Bronchodilatory and anti-inflammatory effects of ASM-024, a nicotinic receptor ligand, developed for the treatment of asthma.
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.
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada ; Asmacure Ltée, Québec, QC, Canada.
Evelyne Israël
EI
Assayag
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada.
Marie-Josée
MJ
Beaulieu
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada ; Asmacure Ltée, Québec, QC, Canada.
Yvon
Y
Cormier
D000280:Administration, Inhalation; D000284:Administration, Oral; D000485:Allergens / Q000276:immunology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D014132:Trachea / Q000187:drug effects
D000485:Allergens; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D001381:Azepines; D001993:Bronchodilator Agents; D008024:Ligands; D011978:Receptors, Nicotinic