ABSTRACT
La enfermedad COVID-19 ha ocasionado una de las crisis sanitarias más importantes de la historia. A propósito, se reporta el caso clínico de un trabajador de la salud sin antecedentes clínicos ni factores de riesgo cardiovascular que resultó contagiado, presentando secuela de hipertensión arterial que requirió tratamiento farmacológico. Existe la necesidad de continuar el estudio fisiopatológico de las consecuencias que genera esta patología, en especial de la relativa a la hipertensión arterial y la potencialidad de establecer una condición crítica y disfunción cardiovascular.
The COVID-19 disease has caused one of the most important health crises in history. In these terms, this clinical case is reported, which is related to a health worker with no medical history or cardiovascular risk factors. This patient was infected, presenting sequelae of arterial hyper-tension that required pharmacological treatment. It was showed the need to continue the pathophysiological study of the consequences generated by this pathology, especially regarding arterial hypertension and the potential to establish a critical condition and cardiovascular dysfunction.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Disease , COVID-19 , Hypertension , Patients , Health , Heart Disease Risk FactorsABSTRACT
A finales de 2019 una nueva cepa de coronavirus (SARS-CoV-2) ocasiona una notable crisis mundial. Los esfuerzos del personal sanitario se han centrado en conocer la novel enfermedad y buscar la manera de frenar las curvas de contagio para en un futuro contar con inmunidad por vacunas. La inmunidad ante la primoinfección mediada por Linfocitos B ha reportado pérdida de inmunoglobulinas en cuestión de semanas. Estas características en el genotipo de la enferme- dad abren la posibilidad de reinfección por cepas distintas. Contados reportes a nivel mundial describen reinfección, los que tuvieron curso clínico leve al determinar algún factor protector luego de la primoinfección. La real posibilidad de volver a enfermarse por COVID-19 enciende las alarmas sobre la respuesta en el control de la pandemia, con las vacunas que están cerca de expenderse y representa un nuevo campo de estudio en la presente emergencia sanitaria.
At the end of 2019, a new strain of coronavirus (SARS-CoV-2) causes a notable global crisis. The efforts of health personnel have focused on learning about the novel disease and finding a way to slow down the contagion curves to have immunity from vaccines in the future. Immunity to primary B lymphocyte-mediated infection has reported loss of immunoglobulins in a matter of weeks. These characteristics in the genotype of the disease open the possibility of reinfection by different strains. Counted reports worldwide describe reinfection, which had a mild clinical course when determining some protective factor after the primary infection. The real possibility of getting sick again from COVID-19 raises the alarms about the response in the control of the pandemic, with the vaccines that are close to being distributed and represents a new field of study in the current health emergency.
Subject(s)
Humans , Male , Female , Coronavirus Infections , Pandemics , Immunity , Vaccines , Health , DiseaseABSTRACT
El proceso investigativo desarrollado fue de tipo observacional, descriptivo, transversal; para lo que se revisaron 52 historias clínicas de pacientes con FA, en el servicio de Medicina Interna del Hospital Provincial General Docente de Riobamba, Ecuador; en el período comprendido desde el 1 de mayo del 2017 hasta el 25 de abril del 2018. Las historias seleccionadas fueron agrupadas en dos conjuntos: el primero compuesto por pacientes con manifestaciones clínicas de FA y con diagnóstico electrocardiográfico de esta arritmia (n=38); mientras que el segundo, integró a los asintomáticos o levemente sintomáticos diagnosticados por electrocardiograma (n=14). Los resultados obtenidos indicaron que el 73,08% de los pacientes estaban sintomáticos. Los mayores de 70 años de edad predominaron en el estudio. La hipertensión arterial y la insuficiencia cardíaca resultaron los principales factores de riesgo presentes en la población estudiada. La prueba estadística el chi cuadrado permitió establecer la existencia de una relación significativa, entre la presencia de factores de riesgo y la aparición de las manifestaciones clínicas correspondientes a la FA, al obtenerse un valor p<0,05 (0,042).
