Effect of Lyophilization on Stability of PEG-Protein Conjugate: A Case Study with Peginterferon alfa-2b

Abstract The purpose of the present study was to develop stable lyophilized formulation of peginterferon alfa-2b which is acquiescent to the short lyophilization process. The present study evaluates the effect of buffering components and cryoprotectant(s) on depegylation of the peginterferon alfa-2b in combination with lyophilization process. Finally, a short lyophilization process was identified which can produce a stable pharmaceutical form of peginterferon alfa-2b without any depegylation during long-term storage. Formulations were analyzed mainly for depegylation by HP-size exclusion chromatography and in-vitro antiviral activity. Residual moisture content in the lyophilized product was also used as a key indicating parameter to check its role with respect to depegylation upon storage under various temperature conditions. It was observed that the peginterferon alfa-2b when formulated in presence of cryoprotectant like sucrose requires longer lyophilization process of about 5 days, irrespective of the buffering components used, to reduce the level of residual moisture content and thereby to produce the stable formulation without depegylation. A stable formulation in presence of high concentration of lactose as a cryoprotectant was developed which can withstand stresses exerted to protein-polymer conjugate during lyophilization phases without any significant depegylation. A short lyophilization process of about 48 hours can be utilized for peginterferon alfa-2b when formulated in presence of lactose as a cryoprotectant through which a stable lyophilized formulation can be produced as against longer process required when sucrose is used a cryoprotectant, which is essential from commercial point of view as lyophilization is a costly process.

Recompensation of complications in patients with hepatitis B virus-related decompensated cirrhosis treated with entecavir antiviral therapy / 中华肝脏病杂志

Objective: To analyze the occurrence of recompensation conditions in patients with chronic hepatitis B virus-related decompensated cirrhosis after entecavir antiviral therapy. Methods: Patients with hepatitis B virus-related decompensated cirrhosis with ascites as the initial manifestation were prospectively enrolled. Patients who received entecavir treatment for 120 weeks and were followed up every 24 weeks (including clinical endpoint events, hematological and imaging indicators, and others) were calculated for recompensation rates according to the Baveno VII criteria. Measurement data were compared using the Student t-test or Mann-Whitney U test between groups. Categorical data were compared by the χ (2) test or Fisher's exact probability method between groups. Results: 283 of the 320 enrolled cases completed the 120-week follow-up, and 92.2% (261/283) achieved a virological response (HBV DNA 20 IU/ml). Child-Pugh and MELD scores were significantly improved after treatment (8.33 ± 1.90 vs. 5.77 ± 1.37, t = 12.70, P < 0.001; 13.37 ± 4.44 vs. 10.45 ± 4.58, t = 5.963, P < 0.001). During the 120-week follow-up period, 14 cases died, two received liver transplants, 19 developed hepatocellular cancer, 11 developed gastroesophageal variceal bleeding, and four developed hepatic encephalopathy. 60.4% (171/283) (no decompensation events occurred for 12 months) and 56.2% (159/283) (no decompensation events occurred for 12 months and improved liver function) of the patients had achieved clinical recompensation within 120 weeks. Patients with baseline MELD scores > 15 after active antiviral therapy achieved higher recompensation than patients with baseline MELD scores ≤15 [50/74 (67.6%) vs. 109/209 (52.2%), χ (2) = 5.275, P = 0.029]. Conclusion: Antiviral therapy can significantly improve the prognosis of patients with hepatitis B virus-related decompensated cirrhosis. The majority of patients (56.2%) had achieved recompensation. Patients with severe disease did not have a lower probability of recompensation at baseline than other patients.

Adverse effects associated with favipiravir in patients with COVID-19 pneumonia: a retrospective study

ABSTRACT BACKGROUND: Favipiravir is generally used in treating coronavirus disease 2019 (COVID-19) pneumonia in Turkey. OBJECTIVE: To determine the side effects of favipiravir and whether it is a good treatment option. DESIGN AND SETTING: Retrospective study conducted in Atatürk Chest Diseases and Chest Surgery Training and Research Hospital, Ankara, Turkey. METHODS: 357 patients who completed favipiravir treatment at the recommended dose were included. 37 patients with drug side effects and 320 patients without drug side effects were examined in two groups. RESULTS: Side effects were observed in 37 (10.36%) out of 357 patients using favipiravir. The most common side effect was liver dysfunction, in 26 (7.28%) of the patients. The following other side effects were also observed: diarrhea (1.4%), nausea (0.84%), abdominal pain (0.28%) and thrombocytopenia (0.28%). One patient (0.28%) presented both increased transaminases and nausea. CONCLUSION: In this study, it was determined that favipiravir may constitute an alternative for treating COVID-19 pneumonia given that its side effects are generally well tolerated and not serious.

