Moguisteine: a Novel Peripheral Non-Narcotic Antitussive Drug 'L
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Br. J. Pharmacol. (1994), 112, 795-800 19." Macmillan Press Ltd, 1994 Moguisteine: a novel peripheral non-narcotic antitussive drug 'L. Gallico, A. Borghi, C. Dalla Rosa, R. Ceserani & S. Tognella Boehringer Mannheim Italia, Research Center, Viale della Liberta, Km 0.750, 1-20052 Monza, Italy 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 29.2mgkg-', p.o.), by 30tiM capsaicin aerosol (19.3 and 15.2 mg kg', p.o.), by mechanical stimulation (22.9 and 26.4mg kg-', p.o.) and by tracheal electrical stimulation (12.5 and 13.9mgkg'1, p.o.). 3 Moguisteine was effective against cough induced by tracheal electrical stimulation in dogs (EDo 17.2mgkg-', 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 (5 mg kg-', s.c.) did not antagonize its antitussive effects. 6 Moguisteine had-no antitussive effect after i.c.v. administration (20 ftg), whilst codeine (2-10 yg) and dextromethorphan (2.5-20 gg) 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. Keywords: Cough; antitussive agents; moguisteine; codeine; naloxone Introduction Cough is a physiological defence mechanism for the clearance afferent fibre nerve inputs or to inhibit the activation of of foreign materials and of excessive bronchial secretion in airway sensory receptors: however, very few studies have the airways, but it is also a common symptom of a variety of attempted to clarify their mechanism of action (Irwin & respiratory diseases (Irwin et al., 1981). The cough reflex is Curley, 1990). Furthermore, the effectiveness in cough triggered by the activation of rapidly adapting receptors (or therapy of peripherally acting drugs has not been con- 'irritant' receptors) within the larynx, trachea and the prox- clusively demonstrated, given the paucity of controlled imal bronchi, and of C-fibre endings found in the airway clinical trials (Banner, 1986). Only local anaesthetics that walls of bronchi (Karlsson et al., 1988b). Afferent signals are interfere with the conduction of afferent nerve impulses have transmitted through the sensory vagal fibres to the cough been shown to be peripherally active antitussive compounds, centre, which has been experimentally identified as being in but their considerable side effects make their use unsuitable the region of the solitary nucleus in the medulla within the (Karlsson, 1983). Therefore the availability of a novel, non- brain (Kase et al., 1970). From the cough centre the impulses narcotic peripheral and effective drug could represent a con- travel through the efferent pathways to the respiratory mus- siderable improvement in the treatment of cough. cles (diaphragm, intercostal and abdominal muscles) and the This paper describes the antitussive profile of moguisteine, airways (Irwin et al., 1977). (R,S)-2- (2-methoxyphenoxy) -methyl-3-ethoxycarbonyl-acetyl Current cough therapy is based on the use of drugs that -1,3 thiazolidine (Figure 1), a non-narcotic compound, in are classified according to their site of action, which may be comparison with that of codeine, as assessed in animal central (applicable to both narcotic and non narcotic drugs), models. Part of this work has been published in abstract or peripheral. The centrally acting antitussives, such as form (Gallico et al., 1990). codeine and dextromethorphan, which depress the cough centre, are considered the most clinically effective, although sedative and addictive effects can limit their use (Eddy et al., Methods 1969). However recent experimental studies have clearly shown that codeine acts also at the peripheral level, as its Cough induced by citric acid aerosol in the guinea-pig antitussive effect was reversed by opiate antagonists with scanty penetration of the blood-brain barrier (Adcock et al., Male Dunkin Hartley guinea-pigs (Charles River, Calco, 1988; Karlsson et al., 1988a). Further support for the concept Italy) 350-400 g were maintained in conditioned quarters of the peripheral component in the action of opiates was (temperature 21 ± 2°C, relative humidity 55 ± 10%, 12 h provided by the investigations performed with BW 443C, a on- 12 h off, light cycle) with food and water ad libitum for novel agonist of opioid receptors that has poor penetration at least 1 week before use. of the blood-brain barrier, which in turn inhibits cough in Guinea-pigs were put into a Perspex box (20 x 12 x 14 cm) animals. The drug's effect was antagonized by peripherally and exposed to a 7.5% citric acid aerosol (Charlier et al., acting opioid receptor antagonists (Adcock et al., 1988). 