Permafrost exerts an important control over hydrological processes in Arctic landscapes and lakes. Recent warming and summer precipitation has the potential to alter water availability and quality in ...this environment through thermal perturbation of near surface permafrost and increased mobility of previously frozen solutes to Arctic freshwaters. We present a unique thirteen-year record (2003-16) of the physiochemical properties of two High Arctic lakes and show that the concentration of major ions, especially SO
, has rapidly increased up to 500% since 2008. This hydrochemical change has occurred synchronously in both lakes and ionic ratio changes in the lakes indicate that the source for the SO
is compositionally similar to terrestrial sources arising from permafrost thaw. Record summer temperatures during this period (2003-16) following over 100 years of warming and summer precipitation in this polar desert environment provide likely mechanisms for this rapid chemical change. An abrupt limnological change is also reflected in the otolith chemistry and improved relative condition of resident Arctic char (Salvelinus alpinus) and increased diatom diversity point to a positive ecosystem response during the same period.
Polyfluoroalkyl compounds (PFAs) have been used for decades in industrial and commercial products and are now detected worldwide. Concentrations of two major PFA groups, carboxylic acids (PFCAs) and ...sulfonic acids (PFSAs), were assessed in plasma of bottlenose dolphins from the Gulf of Mexico (Sarasota Bay, FL) and the Atlantic Ocean (Delaware Bay, NJ, Charleston, SC, Indian River Lagoon (IRL), FL, and Bermuda). Eight PFAs were detected in the plasma of all dolphins. Perfluorooctane sulfonate (PFOS) was the predominant compound at all locations (range from 49 ng/g wet weight (w.w.) in dolphins from Bermuda to 1171 ng/g w.w. in plasma of animals from Charleston). Sum of PFA concentrations were significantly higher in animals from Charleston compared to IRL, Sarasota Bay, and Bermuda. Concentrations of several PFAs were negatively associated with age in animals from IRL and Charleston. No differences between gender were observed for all compounds at all locations. An increase in PFA concentrations was associated with a decrease of blubber thickness in animals from Sarasota Bay and IRL. Fluorotelomer 8:2 and 10:2 unsaturated carboxylic acids (FTUCAs), known degradation products of fluorotelomer alcohols and suspected precursors to PFCAs, were detected for the first time at low concentrations in plasma of dolphins.
Although remifentanil's short-acting pharmacokinetic profile makes it well suited for procedures during which a brief period of intense analgesia is required, setting up an infusion pump for brief ...procedures is inconvenient. The clinical pharmacology of remifentanil administered by bolus injection, a more convenient alternative, has not been explored in detail. The primary aim of this study was to examine the safety of single bolus doses of remifentanil in conscious, healthy, adult volunteers breathing room air. Secondary aims included the evaluation of remifentanil pharmacokinetics and analgesic effects after bolus injection and a comparison of these issues in younger vs older adults.
Using a randomized, double-blind, placebo-controlled, dose-escalation, crossover study design, 64 subjects (16 over 60 years old) received remifentanil or placebo by bolus injection in a fixed unit dose separated by a 1 h washout period. Respiratory effects were assessed using a respiratory intervention scale. Analgesic effects were assessed using pressure algometry. A population pharmacokinetic model was constructed using non-linear, mixed-effects modelling techniques based on arterial blood samples. Computer simulations were performed to illustrate the clinical application of the pharmacokinetic model.
Dose-related increases in both respiratory and analgesic effects were observed. In general, the respiratory depression observed was mild and easily treated with requests to breathe or the administration of oxygen, although the older cohort (and some younger subjects) experienced more substantial respiratory depression at lower doses. The pharmacokinetics of bolus-dose remifentanil were adequately described by a two-compartment model. The pharmacokinetic simulations illustrated the potential utility of bolus-dose remifentanil.
Bolus injection could potentially be a safe and effective means of administering remifentanil in clinical situations requiring a brief period of intense analgesia. Because some subjects, both old and young, experienced significant respiratory depression even at low doses, careful monitoring of respiratory function is essential.
Remifentanil hydrochloride is an ultra-short-acting opioid that undergoes rapid metabolism by tissue and plasma esterases. We aimed to characterize the pharmacokinetics and determine the hemodynamic ...profile of remifentanil after a single-bolus dose in children aged 0 to 18 yr. Forty-two children undergoing elective surgical procedures received remifentanil 5 microg/kg infused over 1 min. Patients were divided into age groups as follows: young infants (< or =2 mo), older infants (> 2 mo to < 2 yr), young children (2 to < 7 yr), older children (7 to < 13 yr), adolescents (13 to < 16 yr), and young adults (16 to < 18 yr). Arterial blood samples were collected and analyzed by mass spectroscopy to determine remifentanil pharmacokinetic profiles. Hemodynamic measurements for remifentanil's effect were made after the infusion. Methods of statistical analysis included analysis of variance and linear regression, with significance at P < or = 0.05. Complete remifentanil pharmacokinetic data were obtained from 34 patients. The volume of distribution was largest in the infants < 2 mo (mean, 452 mL/kg) and decreased to means of 223 to 308 mL/kg in the older patients. There was a more rapid clearance in the infants < 2 mo of age (90 mL. kg(-1). min(-1)) and infants 2 mo to 2 yr (92 mL. kg(-1). min(-1)) than in the other groups (means, 46 to 76 mL. kg(-1). min(-1)). The half-life was similar in all age groups, with means of 3.4 to 5.7 min. Seven subjects (17%) developed hypotension related to the remifentanil bolus. Remifentanil showed an extremely rapid elimination similar to that in adults. The fast clearance rates observed in neonates and infants, as well as the lack of age-related changes in half-life, are in sharp contrast to the pharmacokinetic profile of other opioids. Remifentanil in a bolus dose of 5 microg/kg may cause hypotension in anesthetized children.