Avaliação audiológica em pacientes com hepatite C crônica tratados por antivirais de ação direta / Audiological evaluation in patients with chronic hepatitis C treated by direct-action antivirals

RESUMO Objetivo Verificar se o tratamento com os antivirais de ação direta para a hepatite C provocam efeitos adversos na audição. Métodos A casuística foi composta por 16 indivíduos portadores do vírus da hepatite C, de ambos os gêneros, com média de idade de 51 anos. Foram excluídos do grupo indivíduos com perda auditiva do tipo condutiva ou mista e que apresentassem fatores de risco para perda auditiva. A avaliação foi realizada em dois momentos: antes do uso dos antivirais de ação direta e após o término do tratamento de três meses. Incluiu os seguintes procedimentos: anamnese, inspeção do meato acústico externo, audiometria tonal liminar, limiar de recepção de fala, índice de reconhecimento de fala, medidas de imitância acústica e emissões otoacústicas evocadas por estímulo transiente e produto de distorção. Resultados: Houve baixa ocorrência de zumbido e vertigem. Não houve diferença estatisticamente significativa entre os resultados da avaliação pré-tratamento e pós-tratamento. Conclusão O tratamento com antivirais de ação direta contra o vírus da hepatite C não provocou efeitos adversos na função auditiva.

ABSTRACT Purpose To verify whether treatment with hepatitis C direct-acting antivirals has adverse effects on hearing. Methods The sample consisted of 16 individuals with hepatitis C virus, of both sexes, with an average age of 51 years. Individuals with conductive or mixed hearing loss who presented risk factors for hearing loss were excluded from the group. The evaluation was carried out in two moments: before the use of direct-acting antivirals and after the three-month treatment. It included the following procedures: anamnesis, external auditory canal inspection, pure tone audiometry, speech reception threshold, speech recognition index, acoustic immittance measures and transient and distortion product otoacoustic emissions. Results There was a low incidence of tinnitus and vertigo. There was no statistically significant difference between the results of the pre- and post-treatment assessment. Conclusion The treatment with direct-acting antivirals against the hepatitis C virus did not cause any adverse effects on hearing function.

Development and evaluation of topical formulations that contain hydroethanolic extract from Schinus terebinthifolia against HSV-1 infection

Abstract The therapeutic drugs to treat Herpes simplex virus (HSV) infections have toxic side effects and there has been an emergence of drug-resistant strains. Therefore, the search for new treatments for HSV infections is mounting. In the present study, semi-solid formulations containing a crude hydroethanolic extract (CHE) from Schinus terebinthifolia were developed. Skin irritation, cutaneous permeation, and in vivo therapeutic efficacy of the formulations were investigated. Treatment with the ointment formulations did not result in any signs of skin irritation while the emulsions increased the thickness of the epidermis in Swiss mice. The cutaneous permeation test indicated that the CHE incorporated in the formulations permeated through the skin layers and was present in the epidermis and dermis even 3 h after topical application. In vivo antiviral activity in BALB/c mice treated with the CHE ointments was better than those treated with the CHE emulsions and did not significantly differ from an acyclovir-treated group. Taken together, this suggests that the incorporation of CHE in the ointment may be a potential candidate for the alternative topical treatment of herpetic lesions.

Factores relacionados con eventos adversos por medicamentos en niños hospitalizados en cuatro instituciones de salud colombianas / Factors Related to Adverse Drug Events in Children Hospitalized in Four Colombian Health Institutions

Introducción: Los eventos adversos por medicamentos son más frecuentes en niños, por lo que se buscó establecer los factores relacionados en infantes hospitalizados. Objetivo: Describir los factores relacionados con los eventos adversos por medicamentos en niños internados. Métodos: Investigación descriptiva analítica desarrollada en cuatro instituciones de salud colombianas entre enero de 2014 y junio de 2018, cuya muestra incluyó 160 niños entre un mes y 14 años de edad, en quienes ocurrieron 224 eventos adversos por medicamentos. Se estudiaron variables del niño y del ambiente del cuidado, mediante las historias clínicas, se utilizó Rho Spearman para el análisis estadístico. Resultados: De los infantes, 45,00 por ciento fueron menores de un año de edad; 33,13 por ciento consultó por afecciones respiratorias, 16,52 por ciento presentó alergias que mostraron asociación con los eventos (rs = ,185; p = 0,006); 53,13 por ciento tuvo hospitalizaciones anteriores (rs = ,145; p = 0,003); 23,75 por ciento tuvo entre dos y cuatro errores y 62,50 por ciento flebitis químicas. Hubo relación entre el número de catéteres y los eventos adversos por medicamentos (rs = ,132; p = 0,049); 91,07 por ciento fueron leves y 84,38 por ciento prevenibles. Los betalactámicos fueron responsables del 19,64 por ciento de los casos y causaron prolongación de la internación en 5,80 por ciento. Las fallas fueron: falta de permeabilización del acceso venoso (76,78 por ciento), dilución incorrecta (74,11 por ciento), medicamento equivocado (4,91 por ciento), dosis equivocada (1,76 por ciento) y vía incorrecta (1,34 por ciento). Conclusiones: El motivo de consulta es predictor de severidad del evento adverso por medicamentos; alergias y hospitalizaciones anteriores tuvieron asociación débil. En el entorno, es necesario monitorizar el uso de antivirales. Se requiere mejorar el manejo seguro de fármacos por parte del equipo de enfermería(AU)

