The individual and combined bronchodilator effects of the novel anti-inflammatory compound TPI 1020 and salbutamol in conscious guinea pigs

Dawn L Turner1, Nicolay Ferrari2, William R Ford1, Emma J Kidd1, Luc Paquet2, Kenneth J Broadley1

1Cardiff University, Cardiff, Wales, UK, 2Topigen Pharmaceuticals Inc, Montréal, Canada

Inhaled corticosteroids are frequently prescribed to combat airway inflammation associated with asthma and are regularly co-administered with a β2 agonist to target this multi-component disease. A proportion of the asthma population has severe or difficult-to-control asthma and are dependent on high doses of inhaled corticosteroids which are associated with multiple side effects (Barnes and Woolcock, 1998). Nitric oxide is one of the smallest biologically active molecules and has many roles in the airways (Nevin and Broadley, 2002) including anti-inflammatory effects and a broncho-protective role. It can also relax airway smooth muscle (Carvajal et al., 2000). TPI 1020 is a novel anti-inflammatory compound with a dual mechanism of action involving corticosteroid activity and release of nitric oxide. It is hypothesised that the NO released may exert bronchodilator and anti-inflammatory effects. When co-administered with a β2 agonist, TPI 1020 has the potential to elicit a more potent bronchodilator effect. In this study, the individual and combined bronchodilator effects of TPI 1020 and salbutamol were examined in conscious guinea pigs.

Groups (n=6) of male, Dunkin-Hartley guinea-pigs (350-400g) were exposed to a 20 sec, nose-only, 3 mM histamine challenge. Airway reactivity was measured using whole body plethysmography and readings of specific airway conductance (sGaw) were taken immediately and at 5 and 10 min after the challenge. 24 hrs later, animals were treated via nebulisation in a sealed chamber with either salbutamol (3-30 μg/ml), TPI 1020 (0.1-0.63mg/ml), combined TPI 1020 and salbutamol, or vehicle (30% DMSO: 30% EtOH:40% saline or saline, respectively) for 15 min. 15 min later animals received a 20 sec, nose-only histamine exposure and sGaw readings were taken at 0, 5 and 10 min following the challenge.

Salbutamol caused a concentration-dependent bronchodilator effect which was significant at 30 μg/ml, inhibiting the control histamine response by 84.4±7.2%. Histamine-induced bronchoconstriction was also inhibited in a dose-dependent fashion by TPI 1020, increasing from 16.8±5.6% at 0.1 mg/ml, to 50.5±8.1% at 0.3 mg/ml and 72.1±15.3% at 0.63 mg/ml. Analysis by Student’s paired t-test, showed that significant inhibition was observed at 0.3 and 0.63 mg/ml. Salbutamol at 20 μg/ml did not exert a significant bronchodilator effect (11.4±12.7%); however when co-administered with TPI 1020, significant inhibition was observed at 0.1 mg/ml (76.7±13.2%) and 0.3 mg/ml (106.8±39.4%) of TPI 1020.

This study demonstrated that TPI 1020 exerts a dose-dependent inhibitory effect on histamine-induced bronchoconstriction in conscious guinea pigs. Co-administration of TPI 1020 (0.1 and 0.3 mg/ml) with salbutamol at 20 μg/ml produced a potentiating or synergistic bronchodilating effect compared to either drug administered alone

Supported by Topigen Pharmaceuticals Inc.

Barnes PJ and Woolcock AJ, (1998) Eur Respir J; 12:1209–18.

Carvajal JA et al (2000) J Cell Physiol;184: 409–420.

Nevin, BJ and Broadley, KJ (2002) Pharmacology and therapeutics, 95:259-293.