Onset–potency relationship of nondepolarizing muscle relaxants: a reexamination using simulations

2007 ◽  
Vol 85 (8) ◽  
pp. 774-782 ◽  
Author(s):  
S.B. Bhatt ◽  
A. Amann ◽  
V. Nigrovic
Keyword(s):  
Rate Constant ◽  
Elimination Rate ◽  
Onset Time ◽  
Rapid Onset ◽  
Muscle Relaxants ◽  
Transport Rate ◽  
Effect Compartment ◽  
Double Logarithmic Plot ◽  
Nondepolarizing Muscle Relaxants ◽  
The Impact

Nondepolarizing muscle relaxants (MRs) display an inverse onset–potency relationship, that is, less potent MRs display a more rapid onset. We have conducted the current investigation to estimate the impact of variable pharmacokinetic or pharmacodynamic properties of the MRs on potency and onset time, and on the onset–potency relationship. Using a model of neuromuscular transmission, we changed either the affinity of MRs for the postsynaptic receptors or the pharmacokinetic properties of the MRs. The elimination rate constant, k10, which defines the systemic clearance, was assigned one of 9 values and the transport rate constant, k12, one of 5 values. The transport rate constant into the effect compartment was constant (ke1 = 0.2 min–1). Only one parameter was altered at a time. With constant pharmacokinetics, a 100-fold decrease in affinity caused a proportional decrease in potency, but little change (0.02 min) in onset time. With constant affinity, increasing the clearance from 1 to 250 mL·kg–1·min–1 shortened the onset time from 7.2 to 0.7 min and decreased the potency 12-fold. In a double logarithmic plot, the onset–potency relationship was linear. Lesser affinities produce a nearly parallel rightward shift of the regression lines. The inverse onset–potency relationship may be explained by the pharmacokinetic factors producing changes in both the potency and onset times.

A Pharmacodynamic Explanation for the Rapid Onset/Offset of Rapacuronium Bromide 

1999 ◽  
Vol 90 (1) ◽  
pp. 16-23 ◽  
Author(s):  
Peter M. C. Wright ◽  
Ronald Brown ◽  
Marie Lau ◽  
Dennis M. Fisher
Keyword(s):  
Plasma Concentration ◽  
Time Course ◽  
Plasma Concentrations ◽  
Rapid Onset ◽  
Muscle Relaxants ◽  
Adductor Pollicis ◽  
Effect Compartment ◽  
Nondepolarizing Muscle Relaxants ◽  
Effect Site ◽  
The Hill

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.

Concentration–Effect Relation of Succinylcholine Chloride during Propofol Anesthesia

2002 ◽  
Vol 97 (5) ◽  
pp. 1082-1092 ◽  
Author(s):  
Julie J. Roy ◽  
François Donati ◽  
Daniel Boismenu ◽  
France Varin
Keyword(s):  
Rate Constant ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Quantitative Model ◽  
Concentration Effect ◽  
Pharmacokinetic Parameters ◽  
Effect Compartment ◽  
Duration Of Action ◽  
Arterial Blood ◽  
Effect Relation

Background The pharmacokinetics and pharmacodynamics of succinylcholine were studied simultaneously in anesthetized patients to understand why the drug has a rapid onset and short duration of action. A quantitative model describing the concentration-effect relation of succinylcholine was proposed. The correlation between hydrolysis in plasma and elimination was also examined. Methods Before induction of anesthesia, blood was drawn for analysis in seven adults. Anesthesia was induced with propofol and remifentanil. Single twitch stimulation was applied at the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis was measured. Arterial blood was drawn frequently after succinylcholine injection to characterize the front-end kinetics. Plasma concentrations were measured by mass spectrometry, and pharmacokinetic parameters were derived using compartmental and noncompartmental approaches. Pharmacokinetic-pharmacodynamic relations were estimated. Results The mean degradation rate constant in plasma (1.07 +/- 0.49 min(-1)) was not different from the elimination rate constant (0.97 +/- 0.30 min(-1)), and an excellent correlation (r2 = 0.94) was observed. Total body clearance derived using noncompartmental (37 +/- 7 ml x min(-1) x kg(-1)) and compartmental (37 +/- 9 ml x min(-1) x kg(-1)) approaches were similar. The plasma-effect compartment equilibration rate constant (k(eo)) was 0.058 +/- 0.026 min(-1), and the effect compartment concentration at 50% block was 734 +/- 211 ng/ml. Conclusion Succinylcholine is a low-potency drug with a very fast clearance that equilibrates relatively slowly with the effect compartment. Its disappearance is greatly accountable by a rapid hydrolysis in plasma.

