Sabina A Antoniu

Pirfenidone for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an under-recognised, rare, progressive disease of the lungs with unknown aetiology and high mortality. The currently advocated pathogenic mechanism is represented by progressive multifocal fibrosis. It is diagnosed based on clinical, radiographic, physiological and histopathological criteria. Existing therapeutic guidelines recommend anti-inflammatory and immunosuppressive combinations, despite proven limited efficacy. There is no therapy approved specifically for IPF, but several antifibrotic agents are currently under development for this indication. Pirfenidone is an antifibrotic agent potentially effective for IPF therapy, and preclinical and available clinical data support its use in IPF. Future clinical studies are expected to provide more consistent information on survival benefit, lung function and health-related quality of life.

Targeting RhoA/ROCK pathway in pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease with a complex pathogenesis. It is often associated with an increased vascular resistance, whilst in the more advanced stages there is a remodelling of the vascular walls. PAH has an intricate involvement of various signaling pathways, including the ras homolog family member A (RhoA)–Rho kinase (ROCK) axis. Currently, available therapies are not always able to significantly slow PAH progression. Therefore, newer approaches are needed. Areas covered: In this review, areas covered include the role of the RhoA/ROCK in PAH pathogenesis and the plausibility of its therapeutic targeting. Furthermore, various inhibitory compounds are discussed, including Fasudil and SB-772077-B. Expert opinion: Currently, specific RhoA/ROCK inhibition is the most promising therapeutic approach for PAH. Research has shown that it suppresses both the components of this axis and the upstream upregulating mediators. An inhaled RhoA/ROCK inhibitor may be a successful future therapy; however, further clinical trials are needed to support this approach.

Targeting the TNF-alpha pathway in sarcoidosis.

Importance of the field/Significance: Sarcoidosis is a granulomatous disease with various organ manifestations in which TNF-α has been demonstrated to play a major pathogenic role. The existing conventional therapies are not always able to minimize TNF-α-driven inflammation and other approaches should be used. Areas covered in this review: TNF-α roles in sarcoid inflammation and granuloma formation are reviewed based on the literature published in the last two decades and the therapies able to target it specifically or non-specifically in sarcoidosis are discussed. What the reader will gain: A better understanding of the pathogenic role of TNF-α in sarcoidosis and of the scientific rationale of its therapeutic blockade. Take home message: In some subsets of sarcoidosis with more rapid progession and/or therapeutic refractoriness TNF-α plays a more prominent role in disease pathogenesis, and its blockade might represent an appropriate therapeutic approach.

Inhaled colistin for lower respiratory tract infections

Introduction: Lower respiratory tract infections, due to Pseudomonas aeruginosa or Acinetobacter baumannii, are frequently encountered in patients with cystic fibrosis (CF) or in patients developing nosocomial pneumonias. Both of these conditions bear a high mortality risk and aggressive antibiotic therapy is necessary. Inhaled antibiotics might represent an effective therapeutic approach for these diseases as it has demonstrated good bactericidal efficacy and safety in both preclinical and clinical studies. This colistin formulation might be useful particularly in patients with respiratory tract infections due to multidrug-resistant Gram-negative bacteria. Its main advantages are a better safety profile with a minimal or absent risk of nephrotoxicity. Areas covered: This paper discusses the available systemic formulations of colistin, with pharmacokinetic and safety profiles, followed by an overview of inhaled antibiotics in lower respiratory tract infections. Expert opinion: Inhaled colistin should be used selectively as monotherapy in chronic infections with P. aeruginosa in CF patients, whereas in patients with hospital/ventilator-acquired pneumonia (HAP/VAP), it should be used in a combined regimen with systemic antibiotics.

New therapeutic options in the management of COPD – focus on roflumilast

In chronic obstructive pulmonary disease (COPD) the inflammation occurring in the airways and in other lung tissues is complex and is orchestrated by various mediators including the isoenzyme 4 of the phosphodiesterases family (PDE4), which contributes to bronchoconstriction and inflammation. Various PDE4 inhibitors have been evaluated as potential therapies in asthma or COPD but among these only roflumilast have been authorized in Europe to be used in patients with severe COPD as an add-on to the bronchodilator therapy. This review discusses the existing preclinical and clinical data supporting the use of roflumilast for this therapeutic indication and tackles some of the pending issues related to PDE4 in general and to roflumilast in particular.

