Carlos Moneriz

Antiplasmodial Activity and Mechanism of Action of RSM-932A, a Promising Synergistic Inhibitor of Plasmodium falciparum Choline Kinase

ABSTRACT We have investigated the mechanism of action of inhibition of the choline kinase of P. falciparum (p.f.-ChoK) by two inhibitors of the human ChoKα, MN58b and RSM-932A, which have previously been shown to be potent antitumoral agents. The efficacy of these inhibitors against p.f.-ChoK is investigated using enzymatic and in vitro assays. While MN58b may enter the choline/phosphocholine binding site, RSM-932A appears to have an altogether novel mechanism of inhibition and is synergistic with respect to both choline and ATP. A model of inhibition for RSM-932A in which this inhibitor traps p.f.-ChoK in a phosphorylated intermediate state blocking phosphate transfer to choline is presented. Importantly, MN58b and RSM-932A have in vitro inhibitory activity in the low nanomolar range and are equally effective against chloroquine-sensitive and chloroquine-resistant strains. RSM-932A and MN58b significantly reduced parasitemia and induced the accumulation of trophozoites and schizonts, blocking intraerythrocytic development and interfering with parasite egress or invasion, suggesting a delay of the parasite maturation stage. The present data provide two new potent structures for the development of antimalarial compounds and validate p.f.-ChoK as an accessible drug target against the parasite.

Inhibición dual de la neprilisina y el receptor de angiotensina II: nueva estrategia prometedora en el tratamiento de la enfermedad cardiovascular

La inhibicion de neprilisina y el bloqueo de los receptores de angiotensina II, ofrecen beneficios potenciales para el tratamiento de las enfermedades cardiovasculares. El compuesto LCZ696 es el primer farmaco en fase de estudio como inhibidor de la neprilisina y de los receptores de angiotensina. El aumento de la concentracion de los peptidos natriureticos a traves de la inhibicion de la neprilisina, representa un enfoque terapeutico que tiene el potencial de conferir proteccion cardiaca, renal y vascular. Sin embargo, diversos estudios demuestran que los beneficios clinicos de la inhibicion de la neprilisina pueden ser mejor aprovechados si se inhibe simultaneamente el sistema renina-angiotensina. Esta revision realizada en PubMed, tiene como objetivo presentar los avances prometedores en el mecanismo dual de inhibicion de la neprilisina y el receptor de angiotensina II para el tratamiento de la hipertension y la insuficiencia cardiaca.

Displasia cleidocraneal: reporte de un caso

INTRODUCTION Cleidocraneal dysplasia (CCD) is a rare skeletal autosomal dominant syndrome characterized by dental anomalies and bone abnormalities. These clinical manifestations do not require treatment in most cases. The disease is caused by mutation in the gene RUNX2 (CBAF1), located on the short arm of chromosome 6. OBJECTIVE To report a case of CCD and perform a literature review focused on clinical manifestations and diagnosis. CASE REPORT A 3 year old patient, who was clinically diagnosed with CCD since birth. The patient showed incomplete development of cranial bones, bell-shaped thorax, adequate dentition and presence of clavicles. Molecular analysis reported that the patient is carrying the pathogenic variant c.674G>A in the RUNX2 gene, confirming the diagnosis. CONCLUSIONS The CCD is a rare condition, with special clinical features. It is important to establish early diagnosis in these patients in order to offer a better quality of life, and if necessary, appropriate treatment.Introduction: Cleidocraneal dysplasia (CCD) is a rare skeletal autosomal dominant syndrome characterized by dental anomalies and bone abnormalities. These clinical manifestations do not require treatment in most cases. The disease is caused by mutation in the gene RUNX2 (CBAF1), located on the short arm of chromosome 6. Objective: To report a case of CCD and perform a literature review focused on clinical manifestations and diagnosis. Case Report: A 3 year old patient, who was clinically diagnosed with CCD since birth. The patient showed incomplete development of cranial bones, bell-shaped thorax, adequate dentition and presence of clavicles. Molecular analysis reported that the patient is carrying the pathogenic variant c.674G>A in the RUNX2 gene, confirming the diagnosis. Conclusions: The CCD is a rare condition, with special clinical features. It is important to establish early diagnosis in these patients in order to offer a better quality of life, and if necessary, appropriate treatment.

Canakinumab: un anticuerpo monoclonal prometedor en el tratamiento de enfermedades cardiovasculares

El canakinumab es un anticuerpo monoclonal anti-IL-1β totalmente humano desarrollado por Novartis, cuyo mecanismo de accion se basa en la neutralizacion de la senalizacion IL-1β, lo cual conduce a la supresion de la inflamacion en pacientes con trastornos de origen autoinmune. La IL-1β actua como un mediador de la respuesta inmune periferica durante la infeccion y la inflamacion. Mediante la union antigeno-anticuerpo el canakinumab inhibe la accion de la IL1-β evitando sus efectos pro-inflamatorios. En la actualidad, esta en evaluacion como un nuevo posible agente dirigido frente a la IL-1β, con el objetivo de reducir la tasa de eventos cardiovasculares y la diabetes de aparicion reciente (estudio CANTOS).