Pharaoh Menes' death after an anaphylactic reaction--the end of a myth.
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Anaphylaxis↗
Biomedical subjects
P M Wright
Publications and source records attributed to P M Wright.
Is mixed effects modeling or naïve pooled data analysis preferred for the interpretation of single sample per subject toxicokinetic data?
The purpose of this study was to evaluate whether mixed effects modeling (MEM) performs better than either noncompartmental or compartmental naïve pooled data (NPD) analysis for the interpretation of single sample per subject pharmacokinetic (PK) data. Using PK parameters determined during a toxicokinetic study in rats, we simulated data sets that might emerge from similar experiments. Data sets were simulated with varying numbers of animals at each sampling time (4-48) and the number of samples taken (1-3) from each individual. Each data set was replicated 50 times and analyzed using several variations of MEM that differed in the assumptions made regarding intraindividual error, NPD, and a graphical noncompartmental method. These analyses attempted to retrieve the underlying parameter and covariate effect values. We compared these analysis methods with respect to how well the underlying values were retrieved. All analysis methods performed poorly with single sample per subject data but MEM gave less biased estimates under the simulated conditions used here. MEM performance increased when covariate effects were sought in the analysis compared with analyses seeking only PK parameters. Decreasing the number of animals used per sampling time from 48 to 16 did not influence the quality of parameter estimates but further reductions (< 16 animals per sampling time) resulted in a reduced proportion of acceptable estimates. Parameter estimate quality improved and worsened with MEM and NPD, respectively, when additional samples were obtained from each individual. Assumptions made regarding the magnitude of intraindividual error were unimportant with single sample per subject data but influenced parameter estimates if more samples were obtained from each individual. MEM is preferable to both NPD and noncompartmental approaches for the analysis of single sample per subject data but even with MEM estimates of clearance are often biased.
Animals↗
Analysis of toxicokinetic data using NONMEM: impact of quantification limit and replacement strategies for censored data.
The purpose of this study was to examine how best to incorporate plasma samples which fall below an assay's lower limit of quantification into the process of toxicokinetic data modeling. Secondly to establish what proportion of data can be below the quantification limit without compromising NONMEM's parameter estimates. Using pharmacokinetic parameters determined in a rat toxicokinetic study we simulated datasets that might emerge from similar experiments in which only one sample was obtained per individual. A number of quantification limits were used which resulted in increasing proportions of data values being treated as if they were below the limit of quantification (BQL). For each quantification level we incorporated BQL data into our analyses in number of ways. We compared these analysis methods with respect to how well the underlying parameter values were retrieved. Omitting BQL data values or entering them as zero led to inaccurate and biased study results. We found that incorporating BQL values using more complex substitution methods via a mixed effects model produced more reliable and less biased parameter estimates. The four substitution methods that we investigated performed similarly. Parameter estimates became less reliable and more biased as the quantification level was increased depending on the method of BQL value incorporation. Naive methods of BQL data handling can produce unreliable and biased parameter estimates. An alternative is to incorporate BQL values into a population-type model, our results showed this method to be preferable. We found it advisable that the proportion of BQL data should not exceed one third and, if possible should be less than one quarter.
Animals↗
Repair of oxidative DNA damage: mechanisms and functions.