The research process developed was observational, descriptive, transversal. 52 medical records of patients with AF were reviewed in the Internal Medicine service of the General Hospital of Riobamba-Ecuador in the period from May 1, 2017 to April 25, 2018. The chosen medical records were grouped into two sets: the first consisting of patients with clinical manifestations of AF and with electrocardiographic diagnosis of this arrhythmia (n = 38) ; the second one integrated the asymptomatic or slightly symptomatic diagnosed by electrocardiogram (n = 14). The results obtained indicated that 73.08% of the patients were symptomatic. Those over 70 years of age predominated in the study. Arterial hypertension and heart failure were the main risk factors present in the study population. The chi-square statistical test allowed to establish the existence of a significant relationship, between the presence of risk factors and the appearance of the clinical manifestations corresponding to AF, when a p value <0.05 (0.042) was obtained.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Arrhythmias, Cardiac , Atrial Fibrillation , Cardiology , Risk Factors , Arterial Pressure , Heart FailureABSTRACT
La hemorragia subaracnoidea puede producirse por un traumatismo cráneo encefálico o cuando el denominado aneurisma (defecto en la estructura de la pared de un vaso sanguíneo) se rompe produciendo flujo de sangre en el espacio subaracnoideo. Al respecto, se desarrolló un estudio con enfoque mixto, de tipo no experimental, descriptivo, longitudinal prospectivo; cuyo fin fue describir la hemorragia subaracnoidea aneurismática en pacientes atendidos en la unidad de cuidados intensivos del Hospital Luis Vernaza, en la ciudad de Santiago de Guayaquil, Ecuador, durante el período comprendido desde enero hasta septiembre de 2016. En el mismo participa-ron 31 pacientes con diagnóstico de hemorragia subaracnoidea aneurismática, los que fueron atendidos en ese servicio de la institución en cuestión. Entre los resultados observados se puede destacar que: 24 de los 31 involucrados eran de género femenino, más del 90% de la población de estudio tenían más de 40 años de edad; la arteria comunicante posterior resultó la más afecta-da en los pacientes estudiados (32,26 %); el 58,33% de los casos tuvo compromiso cerebral con distintos grados de afectación; el 38,71% de la población de estudio desarrolló isquemia cere-bral tardía; se estableció una relación estadísticamente significativa entre esa última complica-ción y la administración de ácido tranexámico como parte del tratamiento para evitar resangra-do, el que se presentó solamente en el 16,13% de los pacientes participantes.
Subarachnoid hemorrhage can be caused by a traumatic brain injury or when the so-called aneu-rysm (defect in the structure of the wall of a blood vessel) ruptures causing blood flow in the subarachnoid space. Based on this, it was developed a study with a mixed approach, of a non-ex-perimental, descriptive, longitudinal, prospective type in order to describe aneurysmal subara-chnoid hemorrhage in patients treated in the intensive care unit of Luis Vernaza Hospital, in the city of Santiago de Guayaquil, Ecuador, during the period from January to September 2016. The study population was constituted by 31 patients diagnosed with aneurysmal subarachnoid hemo-rrhage and treated at the service mentioned above. The results were: 24 of the 31 patients were female, more than 90% of the study population were over 40 years of age. The posterior commu-nicating artery was the most affected in the patients representing 32.26%, 58.33% of the cases had cerebral involvement with different degrees of involvement, 38.71% of the patients develo-ped late cerebral ischemia. A statistically significant relationship was established between this last complication and the administration of tranexamic acid as part of the treatment to avoid rebleeding, which occurred only in 16.13% of the participating patients.
Subject(s)
Humans , Male , Female , Middle Aged , Subarachnoid Hemorrhage , Tranexamic Acid , Cerebral Hemorrhage, Traumatic , Signs and Symptoms , Intracranial Aneurysm , NeurologyABSTRACT
(E)-(S)-4-((S)-2-{3-[(5-methyl-isoxazole-3-carbonyl)-amino]-2-oxo-2H-pyridin-1-yl}-pent-4-ynoylamino)-5-((S)-2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid ethyl ester (Compound 1) is a novel, irreversible inhibitor of human rhinovirus (HRV) 3C protease {inactivation rate constant (Kobs/[I]) of 223,000 M-1s-1}. In cell-based assays, Compound 1 was active against all HRV serotypes (35 of 35), HRV clinical isolates (5 of 5), and related picornaviruses (8 of 8) tested with mean 50% effective concentration (EC50) values of 50 nM (range, 14 to 122 nM), 77 nM (range, 72 to 89 nM), and 75 nM (range, 7 to 249 nM), respectively. Compound 1 inhibited HRV 3C-mediated polyprotein processing in infected cells in a concentration-dependent manner, providing direct confirmation that the cell-based antiviral activity is due to inhibition of 3C protease. In vitro and in vivo nonclinical safety studies showed Compound 1 to be without adverse effects at maximum achievable doses. Single oral doses of Compound 1 up to 2,000 mg in healthy volunteers were found to be safe and well tolerated in a phase I-ascending, single-dose study. Compound 1 estimated free observed maximum concentration in plasma (Cmax) for 500-, 1,000-, and 2,000-mg doses were higher than the protein binding-corrected EC50 required to inhibit 80% of the HRV serotypes tested. Treatment of HRV 52-infected cells with one to five 2-h pulses of 150 nM Compound 1 (corresponding to the Cmax at the 500-mg dose) was sufficient to effect a significant reduction in viral replication. These experiments highlight Compound 1 as a potent, orally bioavailable, irreversible inhibitor of HRV 3C protease and provide data that suggest that Cmax rather than the Cmin might be the key variable predicting clinical efficacy.
