Influence of chinoin-170, a novel antitussive, on the mucociliary activity in respiratory airways of rats, rabbits, guinea-pigs and man.

Chinoin-170 (Ch-170; 3,7-dihydro-1,3-dimethyl-7-[(5-methyl-1,2,4- oxadiazol-3-yl)methyl]1H-purine-2,6-dione) is a new antitussive with bronchodilating activity. Its effects on the ciliary beating frequency (CBF) and mucociliary clearance were studied. In tracheal explants of rats, Ch-170 dose-dependently at concentrations 2 and 5 mg mL-1 depressed CBF by 24 and 33%, respectively. In human mucosal explants, however, no effects were seen at concentrations up to 5 mg mL-1. In anaesthetized guinea-pigs, an intravenous 50 mg kg-1 dose of Ch-170 caused no changes, and 100 mg kg-1 increased the CBF by 15%. Intravenous Ch-170 dose-dependently increased by 93 (50 mg kg-1), 179 (70 mg kg-1) and 253% (100 mg kg-1) the tracheobronchial mucociliary clearance in rabbits. The effect, studied using 99mTc-labelled red blood cells as a marker, was of similar quantity to that brought about by administering 16, 25 and 40 mg kg-1 doses of bromhexine. It is concluded that unlike many older antitussives, Ch-170 in-vitro only slightly decreases the CBF in rats and has no adverse effects on the CBF in human mucosal explants at concentrations up to 5 mg mL-1. In-vivo, Ch-170 does not significantly alter the CBF in guinea-pigs, but dose-dependently increases the mucociliary clearance in rabbits. The increase is most probably a result of changes in the production and the properties of respiratory mucus.

[Synthesis, conformation and pharmacological effect of some stereoisomeric condensed 1,3-oxazine-4-ones. 44: Stereochemical studies; 22: Saturated heterocycles]. / Synthese, Konformation und pharmakologische Wirkung einiger stereoisomerer kondensierter 1,3-Oxazin-4-one. 44. Mitteilung: Stereochemische Untersuchungen; 22. Mitt.: Gesättigte Heteroxyxlen.

It has been reported the synthesis, examination of the stereochemistry and biological effect of 2-substituted-cis-5,6-trimethylen-, cis- and trans-5,6-tetramethylene and -5,6-pentamethylene-2,3,5,6-tetrahydro-1,3-oxazine-4-one derivatives. Primarily cis-isomers were synthetized because in the pharmacological test systems the trans isomers were less active. The compounds tested have an antiphlogistic effect of different intrinsic activity.

The effect of alkylating agents on the synaptic transmission in the frog's isolated sympathetic ganglion.

The effect of four alkylating agents, such as dibenamine, phenoxybenzamine, mannomustine and cyclophosphamide, was studied on the isolated sympathetic ganglion of the frog. It has been established that all of these agents were able to bind to the nicotinic receptors through the formation of the reactive ethylenimonium ion not only in the frog ganglion but also in the motor end-plate of the rat skeletal muscle. The binding to the ganglionic receptors showed reversible and irreversible phases being dependent not only on the drug concentrations and the incubation time used but the temperature of the medium as well.

Neurogenic component in the effect of papaverine, drotaverine and bencyclane.

Papaverine, drotaverine and bencyclane, drugs considered to have direct action on the smooth muscle, inhibited synaptic transmission in the isolated a sympathetic ganglion of the frog. Their effect depended upon the concentration applied. The ganglionic blocking effect of papaverine and drotaverine in the concentration range from 10(-8) to 10(-6) mol/l was partially antagonized by naloxone and nalorphine as well as by increasing the Ca2+ concentration in the incubation medium. This refers to an activation of specific opiate receptors in the mechanism of ganglionic action of these drugs. The ganglionic effect of bencyclane may be due to its local anaesthetic property, since it was prevented by neither naloxone nor nalorphine, and an increase in the Ca2+ concentration in the medium had no influence on it.

[Effects of calcium channel blockers on electrical and mechanical responses of rat phrenic nerve-diaphragm preparations]. / Kalcium-csatorna blokkolók hatása patkány nervus phrenicus-diaphragma preparátum elektromos és mechanikus válaszára.

The effects of diltiazem, prenylamine and verapamil on the electrical and mechanical responses of a rat phrenic nerve-diaphragm preparation were investigated as a function of the indirect stimulating frequency. The amplitude of the muscle compound action potential was depressed by all three drugs with stimulation between 3 and 50 Hz. The contractile force of the diaphragm was increased by these drugs in concentrations of 3 x 10(-8)-3 x 10(-5) mol/l at low frequency (3-10 Hz), but the contractility was decreased at higher concentrations (above 3 x 10(-5) mol/l). In contrast, a facilitating effect was not observed at a higher stimulating frequency (above 20 Hz), but a concentration depressant effect did develop above 1 x 10(-6) mol/l. The literature data and our results suggest that low concentrations of calcium channel blocking agents can not influence the trigger calcium current at low frequency (under 15 Hz), but calcium liberation and the contractile force are increased by these drugs. The intracellular calcium liberation triggered by the calcium current or the muscle force was inhibited by these drugs at higher concentrations. Above 15 Hz, the liberated intracellular calcium is insufficient for the contraction, so an adequate quantity of calcium is obtained from the extracellular space. It is suggested that an adequate calcium uptake is inhibited at low concentrations of these drugs at higher frequency, and the contractility is thereby inhibited.

The pharmacological reactivity of an isolated circular smooth muscle strip of the rabbit common bile duct.

An in vitro isolated spiral strip of rabbit common bile duct was prepared and tested for its pharmacological reactivity. It was found to be a suitable preparation with a long lasting and stable sensitivity when exposed to various drugs. The pharmacological reactivity proved to vary along the common bile duct; the different portions (sphincteric, median and hepatic) displayed different activities to the various agonists and antagonists. The following receptors were identified in different sections: alpha and beta-adrenergic, muscarinic cholinergic, bradykinin, H1 and prostaglandin F2 alpha. Only the sphinteric portion exhibited rhythmic peristalsis; the other portions produced merely small, irregular spontaneous contractions.