The effects of sildenafil on ciliary beat frequency in patients with pulmonary non-tuberculous mycobacteria disease: phase I/II trial

BMJ Open Respir Res. 2020 Mar;7(1):e000574. doi: 10.1136/bmjresp-2020-000574.

Abstract

Rationale: Pulmonary non-tuberculous mycobacterial (PNTM) disease has increased over the past several decades, especially in older women. Abnormal mucociliary clearance and abnormal nasal nitric oxide (nNO) have been associated with PNTM disease in other patient cohorts. Mucociliary clearance can be affected by NO-cyclic guanosine monophosphate signalling and, therefore, modulation of the pathway may be possible with phosphodiesterase inhibitors such as sildenafil as a novel therapeutic approach.

Objective: To define ex vivo characteristics of PNTM disease affected by sildenafil.

Methods: Subjects with PNTM infections were recruited into an open-label dose-escalation trial of sildenafil. Laboratory measurements and mucociliary measurements-ciliary beat frequency, nNO and 24-hour sputum production-were collected throughout the study period. Patients received sildenafil daily during the study period, with escalation from 20 to 40 mg three times per day.

Measurements and main results: Increased ciliary beat frequency occurred after a single dose of 40 mg sildenafil and after extended dosing of 40 mg sildenafil. The increase ciliary beat frequency was not seen with 20 mg sildenafil dosing. There were no changes in sputum production, nNO production, Quality of Life-Bronchiectasis-NTM module (QOL-B-NTM) questionnaire or the St George's Respiratory Questionnaire during the study period.

Conclusion: Sildenafil, 40 mg, increased ciliary beat frequency acutely as well as with extended administration.

Keywords: airway epithelium; atypical mycobacterial infection; innate immunity; opportunist lung infections; rare lung diseases; respiratory infection.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Intramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Bronchiectasis
  • Cilia / drug effects*
  • Female
  • Health Surveys
  • Humans
  • Lung Diseases / drug therapy*
  • Lung Diseases / microbiology
  • Middle Aged
  • Mucociliary Clearance / drug effects
  • Mycobacterium Infections, Nontuberculous / drug therapy*
  • Mycobacterium Infections, Nontuberculous / microbiology
  • Nasal Mucosa / chemistry
  • Nasal Mucosa / drug effects
  • Nitric Oxide / analysis
  • Nontuberculous Mycobacteria
  • Phosphodiesterase 5 Inhibitors / administration & dosage*
  • Phosphodiesterase 5 Inhibitors / adverse effects
  • Quality of Life
  • Sildenafil Citrate / administration & dosage*
  • Sildenafil Citrate / adverse effects
  • Treatment Outcome

Substances

  • Phosphodiesterase 5 Inhibitors
  • Nitric Oxide
  • Sildenafil Citrate