Efficacy Of Anti-fibrotic Drugs Research Articles

Cardiac Fibrosis in the Pressure Overloaded Left and Right Ventricle as a Therapeutic Target.

Myocardial fibrosis is a remodeling process of the extracellular matrix (ECM) following cardiac stress. “Replacement fibrosis” is a term used to describe wound healing in the acute phase of an injury, such as myocardial infarction. In striking contrast, ECM remodeling following chronic pressure overload insidiously develops over time as “reactive fibrosis” leading to diffuse interstitial and perivascular collagen deposition that continuously perturbs the function of the left (L) or the right ventricle (RV). Examples for pressure-overload conditions resulting in reactive fibrosis in the LV are systemic hypertension or aortic stenosis, whereas pulmonary arterial hypertension (PAH) or congenital heart disease with right sided obstructive lesions such as pulmonary stenosis result in RV reactive fibrosis. In-depth phenotyping of cardiac fibrosis has made it increasingly clear that both forms, replacement and reactive fibrosis co-exist in various etiologies of heart failure. While the role of fibrosis in the pathogenesis of RV heart failure needs further assessment, reactive fibrosis in the LV is a pathological hallmark of adverse cardiac remodeling that is correlated with or potentially might even drive both development and progression of heart failure (HF). Further, LV reactive fibrosis predicts adverse outcome in various myocardial diseases and contributes to arrhythmias. The ability to effectively block pathological ECM remodeling of the LV is therefore an important medical need. At a cellular level, the cardiac fibroblast takes center stage in reactive fibrotic remodeling of the heart. Activation and proliferation of endogenous fibroblast populations are the major source of synthesis, secretion, and deposition of collagens in response to a variety of stimuli. Enzymes residing in the ECM are responsible for collagen maturation and cross-linking. Highly cross-linked type I collagen stiffens the ventricles and predominates over more elastic type III collagen in pressure-overloaded conditions. Research has attempted to identify pro-fibrotic drivers causing fibrotic remodeling. Single key factors such as Transforming Growth Factor β (TGFβ) have been described and subsequently targeted to test their usefulness in inhibiting fibrosis in cultured fibroblasts of the ventricles, and in animal models of cardiac fibrosis. More recently, modulation of phenotypic behaviors like inhibition of proliferating fibroblasts has emerged as a strategy to reduce pathogenic cardiac fibroblast numbers in the heart. Some studies targeting LV reactive fibrosis as outlined above have successfully led to improvements of cardiac structure and function in relevant animal models. For the RV, fibrosis research is needed to better understand the evolution and roles of fibrosis in RV failure. RV fibrosis is seen as an integral part of RV remodeling and presents at varying degrees in patients with PAH and animal models replicating the disease of RV afterload. The extent to which ECM remodeling impacts RV function and thus patient survival is less clear. In this review, we describe differences as well as common characteristics and key players in ECM remodeling of the LV vs. the RV in response to pressure overload. We review pre-clinical studies assessing the effect of anti-fibrotic drug candidates on LV and RV function and their premise for clinical testing. Finally, we discuss the mode of action, safety and efficacy of anti-fibrotic drugs currently tested for the treatment of left HF in clinical trials, which might guide development of new approaches to target right heart failure. We touch upon important considerations and knowledge gaps to be addressed for future clinical testing of anti-fibrotic cardiac therapies.

Commentary: Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both IPF and non-IPF

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic fibrosing interstitial lung disease associated with a pattern of Usual Interstitial Pneumonia (UIP) based on CT appearances or histology.

Commentary: Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both IPF and non-IPF

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic fibrosing interstitial lung disease associated with a pattern of Usual Interstitial Pneumonia (UIP) based on CT appearances or histology.

A NEW APPROACH TO MORPHOLOGICAL EVALUATION OF THE DEGREE OF LIVER FIBROSIS IN EXPERIMENTAL ANIMALS

Usually, the efficacy of antifibrotic drugs is evaluated using laboratory animals. As the modern scientific literature shows, there is still a number of unsolved problems. First, it is necessary to determine the appropriate models that are able to reflect most accurately the development of fibrosis and cirrhosis in humans. Second, to identify diagnostic and prognostic markers to assess the progression / regression of fibrosis in animals. Third, to examine carefully the generally accepted scales for the semi-quantitative assessment of fibrosis in animal models. Based on the findings obtained, we offer an experimental model that has a number of advantages over others. In rats, thioacetamide induces fibrogenesis followed by transformation into cirrhosis. The model allows the study of fibrosis sequentially or at specific stages and is easily reproducible. The developed morphological scale describes fibrogenesis in detail, takes into account intermediate stages, and possesses a diagnostic and prognostic value.

