No abstract

The quantitative genetic basis of traits can be determined using a pedigree analysis or a selection experiment. Each approach is valuable and the combined data can contribute more than either method alone. Analysis using both sib analysis and selection is particularly essential when there are likely to be nonlinearities in the functional relationships among traits. A class of traits for which this occurs is that of threshold traits, which are characterized by a dichotomous phenotype that is determined by a threshold of sensitivity and a continuously distributed underlying trait called the liability. In this case, traits that are correlated with the liability may show a nonlinear relationship due to the dichotomy of expression at the phenotypic level. For example, in wing dimorphic insects fecundity of the macropterous (long‐winged) females appears in part to be determined by the allocation of resources to the flight muscles, which are almost invariably small or absent in the micropterous (short‐winged, flightless) females. Pedigree analysis of the cricket Gryllus firmus has shown that wing morph, fecundity and the trade‐off between the two have additive genetic (co)variance. It has also been shown that selection on proportion macroptery produced an asymmetric correlated response of fecundity. The present paper details the results of direct selection on fecundity and the correlated response in proportion macroptery. Selection for increased fecundity resulted in increased fecundity within both wing morphs and a correlated decrease in proportion macroptery. Similarly, selection for decreased fecundity resulted in a decrease within morphs and a correlated increase in the proportion of macropterous females. This provides additional evidence that the trade‐off between fecundity and wing morphology has a genetic basis and will thus modulate the evolution of the two traits.

Aims To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. Methods Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of : (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. Results Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX5DOR) plasma AUC(96) (0.04 vs 1.81, P<0.001). The mean (±s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo ( P<0.001; 95% CI of difference +80, +327) and QDEX30/placebo ( P<0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX30 ( P=0.071, −7, +241; P=0.254, −37, +211; P=0.187, −29, +219, respectively). Conclusions A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg ) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.Keywords: antitussive effect, CYP2D6, dextromethorphan, genetic polymorphism tion [8]. N-demethylation to 3-methoxymorphinan also Introduction occurs, largely by CYP3A4 but with contributions from CYPs 2C9 and 2C19 [9][10][11][12]. Both dextrorphan Dextromethorphan, a codeine analogue devoid of opiate side-effects, is widely available over-the-counter as a and 3-methoxymorphinan are further metabolized to 3-hydroxymorphinan, by CYPs 3A4 and 2D6, respectcough suppressant. Its efficacy has been confirmed in both clinical cough [1][2][3][4][5] and in experimental cough ively [13]. It is well established that the overall disposition of dextromethorphan is highly dependent upon CYP2D6 challenge studies [6, 7]. Metabolism of dextromethorphan is largely by CYP2D6-mediated O-demethylation to activity, which varies widely due to genetic polymorphism, and which can be inhibited selectively and dextrorphan, which then undergoes glucuronide formasignificantly by a small dose of quinidine [14][15][16].