Gel transformation as a general strategy for fabrication of highly porous multiscale MOF architectures.

The structure and chemistry of metal-organic frameworks or MOFs dictate their properties and functionalities. However, their architecture and form are essential for facilitating the transport of molecules, the flow of electrons, the conduction of heat, the transmission of light, and the propagation of force, which are vital in many applications. This work explores the transformation of inorganic gels into MOFs as a general strategy to construct complex porous MOF architectures at nano, micro, and millimeter length scales. MOFs can be induced to form along three different pathways governed by gel dissolution, MOF nucleation, and crystallization kinetics. Slow gel dissolution, rapid nucleation, and moderate crystal growth result in a pseudomorphic transformation (pathway 1) that preserves the original network structure and pores, while a comparably faster crystallization displays significant localized structural changes but still preserves network interconnectivity (pathway 2). MOF exfoliates from the gel surface during rapid dissolution, thus inducing nucleation in the pore liquid leading to a dense assembly of percolated MOF particles (pathway 3). Thus, the prepared MOF 3D objects and architectures can be fabricated with superb mechanical strength (>98.7 MPa), excellent permeability (>3.4 × 10-10 m2), and large surface area (1100 m2 g-1) and mesopore volumes (1.1 cm3 g-1).

Clozapine-loaded nanocapsules improve antipsychotic activity in rats: building a sequential PopPK/PD model to discriminate nanocarriers in the preformulation step.

PURPOSE: We investigated the impact of nanoformulations on the dose-exposure-response relationship of clozapine (CZP), a low-solubility antipsychotic with serious adverse effects, using a popPK/PD approach. METHODS: We evaluated the pharmacokinetics and PK/PD profiles of three coated polymeric CZP-loaded nanocapsules functionalized with polysorbate 80 (NCP80), polyethylene glycol (NCPEG), and chitosan (NCCS). Data on in vitro CZP release by dialysis bag, plasma pharmacokinetic profiles in male Wistar rats (n = 7/group, 5 mg kg-1, i.v.), and percentage of head movements in a stereotyped model (n = 7/group, 5 mg kg-1, i.p.) were integrated using a sequential model building approach (MonolixSuiteTM-2020R1-Simulation Plus). RESULTS: A base popPK model developed with CZP solution data collected after the i.v. administration of CZP was expanded to describe the changes in drug distribution caused by nanoencapsulation. Two additional compartments were inserted into the NCP80 and NCPEG models, and a third compartment was included in the NCCS model. The nanoencapsulation showed a decrease in the central volume of distribution for NCCS (V1NCpop = 0.21 mL), while for FCZP, NCP80, and NCPEG, it was ~1 mL. The peripheral distribution volume was higher for the nanoencapsulated groups (19.1 and 129.45 mL for NCCS and NCP80, respectively) than for FCZP. The popPK/PD model showed a formulation-dependent plasma IC50, with 20-, 50-, and 80-fold reductions compared to the CZP solution (NCP80, NCPEG, and NCCS, respectively). CONCLUSION: Our model discriminates the coatings and describes the peculiar PK and PD behavior of nanoencapsulated CZP, especially NCCS, making it an exciting tool for evaluating the preclinical performance of nanoparticles.

Cardiometabolic risk factors and antithrombotic treatment in a Mexican population with atrial fibrillation and heart failure with reduced ejection fraction.

INTRODUCTION: Heart failure in patients with non-valvular atrial fibrillation (NVAF) is two to three times more common than in individuals without NVAF. OBJECTIVE: To identify cardiometabolic risk factors (CMRF) and antithrombotic treatment in patients with NVAF and heart failure with reduced ejection fraction (HFrEF), and to determine if there were differences according to gender. METHODS: CMRF, pro-thrombotic risk, bleeding risk, and antithrombotic therapy were globally analyzed and according to gender. RESULTS: Out of 1,423 patients with NVAF, 336 had HFrEF. On average, females were older than males. There was no difference between genders with regard to the type of NVAF or direct oral anticoagulants use. Hypertension was more common in women. History of transient ischemic attack was reported in 3.6% of the patients and cerebrovascular event in 10%, without differences in terms of gender. The percentage of men with elevated embolic risk was higher, but without antithrombotic treatment, in comparison with women. CONCLUSIONS: Significant differences were found according to gender in patients with NVAF and HFrEF, both in CMRF and some comorbidities, as well as in antithrombotic treatment according to embolic and bleeding risk.

INTRODUCCIÓN: La insuficiencia cardiaca en pacientes con fibrilación auricular no valvular (FANV) es de dos a tres veces más frecuente que en individuos sin FANV. OBJETIVO: Identificar los factores de riesgo cardiometabólico (FRCM) y el tratamiento antitrombótico de pacientes con FANV e insuficiencia cardiaca con fracción de expulsión reducida (IC-FEr), y determinar si existen diferencias conforme al sexo. MÉTODOS: En forma global y de acuerdo con el sexo se analizaron FRCM, riesgo protrombótico, riesgo de sangrado y terapia antitrombótica. RESULTADOS: De 1423 pacientes con FANV, 336 tuvieron IC-FEr. Las mujeres promediaron mayor edad que los hombres. No hubo diferencia entre los sexos respecto al tipo de FANV o uso de anticoagulantes orales directos. La hipertensión arterial sistémica fue más frecuente en mujeres. Un 3.6 % de los pacientes reportó antecedente de ataque isquémico transitorio y 10 % de evento vascular cerebral, sin diferencias en cuanto al sexo. El porcentaje de hombres con riesgo embólico elevado fue mayor, pero sin tratamiento antitrombótico, en comparación con las mujeres. CONCLUSIONES: Se encontraron diferencias significativas de acuerdo con el sexo en pacientes con FANV e IC-FEr, tanto en FRCM y algunas comorbilidades, como en el tratamiento antitrombótico de acuerdo con el riesgo embólico y de sangrado.

