Zopiclone is a cyclopyrrolone hypnotic agent. It possesses a chiral centre and is commercially available as a racemic mixture. Methods involving high performance liquid chromatography (HPLC), gas chromatography, capillary electrophoresis (CE) and high performance thin layer chromatography have been developed for the quantitation of zopiclone and its 2 main metabolites in biological samples. For the chiral determination of the enantiomers of zopiclone and its metabolites, HPLC and CE methods are available. After oral administration, zopiclone is rapidly absorbed, with a bioavailability of approximately 80%. The plasma protein binding of zopiclone has been reported to be between 45 and 80%. Zopiclone is rapidly and widely distributed to body tissues including the brain, and is excreted in urine, saliva and breast milk. Zopiclone is partly metabolised in the liver to form an inactive N-demethylated derivative and an active N-oxide metabolite. In addition, approximately 50% of the administered dose is decarboxylated and excreted via the lungs. Less than 7% of the administered dose is renally excreted as unchanged zopiclone. In urine, the N-demethyl and N-oxide metabolites account for 30% of the initial dose. The terminal elimination half-life (t1/2z) of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), AUC (area under the plasma time-concentration curve) and t1/2z values are higher for the dextrorotatory enantiomer owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the respective antipodes. The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. Drug interactions have been observed with erythromycin, trimipramine and carbamazepine.

The existence of atypical-or β 3 -adrenoceptors has now been generally accepted. These receptors have been shown to be abundant in adipose tissue and in a number of gastrointestinal smooth muscle preparations. A recent study reported that β 3 -adrenoceptor stimulation mediated relaxation of isolated canine bronchial smooth muscle. The aim of the present study was to extend this observation to other species.We investigated the in vitro responses of guinea-pig, human and sheep bronchial smooth muscle to isoprenaline, salbutamol (a selective β 2 -adrenoceptor agonist), and BRL 37344 and SR 58611A (two presumably selective β 3 -adrenoceptor agonists). The preparations were precontracted to 60-70% of maximal tension with histamine 10 -6 M for guinea-pig and human bronchi, or acetylcholine 10 -6 M for sheep bronchi.In each species, SR 58611A produced a slight fall in tension of about 10% of the effects of theophylline (3 mM), but this decrease in tension was not significantly different from the spontaneous and weak relaxation observed with saline addition during the same duration of the experiment. These relaxations were not modified by either the nonselective β-adrenoceptor antagonist propranolol or the selective β 2 -adrenoceptor antagonist ICI 118,551. In contrast, BRL 37344 induced a significant concentration-dependent fall in tension induced by both spasmogens. Its relaxant effects were inhibited both by propranolol and ICI 118,551 in human and guinea-pig airways, whereas on the isolated sheep bronchus BRL 37344-induced relaxations were only slightly, albeit significantly, reduced with either of the β-adrenoceptor antagonists tested. Salbutamol and isoprenaline induced potent relaxations of guinea-pig, human and sheep airway smooth muscle in vitro, which were antagonized both by propranolol and ICI 118,551.Our findings show that β 3 -adrenoceptor stimulation does not induce relaxation in guinea-pig, human and sheep bronchial smooth muscle, and that a β 2 -adrenoceptor agonistic component might be implicated in the relaxant effects of BRL 37344. Eur Respir J., 1994Respir J., , 7, 1610Respir J., -1615 The existence of atypical or β 3 -adrenoceptors has now been generally accepted. The gene encoding for human β 3 -adrenoceptor has been identified and sequenced [1]. These receptors have been shown to be abundant in adipose tissue and in a number of gastrointestinal smooth muscle preparations, for example guinea-pig ileum [2], rat proximal colon [3,4], rat distal colon [5], rat jejunum [6] and rat gastric fundus [7]. They have also been identified in rat skeletal muscle [8], ferret tracheal epithelium [9], and canine airways [10].Furthermore, stimulation of β 3 -adrenoceptors has been shown to induce relaxation of the rat oesophageal muscularis mucosae [11], lipolysis in omental and subcutaneous human fat cells [12], and inotropic effects in human [13] and canine heart [14].In the lung, β 3 -adrenoceptor stimulation increases epithelial fluid movements in ferret trachea [9], and reduces the release of the ...

Bradykinin (Bk) induced a contraction in all small bronchi samples (diameter, 0.5 to 1 mm) from 20 patients. pD2 was 7.7 +/- 0.1 (pD2 = -log EC50) and maximal effect (Emax) was 36.2 +/- 4.7% of the maximal response to acetylcholine. The B2 agonist [Hyp3TyrMe8]Bk contracted airway smooth muscle with a pD2 of 7.8 +/- 0.2 and an Emax of 39 +/- 9%. The B1 agonist [Sar1dPhe8desArg9]Bk induced only a weak contraction at 10(-6) M. The effect of Bk was abolished by the B2 (Hoe 140) but not by the B1 [Leu8desArg9]Bk receptor antagonist. Indomethacin 10(-6) M abolished Bk-induced contraction, suggesting that cyclooxygenase products are involved in Bk action. Capsaicin 10(-5) M, which selectively depletes C fibers from airway mediators through the ruthenium red pathway, and ruthenium red 10(-5) M significantly inhibited the concentration-response curves to Bk. However, tetrodotoxin (+/-)-CP-96,345, SR 48968, and atropine did not significantly affect Bk concentration-response curves, suggesting that nerve conduction, substance P (SP), neurokinin A (NKA), and acetylcholine release are not involved in Bk action. Our data indicate that Bk contracts human distal airway smooth muscle through the Bk B2 receptor and a cyclooxygenase pathway. This effect appears to involve capsaicin and ruthenium red pathways but neither acetylcholine nor NKA and SP release.

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