1961) delivered by an ultrasonic nebulizer (G.B. Elbisonic, BW 443C was also shown to act on sensory nerve endings, Bielin Milan, Italy, particle size 0.5-6 tm, mean output since it reduced spontaneous and chemically induced activity 0.5 ml min-') for 5 min. During this period the animals were in both irritant and C-fibre receptors (Adcock, 1991). The continuously watched by a trained observer and the number peripherally acting non opiate drugs, such as oxolamine, of coughs was counted manually and taken as the control benzonatate and dropropizine are believed to reduce the basal value. Coughs can be recognized easily on the basis of sound associated with a rapid inspiration followed by a rapid expiration. Only the guinea-pigs responding within the range ' Author for correspondence. of 14-22 coughs were selected for further studies. Twenty 796 L. GALLICO et al. compounds, an animal failed to respond to any one of the stimulations. Cough induced by electrical stimulation of the trachea in conscious guinea-pigs The guinea-pigs were anaesthetized (ketamine, 10 mg kg-', i.m. and xylazine 3 mg kg-', i.m.) and the neck region caudal to the cricoid cartilage was incised in the midline and the trachea was exposed. Care was taken to not disturb the recurrent vagus nerves along the dorsolateral side of the Figure 1 Chemical structure of moguisteine. trachea. A silver-plated cuprum electrode (Awg 32-Habia) was wrapped around the trachea at about 1.5 cm above the bifurcation, fixed to the muscular tissue and brought through the skin incision (Cavanagh et al., 1976). The indifferent four hours later, after overnight fasting with water ad libitum, electrode (a stainless steel clip) was fixed to the dorsal skin. the guinea-pigs (n = 8 for each dose), were randomly pre- The animals were then allowed to recover from the anaes- treated by gavage with moguisteine (I5, 30 and 60 mg kg-') thesia under aseptic conditions in warmed cages. After over- and codeine (20, 40 and 80 mg kg-') 1 h before re-exposure night fasting with water ad libitum, the guinea-pigs were to the citric acid aerosol. The experiments were performed assessed, 48 h after the surgical implant, for tussive threshold with a blind design so that the observer was unaware of the to electrical stimulation by the determination of the min- treatment. Antitussive activity was evaluated in each guinea- imum voltage (range of 4-10 V) required to elicit cough with pig as the reduction in the number of coughs in comparison the following stimulus conditions: square wave pulses of with the previously established control basal value. In the 0.6 ms, 40 Hz, 10 s train duration (Stimulator S, Ugo Sachs repeated dosing study (15 days), antitussive activity for each Elektronik, Germany). The number of coughs (7-12) during guinea-pig was determined as described above, 1 h after the the electrical stimulation was recorded for each guinea-pig last administration of either moguisteine or codeine (the and considered as a basal value. The guinea-pigs were then control basal values having been recorded before the beginn- randomly assigned to different experimental groups and ing of the treatment). pretreated by gavage with the test compounds i.e. moguis- Preliminary experiments demonstrated that cough, checked teine (7.5, 15 and 30 mg kg-') and codeine (7.5, 15 and for two consecutive days per week, was consistently rep- 30 mg kg-') (n = 8 for each dose). roducible in the same animal for at least 3 weeks. In a further experiment, animals were treated by the in- tracerebroventricular route (i.c.v.) with moguisteine (10 and Cough induced by capsaicin aerosol in the guinea-pig 20 pg), codeine (1, 2.5, 5 and O fig) and dextromethorphan (2.5, 5, 10 and 20 fg) respectively (n = 7 animals for each In this experimental model, the guinea-pigs could not be used dose). The i.c.v. administration (50 AI volume) was performed as their own controls because of the tachyphylactic effect of through a small cannula inserted under light general anaes- capsaicin, which occurs after two repeated exposures; the thesia (25% urethane, 4mlkg'1, i.p.) at the level of the experimental schedule was therefore modified. After over- bregma above the right cerebral lateral ventricle. At the end night fasting with water ad libitum, the guinea-pigs were of the experiment, 50 fil of methylene blue was injected i.c.v. randomly assigned to the experimental groups (n = 10 for into each guinea-pig; homogeneous spreading of the dye each dose) and orally pretreated with vehicle (controls), within the ventricle demonstrated that the drug had been moguisteine (7.5, 15 and 30 mg kg-') or codeine (10, 20 and correctly administered.