Targeting PDGF pathway in pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) encompasses a rare potentially lethal group of diseases characterized by vasoconstriction, in situ thrombosis and vascular remodeling. Most of the existing therapies including endothelin receptor antagonists, prostacyclin and derivatives, or phsophodiesterase-5 inhibitors tackle mainly the endothelial dysfunction, leaving the remodeling suboptimally inhibited. This explains the disease progression that occurs even with combined therapies and the need for other therapies able to adequately inhibit the vascular remodeling. Areas covered: Platelet-derived growth factor (PDGF) signaling pathway was demonstrated to be involved in the vascular remodeling in PAH, and therefore, it might be a desirable therapeutic target in this setting. This review discusses the pathogenic role of this pathway in PAH and its potential inhibitory approaches, focusing on imatinib as well as on the existing preclinical data on this compound. Expert opinion: Preclinical studies demonstrated that PDGF inhibition with receptor antagonists such as imatinib reduces vascular remodeling. Therefore, PDGF might represent a plausible therapeutic target in this disease. However, compounds able to block this pathway via different mechanisms might also become potential PAH therapies.

Ciprofloxacin DPI in non-cystic fibrosis bronchiectasis: a Phase II randomized study.

Introduction: In non-cystic fibrosis (CF) bronchiectasis, the chronic airways infection is a risk factor for frequent infectious exacerbations and for an overall poor disease prognosis. Its therapy with inhaled antibiotics might be useful alike in the case of the CF-related disease. Areas covered: Analysis and discussion of the results of a Phase II study evaluating the efficacy and safety of the inhaled ciprofloxacin-dry powder (C-DPI) formulation in patients with non-CF bronchiectasis. Expert opinion: On short-term basis C-DPI is able to reduce the sputum bacterial load in such patients but long-term studies are also needed to better characterize the clinical efficacy of this compound.

Nintedanib (BIBF 1120) for IPF: a tomorrow therapy?

Idiopathic pulmonary fibrosis is a rare, life threatening disease characterized by an anarchic fibrogenesis, limited survival and few therapeutic options. Its pathogenesis is complex and involves the interaction among various pathways driven by proinflammatory/profibrogenetic mediators such as platelet -derived growth factor, vascular endothelial growth factor or basic fibroblast growth factor. Given their prominent pathogenic roles in this disease such growth factor might be suitable therapeutic targets.In fact, the existing preclinical and clinical data demonstrated that their therapeutic inhibition results in a delayed progression of the pulmonary fibrosis and in the improvement of the disease outcome. BIBF 1120 is a potent triple blocker of the receptors of these growth factors which is currently evaluated as a potential therapy in the idiopathic pulmonary fibrosis. This review discusses the existing data supporting its potential use in this disease.

Crizotinib for EML4-ALK positive lung adenocarcinoma: a hope for the advanced disease? Evaluation of Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363(18):1693-703.

Introduction: In lung adenocarcinoma, certain mutations such as echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (ALK) are associated with lower sensitivity to chemotherapy, when used conventionally as the first-line therapy in the advanced stage of the disease. Areas covered: This paper discusses the clinical and therapeutic importance of ALK mutations in NSCLC and the early clinical results of a Phase I study assessing crizotinib in patients with ALK mutations. Expert opinion: Abnormal ALK is evolving as an important therapeutic target in patients with more aggressive lung adenocarcinoma. Further clinical studies are needed in order to assess if crizotinib, an ALK inhibitor, is able to increase the efficacy of the conventional chemotherapy in this disease subset.

Effects of inhaled therapy on biomarkers of systemic inflammation in stable chronic obstructive pulmonary disease

In chronic obstructive pulmonary disease (COPD) airways inflammation is associated in more advanced stages with systemic inflammation. COPD-associated systemic inflammation syndrome is defined currently with rather non-specific biomarkers such as C-reactive protein (CRP) but there are also other ‘organ-specific’ biomarkers such as surfactant protein-D which are still not well characterized but might represent more appropriate and reliable alternatives to the non-specific biomarkers. Inhaled therapies are the mainstay in stable COPD and they were demonstrated to reduce airway inflammation and more recently in the case of inhaled corticosteroids alone or combined with long-acting beta-2 agonists to reduce systemic inflammation as well. This paper focuses on current and potential biomarkers of systemic inflammation in COPD and on the systemic anti-inflammatory effects of inhaled therapies in stable COPD.