Cellular genomes suffer extensive damage from exogenous agents and reactive oxygen species formed during normal metabolism. The MutT homologs (MutT/MTH) remove oxidized nucleotide precursors so that they cannot be incorporated into DNA during replication. Among many repair pathways, the base excision repair (BER) pathway is the most important cellular protection mechanism responding to oxidative DNA damage. The 8-oxoG glycosylases (Fpg or MutM/OGG) and the MutY homologs (MutY/MYH) glycosylases along with MutT/MTH protect cells from the mutagenic effects of 8-oxoG, the most stable and deleterious product known caused by oxidative damage to DNA. The key enzymes in the BER process are DNA glycosylases, which remove different damaged bases by cleavage of the N-glycosylic bonds between the bases and the deoxyribose moieties of the nucleotide residues. Biochemical and structural studies have demonstrated the substrate recognition and reaction mechanism of BER enzymes. Cocrystal structures of several glycosylases show that the substrate base flips out of the sharply bent DNA helix and the minor groove is widened to be accessed by the glycosylases. To complete the repair after glycosylase action, the apurinic/apyrimidinic (AP) site is further processed by an incision step, DNA synthesis, an excision step, and DNA ligation through two alternative pathways. The short-patch BER (1-nucleotide patch size) and long-patch BER (2-6-nucleotide patch size) pathways need AP endonuclease to generate a 3' hydroxyl group but require different sets of enzymes for DNA synthesis and ligation. Protein-protein interactions have been reported among the enzymes involved in BER. It is possible that the successive players in the repair pathway are assembled in a complex to perform concerted actions. The BER pathways are proposed to protect cells and organisms from mutagenesis and carcinogenesis.
Amino Acid Sequence↗
A pharmacokinetic-dynamic explanation of the rapid onset-offset of rapacuronium.
The rapid onset and offset of rapacuronium can be explained from its pharmacokinetic and pharmacodynamic characteristics. A unique property of rapacuronium is its high value for ke0, indicating a rapid access to the receptor site. The reason for this high ke0 may be related to the low intrinsic potency of rapacuronium, but this is not yet fully clarified.
Humans↗
The C-terminal domain of MutY glycosylase determines the 7,8-dihydro-8-oxo-guanine specificity and is crucial for mutation avoidance.
Escherichia coli MutY is an adenine DNA glycosylase active on DNA substrates containing A/G, A/8-oxoG, or A/C mismatches and also has a weak guanine glycosylase activity on G/8-oxoG-containing DNA. The N-terminal domain of MutY, residues 1-226, has been shown to retain catalytic activity. Substrate binding, glycosylase, and Schiff base intermediate formation activities of the truncated and intact MutY were compared. MutY has high binding affinity with 8-oxoG when mispaired with A, G, T, C, or inosine. The truncated protein has more than 18-fold lower affinities for binding various 8-oxoG-containing mismatches when compared with intact MutY. MutY catalytic activity toward A/8-oxoG-containing DNA is much faster than that on A/G-containing DNA whereas deletion of the C-terminal domain reduces its catalytic preference for A/8-oxoG-DNA over A/G-DNA. MutY exerts more inhibition on the catalytic activity of MutM (Fpg) protein than does truncated MutY. The tight binding of MutY with GO mispaired with T, G, and apurinic/apyrimidinic sites may be involved in the regulation of MutM activity. An E. coli mutY strain that produces an N-terminal 249-residue truncated MutY confers a mutator phenotype. These findings strongly suggest that the C-terminal domain of MutY determines the 8-oxoG specificity and is crucial for mutation avoidance by oxidative damage.
DNA Glycosylases↗
Pharmacokinetic studies of neuromuscular blocking agents: good clinical research practice (GCRP).
In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.
Body Temperature↗
Rapacuronium 2.0 or 2.5 mg kg-1 for rapid-sequence induction: comparison with succinylcholine 1.0 mg kg-1.
The purpose of this nine-centre study in 602 patients was to show that the frequency of acceptable intubating conditions after rapacuronium 2.0 or 2.5 mg kg-1 is not more than 10% lower than the frequency after succinylcholine 1.0 mg kg-1 during rapid-sequence induction of anaesthesia with fentanyl 1-2 micrograms kg-1 and thiopental 2-7 mg kg-1. Laryngoscopy and intubation were carried out 60 s after administration of muscle relaxant by an anaesthetist blinded to its identity. Intubating conditions were clinically acceptable (excellent or good) in 91.8% of patients given succinylcholine and in 84.1 and 87.6% of patients given rapacuronium 2.0 and 2.5 mg kg-1 respectively. With respect to the percentage of clinically acceptable intubating conditions, the estimated difference (and the upper limit of the one-sided 97.5% confidence interval) between succinylcholine and rapacuronium 2.0 mg kg-1 was 7.8 (14.4)% and between succinylcholine and rapacuronium 2.5 mg kg-1 it was 4.0 (10.2)%. For both comparisons, the upper limit of the one-sided confidence interval exceeded the predefined 10% difference. Hence, it could not be demonstrated that the intubating conditions with either of the two doses of rapacuronium were not inferior to those with succinylcholine 1.0 mg kg-1. The increase in heart rate was significantly greater during the first 5 min in the rapacuronium groups, but the arterial pressure increased significantly only in the succinylcholine group (P < 0.001). Respiratory side-effects were observed in 4.0, 13.5 and 18.5% of patients after succinylcholine and rapacuronium 2.0 and 2.5 mg kg-1 respectively (P < 0.05). As the non-inferiority of intubating conditions after rapacuronium 2.0 and 2.5 mg kg-1 could not be proven, succinylcholine should be considered the neuromuscular blocking agent that provides better intubating conditions for rapid-sequence induction.