Prevalencia y caracterización de la sobrecarga del cuidador primario de pacientes al final de la vida / Prevalence and characterization of overload of the primary caregiver of patients at the end of life

Introducción: El objetivo del presente estudio fue determinar la prevalencia de la sobrecarga del cuidador primario de pacientes al final de la vida que acuden al servicio de urgencias de este hospital y determinar sus características sociodemográficas. Pacientes y métodos: Se realizó un estudio de tipo observacional, descriptivo y prospectivo; se incluyeron 264 cuidadores principales de pacientes que se encontraban en la fase final de la vida, quienes recibieron atención médica por complicaciones de su patología de base en el servicio de urgencias del Hospital General de México “Dr. Eduardo Liceaga”, en un periodo de 6 meses, del 1 de abril de 2021 al 31 de septiembre de 2021, con los siguientes criterios de inclusión: ser el cuidador principal, tener un lazo familiar con un enfermo, con participación voluntaria, tener más de 18 años de edad. Los participantes, previa firma del consentimiento informado, contestaron los cuestionarios de datos demográficos, escala de Zarit abreviada, escala de Katz. Dentro de la valoración multidimensional del paciente con enfermedad terminal, la valoración biológica es fundamentada por la situación funcional del enfermo; para valorar la dependencia para las actividades de la vida diaria se puede emplear el índice de Katz. Resultados: Se incluyeron 264 cuidadores primarios, 187 (70,8 %) fueron del género femenino y 77 (29,2 %) del género masculino; la edad mínima fue de 18 años y máxima de 80 años, con una mediana de 44 años. Del total de cuidadores analizados 219 (83 %) presentaban sobrecarga del cuidador en el momento de la entrevista. De los sujetos estudiados, 138 (52,3 %) eran cuidadores únicos, de los cuales más de la mitad (57 %) padecían sobrecarga del cuidador. (AU)

Introduction: The objective of this study was to determine the prevalence of overload among the primary caregivers of patients at the end of life who attended the emergency department of this hospital, and to determine their sociodemographic characteristics. Patients and methods: An observational, descriptive and prospective study was carried out, including 264 main caregivers of patients who were in the final phase of life, who received medical care for complications of their underlying condition in the emergency department of the General Hospital of Mexico “Dr. Eduardo Liceaga” over a period of 6 months, from April 1, 2021 to September 31, 2021, with the following inclusion criteria: being the main caregiver, having a family relationship with the patient, voluntary participation, being more than 18 years old. The participants, after signing an informed consent, completed the demographic data questionnaires, the abbreviated Zarit scale, and the Katz scale. Within the multidimensional assessment of the terminally ill patient, the biological assessment is based on the patient’s functional status; to assess dependence on activities of daily living, the Katz index can be used. Results: A total of 264 primary caregivers were included, 187 (70,8%) were female and 77 (29,2%) were male; the minimum age was 18 years and the maximum age was 80 years, with a median of 44 years. Of the total number of caregivers analyzed, 219 (83%) presented caregiver collapse syndrome at the time of the interview. Of the subjects studied, 138 (52,3%) were sole caregivers, of which more than half (57%) suffered from caregiver collapse syndrome. (AU)

Quantitative systems pharmacology Model to characterize valproic acid-induced hyperammonemia and the effect of L-carnitine supplementation.

Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial ß-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial ß-oxidation and the microsomal ω-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharmacokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.

Factores de riesgo cardiometabólico y tratamiento antitrombótico en población mexicana con fibrilación auricular e insuficiencia cardiaca con fracción de expulsión reducida / Cardiometabolic risk factors and antithrombotic treatment in a Mexican population with atrial fibrillation and heart failure with reduced ejection fraction

Resumen Introducción: La insuficiencia cardiaca en pacientes con fibrilación auricular no valvular (FANV) es de dos a tres veces más frecuente que en individuos sin FANV. Objetivo: Identificar los factores de riesgo cardiometabólico (FRCM) y el tratamiento antitrombótico de pacientes con FANV e insuficiencia cardiaca con fracción de expulsión reducida (IC-FEr), y determinar si existen diferencias conforme al sexo. Métodos: En forma global y de acuerdo con el sexo se analizaron FRCM, riesgo protrombótico, riesgo de sangrado y terapia antitrombótica. Resultados: De 1423 pacientes con FANV, 336 tuvieron IC-FEr. Las mujeres promediaron mayor edad que los hombres. No hubo diferencia entre los sexos respecto al tipo de FANV o uso de anticoagulantes orales directos. La hipertensión arterial sistémica fue más frecuente en mujeres. Un 3.6 % de los pacientes reportó antecedente de ataque isquémico transitorio y 10 % de evento vascular cerebral, sin diferencias en cuanto al sexo. El porcentaje de hombres con riesgo embólico elevado fue mayor, pero sin tratamiento antitrombótico, en comparación con las mujeres. Conclusiones: Se encontraron diferencias significativas de acuerdo con el sexo en pacientes con FANV e IC-FEr, tanto en FRCM y algunas comorbilidades, como en el tratamiento antitrombótico de acuerdo con el riesgo embólico y de sangrado.

