PubMed · 6112320
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P E Belchetz, J C Davis, M J Diver, L J Hipkin. 1981-04-18. Problems with trilostane.. https://doi.org/10.1016/s0140-6736(81)92171-1
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In a randomised, controlled, double-blind, multicentre trial in 338 patients, we assessed the incidence of residual paralysis following administration of cisatracurium or rocuronium. The incidence at the end of surgery was significantly lower in patients treated with rocuronium (62 of 142 patients, 44%) than in those given cisatracurium (99 of 175 patients, 57%) (p < 0.05). In contrast, with rocuronium the mean (SD) time between skin closure and extubation was 28 (28) min vs 18 (19) min for cisatracurium, and the duration 0.9 (time from administration of last top-up dose to recovery of the train-of-four ratio to 0.9) was significantly longer and more variable for rocuronium than for cisatracurium. Thus, after repeated administration, the duration and variability of duration of action are greater with rocuronium compared with cisatracurium. These pharmacodynamic differences do not necessarily translate into a higher incidence of residual paralysis, because clinicians compensate for the longer duration of action and variability of rocuronium by terminating administration of the neuromuscular blocking earlier.
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The constitutive androstane receptor (CAR; NR1I3) regulates the expression of genes involved in xenobiotic metabolism. Alternative splicing of the human CAR gene yields an array of mRNAs that encode structurally diverse proteins. One form of CAR, termed CAR2, contains an additional four amino acids (SPTV) that are predicted to reshape the ligand-binding pocket. The current studies show a marked, ligand-independent, CAR2-mediated transactivation of reporters containing optimal DR-3, DR-4, and DR-5 response elements, and reporters derived from the natural CYP2B6 and CYP3A4 gene promoters. Overexpression of the RXRalpha ligand binding domain was critical for achieving these effects. CAR2 interaction with SRC-1 was similarly dependent on the coexpression of RXRalpha. Mutagenesis of Ser233 (SPTV) to an alanine residue yielded a receptor possessing higher constitutive activity. Alternatively, mutating Ser233 to an aspartate residue drastically reduced the transactivation capacity of CAR2. The respective abilities of these mutagenized forms of CAR2 to transactivate a DR-4 x 3 reporter element correlated with their ability to interact with RxRalpha and to recruit SRC-1 in a ligand-regulated manner. Together, these results demonstrate a robust RXRalpha-dependent recruitment of coactivators and transactivation by CAR2. In addition, CAR2 displays novel dose responses to clotrimazole and androstanol compared with the reference form of the receptor while at the same time retaining the ability to bind CITCO. This result supports a hypothesis whereby the four-amino-acid insertion in CAR2 structurally modifies its ligand binding pocket, suggesting that CAR2 is regulated by a set of ligands distinct from those governing the activity of reference CAR.