Potential pharmacological candidates Transmembrane protease, serine 2 inhibitors 2019-ncov treatment / Candidatos potenciales farmacológicos inhibidores de proteasa transmembrana de serina 2 en el tratamiento de 2019-ncov

INTRODUCTION: Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus with characteristic of infecting the respiratory tract, causing severe acute respiratory syndrome. The virus uses the ACE II receptors and the transmembrane protein TMPRSS2 initial step to enter the host cell, this contribution described different types of drug, to perform its inhibition in initial step adhesion. METHODOLOGY: Non-systematic review of articles with the help of preset keywords. RESULTS: In this review we will present drugs that inhibitors of this type of receptor therefore these drugs could be considered potential candidates to mitigate the spread of SARS-CoV-2

INTRODUCCIÓN: La Enfermedad por coronavirus 2019 (COVID-19) causada por el virus SARS-CoV-2, con característica de infectar el tracto respiratorio causando un síndrome respiratorio agudo como paso inicial para ingresar a la célula huésped el virus usa los receptores ACE II y la proteína transmembrana TMPRSS2 para causar la infección, Por lo que se ha descrito diferentes tipos de fármacos para realizar su inhibición en la adhesión del paso inicial. METODOLOGÍA: Revisión no sistemática de artículos con la ayuda de palabras clave preestablecidas. RESULTADOS: En esta revisión presentaremos fármacos que inhiben este tipo de receptor, por lo tanto, estos medicamentos podrían considerarse candidatos potenciales para mitigar la propagación del SARS-CoV-2

El SRAA y el SARS-CoV-2: el acertijo a resolver / The RAAS and SARS-CoV-2: ariddle to solve

El 31 de diciembre de 2019 se reportó el primer caso de COVID-19 en Wuhan, China, y desde entonces ha habido un interés creciente y sin precedentes por conocer todos los aspectos vinculados con esta nueva enfermedad. Uno de los temas que ha generado debate se vincula con la asociación entre la terapia antihipertensiva con inhibidores del sistema renina-angiotensina-aldosterona (SRAA) y la infección por el virus SARS-CoV-2. Si bien muchas preguntas siguen hoy día sin poder ser respondidas, la intención de este comunicado es informar a los profesionales de la salud acerca del estado actual de conocimiento. Dado que este es un tema en constante evolución, se recomienda su actualización a medida que se presenten nuevas evidencias. A continuación, daremos revisión a los estudios preclínicos y clínicos que relacionan el coronavirus con el SRAA

The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as tothe association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform healthprofessionals about the current state of knowledge. Because this is an ever-evolvingtopic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS

Rescue of Escherichia coli cells from UV-induced death and filamentation by caspase-3 inhibitor

Escherichia coli cells have been observed earlier to display caspase-3-like protease activity (CLP) and undergo programmed cell death (PCD) when exposed to gamma rays. The presence of an irreversible caspase-3 inhibitor (Ac-DEVD-CMK) during irradiation was observed to increase cell survival. Since radiation is known to induce SOS response, the effect of a caspase-3 inhibitor on SOS response was studied in E. coli. UV, a well-known SOS inducer, was used in the current study. Cell filamentation in E. coli upon UV exposure was found to be inhibited by ninefold in the presence of a caspase-3 inhibitor. CLP activity was found to increase twofold in UV-exposed cells than in control (non-treated) cells. Further, bright fluorescing filaments were observed in UV-exposed E. coli cells treated with FITC-DEVD-FMK, a fluorescent dye tagged with an irreversible caspase-3 inhibitor (DEVD-FMK), indicating the presence of active CLP in these cells. Unlike caspase-3 inhibitor, a serine protease inhibitor, phenylmethanesulfonyl fluoride (PMSF), was not found to improve cell survival after UV treatment. Additionally, a SOS reporter system known as SIVET (selectable in vivo expression technology) assay was performed to reconfirm the inhibition of SOS induction in the presence of caspase-3 inhibitor. SIVET assay is used to quantify cells in which the SOS response has been induced leading to a scorable permanent selectable change in the cell. The SIVET induction frequency (calculated as the ratio of SIVET-induced cells to total viable cells) increased around tenfold in UV-exposed cultures. The induction frequency was found to decrease significantly to 51 from 80% in the cells pre-incubated with caspase-3 inhibitor. On the contrary, caspase-3 inhibitor failed to improve cell survival of E. coli ΔrecA and E. coli DM49 (SOS non-inducible) cells post UV treatment. Summing together, the results indicated a possible linkage of SOS response and the PCD process in E. coli. The findings also indicated that functional SOS pathway is required for CLP-like activity; however, the exact mechanism remains to be elucidated

