Pirfenidone use in fibrotic diseases: What do we know so far?

BACKGROUND: Pirfenidone has demonstrated significant anti-inflammatory and antifibrotic effects in both animal models and some clinical trials. Its potential for antifibrotic activity positions it as a promising candidate for the treatment of various fibrotic diseases. Pirfenidone exerts several pleiotropic and anti-inflammatory effects through different molecular pathways, attenuating multiple inflammatory processes, including the secretion of pro-inflammatory cytokines, apoptosis, and fibroblast activation. OBJECTIVE: To present the current evidence of pirfenidone's effects on several fibrotic diseases, with a focus on its potential as a therapeutic option for managing chronic fibrotic conditions. FINDINGS: Pirfenidone has been extensively studied for idiopathic pulmonary fibrosis, showing a favorable impact and forming part of the current treatment regimen for this disease. Additionally, pirfenidone appears to have beneficial effects on similar fibrotic diseases such as interstitial lung disease, myocardial fibrosis, glomerulopathies, aberrant skin scarring, chronic liver disease, and other fibrotic disorders. CONCLUSION: Given the increasing incidence of chronic fibrotic conditions, pirfenidone emerges as a potential therapeutic option for these patients. However, further clinical trials are necessary to confirm its therapeutic efficacy in various fibrotic diseases. This review aims to highlight the current evidence of pirfenidone's effects in multiple fibrotic conditions.

Eficacia y tolerabilidad Resultados del tratamiento para la fibrosis pulmonar idiopática. Experiencia de la vida real / Efficacy and Tolerability Outcomes of Treatment for Idiopathic Pulmonary Fibrosis. Real-life Experience

Introducción: la fibrosis pulmonar idiopática (FPI) es una enfermedad progresiva y cró-nica con muy mal pronóstico. Actualmente, existen dos fármacos para esta patología. El propósito de nuestro estudio es evaluar los efectos del tratamiento en los pacientes de una consulta en vida real.

Introduction: idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with a very poor prognosis. Two drugs are currently available for this disease. The purpo-se of our study is to evaluate the effects of treatment in patients in a real-life practice.

Brazilian guidelines for the pharmacological treatment of the pulmonary symptoms of cystic fibrosis. Official document of the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association)

A fibrose cística (FC) é uma doença genética que resulta em disfunção da proteína reguladora de condutância transmembrana da FC (CFTR), que é um canal de cloro e bicarbonato expresso na porção apical de células epiteliais de diversos órgãos. A disfunção dessa proteína resulta em manifestações clínicas diversas, envolvendo primariamente os sistemas respiratório e gastrointestinal com redução da qualidade e expectativa de vida. A FC ainda é uma patologia incurável, porém o horizonte terapêutico e prognóstico é hoje totalmente distinto e muito mais favorável. O objetivo destas diretrizes foi definir recomendações brasileiras baseadas em evidências em relação ao emprego de agentes farmacológicos no tratamento pulmonar da FC. As perguntas PICO (acrônimo baseado em perguntas referentes aos Pacientes de interesse, Intervenção a ser estudada, Comparação da intervenção e Outcome [desfecho] de interesse) abordaram aspectos relativos ao uso de moduladores de CFTR (ivacaftor, lumacaftor + ivacaftor e tezacaftor + ivacaftor), uso de dornase alfa, terapia de erradicação e supressão crônica de Pseudomonas aeruginosa, e erradicação de Staphylococcus aureus resistente a meticilina e do complexo Burkholderia cepacia. Para a formulação das perguntas, um grupo de especialistas brasileiros foi reunido e realizou-se uma revisão sistemática sobre os temas, com meta-análise quando aplicável. Os resultados encontrados foram analisados quanto à força das evidências compiladas, sendo concebidas recomendações seguindo a metodologia GRADE. Os autores acreditam que o presente documento represente um importante avanço a ser incorporado na abordagem de pacientes com FC, objetivando principalmente favorecer seu manejo, podendo se tornar uma ferramenta auxiliar na definição de políticas públicas relacionadas à FC.

Cystic fibrosis (CF) is a genetic disease that results in dysfunction of the CF transmembrane conductance regulator (CFTR) protein, which is a chloride and bicarbonate channel expressed in the apical portion of epithelial cells of various organs. Dysfunction of that protein results in diverse clinical manifestations, primarily involving the respiratory and gastrointestinal systems, impairing quality of life and reducing life expectancy. Although CF is still an incurable pathology, the therapeutic and prognostic perspectives are now totally different and much more favorable. The purpose of these guidelines is to define evidence-based recommendations regarding the use of pharmacological agents in the treatment of the pulmonary symptoms of CF in Brazil. Questions in the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) format were employed to address aspects related to the use of modulators of this protein (ivacaftor, lumacaftor+ivacaftor, and tezacaftor+ivacaftor), use of dornase alfa, eradication therapy and chronic suppression of Pseudomonas aeruginosa, and eradication of methicillin-resistant Staphylococcus aureus and Burkholderia cepacia complex. To formulate the PICO questions, a group of Brazilian specialists was assembled and a systematic review was carried out on the themes, with meta-analysis when applicable. The results obtained were analyzed in terms of the strength of the evidence compiled, the recommendations being devised by employing the GRADE approach. We believe that these guidelines represent a major advance to be incorporated into the approach to patients with CF, mainly aiming to favor the management of the disease, and could become an auxiliary tool in the definition of public policies related to CF.

