futuro bioinsecticida para el control de estados inmaduros de Ae. aegypti.(AU)

Objective Evaluating the larvicidal activity of two ether factions from Asteraceae (the aster, daisy or sunflower family, i.e. Heli opsisoppositifolia (L.) Druce (oxeye, sunflower-like) and Jaegeria hirta (Lag.) Less (weed-like)) on Aedes (Stegomyia) aegypti (L.) final third instar or initial fourth instar larvae near the town of Armenia in the Quindío Department in Colombia. Methods H. oppositifolia and J. hirta plants were collected and submitted to phytochemical analysis. Ether fractions were prepared form both species to assess 11 concentrations for determining LC50, LC90 and LC95 lethal concentrations after 24 and 48h. The LC50, LC90 and LC95 results were used to create a mathematical model for describing lethal population-concentration dynamics. Results Phytochemical analysis identified tannins, flavonoids, quinones, cardiac glycosides, sterols, lactones, terpenes, courmarins and alkaloids in H. oppositifolia and J. hirta. LC after 48h regarding J. hirta (LC50 24, LC90 70 and LC95 93ppm) was lower than those for H. oppositifolia (LC50 39, LC90 77 and LC95 94 ppm). A factorial ANOVA test confirmed this trend: 66 %, F=18.5 and p<0.05 for J. hirta and 34 %, F=18.5 and p<0.05 for H. oppositifolia. The mathematical simulation model suggested that using LC50 every 15 days and LC90 and LC95 every 30 days from either of these species led to the same response compared to using LC90 and LC95 every 30 days or LC50 every 15 days. Conclusion Both species had a larvicidal effect. However, J. Hirta turned out to be more promising as an eventual bioinsecticide for controlling A. Aegypti immature states.(AU)

Clinical application of Chamomilla recutita in phlebitis: dose response curve study / Aplicação clínica da Chamomilla recutita em flebites: estudo de curva dose-resposta / Aplicación clínica de la Chamomilla recutita en flebitis: estudio de la curva dosis-respuesta

This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5 percent concentration (mean=29.2h, standard deviation = 8.98) and 5 percent concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.

Neste estudo, buscou-se realizar o controle de qualidade da amostra de Chamomilla recutita, bem como estimar a dose ideal, para efeito anti-inflamatório, do infuso dos seus capítulos florais, em pacientes com flebite, decorrente de infusão intravenosa periférica de quimioterapia antineoplásica, e avaliar a toxicidade desse infuso em seres humanos. Trata-se de estudo experimental, do tipo curva dose-resposta, no qual foi analisada e comparada a eficácia terapêutica, quanto ao potencial anti-inflamatório, de diferentes doses do infuso da Chamomilla recutita, em 25 pacientes. O tempo de regressão da flebite foi menor para os grupos com concentração 2,5 por cento (média=29,2h, desvio padrão=8,98) e 5 por cento (média=38,8h, desvio padrão=17,47) e praticamente não se observou toxicidade local. Esta pesquisa contribui para a inovação da prática clínica em enfermagem, uma vez que sugere alternativa para o tratamento de flebites, por meio da utilização clínica de fitoterápicos.

En este estudio, se buscó realizar el control de calidad de la muestra de Chamomilla recutita, así como estimar la dosis ideal, para efecto antiinflamatorio, de la infusión de sus inflorescencias, en pacientes con flebitis proveniente de introducción intravenosa periférica de quimioterapia antineoplásica y evaluar la toxicidad de esta infusión en los seres humanos. Se trata de estudio experimental, del tipo curva dosis-respuesta, en el cual fue analizada y comparada la eficacia terapéutica, en cuanto al potencial antiinflamatorio, de diferentes dosis de la infusión de la Chamomilla recutita en 25 pacientes. El tiempo de regresión de la flebitis fue menor para los grupos con concentración 2,5 por ciento (promedio = 29,2h, desviación estándar = 8,98) y 5 por ciento (promedio = 38,8h, desviación estándar = 17,47) y prácticamente no se observó toxicidad local. Esta investigación contribuye para la innovación de la práctica clínica en enfermería, una vez que sugiere una alternativa para el tratamiento de la flebitis por medio de la utilización clínica de fitoterapéuticos.