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Las proteasas de serina bacterianas y su implicación en la fisiopatología de la infección / Implication of bacterial serine proteases in the physiopathology of the infection

Las proteasas de serina son enzimas ampliamente distribuidas en la naturaleza, responsables de múltiples e importantes procesos biológicos. Durante las infecciones bacterianas los patógenos secretan y usan sus proteasas de serina como factores de virulencia para combatir contra el huésped, a través de diversos efectos como la desorganización de tejidos, la proteólisis de efectores inmunológicos o la inactivación de componentes relevantes para la fisiología del huésped; sin embargo, desde hace algunos años se ha observado que las proteasas de serina podían modular procesos fisiológicos por un mecanismo altamente específico, a través de la activación de los receptores activados por proteasas. En este artículo resumimos el conocimiento reciente sobre las proteasas de serina bacteriana y su relevancia en la fisiopatología de la infección, y destacamos la oportunidad de nuevas intervenciones antimicrobianas basadas en la inhibición de la interacción receptores activados por proteasas-proteasa

Serine proteases are enzymes widely distributed in nature, and are responsible for multiple and important biological processes. During bacterial infection, pathogens secrete and use their serine proteases as virulent factors to combat against the host, through diverse mechanisms, such as tissue disruption, proteolysis of immunological effectors or inactivation of relevant components for the host physiology. However, some years ago it was observed that serine proteases could modulate physiological processes by a highly specific mechanism, through the activation of protease activated receptors (PARs). In this paper, we review recent knowledge about bacterial serine proteases and their relevance in the pathophysiology of infection. The opportunity for new antimicrobial interventions based on the inhibition of PAR-protease interaction, is also highlighted

Déficit de alfa-1-antitripsina asociado a la variante Mmalton. Descripción de una familia / Alpha-1 antitrypsin deficiency associated with the Mmalton variant. Description of a family

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Safety of vemurafenib in patients with BRAFV600 mutated metastatic melanoma: the Spanish experience

Objectives. Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAFV600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. Methods. Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAFV600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results. 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. Conclusion. Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment (AU)

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Actualización terapéutica en la hepatitis C / Therapeutic update in hepatitis C

La infección por el virus de hepatitis C es un problema de salud que afecta a 130-170 millones de personas en todo el mundo. Aproximadamente un 10-30% de pacientes con hepatitis crónica C progresarán a cirrosis en 20-30 años. El desarrollo de nuevos agentes antivirales de acción directa ha cambiado el manejo de la enfermedad, permitiendo el tratamiento libre de Interferón con eficacia superior a los regímenes terapéuticos previos y mínimos efectos adversos, incluso en algunos subgrupos previamente considerados difíciles de curar como los pacientes cirróticos (AU)

Hepatitis C virus infection is a major health burden affecting 130-170 million people worldwide. Approximately 10-30% of those with chronic hepatitis C will progress to cirrhosis over 20-30 years. The development of new direct-acting antivirals has changed the management of the disease, allowing efficacious Interferon-free therapies superior to prior treatment regimens with minimal side effects, even in some subgroups previously thought to be difficult to cure such as cirrhotic patients (AU)

Toxicodermias por telaprevir en el tratamiento de la infección crónica por el genotipo 1 del virus de la hepatitis C. Estudio prospectivo / Drug eruptions induced by telaprevir in patients with chronic hepatitis C virus genotype 1 infection: a prospective study