Potential antifibrotic effect of blueberry and grape polyphenol extracts in acute and subacute bleomycin-induced lung tissue injury models in mice / Potencial efecto antifibrótico de los extractos de polifenoles de arándano y uva en modelos de lesión tisular pulmonar aguda y subaguda inducida por bleomicina en ratones

SUMMARY: An experimental morphological and morphometric study of the antifibrotic function of blueberry and grape extracts was carried out on a model of lung injury in mice induced by intraperitoneal administration of bleomycin. During intraperitoneal administration of bleomycin to mice, acute and subacute damage to the pulmonary system was noted. Both patterns had the same prevalence and severity. The administration of polyphenolic extracts of blueberry and grape to mice showed a significant reduction in the severity of the acute and subacute pattern of lung injury. Blueberry and grape extracts reduce the acute phase of damage to the microvasculature, enhance phagocytic function, have an anti-inflammatory effect, reducing the degree of lymphohistiocytic infiltration and locoregional foci of residual inflammatory effects.

Se realizó un estudio experimental morfológico y morfométrico de la función antifibrótica de extractos de arándano y uva en un modelo de lesión pulmonar en ratones inducida por la administración intraperitoneal de bleomicina. Durante la administración intraperitoneal de bleomicina a ratones, se observaron daños agudos y subagudos en el sistema pulmonar. Ambos patrones tuvieron la misma prevalencia y severidad. La administración de extractos polifenólicos de arándano y uva a ratones mostró una reducción significativa en la severidad del patrón agudo y subagudo de lesión pulmonar. Los extractos de arándano y uva reducen la fase aguda del daño a la microvasculatura, mejoran la función fagocítica, tienen un efecto antiinflamatorio, reducen el grado de infiltración linfohistiocítica y los focos locorregionales de efectos inflamatorios residuales.

Is it possible to repigment iatrogenic and traumatic hypochromic lesions? A case series using the MMP® drug delivery technique with 5-fluorouracil and bleomycin.

OBJECTIVES: We present the results of 11 patients with hypochromic lesions treated with antifibrotic agents delivered through the MMP® technique. METHODS: Eleven patients with hypochromic lesions because of external injuries were treated at a single clinic with 5-fluorouracil (5-FU) and/or bleomycin using the MMP® drug delivery technique. Treatment sessions were repeated at 30-day intervals until patient satisfaction. The primary outcome was repigmentation of the lesions, assessed independently by two dermatologists and by the patient. RESULTS: The MMP® technique injected 0.048 mg/cm2 of 5-FU or 0.0028 U/cm2 of bleomycin. The accumulated 5-FU and bleomycin density per patient ranged from 0.02 to 0.77 mg and 0.0022 to 0.2800 U/ml, respectively. Patients were treated with 1 to 6 MMP® sessions with 5-FU (3 patients), bleomycin (6 patients), or both drugs (2 patients). After the last session, all patients had a significant improvement (>75%) of the lesions compared to baseline. There were no procedure-related short- or long-term adverse effects in any of the participants up to their last follow-up visit. CONCLUSIONS: The injection of antifibrotic agents using the MMP® technique was effective and safe in the treatment of hypochromic lesions. This can be a new therapeutic option for these lesions.

The antifibrotic and anti-inflammatory effects of FZHY prescription on the kidney in rats after unilateral ureteral obstruction

Purpose: To explore the potential impact of traditional Chinese herb FuZhengHuaYuJiangZhuTongLuo recipe (FZHY) on renal interstitial fibrosis (RIF) in chronic kidney disease (CKD) at cellular and molecular levels. Methods: Unilateral ureteral obstruction (UUO) rats were established as the RIF mo el in vivo. The rats were given intragastric administration with FZHY once a day for consecutive 7, 14 and 21 days, respectively. The renal function parameters and inflammation indicators in kidney tissues were measured using enzyme-linked immunosorbent assay, the CD4+/CD8+ T cells in peripheral blood was detected using flow cytometry, the renal fibrosis degree was estimated using Masson's staining, and the fibrosis-related genes' expression was detected using quantitative polymerase chain reaction, western blotting, and immunohistochemistry analyses. Results: FZHY prescription reduced the serum creatinine and blood urea nitrogen, decreased the levels of c-reactive protein, interleukin-1, interleukin-6 and tumor necrosis factor-α in kidney tissues, and increased the ratio of CD4+/CD8+ T cells in peripheral blood. FZHY prescription suppressed the renal tissue fibrosis and reduced the levels of laminin, fibronectin, collagen I and collagen III. Conclusions: FZHY prescription suppressed the renal fibrosis and improved the condition of "Healthy Qi Deficiency and Evil Qi Excess" in rats with UUO, which may provide an effective method for CKD treatment.