Abstract Introduction: Heart failure in patients with non-valvular atrial fibrillation (NVAF) is two to three times more common than in individuals without NVAF. Objective: To identify cardiometabolic risk factors (CMRF) and antithrombotic treatment in patients with NVAF and heart failure with reduced ejection fraction (HFrEF), and to determine if there were differences according to gender. Methods: CMRF, pro-thrombotic risk, bleeding risk, and antithrombotic therapy were globally analyzed and according to gender. Results: Out of 1,423 patients with NVAF, 336 had HFrEF. On average, females were older than males. There was no difference between genders with regard to the type of NVAF or direct oral anticoagulants use. Hypertension was more common in women. History of transient ischemic attack was reported in 3.6% of the patients and cerebrovascular event in 10%, without differences in terms of gender. The percentage of men with elevated embolic risk was higher, but without antithrombotic treatment, in comparison with women. Conclusions: Significant differences were found according to gender in patients with NVAF and HFrEF, both in CMRF and some comorbidities, as well as in antithrombotic treatment according to embolic and bleeding risk.

Population pharmacokinetics of sublingually administered tacrolimus in infants and young children with liver transplantation.

AIMS: Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post-transplantation. METHODS: Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense-sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. RESULTS: Disposition of tacrolimus was best characterized by a 2-compartment model with clearance achieving half of the maximum elimination capacity (CLMAX  = 4.1 L/h) at 4.6 days post-transplantation (T50 ). Compared to sedated patients, nonsedated status showed an increased first-order absorption rate constant (1.1 vs. 0.1 h-1 ) and a 24% reduction in bioavailability (FNS ) at 14 days post-transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first-pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T50 ). CONCLUSION: A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post-transplant time on clearance and the sedation status may be considered in routine dosing management.

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing.

AIMS: High-dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity. METHODS: Anonymized, de-identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non-profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite. RESULTS: A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three-compartment model adequately fitted the data. Time-dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose-normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence. CONCLUSION: We developed a population pharmacometric model that considers weight, albumin and time-dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.

Fibrilación auricular en población mexicana: Diferencias en presentación, comorbilidades y factores de riesgo entre hombres y mujeres / Atrial fibrillation in Mexican population: Differences in presentation, comorbidities and risk factors between men and women

Resumen Objetivo: Conocer el comportamiento epidemiológico y asociaciones de la FA en población mexicana. Material y métodos: Analizamos 8,686 pacientes de 38 cardiólogos inscritos en REMECAR, divididos por edad y sexo. Comorbilidades estudiadas: obesidad, ERC, HTA, DM, dislipidemia, EVC, EPOC, hipotiroidismo, IC y CI. Programa: IBM SPSS. Resultados: FA en 498 pacientes (5.7%), mayor prevalencia en hombres (6.1 vs. 5.3%), mayor edad en mujeres (74.3 ± 12.1 vs. 70.5 ± 12.3 años, p < 0.0001). En mujeres menores de 60 años la FA se asoció con IC (p = 0.041), en hombres con ERC (p = 0.43), DM (p = 0.009), EVC (p = 0.001), hipotiroidismo (p = 0.001) e IC (p = 0.001). En mujeres mayores de 60 años se asoció con ERC (p = 0.001), dislipidemia (p = 0.001), EVC (p = 0.001), EPOC (p = 0.001) e IC (p = 0.001), en hombres con ERC (p = 0.002), EVC (p = 0.001), EPOC (p = 0.002), hipotiroidismo (p = 0.002), IC (p = 0.001) y CI (p = 0.033). En mujeres la FA se asoció con 1.13 veces mayor probabilidad de obesidad, 1.13 de HTA, 2.8 de ERC, 2.9 de EPOC, 4.3 de EVC y 6.5 de IC, en hombres la FA se asoció con 1.05 veces mas probabilidad de HTA, 1.4 de DM, 2.1 de ERC, 2.4 de EPOC, 3 de hipotiroidismo, 4.7 de EVC y 6 de IC. Conclusiones: La FA es una arritmia muy frecuente, con mayor prevalencia en pacientes que acuden a consulta de cardiología, en hombres y mayor edad de presentación en las mujeres. A mayor edad, mayor prevalencia de FA y de comorbilidades, la IC es la condición más frecuente con la que se asoció la FA.