Nondepolarizing muscle relaxants for surgery in myasthenic patients

2009 ◽  
Author(s):  
Idoris Cordero Escobar ◽  
Javier Espinaco Vald��s ◽  
Angela R Gutierrez Rojas ◽  
Nicolas Parisi L��pez ◽  
Rosa E Jimenez
Keyword(s):  
Muscle Relaxants ◽  
Nondepolarizing Muscle Relaxants

Nondepolarizing muscle relaxants for surgery in myasthenic patients

2007 ◽  
Author(s):  
I Cordero Escobar ◽  
J Espinaco Vald��s ◽  
AR Gutierrez Rojas ◽  
RE Jimenez Paneca ◽  
N Parisi L��pez
Keyword(s):  
Muscle Relaxants ◽  
Nondepolarizing Muscle Relaxants

scholarly journals Kinetic and Microhydrodynamic Modeling of Fenofibrate Nanosuspension Production in a Wet Stirred Media Mill

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1055
Author(s):  
Gulenay Guner ◽  
Dogacan Yilmaz ◽  
Ecevit Bilgili
Keyword(s):  
Rate Constant ◽  
Kinetic Models ◽  
Multiple Linear Regression Model ◽  
Empirical Correlation ◽  
P Value ◽  
Order Kinetic ◽  
Stirrer Speed ◽  
Predictive Capability ◽  
Breakage Rate ◽  
The Impact

This study examined the impact of stirrer speed and bead material loading on fenofibrate particle breakage during wet stirred media milling (WSMM) via three kinetic models and a microhydrodynamic model. Evolution of median particle size was tracked via laser diffraction during WSMM operating at 3000–4000 rpm with 35–50% (v/v) concentration of polystyrene or zirconia beads. Additional experiments were performed at the center points of the above conditions, as well as outside the range of these conditions, in order to test the predictive capability of the models. First-order, nth-order, and warped-time kinetic models were fitted to the data. Main effects plots helped to visualize the influence of the milling variables on the breakage kinetics and microhydrodynamic parameters. A subset selection algorithm was used along with a multiple linear regression model (MLRM) to delineate how the breakage rate constant k was affected by the microhydrodynamic parameters. As a comparison, a purely empirical correlation for k was also developed in terms of the process/bead parameters. The nth-order model was found to be the best model to describe the temporal evolution; nearly second-order kinetics (n ≅ 2) was observed. When the process was operated at a higher stirrer speed and/or higher loading with zirconia beads as opposed to polystyrene beads, the breakage occurred faster. A statistically significant (p-value ≤ 0.01) MLRM of three microhydrodynamic parameters explained the variation in the breakage rate constant best (R2 ≥ 0.99). Not only do the models and the nth-order kinetic–microhydrodynamic correlation enable deeper process understanding toward developing a WSMM process with reduced cycle time, but they also provide good predictive capability, while outperforming the purely empirical correlation.

scholarly journals Independent and combined impact of hypoxia and acute inorganic nitrate ingestion on thermoregulatory responses to the cold

2021 ◽  
Vol 121 (4) ◽  
pp. 1207-1218
Author(s):  
Josh T. Arnold ◽  
Stephen J. Bailey ◽  
Simon G. Hodder ◽  
Naoto Fujii ◽  
Alex B. Lloyd
Keyword(s):  
Blood Flow ◽  
Cooling Rate ◽  
Skin Blood Flow ◽  
Rectal Temperature ◽  
Onset Time ◽  
Rate Of Change ◽  
Vascular Control ◽  
Delta Change ◽  
Core Cooling ◽  
The Impact