Introduction: Adverse drug events are more frequent in children, so we sought to establish the related factors in hospitalized infants. Objective: To describe the factors related to adverse drug events in hospitalized children. Methods: A descriptive analytical research developed in four Colombian health institutions from January 2014 to June 2018 included 160 children as the sample, ages ranged between one month and 14 years. They had 224 adverse drug events. Variables of the child and the care environment were studied, through medical records; Rho Spearman was used for statistical analysis. Results: 45.00 percent of the infants were under one year of age; 33.13 percent consulted for respiratory conditions, 16.52 percent had allergies that showed an association with the events (rs =. 185; p = 0.006); 53.13 percent had previous hospitalizations (rs = .145; p = 0.003); 23.75 percent had between two and 4 errors and 62.50 percent had chemical phlebitis. There was a relationship between the number of catheters and adverse drug events (rs = .132; p = 0.049), 91.07 percent were mild and 84.38 percent preventable. Beta-lactams were responsible for 19.64 percent of the cases causing prolongation of hospitalization in 5.80 percent. The failures were lack of permeabilization of the venous access (76.78 percent), incorrect dilution (74.11 percent), incorrect medication (4.91 percent), incorrect dose (1.76 percent) and incorrect route (1.34 percent). Conclusions: The reason for consultation is a predictor of the severity of the adverse drug event; allergies and previous hospitalizations had weak association. In the environment, it is necessary to monitor the use of antivirals. It is necessary to improve the safe handling of drugs by the nursing staff(AU)

Remdesivir para el tratamiento de COVID-19: una revisión sistemática viva / Remdesivir for the treatment of COVID-19: a living systematic review

OBJETIVO: Esta revisión sistemática viva tiene como objetivo entregar un resumen oportuno, riguroso y continuamente actualizado de la evidencia disponible sobre los efectos de remdesivir en pacientes con COVID-19. MÉTODOS: Se buscaron ensayos aleatorios que evaluaran el uso de remdesivir versus placebo o ningún tratamiento en pacientes con COVID-19. Se realizó una búsqueda en la plataforma L·OVE COVID-19 (Living OVerview of Evidence), un sistema que mantiene búsquedas regulares en bases de datos, registros de ensayos, servidores preprint y sitios web relevantes en COVID-19. Todas las búsquedas fueron realizadas hasta el 25 de agosto de 2020. No se aplicaron restricciones de fecha ni de idioma. Dos revisores evaluaron de forma independiente los artículos potencialmente elegibles, de acuerdo con criterios de selección predefinidos, y extrajeron los datos mediante un formulario estandarizado. Los resultados fueron combinados mediante un metanálisis utilizando modelos de efectos aleatorios y evaluamos la certeza de la evidencia utilizando el método GRADE. Una versión viva de esta revisión estará abiertamente disponible durante la pandemia de COVID-19. RESULTADOS: La búsqueda inicial arrojó 574 referencias. Finalmente, identificamos 3 ensayos aleatorios, que evaluaban el uso de remdesivir adicionado al tratamiento estándar versus tratamiento estándar. La evidencia es muy incierta acerca del efecto del remdesivir sobre la mortalidad (RR 0,7; IC del 95%: 0,46 a 1,05; certeza de la evidencia muy baja) y la necesidad de ventilación mecánica invasiva (RR 0,69; IC del 95%: 0,39 a 1,24; certeza de evidencia muy baja). Por otro lado, es probable que el uso de remdesivir produzca un aumento en la incidencia de efectos adversos en pacientes con COVID-19 (RR 1,29; IC del 95%: 0,58 a 2,84; evidencia de certeza moderada). CONCLUSIONES: La evidencia disponible sobre el papel del remdesivir en el tratamiento de pacientes con COVID-19 es insuficiente en relación a los desenlaces críticos para tomar decisiones, por lo que no es posible realizar un correcto balance entre los beneficios potenciales, los efectos adversos y los costos.

