XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough.
Am J Respir Crit Care Med
; 196(10): 1255-1263, 2017 11 15.
Article
em En
| MEDLINE
| ID: mdl-28650204
ABSTRACT
RATIONALE Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, are characteristic of patients with chronic cough. However, previously, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients, despite small reductions in capsaicin-evoked cough. OBJECTIVES:
XEN-D0501 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough.METHODS:
XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomized, placebo-controlled crossover study evaluating the effect of 14 days of XEN-D0501 (oral, 4 mg twice daily) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough, and patient-reported outcomes. MEASUREMENTS AND MAINRESULTS:
XEN-D0501 was more efficacious and 1,000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus nerve. In vivo XEN-D0501 completely inhibited capsaicin-induced cough, whereas 100 times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline, XEN-D0501, -19.3 ± 16.4) coughs; placebo, -1.8 ± 5.8 coughs; P < 0.0001), but not spontaneous awake cough frequency (mean change from baseline, XEN-D0501, 6.7 ± 16.9 coughs/h; placebo, 0.4 ± 13.7 coughs/h; P = 0.41).CONCLUSIONS:
XEN-D0501 demonstrated superior efficacy and potency in preclinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. Clinical trial registered with www.clinicaltrialsregister.eu (2014-000306-36).Palavras-chave
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Base de dados:
MEDLINE
Métodos Terapêuticos e Terapias MTCI:
Plantas_medicinales
Assunto principal:
Antitussígenos
/
Capsaicina
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Doença Crônica
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Tosse
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Canais de Cátion TRPV
Tipo de estudo:
Clinical_trials
Idioma:
En
Revista:
Am J Respir Crit Care Med
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Reino Unido