Abstract Purpose This study assessed the impact of normobaric hypoxia and acute nitrate ingestion on shivering thermogenesis, cutaneous vascular control, and thermometrics in response to cold stress. Method Eleven male volunteers underwent passive cooling at 10 °C air temperature across four conditions: (1) normoxia with placebo ingestion, (2) hypoxia (0.130 FiO2) with placebo ingestion, (3) normoxia with 13 mmol nitrate ingestion, and (4) hypoxia with nitrate ingestion. Physiological metrics were assessed as a rate of change over 45 min to determine heat loss, and at the point of shivering onset to determine the thermogenic thermoeffector threshold. Result Independently, hypoxia expedited shivering onset time (p = 0.05) due to a faster cooling rate as opposed to a change in central thermoeffector thresholds. Specifically, compared to normoxia, hypoxia increased skin blood flow (p = 0.02), leading to an increased core-cooling rate (p = 0.04) and delta change in rectal temperature (p = 0.03) over 45 min, yet the same rectal temperature at shivering onset (p = 0.9). Independently, nitrate ingestion delayed shivering onset time (p = 0.01), mediated by a change in central thermoeffector thresholds, independent of changes in peripheral heat exchange. Specifically, compared to placebo ingestion, no difference was observed in skin blood flow (p = 0.5), core-cooling rate (p = 0.5), or delta change in rectal temperature (p = 0.7) over 45 min, while nitrate reduced rectal temperature at shivering onset (p = 0.04). No interaction was observed between hypoxia and nitrate ingestion. Conclusion These data improve our understanding of how hypoxia and nitric oxide modulate cold thermoregulation.

scholarly journals Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

2015 ◽  
Vol 59 (6) ◽  
pp. 3501-3508 ◽  
Author(s):  
Gina S. El-Feky ◽  
Wael S. Mohamed ◽  
Hanaa E. Nasr ◽  
Naglaa M. El-Lakkany ◽  
Sayed H. Seif el-Din ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Rate Constant ◽  
Elimination Rate ◽  
New Drugs ◽  
Egg Load ◽  
Potential Cost ◽  
Time Curve ◽  
Content Type ◽  
Mmt Clay

ABSTRACTConsideration of existing compounds always simplifies and shortens the long and difficult process of discovering new drugs specifically for diseases of developing countries, an approach that may add to the significant potential cost savings. This study focused on improving the biological characteristics of the already-existing antischistosomal praziquantel (PZQ) by incorporating it into montmorillonite (MMT) clay as a delivery carrier to overcome its known bioavailability drawbacks. The oral bioavailability of a PZQ-MMT clay nanoformulation and itsin vivoefficacy againstSchistosoma mansoniwere investigated. The PZQ-MMT clay nanoformulation provided a preparation with a controlled release rate, a decrease in crystallinity, and an appreciable reduction in particle size. Uninfected and infected mice treated with PZQ-MMT clay showed 3.61- and 1.96-fold and 2.16- and 1.94-fold increases, respectively, in area under the concentration-time curve from 0 to 8 h (AUC0–8) and maximum concentration of drug in serum (Cmax), with a decrease in elimination rate constant (kel) by 2.84- and 1.35-fold and increases in the absorption rate constant (ka) and half-life (t1/2e) by 2.11- and 1.51-fold and 2.86- and 1.34-fold, respectively, versus the corresponding conventional PZQ-treated groups. This improved bioavailability has been expressed in higher efficacy of the drug, where the dose necessary to kill 50% of the worms was reduced by >3-fold (PZQ 50% effective dose [ED50] was 20.25 mg/kg of body weight for PZQ-MMT clay compared to 74.07 mg/kg for conventional PZQ), with significant reduction in total tissue egg load and increase in total immature, mature, and dead eggs in most of the drug-treated groups. This formulation showed better bioavailability, enhanced antischistosomal efficacy, and a safer profile despite the longer period of residence in the systemic circulation. Although the conventional drug's toxicity was not examined, animal mortality rates were not different between groups receiving the test PZQ-clay nanoformulation and conventional PZQ.

scholarly journals Impact of uncertainties in inorganic chemical rate constants on tropospheric composition and ozone radiative forcing