OBJECTIVE: Provide a timely, rigorous and continuously updated summary of the evidence on the role of remdesivir in the treatment of patients with COVID-19. METHODS: Eligible studies were randomized trials evaluating the effect of remdesivir versus placebo or no treatment. We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in databases, trial registries, preprint servers and websites relevant to COVID-19. All the searches covered the period until 25 August 2020. No date or language restrictions were applied. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria, and extracted data on study characteristics, methods, outcomes, and risk of bias, using a predesigned, standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. RESULTS: Our search strategy yielded 574 references. Finally, we included three randomized trials evaluating remdesivir in addition to standard care versus standard care alone. The evidence is very uncertain about the effect of remdesivir on mortality (RR 0.7, 95% CI 0.46 to 1.05; very low certainty evidence) and the need for invasive mechanical ventilation (RR 0.69, 95% CI 0.39 to 1.24; very low certainty evidence). On the other hand, remdesivir likely results in a large increase in the incidence of adverse effects in patients with COVID-19 (RR 1.29, 95% CI 0.58 to 2.84; moderate certainty evidence). CONCLUSIONS: The evidence is insufficient for the outcomes critical for making decisions on the role of remdesivir in the treatment of patients with COVID-19, so it is impossible to balance potential benefits, if there are any, with the adverse effects and costs.

Lopinavir/ritonavir for COVID-19: a living systematic review / Lopinavir/ritonavir para COVID-19: una revisión sistemática viva

Objective: Provide a timely, rigorous, and continuously updated summary of the evidence on the role of lopinavir/ritonavir in the treatment of patients with COVID-19. Methods: We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in PubMed, Embase, CENTRAL, and other 33 sources. We searched for randomized trials and non-randomized studies evaluating the effect of lopinavir/ritonavir versus placebo or no treatment in patients with COVID-19. Two reviewers independently evaluated potentially eligible studies, according to predefined selection criteria, and extracted data using a predesigned standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. Results: Our search strategy yielded 862 references. Finally, we identified 12 studies, including two randomized trials, evaluating lopinavir/ritonavir, in addition to standard care versus standard care alone in 250 adult inpatients with COVID-19. The evidence from randomized trials shows lopinavir/ritonavir may reduce mortality (relative risk: 0.77; 95% confidence interval: 0.45 to 1.3; low certainty evidence), but the anticipated magnitude of the absolute reduction in mortality, varies across different risk groups. Lopinavir/ritonavir also had a slight reduction in the risk of requiring invasive mechanical ventilation, developing respiratory failure, or acute respiratory distress syndrome. However, it did not lead to any difference in the duration of hospitalization and may lead to an increase in the number of total adverse effects. The overall certainty of the evidence was low or very low. Conclusions: For severe and critical patients with COVID-19, lopinavir/ritonavir might play a role in improving outcomes, but the available evidence is still limited. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers soon.

Objetivo: Esta revisión sistemática viva tiene como objetivo entregar un resumen oportuno, riguroso y constantemente actualizado de la evidencia disponible sobre los efectos de lopinavir/ritonavir en pacientes con COVID-19. Métodos: Se realizó una búsqueda en la plataforma L·OVE COVID-19 (Living OVerview of Evidence), un sistema que mantiene búsquedas regulares en PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) y otras 33 fuentes. Se buscaron ensayos aleatorios y estudios no aleatorios que evaluaran el uso de lopinavir/ritonavir versus placebo o ningún tratamiento en pacientes con COVID-19. Dos revisores evaluaron de forma independiente los artículos potencialmente elegibles, de acuerdo con criterios de selección predefinidos, y extrajeron los datos mediante un formulario estandarizado. Los resultados fueron combinados mediante un metanálisis utilizando modelos de efectos aleatorios y evaluamos la certeza de la evidencia utilizando el método GRADE. Una versión viva de esta revisión estará disponible durante la pandemia de COVID-19. Resultados: La búsqueda inicial arrojó 862 referencias. Finalmente, identificamos 12 estudios incluyendo 2 ensayos aleatorios, que evaluaban lopinavir/ritonavir adicionado al tratamiento estándar versus tratamiento estándar en 250 pacientes adultos hospitalizados con COVID-19. Los resultados provenientes de los ensayos aleatorios muestran que el uso de lopinavir/ritonavir puede reducir la mortalidad (riesgo relativo: 0,77; intervalo de confianza 95%: 0,45 a 1,3; certeza de evidencia baja), pero la magnitud de la reducción absoluta de la mortalidad varía según los diferentes grupos de riesgo. El uso de lopinavir/ritonavir mostró además una ligera reducción en el riesgo de requerir ventilación mecánica invasiva, desarrollar insuficiencia respiratoria o síndrome de dificultad respiratoria aguda. No se observó diferencias en la duración de la hospitalización y su uso puede producir un aumento en el número de efectos adversos totales. La certeza global de la evidencia fue baja o muy baja. Conclusiones: Para pacientes graves y críticos con COVID-19, el uso de lopinavir/ritonavir podría desempeñar un papel en la mejora de los resultados, pero la evidencia disponible aún es limitada. La gran cantidad de estudios en curso deberían proporcionar evidencia valiosa para informar a los investigadores y los tomadores de decisiones en el futuro cercano.