Advances with pharmacotherapy for the treatment of interstitial lung disease

ABSTRACT Introduction In recent decades, the primary focus of pharmaceutical research in interstitial lung diseases (ILD) has been on idiopathic pulmonary fibrosis (IPF). Recently, pharmaceutical development has also focused on other forms of ILDs, including connective tissue diseases associated ILD, fibrotic hypersensitivity pneumonitis, and sarcoidosis. Areas Covered The authors summarize the advances in pharmacotherapy for the treatment of ILD. Specifically, the authors review the most recent studies and discuss the most recent research findings and future prospects. Expert opinion Data collected over the past years have confirmed the efficacy of antifibrotic drugs on slowing disease progression in IPF. The usual strategy for CTD-ILD management is represented by the combined use of corticosteroids and immunosuppressive agents. There is an urgent need for new target therapies. The concept of progressive fibrosing ILD has emerged in the ILD community in recent years, which has led to grouping several diseases with a common disease behavior to find an effective treatment . At present, selecting the best therapy in ILDs should be reasonably performed on a case-by-case basis through a multidisciplinary team discussion in tertiary ILD centers, taking into consideration patients’ symptoms, lung functional trends, and radiological changes.

Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both idiopathic pulmonary fibrosis (IPF) and non-IPF: a systematic review and meta-analysis

BackgroundResearch questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic therapy (grouping nintedanib and pirfenidone together) in patients with IPF versus patients with progressive lung fibrosis not classified as IPF.Study design and methodsA search of databases including MEDLINE, EMBASE, PubMed, and clinicaltrials.gov was conducted. Studies were included if they were randomised controlled trials of pirfenidone or nintedanib in adult patients with IPF or non-IPF patients, and with extractable data on mortality or decline in forced vital capacity (FVC). Random effects meta-analyses were performed on changes in FVC and where possible on mortality in the selected studies.Results13 trials of antifibrotic therapy were pooled in a meta-analysis (with pirfenidone and nintedanib considered together as anti-fibrotic therapy). The change in FVC was expressed as a standardised difference to allow pooling of percentage and absolute changes. The mean effect size in the IPF studies was − 0.305 (SE 0.043) (p < 0.001) and in the non-IPF studies the figures were − 0.307 (SE 0.063) (p < 0.001). There was no evidence of any difference between the two groups for standardised rate of FVC decline (p = 0.979). Pooling IPF and non-IPF showed a significant reduction in mortality, with mean risk ratio of 07.01 in favour of antifibrotic therapy (p = 0.008). A separate analysis restricted to non-IPF did not show a significant reduction in mortality (risk ratio 0.908 (0.547 to 1.508), p = 0.71.InterpretationAnti-fibrotic therapy offers protection against the rate of decline in FVC in progressive lung fibrosis, with similar efficacy shown between the two anti-fibrotic agents currently in clinical use. There was no significant difference in efficacy of antifibrotic therapy whether the underlying condition was IPF or non-IPF with progressive fibrosis, supporting the hypothesis of a common pathogenesis. The data in this analysis was insufficient to be confident about a reduction in mortality in non-IPF with anti-fibrotic therapy.Trial Registration PROSPERO, registration number CRD42021266046.