Pirfenidona en fibrosis pulmonar / Pirfenidone in pulmonary fibrosis

CONTEXTO: La fibrosis pulmonar es una enfermedad pulmonar intersticial (EPI) caracterizada por la sustitución de tejido pulmonar por tejido cicatricial de colágeno. La EPI, a menudo denominada enfermedad pulmonar parenquimatosa difusa, son un grupo heterogéneo de trastornos que se clasifican juntos debido a manifestaciones clínicas, radiológicas, fisiológicas o patológicas similares. Las enfermedades pulmonares parenquimatosas difusas se dividen en aquellas asociadas con causas conocidas y las idiopáticas. Las neumonías intersticiales idiopáticas son enfermedades difusas pulmonares parenquimatosas, de las cuales la fibrosis pulmonar idiopática (FPI) es el tipo más común de enfermedad fibrótica pulmonar. Un consenso de la Sociedad Torácica Estadounidense (ATS, su sigla del inglés American Thoracic Society) definió la FPI como una forma específica y espontânea (idiopática) de neumonía intersticial fibrosa crónica limitada al pulmón y asociada con un patrón de neumonía intersticial usual en tomografía computada de alta resolución o apariencia histológica em biopsia quirúrgica de pulmón (toracoscópica o abierta).TECNOLOGÍA: La pirfenidona es un agente antifibrótico que inhibe la síntesis de colágeno estimulada por el fator de crecimiento transformante beta (TGF-b), disminuye la matriz extracelular y bloquea la proliferación de fibroblastos in vitro. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de pirfenidona en fibrosis pulmonar. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron una RS con meta-análisis en red (MAR), un ECA, dos estudios de fase 2, dos ETS, cuatro GPC y 20 informes de políticas de cobertura de pirfenidona en fibrosis pulmonar. CONCLUSIÓN: Evidencia de moderada calidad sugiere que la pirfenidona reduce la mortalidad frente a placebo em pacientes con fibrosis pulmonar idiopática leve o moderada a las 52 semanas, y muy probablemente también a las 72 semanas y que no hay diferencias en mortalidad comparada con nintedanib a las 52 semanas. También la pirfenidona fue superior que el placebo en diversos desenlaces respiratorios (en el cambio de la capacidad vital forzada-capacidad vital, en el cambio de la capacidad vital forzada-capacidad vital predicha y en la reducción mayor o igual al 10% de la capacidad vital forzada-capacidad vital predicha) a las 52 semanas. Evidencia de muy baja calidad no permite concluir acerca del beneficio de la pirfenidona frente a placebo en pacientes con fibrosis pulmonar no idiopática o asociada a otras enfermidades (síndrome de Hermansky-Pudlak, esclerodermia sistémica asociada a enfermedad pulmonar intersticial, enfermedad del colágeno vascular, neumonía intersticial fibrótica inespecífica, neumonitis crónica por hipersensibilidad y fibrosis pulmonar relacionada con el asbesto). No se hallaron evaluaciones económicas ni análisis de impacto presupuestario en Argentina. Si bien su precio de venta al público es elevado, el costo del tratamiento con el mismo es menor que com nintedanib, medicación con eficacia similar. Evaluaciones económicas provenientes de países de altos ingresos sugieren que la terapia con pirfenidona no sería una opción costo-efectiva em pacientes con fibrosis pulmonar idiopática. Reino Unido posee un acuerdo confidencial sobre el precio de lista con la industria farmacéutica para poder brindar cobertura. Las guías de práctica clínica identificadas recomiendan el tratamiento con pirfenidona o nintedanib como opciones válidas en pacientes con fibrosis pulmonar idiopática. En Argentina la Superintendencia de Servicios de Salud no incluye a la pirfenidona para la indicación evaluada en el Plan Médico Obligatorio y tampoco es reembolsada por el Sistema Único de Reintegro. Un país de Latinoamérica y cinco países de altos ingresos prestan cobertura para pirfenidona en fibrosis pulmonar idiopática. Brasil expresamente recomienda no dar cobertura para pirfenidona en fibrosis pulmonar idiopática.