2017 ◽  
Author(s):  
Ben Newsome ◽  
Mat Evans
Keyword(s):  
Rate Constant ◽  
Atmospheric Chemistry ◽  
Rate Constants ◽  
Tropospheric Ozone ◽  
Radiative Forcing ◽  
Transport Model ◽  
Surface Ozone ◽  
Photolysis Rates ◽  
The Impact ◽  
Chemical Rate

Abstract. Chemical rate constants determine the composition of the atmosphere and how this composition has changed over time. They are central to our understanding of climate change and air quality degradation. Atmospheric chemistry models, whether online or offline, box, regional or global use these rate constants. Expert panels synthesise laboratory measurements, making recommendations for the rate constants that should be used. This results in very similar or identical rate constants being used by all models. The inherent uncertainties in these recommendations are, in general, therefore ignored. We explore the impact of these uncertainties on the composition of the troposphere using the GEOS-Chem chemistry transport model. Based on the JPL and IUPAC evaluations we assess 50 mainly inorganic rate constants and 10 photolysis rates, through simulations where we increase the rate of the reactions to the 1σ upper value recommended by the expert panels. We assess the impact on 4 standard metrics: annual mean tropospheric ozone burden, surface ozone and tropospheric OH concentrations, and tropospheric methane lifetime. Uncertainty in the rate constants for NO2 + OH    M →  HNO3, OH + CH4 → CH3O2 + H2O and O3 + NO → NO2 + O2 are the three largest source of uncertainty in these metrics. We investigate two methods of assessing these uncertainties, addition in quadrature and a Monte Carlo approach, and conclude they give similar outcomes. Combining the uncertainties across the 60 reactions, gives overall uncertainties on the annual mean tropospheric ozone burden, surface ozone and tropospheric OH concentrations, and tropospheric methane lifetime of 11, 12, 17 and 17 % respectively. These are larger than the spread between models in recent model inter-comparisons. Remote regions such as the tropics, poles, and upper troposphere are most uncertain. This chemical uncertainty is sufficiently large to suggest that rate constant uncertainty should be considered when model results disagree with measurement. Calculations for the pre-industrial allow a tropospheric ozone radiative forcing to be calculated of 0.412 ± 0.062 Wm−2. This uncertainty (15 %) is comparable to the inter-model spread in ozone radiative forcing found in previous model-model inter-comparison studies where the rate constants used in the models are all identical or very similar. Thus the uncertainty of tropospheric ozone radiative forcing should expanded to include this additional source of uncertainty. These rate constant uncertainties are significant and suggest that refinement of supposedly well known chemical rate constants should be considered alongside other improvements to enhance our understanding of atmospheric processes.

Validation of a Migraine Work and Productivity Loss Questionnaire for use in Migraine Studies

Cephalalgia ◽  
1999 ◽  
Vol 19 (5) ◽  
pp. 497-502 ◽  
Author(s):  
GM Davies ◽  
N Santanello ◽  
W Gerth ◽  
D Lerner ◽  
GA Block
Keyword(s):  
Functional Disability ◽  
Productivity Loss ◽  
Rapid Onset ◽  
Paid Work ◽  
Open Label ◽  
Migraine Therapy ◽  
Work Related ◽  
Productivity Losses ◽  
Open Label Extension ◽  
The Impact

Migraine symptoms and therapy side effects cause significant functional disability that can result in work and productivity losses. Effective, well-tolerated migraine therapy with rapid onset of relief could decrease work and productivity losses. The Migraine Work and Productivity Loss Questionnaire (MWPLQ) evaluates the impact of migraine and migraine therapy on paid work. Data from a randomized, open-label extension study were collected over 3 months. Migraineurs were randomized to either rizatriptan (5HT1B/1D receptor agonist) or their usual migraine therapy. Data were analyzed from 164 patients who experienced at least one work-related migraine. Internal consistency (Cronbach's α) for the work difficulty domains ranged from 0.80 to 0.95. Work loss and work difficulty were moderately correlated ( r=0.39-0.58) with migraine severity and functional ability. Differences were found favoring rizatriptan for absenteeism (1.3 vs 2.4 h), effectiveness at work (62% vs 49%), and difficulty with work-related tasks ( p < 0.01). The MWPLQ demonstrated favorable measurement characteristics in this study and could be an important research tool for future evaluations of migraine-related work disability.

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