Rocuronium bromide An assessment of its neuromuscular and other effects in clinical anaesthesia

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Pharmacokinetics of rocuronium after bolus and continuous infusion during halothane anaesthesia

We have studied the pharmacokinetics of a single bolus of rocuronium (Org 9426), followed by an infusion, in eight patients during anaesthesia with halothane and nitrous oxide in oxygen. Neuromuscular block was monitored using train-of-four (TOF) stimulation and recording the force of contraction of the adductor pollicis muscle. Rocuronium was administered as an initial bolus dose of 0.45 mg kg(-1) followed by an infusion adjusted manually to maintain T1 (first response in the TOF) at 10% of control. Mean onset time and time to recovery of T1 to 10% were 72 (SD 19.6) s and 27 (9.6) min, respectively. The infusion rates were stable in 19.8 (6.5) min. The mean requirement for rocuronium for steady state 90% block of T1 was 528 (163.3) mu g kg(-1) h(-1). After cessation of surgery the infusion was stopped and patients were allowed to recover spontaneously. The times to attain a T1 of 90% and a TO F ratio of 0.7 were 31 (11.7) min and 36 (7.3) min, respectively. Blood samples were collected for 390 min after cessation of infusion and concentrations of rocuronium and its putative metabolites measured using HPLC. A two-exponential equation was used to describe the pharmacokinetic data. The rate of clearance, mean residence time and volume of distribution at steady state were 3.3 (0.77) ml kg(-1) min(-1), 67.2 (18.8) min and 212.5 (40.1) ml kg(-1), respectively. The distribution (T-1/2(alpha)) and elimination (T-1/2(beta)) half-lives were 7.5 (3.33) min and 85.6 (18.4) min, respectively. These values were not significantly different from previously published data for a single bolus dose of rocuronium

Twitch potentiation influences the time course of twitch depression in muscle relaxant studies:A pharmacokinetic-pharmacodynamic explanation

The time course of twitch depression following neuromuscular blocking agent (NMBA) administration is influenced by the duration of control neuromuscular monitoring (twitch stabilization). The physiological mechanism for this interaction is not known. During twitch stabilization twitch response often increases to a plateau, this is known as twitch potentiation or the staircase phenomenon. Since twitch potentiation contributes to the observed twitch response it may also influence the time course of twitch depression following NMBA administration. Our objective was to estimate the degree that twitch potentiation influences the time course of twitch depression following NMBA administration under conditions typical for muscle relaxation studies. We used previously described pharmacokinetic-pharmacodynamic (PK-PD) and twitch potentiation models to simulate twitch data. Simulations consisted of twitch stabilization followed by a NMBA bolus close and subsequent onset and recovery front muscle relaxation. Twitch data were analyzed for onset and recovery characteristics and the results compared to clinical muscle relaxation studies in existing literature. We found that twitch potentiation likely plays a minor role in shortened onset time and increased duration of twitch depression observed with long periods of twitch stabilization

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

Contains fulltext : 208676.pdf (publisher's version ) (Closed access)Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development