Adolescent↗
Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium.
BACKGROUND: The authors evaluated the influence of temperature on the pharmacokinetics and pharmacodynamics of vecuronium because mild core hypothermia doubles its duration of action. METHODS: Anesthesia was induced with alfentanil and propofol and maintained with nitrous oxide and isoflurane in 12 healthy volunteers. Train-of-four stimuli were applied to the ulnar nerve, and the mechanical response of the adductor pollicis was measured. Volunteers were actively cooled or warmed until their distal esophageal temperatures were in one of four ranges: < 35.0 degrees C, 35.0-35.9 degrees C, 36.0-36.9 degrees C, and > or = 37.0 degrees C. With temperature stabilized, vecuronium was infused at 5 microg x kg(-1) x min(-1) until the first response of each train-of-four had decreased by 70%. Arterial blood (for vecuronium analysis) was sampled at intervals until the first response recovered to at least 90% of its prevecuronium level. Vecuronium, 20 microg x kg(-1) x min(-1), was then infused for 10 min, and arterial blood was sampled at intervals for up to 7 h. Population-based nonlinear mixed-effects modeling was used to examine the effect of physical characteristics and core temperature on vecuronium pharmacokinetics and pharmacodynamics. RESULTS: Decreasing core temperature over 38.0-34.0 degrees C decreases the plasma clearance of vecuronium (11.3% per degrees C), decreases the rate constant for drug equilibration between plasma and effect site (0.023 min(-1) per degrees C), and increases the slope of the concentration-response relationship (0.43 per degrees C). CONCLUSIONS: Our results show that reduced clearance and rate of effect site equilibration explain the increased duration of action of vecuronium with reducing core temperature. Tissue sensitivity to vecuronium is not influenced by core temperature.
Adult↗
The active site of the Escherichia coli MutY DNA adenine glycosylase.
Escherichia coli MutY is an adenine DNA glycosylase active on DNA substrates containing A/G, A/C, or A/8-oxoG mismatches. Although MutY can form a covalent intermediate with its DNA substrates, its possession of 3' apurinic lyase activity is controversial. To study the reaction mechanism of MutY, the conserved Asp-138 was mutated to Asn and the reactivity of this mutant MutY protein determined. The glycosylase activity was completely abolished in the D138N MutY mutant. The D138N mutant and wild-type MutY protein also possessed different DNA binding activities with various mismatches. Several lysine residues were identified in the proximity of the active site by analyzing the imino-covalent MutY-DNA intermediate. Mutation of Lys-157 and Lys-158 both individually and combined, had no effect on MutY activities but the K142A mutant protein was unable to form Schiff base intermediates with DNA substrates. However, the MutY K142A mutant could still bind DNA substrates and had adenine glycosylase activity. Surprisingly, the K142A mutant MutY, but not the wild-type enzyme, could promote a beta/delta-elimination on apurinic DNA. Our results suggest that Asp-138 acts as a general base to deprotonate either the epsilon-amine group of Lys-142 or to activate a water molecule and the resulting apurinic DNA then reacts with Lys-142 to form the Schiff base intermediate with DNA. With the K142A mutant, Asp-138 activates a water molecule to attack the C1' of the adenosine; the resulting apurinic DNA is cleaved through beta/delta-elimination without Schiff base formation.