INTRODUCCIÓN: Telaprevir es un fármaco que administrado junto a interferón y ribavirina incrementa de forma significativa la respuesta al tratamiento de la infección por el virus de la hepatitis C. Sin embargo, su empleo incrementa también la probabilidad de desarrollar efectos adversos, en muchos casos cutáneos que pueden condicionar el mantenimiento del tratamiento. OBJETIVO: Conocer la incidencia, características clínicas y evolutivas y respuesta al tratamiento de las toxicodermias por telaprevir en el contexto del tratamiento de la infección por el virus de la hepatitis C. MATERIAL Y MÉTODOS: Estudio prospectivo observacional realizado entre mayo de 2012 y julio de 2013 en el que se incluyeron aquellos pacientes que iniciaron tratamiento con telaprevir durante ese periodo. En aquellos en los que se detectaron toxicodermia se recogieron los datos demográficos de los pacientes, las características clínicas de las lesiones y la evolución tras la aplicación de las recomendaciones de las guías clínicas. RESULTADOS: De un total de 43 pacientes que recibieron tratamiento triple un 46% presentó toxicodermia atribuible a telaprevir. En el 90% de los casos esta fue leve o moderada (grados 1 o 2) y consistió en un exantema constituido por pápulas y placas eritematoedematosas y descamativas. En alrededor de un tercio de los pacientes se comprobó la progresión de la toxicodermia, principalmente en extensión, durante el curso del tratamiento. En 2 casos (4,6%) las lesiones cutáneas condicionaron la suspensión del fármaco. Un 79% de los tratados (34 pacientes) alcanzó una respuesta viral sostenida tras el tratamiento. CONCLUSIONES: Las toxicodermias asociadas a telaprevir son frecuentes en el curso del tratamiento y a menudo progresivas. Sin embargo, solo de forma excepcional condicionan su suspensión

INTRODUCTION: When co-administered with interferon and ribavirin, the prescription drug telaprevir significantly improves treatment response in patients with chronic hepatitis C virus (HCV) infection. Its use, however, also increases the likelihood of adverse effects that may lead to discontinuation of treatment. Cutaneous adverse effects are particularly common. OBJECTIVE: To determine the frequency and clinical characteristics of drug eruptions induced by telaprevir in patients receiving HCV treatment and to analyze the clinical course of lesions and response to treatment. MATERIAL AND METHODS: We performed a prospective observational study of all patients who started a treatment regimen that included telaprevir between May 2012 and July 2013. We recorded the demographic characteristics of the patients who developed telaprevir-induced eruptions, and analyzed the clinical characteristics of the lesions and their clinical course following the application of guideline-based treatment recommendations. RESULTS: Twenty (46%) of the 43 patients who received triple therapy with interferon, ribavirin, and telaprevir during the study period developed drug reactions attributable to telaprevir. The reaction was classified as mild or moderate (grades 1 or 2) in 90% of cases and consisted of an exanthem with erythematous-edematous scaling plaques and papules. The rash worsened, mainly by spreading, in about one-third of cases. The skin lesions led to discontinuation of treatment in 2 patients (4.6%). Sustained viral response was achieved in 34 patients (79%). CONCLUSIONS: Telaprevir-induced eruptions are common and often progress, but they rarely require patients to discontinue treatment

The new latex allergen hev b 15: IgE-binding properties of a recombinant serine protease inhibitor

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Serine protease inhibitor gabexate mesilate attenuates american cockroach-induced bronchial damage and inflammatory cytokine release

Background and objective: Allergic airway diseases are not only a TH2-mediated chronic airway inflammation, but also a condition of epithelial barrier defects and dysfunction. Allergens with protease activities are known factors that initiate respiratory epithelial damage. Cockroach allergy is the second leading cause of allergic respiratory airway diseases in Taiwan, and cockroach allergens have strong serine protease activity. This study aimed to determine the protective effect of the direct local administration of gabexate mesilate (GM) on American cockroach allergen (CraA)-induced human bronchial epithelial cell inflammation. Methods: BEAS-2B cells, from the human bronchial epithelial cell line, were stimulated with CraA or co-cultured with different doses of GM. Cellular morphologic changes were observed by microscopy and changes in chemokine mRNA expression and protein levels were determined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and ELISA. Effects of specific inhibitors of ERK1/2 (U0126), JNK (SP600125), and p38 MAPK (SB203580) on CraA-induced chemokine mRNA expression were also tested by RT-PCR. Results: GM prevented CraA-induced bronchial epithelial cell detachment and morphological changes. It had superior and more extensive suppression effects than specific target MAPK inhibitors in CraA-induced mRNA expression of IL-8, monocyte chemotactic protein (MCP) 1, chemokine (C-C motif) ligand 20, and granulocyte-macrophage colony-stimulating factor from the cells in a dose-dependent manner. CraA-induced IL-8 and MCP-1 protein production from BEAS-2B cells was also attenuated by GM. Conclusions: The serine protease inhibitor GM has local protective effects against CraA-induced bronchial epithelial inflammation. The development of an inhaled or intranasal protease inhibitor may be a potential strategy for the treatment of allergic airway diseases induced by allergens with protease activities (AU)