Hidroxicloroquina: Mensajes desde la cardiología en tiempos de pandemia por Coronavirus / Hydroxychloroquine. Cardiology's viewpoint in times of coronavirus pandemic

Ante la pandemia de COVID-19 (del inglés coronavirus disease 2019), uno de los fármacos propuesto para su tratamiento es la hidroxicloroquina. Se revisan aquí aspectos cardiológicos del uso de cloroquina e hidroxicloroquina. Se realizó una revisión no sistemática en la literatura médica orientada a la búsqueda de información acerca de su seguridad y eficacia como antimaláricos y antivirales, así como en el tratamiento prolongado de enfermedades reumatológicas. Se halló un efecto antiinflamatorio con reducción de eventos cardiovasculares a largo plazo, una cardiopatía muy infrecuente por un efecto lisosomal del fármaco, y a nivel hemodinámico hipotensión, taquicardia, y prolongación del intervalo QT, exacerbado si se combina con azitromicina. Sin embargo, la tasa de eventos adversos cardíacos de la hidroxicloroquina y la cloroquina fue baja.

Due to the coronavirus disease 2019 (COVID-19) pandemic, a wide number of compounds are under scrutiny regarding their antiviral activity, one of them being hydroxychloroquine. Cardiac aspects of the use of chloroquine and hydroxychloroquine are reviewed in this manuscript. A non-systematic review of the medical literature was performed. Information about their safety and efficacy as antimalarials, antivirals, as well as in the long-term treatment of rheumatic diseases was collected. We found an anti-inflammatory effect with reduction of long-term cardiovascular events, a very infrequent heart disease due to a lysosomal effect of the drug, and at the hemodynamic level hypotension, tachycardia, and QT interval prolongation, exacerbated when combined with azithromycin. However, the rate of adverse cardiac events of hydroxychloroquine (and chloroquine) was low.

Off label, compassionate and irrational use of medicines in Covid-19 pandemic, health consequences and ethical issues / Uso off label, compassivo e irracional de medicamentos na pandemia de Covid-19, consequências para a saúde e questões éticas

Abstract When Covid-19 emerged in December last year, there was no vaccine nor was there specific effective treatment for this fast-spreading and life-threatening viral respiratory infection. Clinical trials were planned and are in progress to investigate whether drugs used for influenza, HIV and other viruses, and also anthelmintics (ivermectin, nitazoxanide, niclosamide), and antimalarials (chloroquine, hydroxychloroquine) showing antiviral activity in in vitro assays, are effective and safe for Covid-19. So far there is no convincing evidence that these antiviral and antiparasitic drugs are of any benefit for Covid-19. Notwithsanding the absence of evidence of clinical efficacy, these drugs are widely used outside of clinical trials (off label) for prophylaxis and treatment of this viral infection. The rationale behind the prescription of macrolide antibiotics (azithromycin) for Covid-19 is obscure as well. The widespread prescription and use of drugs of unproven efficacy and safety for Covid-19 is at odds with the rational use of medicines, a cornerstone principle of pharmacotherapy advanced by WHO in 1985. This irrational use of drugs is cause for concern because some of them are associated with serious heart disorders and deaths.

Resumo Quando a Covid-19 surgiu em dezembro do ano passado, não havia vacina nem tratamento eficaz específico para esta infecção respiratória viral de rápida disseminação e risco de vida. Ensaios clínicos foram planejados e estão em andamento para investigar se os medicamentos usados para influenza, HIV e outros vírus e também anti-helmínticos (ivermectina, nitazoxanida, niclosamida) e antimaláricos (cloroquina, hidroxicloroquina) mostrando atividade antiviral em ensaios in vitro são eficazes e seguros para Covid-19. Até o momento, não há evidências convincentes de que esses medicamentos antivirais e antiparasitários sejam benéficos para a Covid-19. Não obstante a ausência de evidência de eficácia clínica, esses medicamentos são amplamente utilizados fora dos ensaios clínicos (off label) para profilaxia e tratamento dessa infecção viral. A lógica por trás da prescrição de antibióticos macrolídeos (azitromicina) para a Covid-19 também é obscura. A ampla prescrição e uso de medicamentos de eficácia e segurança não comprovadas para a Covid-19 está em desacordo com o uso racional de medicamentos, um princípio fundamental da farmacoterapia promovido pela OMS em 1985. Esse uso irracional de medicamentos é motivo de preocupação, porque alguns deles estão associados a graves doenças cardíacas e mortes.

