cian played by Cary Grant, is followed everywhere by a large, silent man. The man is with him as he addresses an anatomy class, as he conducts the student orchestra, as he stands over a patient in the operating room. The man speaks only at rare moments, each crucial, coming to Noah's aid as the voice of wisdom, of conscience, or of the past. When Noah is finally challenged by a university tribunal to defend his relationship with the odd man he calls "my friend," the story comes out: the man is a convicted murderer, executed by hanging and sent 20 years earlier to Noah, a medical student who needed "a cadaver of my own." The "cadaver" awakened as soon as Noah stuck a gloved finger in his mouth, and has never since left his side. Early experiences in the anatomy laboratory underpin later practice in ways that are not easy to articulate. The knowledge gained there guides diagnosis, allows us to link phenomena that seem on the body's surface to be unrelated, and gives us fluency in a discourse that lets us to describe what is happening to our patients. Visualizing the structures hidden beneath the skin allows us to identify conditions otherwise beyond our grasp. Although the overwhelming bulk of the knowledge we use to care for patients is learned outside the lab, and the centrality of the experience wanes even by the end of first year, what we learn in anatomy lab is somehow, quietly, always there. In this issue of MSJAMA, literature professor John Bender recounts his season as an outsider in the lab and describes how the process serves as a ritual entry into the medical profession. Beyond the technical knowledge it affords, anatomy lab links us to the past and begins our socialization to future practice. We dissect knowing that we are making the same cuts and seeking the same structures as physicians centuries earlier. But today, we pride ourselves on taking more from the experience, on engaging with the gift that is the donation. Samantha Stewart and Rita Charon describe anatomy study as an initial confrontation with life and death that will follow us throughout our careers, and discuss a way these early lessons might be retrieved. S. Ryan Gregory and Thomas Cole describe the history of dissection across centuries, while Aaron Tward and Hugh Patterson account for the shift from grave robbing to cadaver donation in the United States. Finally, to launch our new creative writing section murmur, Matthew Ehrlich evaluates his cadaver's chief complaint. The first body in our care has neither the needs nor the agency of a patient, and yet for many of us, it is the body we will envision as we examine the intact surface of each patient who comes to us. Whether it is our initiation into "the professional tribe of physicians" (Bender), "the scientific method" (Gregory and Cole), or "the use of affective responses" (Stewart and Charon), anatomy lab is as much a part of how we see as what we know. "The trouble with you, Elwell," Noah's ally says to his accuser at the end, "is you've never had a cadaver of your own." ON THE COVER
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].
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