Antecedentes y objetivo: Las enfermedades alergicas de las vias respiratorias no son solo fruto de una inflamacion cronica de las vias respiratorias mediada por Th2, sino que tambien se encuentran defectos fisicos y funcionales de la barrera epitelial. En este sentido, es conocido el papel de los alergenos con actividad proteasa que son los factores conocidos de inicio del dano epitelial respiratorio. La alergia a las cucarachas es la segunda causa principal de enfermedades alergicas de las vias respiratorias en Taiwan y estos alergenos poseen una potente actividad serin-proteasa. Este estudio tuvo como objetivo determinar el efecto protector del mesilato de gabexate (GM) contra la inflamacion inducida por la administracion local directa de alergenos de la cucaracha americana (CRAA), sobre las celulas epiteliales bronquiales humanas. Metodos: Se empleo la linea de celulas epiteliales bronquiales, celulas BEAS-2B, las cuales se estimularon con CRAA o fueron co-cultivadas con diferentes dosis de GM. Se analizaron los cambios morfologicos celulares por microscopia y los cambios en la expresion de ARNm de diferentes quimiocinas, asi como los niveles de proteina. Se utilizaron metodos semi-cuantitativos de RT-PCR y ELISA. Los efectos de inhibidores especificos de ERK1/2 (U0126), JNK (SP600125), y p38 MAPK (SB203580) en las expresion de ARNm de quimiocinas inducidas por CRAA, tambien se ensayaron por RT-PCR. Resultados: El mesilato de gabexate impidio el desprendimiento de las celulas epiteliales y los cambios morfologicos inducidos con CRAA a nivel bronquial. Sus efectos supresores fueron mas potentes y prolongados que los obtenidos con inhibidores especificos de MAPK sobre la expresion del ARNm de IL-8, MCP-1, CCL20 y GMSF en una forma dosis-dependiente. La produccion proteica de IL-8 y MCP-1 de las celulas BEAS-2B tambien fue menor cuando se anadio GM. Conclusiones: El mesilato de gabexate, inhibidor serin-proteasa , tiene efectos protectores locales contra la inflamacion bronquial epitelial inducida por la cucaracha americana. El desarrollo de un inhibidor de la proteasa, por via inhalada o intranasal, puede ser una estrategia potencial para el tratamiento de enfermedades de las vias respiratorias alergicas inducidas por alergenos con actividad proteasa (AU)

Niveles intraoculares del factor derivado del epitelio pigmentario en pacientes con uveítis activa / Intraocular levels of pigment epithelium-derived factor in patients with active uveitis

Objetivo: El factor derivado del epitelio pigmentario (PEDF) es un factor antiangiogénico yneurotrófico que recientemente también ha demostrado tener poder antioxidante y antiinflamatorio.El objetivo de nuestro estudio fue determinar los niveles de PEDF en humoracuoso de ojos con uveítis anterior aguda idiopática (UAAI).Métodos: Se realizó un estudio comparativo con grupo control. El humor acuoso fue estudiadoen 20 ojos de 20 pacientes con UAAI. El grupo control comprendía 20 muestras de humoracuoso de 20 pacientes intervenidos de cataratas, sin ninguna otra enfermedad ocular nisistémica. Los niveles de PEDF se determinaron mediante el test de ELISA.Resultados: La concentración de PEDF en humor acuoso fue marcadamente superior en lospacientes con UAAI que en los sujetos control (test U Mann-Whitney, p < 0,001). Los nivelesde PEDF fueron 6.291.637,70±8.564.836,48 pg/ml (media±DS) en los ojos con UAAI y449.178,10±158.670,19 pg/ml en los ojos del grupo control.Conclusiones: Los niveles de PEDF en humor acuoso están aumentados en ojos con UAAI locual podría considerarse como un mecanismo de autoprotección frente a la inflamación(AU)

