Licia Gallico

Moguisteine: a novel peripheral non-narcotic antitussive drug.

1 The antitussive effects of moguisteine have been compared with codeine in several experimental models of cough in guinea‐pigs and dogs. 2 Moguisteine and codeine dose‐dependently (respective ED50 values are given in parentheses) inhibited cough induced in guinea‐pigs by 7.5% citric acid aerosol (25.2 and 29.2 mg kg−1, p.o.), by 30 μm capsaicin aerosol (19.3 and 15.2 mg kg−1, p.o.), by mechanical stimulation (22.9 and 26.4 mg kg−1, p.o.) and by tracheal electrical stimulation (12.5 and 13.9 mg kg−1, p.o.). 3 Moguisteine was effective against cough induced by tracheal electrical stimulation in dogs (ED50 17.2 mg kg−1, p.o.); codeine was not tested because of its emetic effect. 4 After repeated dosing (12–15 days), moguisteine did not induce tolerance in either guinea‐pigs or dogs. 5 Moguisteine did not interact with opiate receptors, since it did not show affinity for [3H]‐naloxone binding sites and furthermore naloxone (5mg kg−1, s.c.) did not antagonize its antitussive effects. 6 Moguisteine had no antitussive effect after i.c.v. administration (20 μg), whilst codeine (2–10 μg) and dextromethorphan (2.5–20 μg) were highly effective. 7 Our findings demonstrate that moguisteine is a novel peripherally acting non‐narcotic antitussive agent, the mode of action of which remains to be elucidated fully.

Effects of moguisteine on the cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve in guinea pigs

The study aimed to further demonstrate the peripheral antitussive properties of moguisteine. Firstly, the antitussive effect of moguisteine on the cough reflex induced by inhalation of citric acid aerosol was evaluated in conscious guinea pigs. Secondly, the effects of both moguisteine and codeine on the centrally mediated cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve were investigated in anesthetized guinea pigs. Moguisteine (2.5-10 mg/kg, intravenously, i.v.) reduced the cough reflex induced by 7.5% citric acid aerosol in a dose-dependent manner, with an ED50 value of 0.55 mg/kg. Both i.v. (0.5-4 mg/kg) and intracerebroventricular (i.c.v., 5-20 microg) injection of codeine dose dependently inhibited the cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve; the ED50 values were 0.91 mg/kg and 7.90 microg, respectively. The inhibitory effect of codeine (4 mg/kg i.v.) was abolished by pretreatment with naloxone (2 mg/kg intraperitoneally). In contrast to codeine, neither i.v. (4 and 20 mg/kg) nor i.c.v. (20 microg) injection of moguisteine affected the cough reflex. These results suggest that the antitussive effect of codeine is mediated by central opioid mechanisms, whereas the antitussive effect of moguisteine is mediated by peripheral mechanisms.

Effects of moguisteine, a peripheral nonnarcotic antitussive agent, on airway inflammation in guinea-pigs in vivo

Cough is a common symptom of respiratory diseases associated with irritation or inflammation of the airways, and symptomatic antitussive drugs are frequently prescribed to control an abnormal cough reflex. Our aim was to evaluate the effects of moguisteine, a novel, peripheral, nonnarcotic antitussive agent, on airway inflammation induced in guinea-pigs with a variety of stimuli. These stimuli included exposure to tobacco smoke for 10 min, to elicit airway hyperreactivity, eosinophil recruitment in bronchoalveolar lavage (BAL), airway epithelial damage and plasma exudation; graded platelet-activating factor (PAF) infusion (600 ng.kg-1 over one h), to induce airway hyperreactivity; 2% ovalbumin (OA) aerosol challenge in 1% OA-sensitized animals, to induce late-phase (17 and 72 h) airway leucocyte accumulation. We also assessed the activity of moguisteine on plasma leakage induced by capsaicin, on bronchoconstriction induced by acetylcholine (ACh), histamine (H) and PAF, and on leukotriene mediated allergic bronchospasm in OA-sensitized guinea-pig. Moguisteine (p.o. and i.m.) and dexamethasone (p.o. and i.m.) dose-dependently reduced tobacco smoke-induced bronchial hyperreactivity. Moguisteine and dexamethasone abolished eosinophil recruitment in BAL, prevented the sloughing of the epithelium and significantly reduced airway microvascular leakage. Both agents were also highly effective in reducing bronchial hyperreactivity elicited by PAF infusion. In addition, moguisteine was active in inhibiting airway neutrophil and eosinophil accumulation in BAL observed 17 and 72 h after OA challenge in sensitized guinea-pigs. In contrast to dexamethasone, moguisteine did not prevent capsaicin-induced plasma leakage. It was also ineffective against bronchoconstriction as induced by ACh, H, and PAF and failed to inhibit leukotriene-dependent bronchospasm. Our data suggest that moguisteine represents an antitussive compound endowed with interesting airway anti-inflammatory properties in guinea-pigs in vivo. Its mechanism of action remains to be elucidated.

Antitussive activity of moguisteine enantiomers in guinea-pigs and rats.

The antitussive effect of the R‐(+)‐ and S‐(‐)‐enantiomers of moguisteine were evaluated in comparison with the racemate in cough induced by 7ṁ5% citric acid and 30 μM capsaicin aerosol in conscious guinea‐pigs.