Abstract Objective: To know the epidemiological behavior and associations of AF in Mexican population. Material and methods: 8,686 patients from 38 cardiologists participating in REMECAR were analyzed. They were divided by gender and age, the comorbidities studied were obesity, chronic kidney disease (CKD), high blood pressure (HBP), diabetes mellitus (DM), dyslipidemia, stroke, chronic obstructive pulmonary disease (COPD), hypothyroidism, heart failure (HF) and ischemic heart disease (IHD). Program used: IBM SPSS Statistic. Results: AF was diagnosed in 498 patients (5.7%), with higher prevalence in men (6.1% vs. 5.3%) and older age in women (74.3 ± 12.1 vs. 70.5 + -12.3 years, p<0.0001). In those under 60 years, AF was associated in women with HF, in men with CKD, DM, stroke, hypothyroidism and HF. In women older than 60 years, AF was associated with CKD, dyslipidemia, stroke, chronic COPD and HF, in men with CKD, stroke, COPD, hypothyroidism, HF and IHD. AF in women increase the probability 1.13 for obesity, 1.13 for HBP, 2.8 for CKD, 2.9 for COPD, 4.3 for stroke and 6.5 for HF, in men increase the probability 1.05 for HBP, 1.4 for DM, 2.1 for CKD, 2.4 for COPD, 3.0 for hypothyroidism, 4.7 for stroke and 6.0 for HF. Conclusions: AF is a very common arrhythmia, with a higher prevalence in patients attending the cardiology consultation, in men and with an older age of presentation in women. The older the age, the higher the prevalence of AF and comorbidities, HF is the most frequent condition associated with AF.

Mathematical and Pharmacokinetic Approaches for the Design of New 3D Printing Inks Using Ricobendazole.

PURPOSE: 3D printing (3DP) makes it possible to obtain systems that are not achievable with current conventional methods, one of them, sustained release floating systems. Floating systems using ricobendazole (RBZ) as a model drug and a combination of polymers were designed and obtained by melt solidification printing technique (MESO-PP). METHODS: Four different MESO-PP inks were formulated based on combinations of the polymers Gelucire 43/01 and Gelucire 50/13 in different ratios. For each of the formulated inks, physicochemical characterization was performed by thermal analysis (thermogravimetric analysis [TGA] and differential scanning calorimetry [DSC]), fourier transform infrared spectrophotometer (FTIR) and X-ray diffraction (XRD). Pharmaceutical characterization was performed by in vitro assays to determine pharmaceutically relevant parameters. These parameters were calculated by applying mathematical models developed to evaluate in vitro drug release profiles. On the other hand, a physiologically based pharmacokinetic (PBPK) model was developed to predict the in vivo performance of RBZ loaded in the different inks by determining the Cmax, and the AUC0-∞. RESULTS: By increasing the proportion of Gelucire 50/13 co-surfactant in the mixtures (the proportion in Ink 1 was 33%, while the proportion in Ink 4 was 80%), the dissolution capacity of RBZ increases substantially, decreasing flotation times. CONCLUSION: MESO-PP produced ink 1 (50% Gelucire 43/01, 25% Gelucire 50/13 and 25% RBZ), which has a zero-order release (RR = 0.180%/min) and the longest flotation time (545 ± 23 min), and in turn would produce a significant increase in oral absorption of the drug, with an AUC0-∞ 2.16-fold higher than that obtained in animals treated with RBZ loaded in conventional tablets.

3d Metal Doping of Core@Shell Wüstite@ferrite Nanoparticles as a Promising Route toward Room Temperature Exchange Bias Magnets.

Nanometric core@shell wüstite@ferrite (Fe1-x O@Fe3 O4 ) has been extensively studied because of the emergence of exchange bias phenomena. Since their actual implementation in modern technologies is hampered by the low temperature at which bias is operating, the critical issue to be solved is to obtain exchange-coupled antiferromagnetic@ferrimagnetic nanoparticles (NPs) with ordering temperature close to 300 K by replacing the divalent iron with other transition-metal ions. Here, the effect of the combined substitution of Fe(II)  with Co(II)  and Ni(II)  on the crystal structure and magnetic properties is studied. To this aim, a series of 20 nm NPs with a wüstite-based core and a ferrite shell, with tailored composition, (Co0.3 Fe0.7 O@Co0.8 Fe2.2 O4  and Ni0.17 Co0.21 Fe0.62 O@Ni0.4 Co0.3 Fe2.3 O4 ) is synthetized through a thermal-decomposition method. An extensive morphological and crystallographic characterization of the obtained NPs shows how a higher stability against the oxidation process in ambient condition is attained when divalent cation doping of the iron oxide lattice with Co(II)  and Ni(II)  ions is performed. The dual-doping is revealed to be an efficient way for tuning the magnetic properties of the final system, obtaining Ni-Co doped iron oxide core@shell NPs with high coercivity (and therefore, high energy product), and increased antiferromagnetic ordering transition temperature, close to room temperature.

In Vivo Evaluation of Sgc8-c Aptamer as a Molecular Imaging Probe for Colon Cancer in a Mouse Xenograft Model.

