Abstract
Conventional asthma and COPD treatments include the use of bronchodilators, mainly β2-adrenergic agonists, muscarinic receptor antagonists and corticosteroids or leukotriene antagonists as anti-inflammatory agents. These active drugs are administered either separately or given as a fixed-dose combination medication into a single inhaler. ASM-024, a homopiperazinium compound, derived from the structural modification of diphenylmethylpiperazinium (DMPP), has been developed to offer an alternative mechanism of action that could provide symptomatic control through combined anti-inflammatory and bronchodilator properties in a single entity. A dose-dependent inhibition of cellular inflammation in bronchoalveolar lavage fluid was observed in ovalbumin-sensitized mice, subsequently treated for 3 days by nose-only exposure with aerosolized ASM-024 at doses up to 3.8 mg/kg (ED50 = 0.03 mg/kg). The methacholine ED250 values indicated that airway hyperresponsivenness (AHR) to methacholine decreased following ASM-024 administration by inhalation at a dose of 1.5 mg/kg, with a value of 0.145±0.032 mg/kg for ASM 024-treated group as compared to 0.088±0.023 mg/kg for untreated mice. In in vitro isometric studies, ASM-024 elicited dose-dependent relaxation of isolated mouse tracheal, human, and dog bronchial preparations contracted with methacholine and guinea pig tracheas contracted with histamine. ASM-024 showed also a dose and time dependant protective effect on methacholine-induced contraction. Overall, with its combined anti-inflammatory, bronchodilating and bronchoprotective properties, ASM-024 may represent a new class of drugs with a novel pharmacological approach that could prove useful for the chronic maintenance treatment of asthma and, possibly, COPD.
Highlights
bronchoalveolar alveolar lavage (BAL) cell differential counts showed that all cell populations, including eosinophils, were decreased and that the relative percentages remained similar
This study was not designed to address the toxicology profile of ASM-024, the results show that this drug can induce significant pharmarcological activities relevant to asthma at doses that showed no evidence of toxicity either in in vivo or in vitro models
In the course of the clinical development of ASM-024, a comprehensive nonclinical safety program was conducted with ASM-024 in rats and dogs including safety pharmacology, toxicology, and genotoxicity studies
Summary
Asthma is a respiratory disease characterised by airway inflammation and hyperresponsiveness resulting in reversible bronchoconstriction that affects between 8 to 10% of the population in industrialised countries [1]. Current treatment is mostly based on inhaled corticosteroids and b2 receptor agonists used individually or in combination [2] Despite these effective treatments, half of asthmatics are not adequately controlled [3]. High doses and long term use of inhaled corticosteroids have been associated with significant and sometimes serious side effects [2]. Because of these unmet needs, the development of new treatments for asthma is warranted, especially for drugs that have a different mode of action, potentially bypassing the limitations of current medication [9]
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