Implicaciones cardiovasculares de la infección por SARS-CoV-2: revisión de literatura / Cardiovascular implications of SARS-CoV-2 infection: a literature review

En diciembre de 2019 se reportó en Wuhan, China, la aparición de una nueva cepa de coronavirus SARS-CoV-2 que producía un compromiso pulmonar severo y progresaba a estrés respiratorio agudo. A la fecha, son más de diecisiete millones los casos confirmados y más de medio millón los fallecidos en todo el mundo a causa de COVID-19. Los estudios reportan que los pacientes con enfermedad cardiovascular son más susceptibles a contraer esta enfermedad y a presentar más complicaciones. El propósito de esta revisión es proporcionar información actualizada para los profesionales de la salud que atienden a pacientes con COVID-19 y que tienen además enfermedad cardiovascular y por ende un riesgo elevado de complicaciones y mortalidad. Realizamos una búsqueda de bibliografía científica acerca de la asociación de enfermedad cardiovascular y COVID-19 en diferentes bases de datos como Scopus, MEDLINE vía PubMed y Cochrane Library. El tratamiento con inhibidores de la enzima convertidora de angiotensina y bloqueadores del receptor de angiotensina ha sido motivo de discusión y no hay evidencia sólida para contraindicarlo en pacientes con COVID-19. Respecto al tratamiento con hidroxicloroquina asociado o no con azitromicina, hay evidencia que demuestra un mayor riesgo con su utilización, que beneficio clínico y/o disminución de mortalidad. En este contexto, los pacientes con insuficiencia cardíaca representan un grupo importante de riesgo por su condición per se y por el dilema diagnóstico generado al evaluar un paciente con COVID-19, en el que los signos de insuficiencia cardíaca aguda podrían enmascararse. Por otro lado, en los pacientes con síndrome coronario agudo, el enfoque terapéutico inicial podría cambiar en el contexto de la pandemia, aunque sólo sobre la base de opiniones de expertos. Quedan, sin embargo, muchos temas en controversia que serán motivo de investigaciones futuras.

In December 2019, a new strain of the SARS-CoV-2 coronavirus was reported in Wuhan, China, which produced severe lung involvement and progressed to respiratory distress. To date, more than seventeen million confirmed cases and more than half a million died worldwide from COVID-19. Patients with cardiovascular disease are more susceptible to contracting this disease and presenting more complications. We did a literature search on the association of cardiovascular disease and COVID-19 in databases such as Scopus, PubMed/MEDLINE, and the Cochrane Library. The purpose of this review is to provide updated information for health professionals who care for patients with COVID-19 and cardiovascular disease, given that they have a high risk of complications and mortality. Treatment with angiotensin-converting enzyme inhibitors and receptor blockers is controversial, and there is no evidence not to use these medications in patients with COVID-19. Regarding treatment with hydroxychloroquine associated or not with azithromycin, there is evidence of a higher risk with its use than clinical benefit and decreased mortality. Likewise, patients with heart failure are an important risk group due to their condition per se. Patients with heart failure and COVID-19 are a diagnostic dilemma because the signs of acute heart failure could be masked. On the other hand, in patients with acute coronary syndrome, the initial therapeutic approach could change in the context of the pandemic, although only based on expert opinions. Nonetheless, many controversial issues will be the subject of future research.

La evidencia en tiempos de coronavirus (COVID-19) / Evidence in times of coronavirus (COVID-19)

La pandemia de COVID-19 está generando información epidemiológica y clínica en una escala sin precedentes para una enfermedad de reciente aparición. Aunque ya se han iniciado numerosos ensayos clínicos de fármacos antiguos y nuevos como potenciales antivirales específicos, la mayor parte de la información publicada hasta ahora carece de los controles básicos para la evaluación de la eficacia de un medicamento. Los medios de comunicación amplifican estos resultados preliminares y suman presión a los médicos asistenciales y a los decisores de políticas públicas. Este artículo revisa las pruebas disponibles sobre los cuatro tratamientos antivirales específicos más prometedores: hidroxicloroquina, lopinavir/ritonavir, remdesvir e interferones alfa y beta. Se comprueba en todos ellos que no hay demostración suficiente de eficacia como para recomendar su uso fuera de una investigación experimental adecuadamente controlada. En el uso individual de un medicamento no hay forma de saber si está beneficiando o perjudicando al paciente. Es erróneo asumir que la eventual curación se debe al fármaco y un mal desenlace debe atribuirse a la enfermedad. Sólo la comparación entre grupos de pacientes asignados al tratamiento experimental o a un control adecuado permite conocer la eficacia y seguridad de las intervenciones. El desafío es conciliar la urgencia de actuar con la generación de nuevos conocimientos.Aunque no resulta sencillo organizar ensayos clínicos en este contexto, las instituciones pueden sumarse a los proyectos en marcha a nivel nacional e internacional. El uso de estos fármacos debe considerarse experimental, por lo que es necesario obtener el consentimiento informado del paciente. (AU)