ЕВОЛЮЦІЯ ПРИНЦИПІВ ДІАГНОСТИКИ І ТЕРАПІЇ ІДІОПАТИЧНОГО ЛЕГЕНЕВОГО ФІБРОЗУ У ПОЛОЖЕННЯХ МІЖНАРОДНИХ КЛІНІЧНИХ НАСТАНОВ

EVOLUTION OF PRINCIPLES OF DIAGNOSIS AND TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS IN THE INTERNATIONAL GUIDELINE STATEMENTS Y. I. Feshchenko, V. K. Gavrysyuk, N. G. Gorovenko, Y. A. Dziublyk, I. V. Liskina Abstract Idiopathic pulmonary fibrosis (IPF) is specific form of chronic progressive interstitial fibrosing pneumonia of unknown nature, mainly occurring in patients &gt; 50 years of age, limited to the lungs and associated with histological and/or radiological pattern of usual interstitial pneumonia. Epidemiological studies estimate that prevalence of ILF in different countries varies between 1,25 and 63 cases per 100 000 persons. Along with that, ILF is characterized by unfavorable prognosis — median survival time ranges within 2,5−3,5 years from the time of diagnosis. In 2000 American thoracic society (ATS) and European respiratory society (ERS) published first international statement on diagnosis and treatment of ILF — American Thoracic Society, European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Data from studies, accumulated during next 10 years of research, determined the necessity of update of certain diagnostic criteria and principles of therapy. In this regard, a new guideline for diagnosis and treatment of IPF was published in 2011 and approved by ATS, ERS, Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT) — An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. A new update on “Treatment of IPF” was published in 2015, and chapter “Diagnosis” was updated later in 2018. Current literature review focuses on the principles and algorithms of IPF treatment and the changes in guidelines, occurred from the time of first Statement published. Summarizing review results, we can conclude, that evolution of diagnostics principles, which limited the indications for surgical lung biopsy for the purpose of diagnosis verification, is caused by explosive technological advances in the field of chest computed tomography. The capability of computed tomography has grown to such an extent, that in terms of morphological diagnosing this method can compete with histological examination. The changes in management principles were evoked by the revision of IPF pathogenesis mechanisms. Since 2000, most of the experts concluded, that fibrosis, rather than inflammation, was the leading link of pathogenesis. A fibrosing process, initially playing a reparative role, further due to unknown reasons, gains an uncontrolled progressive character. Accordingly, antifibrotic compounds, such as pirfenidone and nintedanib, came to substitute glucocorticosteroids, known for their powerful antiinflammatory potential. The publication also presents the review of most relevant randomized clinical trials on safety and efficacy of antifibrotic drugs — pirfenidone and nintedanib. Key words: idiopathic pulmonary fibrosis, diagnostics, treatment, algorithms, pirfenidone, nintedanib. Ukr. Pulmonol. J. 2021;29(3):5–23.

Safety and efficacy of bridging to lung transplantation with antifibrotic drugs in idiopathic pulmonary fibrosis: a case series.

BackgroundFollowing recent approval of pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF), questions arise about the use of these antifibrotics in patients awaiting lung transplantation (LTx).MethodsSafety and efficacy of antifibrotic drugs in IPF patients undergoing LTx were investigated in a single-centre retrospective cohort analysis.ResultsA total of nine patients, receiving antifibrotic therapy for 419 ± 315 days until subsequent LTx, were included. No major side effects were noted. Significant weight loss occurred during antifibrotic treatment (p = 0.0062). FVC tended to stabilize after 12 weeks of treatment in most patients. A moderate decline in FVC, TLC and DLCO was noted during the whole pretransplant time period of antifibrotic therapy. Functional exercise capacity and lung allocation score remained unchanged. No post-operative thoracic wound healing problems, nor severe early anastomotic airway complications were attributable to prior antifibrotic treatment. None of the patients developed chronic lung allograft dysfunction after a median follow-up of 19.8 (11.2–26.5) months; and post-transplant survival was 100% after 1 year and 80% after 2 years.ConclusionsAntifibrotic drugs can probably be safely administered in IPF patients, possibly attenuating disease progression over time, while awaiting LTx.

Hepatic Fibrosis and Its Serum Markers: A Review

Hepatic fibrosis is characterized by a progressive increase in extracellular matrix in the liver, formed by collagens, proteoglycans and glycoproteins, qualitatively similar but quantitatively different from that in normal liver. A great number of matrix-related substances have been investigated in serum in order to identify reliable serum markers of liver fibroplasia. Among the various cleavage products of collagen precursor, the NPIIIP collagen is at present considered the most reliable serum marker of active fibrogenesis in liver, useful in monitoring the progression of fibrosis and in assessing the therapeutic efficacy of antifibrotic drugs. Lam-P1 and type IV collagen are now regarded as putative markers of basement membrane formation and sinusoids capillarization, an important pathological process in fibrosing disease, related to the impairment of hepatic circulation. Other serum-measured matrix-related substances, e.g. enzymes involved in collagen metabolism, fibronectin and proteoglycans, have not proved to reflect liver fibroplasia reliably. In spite of the availability of useful serum markers, the assessment of hepatic fibrosis is still based on liver biopsy.