Effectiveness of combined therapy with pirfenidone and inhaled <scp>N</scp>‐acetylcysteine for advanced idiopathic pulmonary fibrosis: A case–control study

Sakamoto, Susumu; Muramatsu, Yoko; Satoh, Keita; Ishida, Fumiaki; Kikuchi, Naoshi; Sano, Go; Sugino, Keishi; Isobe, Kazutoshi; Takai, Yujiro; Homma, Sakae

doi:10.1111/resp.12477

Cited by 47 publications

(71 citation statements)

References 27 publications

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“…Replication of our findings in this manner would identify an inexpensive, readily available therapy for approximately 25% of individuals with IPF and determine whether NAC is detrimental to those carrying both rs3750920 ancestral alleles. Such a trial would also be an excellent opportunity to explore synergy between NAC and newly approved therapies for IPF, as has been recently suggested (19). Finally, our findings highlight the importance of pharmacogenetics in IPF and strongly support an effort to systematically acquire biospecimens from all individuals participating in clinical trials.…”

Section: Original Articlesupporting

confidence: 73%

“…Oxidative signaling plays a key role in the lung immune response, and can be modulated by the presence of antioxidants, such as N-acetylcysteine (NAC) (15)(16)(17). Although NAC therapy was recently shown to be no better than placebo in treating IPF (18), it remains a common off-label therapy for the disease (19,20). Whether polymorphisms in TOLLIP and MUC5B influence antioxidant effects is unknown.…”

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confidence: 99%

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TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis

Oldham

Fan

Martínez

et al. 2015

Am J Respir Crit Care Med

273

191

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown.Objectives: To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial.Methods: SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/ rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of >10% in FVC.Measurements and Main Results: Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (P interaction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort.Conclusions: NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.

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Section: Original Articlesupporting

confidence: 73%

mentioning

confidence: 99%

TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis

Oldham

Fan

Martínez

et al. 2015

Am J Respir Crit Care Med

273

191

View full text Add to dashboard Cite

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“…Other investigators are looking to see if additional benefit may be seen from combination therapy with pirfenidone and inhaled NAC when compared to pirfenidone alone [38]. The sense of hopefulness is not shared by all clinicians it seems, as many experts question the role of pirfenidone or nintedanib in all patients, or restricting use to patients who met the criteria of the clinical trials that evaluated their use [39], a practice that would remove many patients with severe IPF from qualifying for treatment.…”

Section: Adverse Effectsmentioning

confidence: 97%

Update on New Treatments for Idiopathic Pulmonary Fibrosis

DeGrado

Gilmore

2015

Curr Emerg Hosp Med Rep

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Idiopathic pulmonary fibrosis (IPF) is a chronic disorder that results in significant declines in respiratory function and a high mortality rate only a few years after diagnosis. Medical management of IPF has been attempted with various types of medications, such as immunosuppressants, anticoagulants, endothelin receptor antagonists, and anti-inflammatory drugs with less than conclusive results. However, with the approval of nintedanib and pirfenidone following the IMPULSIS-1, IMPULSIS-2, and ASCEND data, there is hope that medical therapy may be able to slow the progression of IPF and decrease the rate of acute exacerbations in this patient population.

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“…Pirfenidone decreases PSCs proliferation, invasion and migration in vitro and inhibits subcutaneous tumor formation in mice co-transplanted with PCCs and PSCs [11]. A recent study has shown a better patient outcome with combined therapy of pirfenidone and N-acetylcystein (NAC) in advanced idiopathic pulmonary fibrosis patients [12]. Moreover, NAC sensitizes human PCCs to gemcitabine by inhibiting NFκB pathway [13]; and cultivation of PSCs on extracellular matrix proteins and treatment with NAC induced deactivation of PSCs and reduced their proliferation and fibrogenic property [14].…”

Section: Introductionmentioning

confidence: 99%

Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia

Suklabaidya

Das

Ali³

et al. 2016

Oncotarget

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Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC. Protein profiling of activated hamster pancreatic stellate cells (ha-PSCs) revealed expression of proteins involved in fibrosis, cancer cells growth and metastasis. Pirfenidone, suppressed growth of HapT1 cells and the desmoplastic response in vivo; these effects were enhanced by co-administration of NAC. Disulfiram alone or in combination with copper (Cu) was toxic to HapT1 cells and PSCs in vitro; but co-administration of DSF and Cu accelerated growth of HapT1 cells in vivo. Moreover, DSF had no effect on tumor-associated desmoplasia. Overall, this study identifies HapT1-derived orthotopic tumors as a useful model to study desmoplasia and tumor-directed therapeutics in PC. Pirfenidone in combination with NAC could be a novel combination therapy for PC and warrants investigation in human subjects.

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Effectiveness of combined therapy with pirfenidone and inhaled N‐acetylcysteine for advanced idiopathic pulmonary fibrosis: A case–control study

Abstract: Combination treatment with inhaled NAC and oral pirfenidone reduced the rate of annual FVC decline and improved PFS in patients with advanced IPF.

Cited by 47 publications

References 27 publications

TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis

TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis

Update on New Treatments for Idiopathic Pulmonary Fibrosis

Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia

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