The COVID-19 pandemic is generating epidemiological and clinical information on an unprecedented scale for a newly emerging disease. Although numerous clinical trials of old and new drugs as potential specific antivirals have already been started, most of the information published so far lacks basic controls for evaluating drug efficacy. The media amplify these preliminary results and add pressure to doctors and policymakers. This article reviews the available evidence for the four most promising specific antiviral treatments: hydroxychloroquine, lopinavir / ritonavir, remdesvir, and alpha and beta interferons. The findings show that none of them has sufficient demonstration of efficacy to recommend its use outside ofthe adequately controlled experimental study. In the individual use of a drug there is no way of knowing if it is benefiting orharming the patient. It is wrong to assume that the eventual cure is due to the drug and a poor outcome must be attributed to the disease. Only the comparison between groups of patients assigned to the experimental treatment or to an adequate control can establish the efficacy and safety of the interventions. The challenge is to reconcile the urgency to act with the generation of new knowledge. Although it is not easy to organize clinical trials in this context, the institutions can join theongoing projects at the national and international levels. The use of these drugs should be considered experimental, so it is necessary to obtain the informed consent of the patient. (AU)

Potenciales efectos pro-arrítmicos de la farmacoterapia contra SARS-CoV-2 / Potential pro-arrhythmic effects of pharmacotherapy against SARS-CoV-2

Resumen La pandemia por el virus SARS-COV-2 causante de la enfermedad COVID-19 representa un reto mundial dada su alta tasa de transmisión y ausencia de una terapia efectiva o vacuna. Este escenario ha propiciado el uso de diversos fármacos que in vitro han demostrado un potencial efecto contra el virus. Sin embargo, el tiempo no ha sido suficiente para evaluar su efectividad clínica con el adecuado rigor científico que precede a la prescripción de medicamentos. El uso de cloroquina/hidroxicloroquina, azitromicina y esquemas antivirales ha sido propuesto por diversos grupos, apoyado por series de pacientes limitada en número. Si bien puede representar la única esperanza para muchos enfermos, es importante conocer los principales efectos adversos asociados al uso de estas drogas y seleccionar mejor a los pacientes que puedan beneficiarse de ellas. El riesgo de arritmias ventriculares incrementa tanto por el uso de fármacos como por la gravedad de la propia enfermedad viral.

Abstract The pandemic caused by the SARS-COV-2 or COVID-19 virus has been a global challenge given its high rate of transmission and lack of effective therapy or vaccine. This scenario has led to the use of various drugs that have demonstrated a potential effect against the virus in vitro. However, time has not been enough to properly evaluate their clinical effectiveness. The use of chloroquine/hydroxychloroquine, azithromycin and antiviral treatment and has been proposed by various groups, supported by in-vitro studies and limited patient series, without the adequate scientific rigor that precedes drug prescription. Although it may represent the only hope for many patients, it is important to know the main adverse effects associated with the use of these drugs and to better select patients who may benefit from them.

Cardiac Disorder in Chronic Hepatitis C

Chronic hepatitis C (CHC) has a high prevalence in the world. In addition to hepatic complications with cirrhosis in about 20% of patients and high risk for hepatocarcinoma, extrahepatic manifestations may also occur. Cardiac involvement in patients with CHC is associated with several factors, such as increased risk for coronary artery disease, primary cardiomyopathies, or hemodynamic and electrophysiological changes observed in liver cirrhosis. Furthermore, antiviral treatment may, in rare cases, causes cardiovascular adverse effects. Cardiac arrhythmias are the main form of clinical presentation, and, often, markers of poor prognosis in individuals with advanced liver disease. Although some mechanisms that justify these changes have already been reported, many questions remain unanswered, especially about the true involvement of the hepatitis C virus in the genesis of primary cardiac abnormalities, and the risk factors for cardiac-related complications of antiviral treatment

Infección letal por adenovirus: presentación de un caso / Lethal infection for adenovirus: case report

Adenovirus (ADV) can cause serious, localized or disseminated, sometimes lethal disease. There is no specific treatment, only support management according to requirements and severity of disease. Extracorporeal membrane oxygenation (ECMO) has been used in severe ADV infection. Cidofovir has been reported as a therapeutic option. This case reports a lethal case of ADV respiratory infection despite the treatment with cidofovir an ECMO.

El adenovirus (ADV) puede causar infección respiratoria grave, localizada o diseminada y letal en pacientes susceptibles. No existe terapia específica, solo de soporte según requerimientos y gravedad. En este sentido el manejo con oxigenación por membrana extracorpórea (ECMO) ha sido utilizado en niños con infección grave por ADV. Si bien no existe terapia específica actual se ha reportado uso de cidofovir que ha ganado espacio como posibilidad terapéutica en caso de enfermedad grave. Se presenta el caso clínico de un paciente que cursó con infección letal por ADV a pesar del tratamiento de soporte con ECMO y el tratamiento con cidofovir.