Recent biotechnological applications in the field of clinical oncology led to the identification of new biomarkers as molecular targets of cancer, and to broad developments in the field of personalized medicine. Aptamers are oligonucleotides (ssDNA or RNA) that are selected to specifically recognize a molecular target with high affinity and specificity. Based on this, new horizons for their use as molecular imaging probes are being explored. The objective of this work was to evaluate the Sgc8-c aptamer conjugated with Alexa Fluor 647 fluorophore as an imaging probe in a colon tumor xenograft mouse model, with potential application in molecular imaging. In this study, the LS174T cell line was used to induce colorectal adenocarcinoma in nude mice. After confirmation of PTK7 overexpression by immunohistochemistry, in vivo studies were performed. Pharmacokinetic, in vivo and ex vivo biodistribution imaging, and a competition assay were evaluated by fluorescence imaging. In vivo visualization of the probe in the tumors was assessed two hours after aptamer probe administration, exhibiting excellent tumor-to-background ratios in biodistribution studies and high specificity in the competition test. Our results demonstrated the functionality of Scg8-c as an imaging probe for colon cancer, with potential clinical applications.

Guía de práctica clínica mexicana para el diagnóstico y tratamiento de las dislipidemias y enfermedad cardiovascular aterosclerótica.

ANTECEDENTES: Las enfermedades cardiovasculares son la principal causa mundial de mortalidad y México no es la excepción. Los datos epidemiológicos obtenidos en 1990 mostraron que los padecimientos cardiovasculares representaron el 19.8% de todas las causas de muerte en nuestro país; esta cifra se incrementó de manera significativa a un 25.5% para 2015. Diversas encuestas nacionales sugieren que más del 60% de la población adulta tiene al menos un factor de riesgo para padecer enfermedades cardiovasculares (obesidad o sobrepeso, hipertensión, tabaquismo, diabetes, dislipidemias). Por otro lado, datos de la Organización Panamericana de la Salud han relacionado el proceso de aterosclerosis como la primer causa de muerte prematura, reduciendo la expectativa de vida de manera sensible, lo que tiene una enorme repercusión social. OBJETIVO: Este documento constituye la guía de práctica clínica (GPC) elaborada por iniciativa de la Sociedad Mexicana de Cardiología en colaboración con la Sociedad Mexicana de Nutrición y Endocrinología, A.C., Asociación Nacional de Cardiólogos de México, A.C., Asociación Mexicana para la Prevención de la Aterosclerosis y sus Complicaciones, A.C., Comité Normativo Nacional de Medicina General, A.C., Colegio Nacional de Medicina Geriátrica, A.C., Colegio de Medicina Interna de México, A.C., Sociedad Mexicana de Angiología y Cirugía Vascular y Endovenosa, A.C., Instituto Mexicano de Investigaciones Nefrológicas, A.C. y la Academia Mexicana de Neurología, A.C.; con el apoyo metodológico de la Agencia Iberoamericana de Desarrollo y Evaluación de Tecnologías en Salud, con la finalidad de establecer recomendaciones basadas en la mejor evidencia disponible y consensuadas por un grupo interdisciplinario de expertos. El objetivo de este documento es el de brindar recomendaciones basadas en evidencia para ayudar a los tomadores de decisión en el diagnóstico y tratamiento de las dislipidemias en nuestro país. MATERIAL Y MÉTODOS: Este documento cumple con estándares internacionales de calidad, como los descritos por el Instituto de Medicina de EE.UU., el Instituto de Excelencia Clínica de Gran Bretaña, la Red Colegiada para el Desarrollo de Guías de Escocia y la Red Internacional de Guías de Práctica Clínica. Se integró un grupo multidisciplinario de expertos clínicos y metodólogos con experiencia en revisiones sistemáticas de la literatura y el desarrollo de guías de práctica clínica. Se consensuó un documento de alcances, se establecieron las preguntas clínicas relevantes, se identificó de manera exhaustiva la mejor evidencia disponible evaluada críticamente en revisiones sistemáticas de la literatura y se desarrollaron las recomendaciones clínicas. Se utilizó la metodología de Panel Delphi modificado para lograr un nivel de consenso adecuado en cada una de las recomendaciones contenidas en esta GPC. RESULTADOS: Se consensuaron 23 preguntas clínicas que dieron origen a sus respectivas recomendaciones clínicas. CONCLUSIONES: Esperamos que este documento contribuya a la mejor toma de decisiones clínicas y se convierta en un punto de referencia para los clínicos y pacientes en el manejo de las dislipidemias y esto contribuya a disminuir la morbilidad y mortalidad derivada de los eventos cardiovasculares ateroscleróticos en nuestro país. BACKGROUND: Cardiovascular diseases are the leading cause of mortality worldwide and Mexico is no exception. The epidemiological data obtained in 1990 showed that cardiovascular diseases represented 19.8% of all causes of death in our country. This figure increased significantly to 25.5% for 2015. Some national surveys suggest that more than 60% of the adult population has at least one risk factor for cardiovascular disease (obesity or overweight, hypertension, smoking, diabetes, dyslipidemias). On the other hand, data from the Pan American Health Organization have linked the process of atherosclerosis as the first cause of premature death, significantly reducing life expectancy, which has enormous social repercussions. OBJECTIVE: This document constitutes the Clinical Practice Guide (CPG) prepared at the initiative of the Mexican Society of Cardiology in collaboration with the Mexican Society of Nutrition and Endocrinology, AC, National Association of Cardiologists of Mexico, AC, Mexican Association for the Prevention of Atherosclerosis and its Complications, AC, National Normative Committee of General Medicine, AC, National College of Geriatric Medicine, AC, College of Internal Medicine of Mexico, AC, Mexican Society of Angiology and Vascular and Endovenous Surgery, AC, Mexican Institute of Research Nephrological, AC and the Mexican Academy of Neurology, A.C.; with the methodological support of the Ibero-American Agency for the Development and Evaluation of Health Technologies, in order to establish recommendations based on the best available evidence and agreed upon by an interdisciplinary group of experts. The objective of this document is to provide evidence-based recommendations to help decision makers in the diagnosis and treatment of dyslipidemias in our country. MATERIAL AND METHODS: This document complies with international quality standards, such as those described by the Institute of Medicine of the USA, the Institute of Clinical Excellence of Great Britain, the Scottish Intercollegiate Guideline Network and the Guidelines International Network. A multidisciplinary group of clinical experts and methodologists with experience in systematic reviews of the literature and the development of clinical practice guidelines was formed. A scope document was agreed upon, relevant clinical questions were established, the best available evidence critically evaluated in systematic literature reviews was exhaustively identified, and clinical recommendations were developed. The modified Delphi Panel methodology was used to achieve an adequate level of consensus in each of the recommendations contained in this CPG. RESULTS: 23 clinical questions were agreed upon which gave rise to their respective clinical recommendations. CONCLUSIONS: We consider that this document contributes to better clinical decision-making and becomes a point of reference for clinicians and patients in the management of dyslipidemias and this contributes to reducing the morbidity and mortality derived from atherosclerotic cardiovascular events in our country.