Binding Sites↗
A large simple randomized trial of rocuronium versus succinylcholine in rapid-sequence induction of anaesthesia along with propofol.
BACKGROUND: Rocuronium has an onset of action more rapid than other non-depolarizing neuromuscular blocking agents, but it is unclear whether it and succinylcholine give equivalent intubating conditions during rapid-sequence induction of anaesthesia. We performed this study to answer the question--are there clinically relevant differences between the use of rocuronium and succinylcholine to secure acceptable intubating conditions during rapid-sequence induction of anaesthesia with propofol? METHODS: Anaesthesia was induced using propofol 2.5 mg/kg in 349 ASA physical status grade I-IV patients who were undergoing either elective or emergency surgery. Propofol was followed immediately by either rocuronium 0.6 or 1 mg/kg or succinylcholine 1.0 mg/kg (randomly selected). Fifty seconds after the end of muscle relaxant injection laryngoscopy was performed and intubating conditions were graded by an experienced anaesthetist blind to the muscle relaxant allocation. This study design was selected so that a 10% difference in clinically acceptable intubating conditions between drugs would be detectable. RESULTS: In this setting rocuronium 1.0 mg/kg provided superior intubating conditions compared with rocuronium 0.6 mg/kg. The incidence of clinically acceptable intubating conditions with rocuronium 1.0 mg/kg and succinylcholine 1.0 mg/kg was 93.2% and 97.1% respectively, the difference being -3.9% (95% C.I. -9.7% to 1.9%). CONCLUSION: Rocuronium 1.0 mg/kg given along with propofol in a rapid-sequence induction of anaesthesia is clinically equivalent to succinylcholine 1.0 mg/kg.
Adolescent↗
Antagonism of rapacuronium using edrophonium or neostigmine: pharmacodynamics and pharmacokinetics.
We have studied the pharmacodynamics and pharmacokinetics of rapacuronium (Org 9487) in 70 healthy patients. Neuromuscular transmission was monitored using TOF stimulation of the ulnar nerve and mechanomyography of the adductor pollicis muscle. Half of the patients were given a single dose of rapacuronium 1.5 mg kg-1 and the remainder rapacuronium 1.5 mg kg-1 with three incremental doses of 0.5 mg kg-1, each given when T1/T0 had recovered to 25%. In all patients, neuromuscular block was antagonized using neostigmine 0.05 mg kg-1 or edrophonium 1.0 mg kg-1 (allocated randomly), 2 min after the final dose of rapacuronium. All patients developed complete block after rapacuronium 1.5 mg kg-1. Mean onset time was 66 (SD 24) s. In patients who received an antagonist 2 min after the first dose of rapacuronium, time to recovery of T1/T0 to 25% was similar after neostigmine (9.8 (3.8) min) and edrophonium (10.3 (4.3) min): in patients who received incremental doses of rapacuronium, spontaneous recovery of T1/T0 to 25% after the first dose was 18.9 (4.7) min. In those who received an antagonist 2 min after the first dose of rapacuronium, times to recovery of T4/T1 to 0.7 were also similar after neostigmine (23.7 (7.7) min) and edrophonium (29.1 (10.7) min). After three incremental doses of rapacuronium, there was a longer time to recovery of T1/T0 = 25% after neostigmine compared with edrophonium (5.1 (1.0) vs 3.3 (1.3) min; P < 0.05) but more rapid recovery to T1/T0 = 75% (10.1 (2.9) vs 16.8 (10.1) min; P < 0.05) and T4/T1 = 0.7 (19.8 (6.3) vs 35.1 (10.4) min; P < 0.05). A three-compartment pharmacokinetic model was justified. Typical values for clearance and initial volume of distribution (V1) were 4.4 ml kg-1 min-1 and 94.8 ml kg-1, respectively. In females, clearance was decreased by 38.5% compared with males and V1 was decreased by 25% in patients aged more than 65 yr.