The pharmacokinetics of remifentanil were studied in children from birth to 18 yr. Remifentanil was found to have age-related changes in clearance and volume of distribution, but not half-life. The increased clearance observed in young infants is in contrast to other opioids.
Remifentanil (GI87084B) is a new short-acting opioid with a unique ester structure. Metabolism of remifentanil by ester hydrolysis results in very rapid elimination. The aim of this study was to ...characterize in detail the pharmacokinetic profile of remifentanil in healthy male volunteers.
Ten healthy adult male volunteers received a zero-order infusion of remifentanil at doses ranging from 1 to 8 micrograms.kg-1.min-1 for 20 min. Frequent arterial blood samples were drawn and analyzed by gas chromatographic mass spectroscopy to determine the remifentanil blood concentrations. The raw pharmacokinetic data were analyzed using three different parametric compartmental modeling methods (traditional two-stage, naive pooled data, and NONMEM). The raw pharmacokinetic data also were analyzed using numeric deconvolution and a nonparametric moment technique. A computer simulation using hte pharmacokinetic parameters of the NONMEM compartmental model was performed to provide a more intuitively meaningful and clinically relevant description of the pharmacokinetics. The simulation estimated the time necessary to achieve a 50% decrease in remifentanil concentration after a variable-length infusion.
For each parametric method, a three-compartment mamillary model that accurately describes remifentanil's concentration decay curve was constructed. The NONMEM analysis population pharmacokinetic parameters included a central clearance of 2.8 l/min, a volume of distribution at steady state of 32.8 l, and a terminal half-life of 48 min. The mean results of the nonparametric moment analysis included a clearance of 2.9 l/min, a volume of distribution at steady state of 31.8 l, and a mean residence time of 10.9 min. The computer simulation revealed the strikingly unique pharmacokinetic profile of remifentanil compared to that of the currently available fentanyl family of opioids.
Remifentanil is a new, short-acting opioid with promising clinical potential in anesthesiology.
The context-sensitive half-time, rather than the terminal elimination half-life, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of ...a given duration. The context-sensitive half-time is derived from computer modelling using known pharmacokinetic parameters. The modelled context-sensitive half-time for a 3-h infusion of alfentanil is 50-55 min and is 3 min for remifentanil. The terminal elimination half-life is 111 min for alfentanil and 12-30 min for remifentanil. It has not been tested whether the modelled context-sensitive half-time reflects the true time for a 50% decrease in drug concentration or drug effect.
Thirty volunteers received a 3-h infusion of remifentanil or alfentanil at equieffective concentrations. Depression of minute ventilation to 7.5% ETCO2 was used as a measure of drug effect. Minute ventilation response was measured, and blood samples for drug concentration were taken during and after drug infusion. The recovery of minute ventilation (drug effect) and decrease in blood drug concentration was plotted, and the time for a 50% change was determined.
The measured pharmacokinetic context-sensitive half-time for remifentanil after a 3-h infusion was 3.2 +/- 0.9 min, and its pharmacodynamic offset was 5.4 +/- 1.8 min. Alfentanil's measured pharmacokinetic context-sensitive half-time was 47.3 +/- 12 min, and its pharmacodynamic offset was 54.0 +/- 48 min. The terminal elimination half-life modelled from the volunteers was 11.8 +/- 5.1 min for remifentanil and 76.5 +/- 12.6 min for alfentanil.
The measured context-sensitive half-times were in close agreement with the context-sensitive half-times previously modelled for these drugs. The results of this study confirm the value of the context-sensitive half-time in describing drug offset compared to the terminal elimination half-life.
Remifentanil is an esterase-metabolized opioid with a rapid clearance. The aim of this study was to contrast the pharmacokinetics and pharmacodynamics of remifentanil and alfentanil in healthy, adult ...male volunteers.
Ten volunteers received infusions of remifentanil and alfentanil on separate study sessions using a randomized, open-label crossover design. Arterial blood samples were analyzed to determine drug blood concentrations. The electroencephalogram was employed as the measure of drug effect. The pharmacokinetics were characterized using a moment analysis, a nonlinear mixed effects model (NONMEM) population analysis, and context-sensitive half-time computer simulations. After processing the raw electroencephalogram to obtain the spectral edge parameter, the pharmacodynamics were characterized using an effect compartment, inhibitory maximum effect model.