SPARC-mediated long-term retention of nab-paclitaxel in pediatric sarcomas.

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein overexpressed by several cancers. Because SPARC shows high binding affinity to albumin, we reasoned that pediatric sarcoma xenografts expressing SPARC would show enhanced uptake and accumulation of nanoparticle albumin-bound (nab)-paclitaxel, a potent anticancer drug formulation. We first evaluated the expression of SPARC in patient-derived xenografts (PDXs) of Ewing sarcoma, rhabdomyosarcoma and osteosarcoma, finding variable SPARC gene expression that correlated well with SPARC protein measured by immunoblotting. We revealed that the activity of the fusion gene chimera EWSR1-FLI1, the genetic driver of Ewing sarcoma, leads to lower expression of the gene SPARC in these tumors, likely due to enriched acetylation marks of the histone H3 lysine 27 at regions including the SPARC promoter and potential enhancers. Then, we used SPARC-edited Ewing sarcoma cells (A673 line) to demonstrate that SPARC knocked down (KD) cells accumulated significantly less amount of nab-paclitaxel in vitro than SPARC wild type (WT) cells. In vivo, SPARC KD and SPARC WT subcutaneous xenografts in mice achieved similar maximum intratumoral concentrations of nab-paclitaxel, though drug clearance from SPARC WT tumors was significantly slower. We confirmed such SPARC-mediated long-term intratumoral accumulation of nab-paclitaxel in Ewing sarcoma PDX with high expression of SPARC, which accumulated significantly more nab-paclitaxel than SPARC-low PDX. SPARC-high PDX responded better to nab-paclitaxel than SPARC-low tumors, although these results should be taken cautiously, given that the PDXs were established from different patients that could have specific determinants predisposing response to paclitaxel. In addition, SPARC KD Ewing sarcoma xenografts responded better to soluble docetaxel and paclitaxel than to nab-paclitaxel, while SPARC WT ones showed similar response to soluble and albumin-carried drugs. Overall, our results show that pediatric sarcomas expressing SPARC accumulate nab-paclitaxel for longer periods of time, which could have clinical implications for chemotherapy efficacy.

Atrial fibrillation in Mexican population: Differences in presentation, comorbidities and risk factors between men and women / Fibrilación auricular en población mexicana: Diferencias en presentación, comorbilidades y factores de riesgo entre hombres y mujeres

OBJECTIVE: To know the epidemiological behavior and associations of AF in Mexican population. MATERIAL AND METHODS: 8,686 patients from 38 cardiologists participating in REMECAR were analyzed. They were divided by gender and age, the comorbidities studied were obesity, chronic kidney disease (CKD), high blood pressure (HBP), diabetes mellitus (DM), dyslipidemia,stroke, chronic obstructive pulmonary disease (COPD), hypothyroidism, heart failure (HF) and ischemicheart disease (IHD). Program used: IBM SPSS Statistic. RESULTS: AF was diagnosed in 498 patients (5.7%), with higher prevalence in men (6.1% vs. 5.3%) and older age in women (74.3 ± 12.1 vs. 70.5 + -12.3 years, p<0.0001). In those under 60 years, AF was associated in women with HF, in men with CKD, DM, stroke, hypothyroidism and HF. In women older than 60 years, AF was associated with CKD, dyslipidemia, stroke, chronic COPD and HF, in men with CKD, stroke, COPD, hypothyroidism, HF and IHD. AF in women increase the probability 1.13 for obesity, 1.13 for HBP, 2.8 for CKD, 2.9 for COPD, 4.3 for stroke and 6.5 for HF, in men increase the probability 1.05 for HBP, 1.4 for DM, 2.1 for CKD, 2.4 for COPD, 3.0 for hypothyroidism, 4.7 for stroke and 6.0 for HF. CONCLUSIONS: AF is a very common arrhythmia, with a higher prevalence in patients attending the cardiology consultation, in men and with an older age of presentation in women. The older the age, the higher the prevalence of AF and comorbidities, HF is the most frequent condition associated with AF.