Adolescent↗
A pharmacodynamic explanation for the rapid onset/offset of rapacuronium bromide.
BACKGROUND: Nondepolarizing muscle relaxants differ in their time course at the laryngeal adductors and the adductor pollicis, a result of differences in equilibration delays between plasma and effect sites, the sensitivity of each muscle to the relaxant, and the steepness of the concentration-effect relation at each muscle (the Hill factor). To determine whether similar differences exist for rapacuronium, a muscle relaxant with rapid onset and offset, the authors determined its pharmacodynamic characteristics. METHODS: The twitch tensions of the adductor pollicis and the laryngeal adductors (via a tracheal tube cuff positioned at the vocal cords) were measured in 10 volunteers who were anesthetized with propofoL Rapacuronium, 1.5 mg/kg, was given and blood samples were collected. A semiparametric effect compartment pharmacodynamic model was fit to values for rapacuronium plasma concentrations and twitch tension of the adductor pollicis and laryngeal adductors. RESULTS: Equilibration between the rapacuronium plasma concentration and both effect sites was rapid (typical values for the rate constant for equilibration between plasma and the effect site are 0.405 per min for the adductor pollicis and 0.630 per min for the laryngeal adductors) and was more rapid at the laryngeal adductors than at the adductor pollicis (ratio, 1.59+/-0.16; mean +/- SD). The steady state rapacuronium plasma concentration that depressed twitch tension by 50% and the Hill factor were similar for the two muscles. CONCLUSIONS: The rapid onset and offset of rapacuronium can be explained by the rapid equilibration between concentrations in plasma and at the effect site. Unlike the finding for other nondepolarizing muscle relaxants, the laryngeal muscles are not resistant to rapacuronium.
Adult↗
Influence of renal failure on the pharmacokinetics and neuromuscular effects of a single dose of rapacuronium bromide.
BACKGROUND: Because renal function affects the elimination of muscle relaxants, each new muscle relaxant must be evaluated in patients with renal failure. Accordingly, the neuromuscular effects and pharmacokinetics of rapacuronium were identified in patients with renal failure. METHODS: Rapacuronium (1.5 mg/kg) was administered to 10 healthy volunteers and 10 patients with renal failure who were undergoing non-transplant surgery, were 18-45 yr old, and were anesthetized with propofol. The adductor pollicis muscle twitch tension was monitored. Plasma samples were obtained frequently for a period of 8 h to measure the concentrations of ORG9487 and its metabolite, ORG9488. Pharmacokinetic parameters were determined using mixed-effects modeling. RESULTS: One patient was excluded from analysis because he was taking phenytoin chronically. Twitch depression at 1 min was less in patients than in healthy volunteers (median values: 92% in patients, 99% in volunteers). The times to 90% and peak twitch depression; to 10%, 25%, and 75% twitch recovery; and to 70% and 80% train-of-four ratios were similar in volunteers and patients. Rapacuronium's clearance was 32% less in patients with renal failure; in both groups, clearance decreased 0.909% per year of age compared with the value in a 30 yr old. The steady state distribution volume was 14% less in women than in men and 16% less in patients than in volunteers. For ORG9488, clearance was 85% less in patients than in volunteers. CONCLUSIONS: The neuromuscular effects of a single dose of rapacuronium are affected minimally by renal failure. However, the decreased clearance of rapacuronium and its potent metabolite in renal failure suggests that repeated dosing of rapacuronium may lead to prolonged effects in patients with renal failure.
Adolescent↗
Functional oral-motor skills: Do they change with age?
