Bronchoprotection in conscious guinea pigs by budesonide and the NO‐donating analogue, TPI 1020, alone and combined with tiotropium or formoterol

Abstract

BACKGROUND AND PURPOSEInhaled corticosteroids, anticholinergics and b2-adrenoceptor agonists are frequently combined for treating chronic respiratory diseases. We examine the corticosteroid, budesonide, and novel NO-donating derivative, TPI 1020, against histamine-and methacholine-induced bronchoconstriction and whether they enhance the b2-adrenoceptor agonist formoterol or muscarinic antagonist tiotropium in conscious guinea pigs. EXPERIMENTAL APPROACHDunkin-Hartley guinea pigs received inhaled histamine (3 mM) or methacholine (1.5 mM) and specific airway conductance (sGaw) was measured before and 15 or 75 min after treatment with budesonide, TPI 1020, tiotropium or formoterol alone or in combinations. KEY RESULTSFormoterol (0.7-10 mM) and budesonide (0.11-0.7 mM) inhibited histamine-induced bronchoconstriction and tiotropium (2-20 mM) inhibited methacholine-induced bronchoconstriction by up to 70.8 Ϯ 16.6%, 34.9 Ϯ 4.4% and 85.1 Ϯ 14.3%, respectively. Formoterol (2.5 mM) or tiotropium (2 mM) alone exerted small non-significant bronchoprotection. However, when co-administered with TPI 1020 0.11 mM, which alone had no significant effect, there was significant inhibition of the bronchoconstriction (45.7 Ϯ 12.2% and 79.7 Ϯ 21.4%, respectively). Co-administering budesonide (0.11 mM) with tiotropium (2 mM), which alone had no effect, also significantly inhibited the methacholine bronchoconstriction (36.5 Ϯ 13.0%), but there was no potentiation of formoterol against histamine. The NO scavenger, CPTIO, prevented the bronchoprotection by SNAPand TPI 1020. CONCLUSIONS AND IMPLICATIONSTPI 1020 potentiated the bronchoprotection by formoterol and tiotropium. Budesonide also enhanced the effects of tiotropium but not formoterol. Combination of TPI 1020 with a long-acting b2-adrenoceptor agonist or muscarinic receptor antagonist may therefore be a more potent therapeutic approach for treatment of chronic respiratory diseases.

<p>Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review</p>

“…Obtained data were extracted from 35 studies, among which 12 were in vitro studies, [21][22][23][24][25][26][27][28][29][30][31][32][33] five were performed in vivo, [34][35][36][37][38][39] three were both in vitro and in vivo, [40][41][42] and 15 were RCTs, 43-64 the characteristics of which are reported in Table 1.…”

“…In general, TPI1020 is effective against airway inflammation and AHR, 36 and when combined with a LABA, it elicited a greater bronchodilation compared to monocomponents. 34,35 TPI1020 was as effective as BUD, generally safe, and characterized by a favorable PK profile with no effects on cortisol level. 62…”

“…34 In another pre-clinical study on conscious guinea-pigs, only high doses of TPI1020 (0.33-0.7 mM) induced short-term inhibition of histamine-induced bronchoconstriction. 35 Combining TPI1020 0.11 mM with either formoterol 2.5 μM or tiotropium 2 μM increased the bronchoprotection against provocation with histamine and methacholine compared to monocomponents. 35 According to a randomized escalated-dose study performed on smokers with mild asthma, TPI1020 had similar effects to equivalent doses of BUD on FEV 1 , PEF, rescuemedication use, response to methacholine, asthma control scoring system, F E NO, and sputum and blood eosinophils.…”

“…35 Combining TPI1020 0.11 mM with either formoterol 2.5 μM or tiotropium 2 μM increased the bronchoprotection against provocation with histamine and methacholine compared to monocomponents. 35 According to a randomized escalated-dose study performed on smokers with mild asthma, TPI1020 had similar effects to equivalent doses of BUD on FEV 1 , PEF, rescuemedication use, response to methacholine, asthma control scoring system, F E NO, and sputum and blood eosinophils. 62 TPI1020 was more effective than BUD on sputum neutrophils in patients with neutrophilia at baseline.…”

Protective effects of tiotropium alone or combined with budesonide against cadmium inhalation induced acute neutrophilic pulmonary inflammation in rats

“…It has been demonstrated that the combination of an ICS with an anticholinergic agent can improve COPD patients' lung function, clinical symptoms, exercise tolerance and life quality [ 9 ]. In conscious guinea pigs, co-administration of budesonide with tiotropium exerted a significant protection against methacholine-induced bronchoconstriction [ 10 ]. In contrast, some studies mentioned no additional efficacy to reduce the incidence of AECOPD when tiotropium was added to ICS/long-acting β 2 -adrenergic agonist (LABA) [ 11 ].…”