Objective: Pigment epithelium-derived factor (PEDF) is an antiangiogenic/neurotrophic dualfunctional factor, and recently it was also shown to mediate antioxidative and antiinflammatoryaction. The purpose of this study was to evaluate the levels of PEDF in theaqueous humor in eyes with idiopathic acute anterior uveitis (IAAU).Methods: A comparative control study. Aqueous humor was collected from 20 eyes of 20 patients with IAAU. The control group included 20 aqueous humor samples from 20 patients who underwent a cataract surgery and without any other ocular or systemic diseases. Levels of PEDF were determined with the ELISA test. Results: Concentration of PEDF in aqueous humor was remarkably higher in patientswith IAAU than in control subjects (Mann-Whitney U test, P < .001). Levels of PEDF were6,291,637.70±8,564,836.48 pg/ml (mean±SD) in eyes with IAAU and 449,178.10±158,670.19pg/ml in the eyes of the control group.Conclusion: The aqueous humor PEDF levels are increased in eyes with IAAU and may beincreased as self-protection against inflammation(AU)

Las serina proteasas y su función en los procesos de muerte neuronal / The serine proteases and their function in neuronal death processes

Objetivo. En esta revisión analizamos el papel de las serina proteasas en el sistema nervioso y nos centramos en su participación en los procesos degenerativos. Desarrollo. Estas enzimas proteolíticas, junto a las caspasas, desempeñan un papel esencial en los procesos de regulación de funciones celulares, tanto en etapas del desarrollo como tras la respuesta ante un estímulo dañino. Dentro de esta familia de proteasas se engloban las granzimas y la trombina (TR). Las primeras, altamente relacionadas con las proteasas I y II y la catepsina G, se localizan en los gránulos citoplasmáticos de los linfocitos T activados, junto a otras proteínas como la perforina o citolisina. Las granzimas A y B se relacionan con los procesos degenerativos. Éstas entran en el interior de las células diana gracias a la acción de la perforina, y una vez en su interior se translocan al núcleo. La granzima A se ha aislado e identificado como el agente responsable de la inmediata y completa retracción de las neuritas en diversos modelos, y entre sus sustratos fisiológicos se encuentran la fibronectina, el colágeno de tipo IV y los proteoglicanos. La granzima B se caracteriza por ser una cisteína proteasa con sustratos como la prointerleucina-1Beta, el receptor de TR y la polimerasa poli(ADP-ribosa). La familia de las proteasas del tipo TR engloba proteasas como la propia TR, la plasmina, la kallikreína, el activador del plasminógeno urocinasa, y el activador del plasminógeno tisular. La TR se considera como un modulador temprano en los tejidos dañados, que sirve como señal extracelular de muerte que conduce a la activación de mecanismos intracelulares por un mecanismo que parece mediarse por calcio. La actividad de las serina proteasas se regula por inhibidores endógenos, como el inhibidor de activador del plasminógeno, la proteasa nexina-1 y la neuroserpina. Conclusión. Alteraciones en el equilibrio proteasainhibidor resultan cruciales en los procesos implicados en plasticidad y muerte neuronal inducidos por isquemia en el cerebro y por excitotoxinas (AU)

Aims. In this review we analyse the role played by the serine proteases in the nervous system and we focus on the role they play in degenerative processes. Development. These proteolytic enzymes, together with the caspases, play a vital role in the processes regulating cell functioning, both in the development stages and following the response to a harmful stimulus. This family of proteases includes the granzymes and thrombin (TR). The former, which are closely related to proteases I and II and cathepsin G, are situated in the cytoplasmic granules of the activated T lymphocytes, together with other proteins such as perforin or cytolysin. Granzymes A and B are linked to degenerative processes. These enter the target cells thanks to the action of perforin and once inside they are translocated to the nucleus. Granzyme A has been isolated and identified as the agent responsible for the immediate and complete retraction of neurites in different models. Its physiological substrates include fibronectin, type IV collagen and the proteoglycans. Granzyme B is characterised by its being a cysteine protease with substrates such as prointerleukin-1β, TR receptor and poly(ADP-ribose) polymerase. The family of TR-type proteases includes proteases such as TR itself, plasmin, kallikrein, urokinase plasminogen activator and tissue plasminogen activator. TR is considered to be an early modulator in damaged tissues which acts as an extracellular signal of death, leading to the activation of intracellular mechanisms that appear to be mediated by calcium. Serine protease activity is regulated by endogenous inhibitors, such as plasminogen activator inhibitor, protease nexin-1 and neuroserpin. Conclusions. Upsets in the proteaseinhibitor balance are crucial in the processes involved in the neuronal plasticity and death induced by ischemia in the brain and by excitotoxins (AU)

Otras formas de inmunomodulación en pacientes alérgicos / Other forms of immunomodulation in allergic patients

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