Dysphagia, a difficulty eating or drinking, appears to increase with age and is a concern for our growing elderly population. Mastication, tongue mobility, and lip closure are skills of the oral phase of ingestion, and have been shown to deteriorate with age. However, it is not clear whether these changes affect functional feeding. It is also unclear whether dysphagia is the result of the aging process itself, or whether it is secondary to disease. Therefore, the purpose of this study was to identify changes during the oral phase of ingestion in a group of healthy seniors. Functional feeding skills and oral praxis abilities were measured in 79 healthy adults aged 60-97 years. The Modified Functional Feeding Assessment (FFAm) subscale of the Multidisciplinary Feeding Profile (MFP) and the Oral Praxis Subtest (OPS) of the Southern California Sensory Integration Test were administered respectively. An interview followed to obtain information on denture wear, use of hearing aids and glasses, and types of foods avoided. Seniors maintained functional feeding skills throughout the four decades studied. These skills were not age-dependent, but depended on whether or not subjects wore full dentures. Even though all of the seniors maintained functional feeding skills, more seniors in the younger group (7th decade 60%, 8th decade 67%) had difficulty with a variety of food textures such as soft, hard, fibrous, and some with tough skins, than the older group (9th decade 40%, 10th decade 44%). Oral praxis abilities were correlated significantly with age, but not with hearing aid use. Overall, healthy seniors maintained their functional feeding and oral praxis skills. Good health and natural dentition appear to be excellent indicators for functional feeding ability.
Aged↗
Can bioavailability of low-variance drugs be estimated with an unpaired, sparse sampling design?
OBJECTIVE: Bioavailability (F) with nonintravenous administration is traditionally estimated by comparison of the area under the plasma concentration versus time curve (AUC) after drug administration by each of the nonintravenous and intravenous routes in the same individual. This paired approach may not always be possible. We simulated whether F and the absorption rate constant (ka) could be estimated accurately for a drug with low variance using different patients for nonintravenous and intravenous routes and whether sparse sampling permitted accurate estimates. METHODS: Using pharmacokinetic parameters for cisatracurium besylate (INN, cisatracurium besilate), we simulated data sets representing 20 administrations (10 intravenous and 10 nonintravenous) with either three (sparse) or 16 (extensive) samples per administration. Simulations were performed twice, with ka values of 0.1 (slow absorption) or 0.3 (rapid absorption) min-1. With use of NONMEM, we estimated F and ka for each data set using both two-stage and mixed-effects modeling approaches and paired and unpaired designs to determine the percentage of estimates that deviated > 25% from the simulated value. RESULTS: Estimates of F with extensive data were satisfactory for all approaches. With sparse sampling, two-stage analysis of unpaired data were not possible, two-stage analysis of paired data yielded erroneous estimates, and mixed-effects modeling gave satisfactory estimates. Estimates of ka were sometimes erroneous with all approaches except for paired analysis of extensive data with slow absorption; sparse data and two-stage analysis increased the likelihood of errors compared with extensive data and mixed-effects modeling. CONCLUSIONS: Mixed-effects modeling facilitates estimation of F and ka for low-variance drugs in situations in which traditional paired extensive data designs are not possible.
Administration, Oral↗
Population based pharmacokinetic analysis: why do we need it; what is it; and what has it told us about anaesthetics?
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Analgesics, Opioid↗
Do the pharmacokinetics of vecuronium change during prolonged administration in critically ill patients?
Neuromuscular blocking drugs may be administered over several days to patients in the intensive care unit (ICU), but their pharmacokinetics have been studied at only one point in time, or assumed to be constant throughout the period of administration. We sought to determine if, in individual patients, the pharmacokinetics of vecuronium changed over the course of its administration in the ICU. In six critically ill patients, we measured plasma vecuronium concentrations during two periods: first, during initial administration of vecuronium and second, after its administration continuously for 3-6 days. A pharmacokinetic model was fitted to these plasma concentration data, and its parameters permitted to vary between the periods to determine if they had altered. Individual clearance values during the study ranged from 1.4 to 4.4 ml kg-1 min-1. During prolonged administration, vecuronium clearance increased in three and decreased in two patients. This change ranged from a 61% decrease to a 58% increase, and was not linked to any clinical factor. The steady-state volume of distribution (range 368-1765 ml kg-1; median 494 ml kg-1) did not change in any patient during the study. The change in clearance of vecuronium during its prolonged administration in critically ill patients suggests that future studies of neuromuscular blocking drugs in the ICU should take account of their changing pharmacokinetics over the course of administration.
Adult↗