Subject(s)
Antiviral Agents , Cysteine Proteinase Inhibitors , Rhinovirus/drug effects , Viral Proteins/antagonists & inhibitors , 3C Viral Proteases , Administration, Oral , Adolescent , Adult , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , Cysteine Endopeptidases , Cysteine Proteinase Inhibitors/administration & dosage , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Cysteine Proteinase Inhibitors/pharmacology , Dogs , HeLa Cells , Humans , Male , Middle Aged , Rhinovirus/classification , Rhinovirus/enzymology , Serotyping , Treatment OutcomeABSTRACT
The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cysteine Endopeptidases/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Rhinovirus/enzymology , Viral Proteins/metabolism , 3C Viral Proteases , Animals , Antiviral Agents/pharmacokinetics , Biological Availability , Blood Proteins/metabolism , Caco-2 Cells , Dogs , Drug Design , Half-Life , Hepatocytes/metabolism , Humans , In Vitro Techniques , Indicators and Reagents , Macaca fascicularis , Magnetic Resonance Spectroscopy , Male , Microsomes, Liver/metabolism , Protease Inhibitors/pharmacokinetics , Protein Binding , Rhinovirus/drug effects , Solubility , Structure-Activity RelationshipABSTRACT
Utilizing the tools of parallel synthesis and structure-based design, a new class of Michael acceptor-containing, irreversible inhibitors of human rhinovirus 3C protease (HRV 3CP) was discovered. These inhibitors are shown to inhibit HRV-14 3CP with rates of inactivation ranging from 886 to 31 400 M(-1) sec(-1). These inhibitors exhibit antiviral activity when tested against HRV-14 infected H1-HeLa cells, with EC(50) values ranging from 1.94 to 0.15 microM. No cytotoxicity was observed at the limits of the assay concentration. A crystal structure of one of the more potent inhibitors covalently bound to HRV-2 3CP is detailed. These compounds were also tested against HRV serotypes other than type 14 and were found to have highly variable activities.
Subject(s)
Antiviral Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Rhinovirus/drug effects , Viral Proteins/antagonists & inhibitors , 3C Viral Proteases , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Cysteine Endopeptidases , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , HeLa Cells , Humans , Protein Binding , Rhinovirus/chemistry , Structure-Activity RelationshipABSTRACT
The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and a Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The 2-pyridone-containing inhibitors typically display improved 3CP inhibition properties relative to related peptide-derived molecules along with more favorable antiviral properties. The cocrystal structure of one pyridone-derived 3CP inhibitor complexed with HRV-2 3CP is also described along with certain ab initio conformation analyses. Optimization of the 2-pyridone-containing compounds is shown to provide several highly active 3CP inhibitors (k(obs)/[I] > 500,00 M(-1) s(-1)) that function as potent antirhinoviral agents (EC(50) = <0.05 microM) against multiple virus serotypes in cell culture. One 2-pyridone-containing 3CP inhibitor is shown to be bioavailable in the dog after oral dosing (F = 48%).
Subject(s)
Antiviral Agents/chemical synthesis , Peptides/chemistry , Protease Inhibitors/chemical synthesis , Pyridones/chemical synthesis , Rhinovirus/enzymology , Viral Proteins/antagonists & inhibitors , 3C Viral Proteases , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Biological Availability , Crystallography, X-Ray , Cysteine Endopeptidases , Dogs , Drug Stability , Humans , In Vitro Techniques , Ligands , Microsomes, Liver/metabolism , Models, Molecular , Molecular Mimicry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protein Binding , Pyridones/chemistry , Pyridones/pharmacology , Structure-Activity RelationshipABSTRACT
The structure-based design, chemical synthesis, and biological evaluation of bicyclic 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. An optimized compound is shown to exhibit antiviral activity when tested against a variety of HRV serotypes (EC(50)'s ranging from 0.037 to 0.162 microM).