OBJETIVO: Conocer el comportamiento epidemiológico y asociaciones de la FA en población mexicana. MATERIAL Y MÉTODOS: Analizamos 8,686 pacientes de 38 cardiólogos inscritos en REMECAR, divididos por edad y sexo. Comorbilidades estudiadas: obesidad, ERC, HTA, DM, dislipidemia, EVC, EPOC, hipotiroidismo, IC y CI. Programa: IBM SPSS. RESULTADOS: FA en 498 pacientes (5.7%), mayor prevalencia en hombres (6.1 vs. 5.3%), mayor edad en mujeres (74.3 ± 12.1 vs. 70.5 ± 12.3 años,p < 0.0001). En mujeres menores de 60 años la FA se asoció con IC (p = 0.041), en hombres con ERC (p = 0.43), DM(p = 0.009), EVC (p = 0.001), hipotiroidismo (p = 0.001) e IC (p = 0.001). En mujeres mayores de 60 años se asoció conERC (p = 0.001), dislipidemia (p = 0.001), EVC (p = 0.001), EPOC (p = 0.001) e IC (p = 0.001), en hombres con ERC(p = 0.002), EVC (p = 0.001), EPOC (p = 0.002), hipotiroidismo (p = 0.002), IC (p = 0.001) y CI (p = 0.033). En mujeres la FA se asoció con 1.13 veces mayor probabilidad de obesidad, 1.13 de HTA, 2.8 de ERC, 2.9 de EPOC, 4.3de EVC y 6.5de IC, en hombres la FA se asoció con 1.05 veces mas probabilidad de HTA, 1.4 de DM, 2.1 de ERC, 2.4 de EPOC, 3 dehipotiroidismo, 4.7 de EVC y 6 de IC. CONCLUSIONES: La FA es una arritmia muy frecuente, con mayor prevalencia en pacientes que acuden a consulta de cardiología, en hombres y mayor edad de presentación en las mujeres. A mayor edad, mayor prevalencia de FA y de comorbilidades, la IC es la condición más frecuente con la que se asoció la FA.

Risk stratification and lipid evaluation in mexican patients, evidence of lipid and cardiovascular analysis in REMECAR. The mexican registry of cardiovascular diseases (REMECAR group).

Background and aims: Dyslipidaemia is a significant risk factor for cardiovascular disease in the Mexican population. This analysis aimed to describe the baseline LDL-c levels of patients presenting to cardiovascular clinics and evaluate the proportion who achieved their risk-based LDL-c goals as recommended by 2021 ESC prevention guidelines. Methods: The REMECAR registry is an observational study of patients attending a specialized cardiovascular clinic for their first visit. The cardiovascular risk was retrospectively determined using the 2021 ESC guideline stratification and the SCORE2 and SCORE-OP. Results: A total of 5443 patients were included in the analysis. Within this population, 55.96% presented as very high, 39.98% as high and 4.06% as moderate to low risk. 63% of the participants were not on any lipid-lowering treatment at entry, while 12.4% were receiving high-intensity statin therapy. Patients presenting with established atherosclerotic cardiovascular disease had a mean LDL-c of 90.9 ± 40.7 mg/dL. Of these, 14.1% were achieving LDL-c levels of 70-55 mg/dL and 19.3% were achieving LDL-c levels <55 mg/dL. In diabetic patients at very high risk, only 25.7% achieved their LDL-c goal. Finally, in patients without another risk factor and very high-risk evaluated by SCORE2 & SCORE-OP, only 14% of patients achieved their LDL-c goals. Conclusions: An important number of patients were not receiving any lipid-lowering therapy. Furthermore, in those who were, a significant portion did not achieve LDL-c recommended thresholds. Our results underline the urgent need to improve the prescription and optimization of lipid-lowering therapy as the current management appears to be insufficient for achieving optimal recommended goals. Identifying key barriers in lipid management is fundamental to establishing better strategies and health system policies to reduce cardiovascular risk.

Guía de práctica clínica mexicana para el diagnóstico y tratamiento de las dislipidemias y enfermedad cardiovascular aterosclerótica / Mexican clinical practice guideline for the diagnosis and treatment of dyslipidemias and atherosclerotic cardiovascular disease

