Antitussive action of the new anilide derivative vadocaine hydrochloride compared with codeine phosphate in four animal models.

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) is a novel antitussive compound structurally resembling local anaesthetics. Its antitussive profile was studied in several animal models. In guinea-pigs, vadocaine reduced by about 70% the cough episodes induced by sulphur dioxide or ammonia. The effective dose was 2.5 mg/kg p.o., and codeine phosphate was less effective. In cats, vadocaine (3 mg/kg i.v.) inhibited by about 80% for 10 min the cough reflex initiated by mechanical irritation of the trachea. When vadocaine was given via the vertebral artery, it was about 10 times more active than by the intravenous route. Codeine was 3 times as active as vadocaine by both routes. This result indicates an important central component in the antitussive action of vadocaine. In another cat model, 5 mg/kg of vadocaine was somewhat weaker than 1 mg/kg of codeine in inhibiting the cough caused by electrical stimulation of the laryngeal nerve (Domenjoz' method). In dogs, both oral and intravenous doses of 6 mg/kg of vadocaine and 2 mg/kg of codeine were approximately equiactive, inhibiting by 60-80% the cough induced by electrical stimulation of the trachea. Concentrations of vadocaine in serum were around 1 microgram/ml during oral administration. By both routes, the antitussive activity (inhibition of cough by 50% or more) lasted at least 2 h. Vadocaine caused local anaesthesia in the guinea-pig wheal preparation at concentrations of 0.25% and 0.5%, and on the guinea-pig cornea at 0.5%. Duration of anaesthesia was longer than that of lidocaine. Vadocaine did not affect the guinea-pig tracheal strip preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the nonspecific central nervous system effects of the novel antitussive compound vadocaine hydrochloride.

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) is a novel antitussive compound which is effective in several animal models at doses of 2.5-6 mg/kg. It has both central and peripheral local anaesthetizing properties. The present studies were aimed at exploring the specificity of the central antitussive activity of vadocaine. Vadocaine administered in doses of 25 and 50 mg/kg was not found to be effective in any of a series of experiments, although some antinociceptive activity was shown in the hotplate test and in the writhing test at a dose of 75 mg/kg. Some deteriorative activity was noted at a dose of 75 mg/kg in tests measuring motor coordination (rotarod) and spontaneous motility. This high dose of vadocaine did not affect pentobarbital sodium-induced sleeping time nor protect the animal from pentetrazole-induced convulsions. As expected, codeine phosphate was found to be a more potent antinociceptive drug than vadocaine, also enhancing spontaneous motility. Both the control anaesthetics benzonatate and lidocaine proved rather ineffective. Benzonatate (50 mg/kg) did not alter any of the results, whereas lidocaine (50 mg/kg) caused a decrease in the number of writhings. In conclusion, vadocaine can be said to initiate minor deterioration of the central nervous system only at doses about 10 times higher than those which show antitussive activity. Acute lethal doses are still 2 to 5 times higher. The central antitussive action of vadocaine can therefore be considered fairly specific.

Plasma renin activity and in vitro synthesis of aldosterone by the adrenal glands of rats with spontaneous, renal, or pinealectomy-induced hypertension.

In the present study a comparison was made on the role of the renin-aldosterone system in rats with various forms of experimental hypertension (pinealectomy-induced, renal and spontaneous). The plasma sodium and potassium concentrations as well as renin activity were measured. The in vitro production of aldosterone by quartered adrenal glands of these rats was also determined. 5 weeks after the operations the blood pressure of the pinealectomized and renal operated rats was significantly increased. The plasma sodium concentration did not differ in various groups, but that of potassium was decreased in the renal hypertensive animals. The plasma renin activity of the pinealectomized rats was elevated while in other forms of hypertension it was at the control level. The basal aldosterone production by the adrenal quarters was equal in all the groups. ACTH, dibutyryl cyclic adenosine-3',5'-monophosphate (DBA) and 5HT stimulated the aldosterone production. The responses to ACTH and DBA were greater in the adrenals of renal hypertensive rats than in the other forms of hypertension or in the controls. We suggest that the renin-aldosterone system is of importance in the maintenance of renal hypertension, while in pinealectomy-induced hypertension elevated plasma renin activity reflects an increased sympathetic activity which probably is the main cause of hypertension in these animals.