Pharmacokinetically, the two drugs are similar in terms of steady-state distribution volume (VD(SS)), but remifentanil's central clearance (CLc)) is substantially greater. The NONMEM analysis population pharmacokinetic parameters for remifentanil include a CLc of 2.9 l x min(-1), a VDss of 21.81, and a terminal half-life of 35.1 min. Corresponding NONMEM parameters for alfentanil are 0.36 l x min(-1), 34.11, and 94.5 min. Pharmacodynamically, the drugs are similar in terms of the time required for equilibration between blood and the effect-site concentrations, as evidenced by a T(12)k(e0) for remifentanil of 0.75 min corrected and 0.96 min for alfentanil. However, remifentanil is 19 times more potent than alfentanil, with an effective concentration for 50% maximal effect of 19.9 ng x ml(-1) versus 375.9 ng x ml(-1) for alfentanil.
Compared to alfentanil, the high clearance of remifentanil, combined with its small steady-state distribution volume, results in a rapid decline in blood concentration after termination of an infusion. With the exception of remifentanil's nearly 20-times greater potency (30-times if alfentanil partitioning between whole blood and plasma is considered), the drugs are pharmacodynamically similar.
Remifentanil is a short-acting opioid whose pharmacokinetics have been characterized in detail. However, the impact of obesity on remifentanil pharmacokinetics has not been specifically examined. The ...goal of this study was to investigate the influence of body weight on remifentanil pharmacokinetics.
Twelve obese and 12 matched lean subjects undergoing elective surgery received a 1-min remifentanil infusion after induction of anesthesia. Arterial blood samples were collected for determination of remifentanil blood concentrations. Each subject's pharmacokinetic parameters were estimated by fitting a two-compartment model to the concentration versus time curves. Nonlinear mixed-effects population models examining the influence of lean body mass (LBM) and total body weight (TBW) were also constructed. Clinical simulations using the final population model were performed.
The obese patient cohort reached substantially higher remifentanil concentrations. The individual pharmacokinetic parameters of a two-compartment model were not significantly different between the obese versus lean cohorts (unless normalized to TBW). The final population model scaled central clearance and the central and peripheral distribution volumes to LBM. The simulations illustrated that remifentanil pharmacokinetics are not grossly different in obese versus lean subjects and that TBW based dosing in obese patients can result in excessively high remifentanil concentrations.
The essential findings of the study are that remifentanil's pharmacokinetics are not appreciably different in obese versus lean subjects and that remifentanil pharmacokinetic parameters are therefore more closely related to LBM than to TBW. Clinically this means that remifentanil dosing regimens should be based on ideal body weight (or LBM) and not TBW.
Remifentanil is a highly potent opioid with a rapid onset and a short duration of action due to its rapid hydrolysis by esterases in blood and tissues. The major metabolite of remifentanil, GI90291, ...is much less potent than remifentanil.
The pharmacokinetics of remifentanil and its major metabolite, GI90291, were determined in 24 patients undergoing elective inpatient surgery. Remifentanil was administered as a 1-min infusion (2, 5, 15, and 30 micrograms/kg) after the induction of anesthesia and tracheal intubation. Serial arterial blood samples were collected over 6 h and assayed for remifentanil and GI90291.
The pharmacokinetics of remifentanil were described using a three-compartment model. Total clearance (250-300 l/h) of remifentanil was independent of dose and was approximately three to four times greater than the normal hepatic blood flow. Volume of distribution at steady state (25-40 l) also was independent of dose. The terminal half-life of remifentanil ranged from 10 to 21 min. Covariate analysis of remifentanil clearance and patient demographics showed that patient body weight, age, and gender did not influence total clearance. This suggests that remifentanil may not need to be dosed according to body weight in adult patients. A simulation was conducted to determine the time required for a 50% reduction in effect site concentration after an infusion designed to maintain a constant effect site concentration. The time required for a 50% reduction in the effect site concentration of remifentanil (3.65 min) was considerably less than that for sufentanil (33.9 min), alfentanil (58.5 min), and fentanyl (262 min). The pharmacokinetics of the major metabolite, GI90291, were independent of the dose of remifentanil. The mean terminal half-life of GI90291 ranged from 88 to 137 min.
The pharmacokinetics of remifentanil are consistent with its rapid elimination by blood and tissue esterases; its major metabolite is eliminated more slowly but is not likely to make any significant contribution to the total effect because of its much lower potency. The rapid onset and short duration of action of remifentanil make it well suited for titration of dose (infusion rate) to the desired degree of effect.
AbstractObjectivesTo develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age.DesignAnalysis of ...genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa.SettingMultiple institutions that were members of international PRACTICAL consortium.ParticipantsAll consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men.Main outcome measuresPrediction with hazard score of age of onset of aggressive cancer in validation set.ResultsIn the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10−16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score.ConclusionsPolygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.
PDF