Tratamiento de infección crónica por virus de hepatitis C en niños, ¿perspectiva hacia la curación o lejos de la meta? / Treatment of chronic hepatitis C virus infection in children, prospect towards cure or far from the goal?

Resumen La infección por el virus de hepatitis C es un problema global de salud pública; en México aproximadamente 2 % de la población se encuentra infectada. En niños, los datos de prevalencia son variables según la edad, pero se estima que 0.1 a 2 % de los niños presenta infección crónica por virus de hepatitis C, cuya principal vía de transmisión es la perinatal. Actualmente existen antivirales de acción directa aprobados en adultos con una tasa de respuesta viral sostenida superior a 95 %; sin embargo, en niños aún son pocos los estudios que confirman su seguridad y efectividad. Aunque todavía estamos lejos de la meta, avanzamos rápidamente hacia un tratamiento óptimo de curación también para pacientes pediátricos.

Abstract Infection with hepatitis C virus is a global health problem; in Mexico, approximately 2% of the population is infected. In children, data on prevalence are variable according to the age group, but 0.1-2% of children are estimated to have chronic infection with hepatitis C virus, the main way of transmission of which is perinatal. Currently, there are direct-acting antiviral agents approved in adults that offer a sustained viral response rate higher than 95%; however, in children there are still only few studies confirming their safety and effectiveness. Although we are still far from the goal, we are rapidly advancing towards an optimal curative treatment also for pediatric patients.

Hand-foot syndrome due to hepatitis C therapy

SUMMARY INTRODUCTION Direct-acting antivirals are new drugs for chronic hepatitis C treatment. They are usually safe and well tolerated, but can sometimes cause serious adverse effects and there is no consensus on how to treat or prevent them. We described a case of hand-foot syndrome due to hepatitis C virus interferon-free therapy. METHODS We report the case of a 49-year-old man with compensated liver cirrhosis due to chronic hepatitis C genotype 1, treatment-naïve, who started viral treatment with sofosbuvir, simeprevir and ribavirin for 12 weeks. RESULTS At the sixth week of treatment he had anemia, requiring a lower dose of ribavirin. At the tenth week, he had erythematous, pruritic, scaly and flaky lesions on hands and feet, which showed a partial response to oral antihistamines and topical corticosteroids. It was not necessary to discontinue antiviral treatment, but in the first week after the end of treatment, there was worsening of injuries, including signs of secondary infection, that required hospitalization, antibiotics and oral corticosteroid, with progressive improvement. Biopsy of the lesions was consistent with pharmacodermia. The patient had sustained a virological response, despite the side effect. He had a history of pharmacodermia one year ago attributed to the use of topiramate, responsive to oral corticosteroid. CONCLUSION Interferon-free therapies can rarely lead to severe adverse reactions, such as skin lesions. Patients receiving ribavirin combinations and those who had a history of pharmacodermia or skin disease may be more susceptible. There is no consensus on how to prevent skin reactions in these patients.

RESUMO INTRODUÇÃO Antivirais de ação direta são as novas drogas utilizadas no tratamento da hepatite C crônica. São geralmente seguros, com boa tolerância, mas eventualmente podem causar efeitos adversos graves, e não há consenso sobre como tratá-los ou preveni-los. Descrevemos um caso de síndrome mão-pé secundária à terapia livre de interferon para hepatite C crônica. Materiais e métodos Relatamos o caso de um paciente de 49 anos com cirrose hepática compensada secundária à hepatite C crônica, genótipo 1, virgem de tratamento, que iniciou terapia com sofosbuvir, simeprevir e ribavirina por 12 semanas. Resultados Na sexta semana de tratamento, apresentou anemia, sendo necessária redução de dose da ribavirina. Na 20a semana, apresentou lesões eritematosas e descamativas, com prurido em mãos e pés, que teve resposta parcial ao uso de anti-histamínico oral e corticoide tópico. Não foi necessário descontinuar os antivirais, mas na primeira semana após o término do tratamento, houve piora das lesões, com sinais de infecção secundária, sendo necessárias hospitalização e terapia com antibiótico e corticoide oral, com melhora progressiva. Biópsias das lesões foram compatíveis com farmacodermia. O paciente teve resposta virológica sustentada, apesar dos efeitos adversos. Tinha história de farmacodermia há um ano, atribuída ao uso de topiramato, responsiva a corticoterapia oral. Conclusão Os tratamentos livres de interferon raramente causam eventos adversos graves, como lesões cutâneas. Pacientes em uso de ribavirina e com história de farmacodermia ou doença cutânea prévia podem ser mais susceptíveis. Não existe consenso sobre como prevenir reações cutâneas nesses pacientes.