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Abstract Background: Cardiovascular diseases are the leading cause of mortality worldwide and Mexico is no exception. The epidemiological data obtained in 1990 showed that cardiovascular diseases represented 19.8% of all causes of death in our country. This figure increased significantly to 25.5% for 2015. Some national surveys suggest that more than 60% of the adult population has at least one risk factor for cardiovascular disease (obesity or overweight, hypertension, smoking, diabetes, dyslipidemias). On the other hand, data from the Pan American Health Organization have linked the process of atherosclerosis as the first cause of premature death, significantly reducing life expectancy, which has enormous social repercussions. Objective: This document constitutes the Clinical Practice Guide (CPG) prepared at the initiative of the Mexican Society of Cardiology in collaboration with the Mexican Society of Nutrition and Endocrinology, AC, National Association of Cardiologists of Mexico, AC, Mexican Association for the Prevention of Atherosclerosis and its Complications, AC, National Normative Committee of General Medicine, AC, National College of Geriatric Medicine, AC, College of Internal Medicine of Mexico, AC, Mexican Society of Angiology and Vascular and Endovenous Surgery, AC, Mexican Institute of Research Nephrological, AC and the Mexican Academy of Neurology, A.C.; with the methodological support of the Ibero-American Agency for the Development and Evaluation of Health Technologies, in order to establish recommendations based on the best available evidence and agreed upon by an interdisciplinary group of experts. The objective of this document is to provide evidence-based recommendations to help decision makers in the diagnosis and treatment of dyslipidemias in our country. Material and methods: This document complies with international quality standards, such as those described by the Institute of Medicine of the USA, the Institute of Clinical Excellence of Great Britain, the Scottish Intercollegiate Guideline Network and the Guidelines International Network. A multidisciplinary group of clinical experts and methodologists with experience in systematic reviews of the literature and the development of clinical practice guidelines was formed. A scope document was agreed upon, relevant clinical questions were established, the best available evidence critically evaluated in systematic literature reviews was exhaustively identified, and clinical recommendations were developed. The modified Delphi Panel methodology was used to achieve an adequate level of consensus in each of the recommendations contained in this CPG. Results: 23 clinical questions were agreed upon which gave rise to their respective clinical recommendations. Conclusions: We consider that this document contributes to better clinical decision-making and becomes a point of reference for clinicians and patients in the management of dyslipidemias and this contributes to reducing the morbidity and mortality derived from atherosclerotic cardiovascular events in our country.

Improving the in vitro dissolution rate and pharmacokinetic performance of fenbendazole in sheep using drug nanocrystals.

Benzimidazole methylcarbamate anthelmintics, including fenbendazole (FBZ), have only limited water solubility and small differences in drug solubility may have a major influence on their absorption, pharmacokinetic behavior and anthelmintic efficacy. To improve FBZ water solubility and dissolution rate, novel self-dispersible nanocrystals (SDNCs) of FBZ were recently described. In this work, the pharmacokinetic behavior of the SDNCs of FBZ and Poloxamer 188 was compared against a physical mixture (PM) of its components. The experiment was conducted following a crossover design with two different experimental phases. In phase I, sheep were treated with the SDNC (n = 3) or the PM (n = 3) formulations by the intraruminal route at the same dose rate (5 mg/kg). The treatment groups were reversed after a 7-days washout period. A non-compartmental analysis of the concentration in plasma versus time results showed that the calculated Cmax and AUC0-T were significantly higher (p < 0.05) for FBZ and its metabolites after the SDNC treatment compared to the PM (for FBZ: Cmax 0.346 µg/mL and AUC0-T 10.1 µg.h/mL after the SDNC vs Cmax 0.157 µg/mL and AUC0-T 5.1 µg.h/mL after the PM treatment). Additionally, population pharmacokinetic parameters of FBZ were estimated for the first time in sheep. In conclusion, the formulation of FBZ as SDNCs is a promising approach to improve FBZ dissolution reaching a higher drug plasma exposure in ruminants.

Development of a Population Pharmacokinetic Model for Cyclosporine from Therapeutic Drug Monitoring Data.

AIM: To develop a population pharmacokinetic model for Uruguayan patients under treatment with cyclosporine (CsA) that can be applied to TDM. Patients and Methods. A total of 53 patients under treatment with CsA were included. 37 patients with at least one pharmacokinetic profile described with four samples were considered for model building, while the remaining 16 were considered for the assessments of predictive performances. Pharmacokinetic parameter estimation was performed using a nonlinear mixed effect modelling implemented in the Monolix® software (version 2019R1, Lixoft, France); meanwhile, simulations were performed in R v.3.6.0 with the mlxR package. RESULTS: A two-compartment model with a first-order disposition model including lag time was used as a structural model. The final model was internally validated using prediction corrected visual predictive check (pcVPC) and other graphical diagnostics. A total of 621 CsA steady-state concentrations were analyzed for model development. Population estimates for the absorption constant (ka) and lag time were 0.523 h-1 and 0.512 h, respectively; apparent clearance (CL/F) was 30.3 L/h (relative standard error [RSE] ± 8.25%) with an interindividual variability of 39.8% and interoccasion variability of 38.0%; meanwhile, apparent clearance of distribution (Q/F) was 17.0 L/h (RSE ± 12.1%) with and interindividual variability of 53.2%. The covariate analysis identified creatinine clearance (ClCrea) as an individual factor influencing the Cl of CsA. The predictive capacity of the population model was demonstrated to be effective since predictions made for new patients were accurate for C1 and C2 (MPPEs below 50%). Bayesian forecasting improved significantly in the second and third occasions. CONCLUSION: A population pharmacokinetic model was developed to reasonably estimate the individual cyclosporine clearance for patients. Hence, it can be utilized to individualize CsA doses for prompt and adequate achievement of target blood concentrations of CsA.