Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals

1995 ◽  
Vol 268 (1) ◽  
pp. R85-R91 ◽  
Author(s):  
G. A. Gronert ◽  
D. L. Fung ◽  
J. H. Jones ◽  
S. L. Shafer ◽  
S. V. Hildebrand ◽  
...  

We investigated the effects of body size on the pharmacokinetics and pharmacodynamics of the renally cleared muscle relaxant metocurine. We hypothesized that pharmacokinetics of the drug would change allometrically in proportion to physiological time [infinity Mb0.25, where Mb is body mass] and that pharmacodynamics would be independent of size because of the highly conserved structure of the acetylcholine receptor. Metocurine effects during general anesthesia were examined in 17 rats, 8 cats, 6 dogs, 5 pigs, 7 sheep, and 12 horses. Allometric analysis demonstrated size dependence for pharmacokinetics, which were affected by physiological time (Mb0.25). Pharmacodynamics were size independent, except for the value for effect compartment concentration associated with 50% twitch paralysis (IC50). Data from individual species had a bimodal distribution that was significant: pigs and sheep were more sensitive than other large species, and their IC50 appeared size independent. IC50 was size dependent in more active species (horse, dog, cat, rat). Although the mechanism is unknown, we speculate that this trend might relate to receptor density within the end plate. Thus pharmacokinetics changed in proportion to physiological time, and pharmacodynamics were in part size independent.

2021 ◽  
Vol 12 ◽  
Author(s):  
Li-Xiang Ye ◽  
Hui-Hui Huang ◽  
Shui-Hua Zhang ◽  
Jing-Shan Lu ◽  
Da-Xuan Cao ◽  
...  

Koumine (KM), the most abundant alkaloid in Gelsemium elegans, has anti-neuropathic, anti-inflammatory, and analgesic activities; thus, it has the potential to be developed as a broad-spectrum analgesic drug. However, factors determining the relationship between analgesic efficacy and the corresponding plasma KM concentration are largely unclear. The pharmacokinetics and pharmacodynamics of KM and their optimization in the context of neuropathic pain have not been reported. We investigated the pharmacokinetics and pharmacodynamics of KM after oral administration in a streptozotocin-induced rat model of diabetic neuropathic pain (DNP) using a population approach. A first-order absorption and elimination pharmacokinetics model best described the plasma KM concentration. This pharmacokinetic model was then linked to a linear pharmacodynamic model with an effect compartment based on the measurement of the mechanical withdrawal threshold. KM was rapidly absorbed (time to maximum plasma concentration: 0.14–0.36 h) with similar values in both DNP and naïve rats, suggesting that DNP did not influence the KM absorption rate. However, the area under the curve (AUC0–∞) of KM in DNP rats was over 3-fold higher than that in naïve rats. The systemic clearance rate and volume of KM distribution were significantly lower in DNP rats than in naïve rats. Blood glucose value prior to KM treatment was a significant covariate for the systemic clearance rate of KM and baseline value of the threshold. Our results suggest that streptozotocin-induced hyperglycemia is an independent factor for decreased KM elimination and its anti-allodynic effects in a DNP rat model. To the best of our knowledge, this is the first study to investigate the role of DNP in the pharmacokinetics and pharmacokinetics-pharmacodynamics of KM in streptozotocin-induced diabetic rats.


1998 ◽  
Vol 4 (2) ◽  
pp. 155 ◽  
Author(s):  
G. W. Arnold ◽  
J. R. Weeldenburg

The numbers of species, and the frequency of occurrence of individual species, in patches of Gimlet Eucalyptus salubris woodland in remnants of native vegetation in the central wheatbelt of Western Australia were recorded over a year. These values were examined in relation to the structural characteristics of the patches and the biogeographic attributes of the remnants (i.e., size and various indices of isolation from other native vegetation). There were five patches in large remnants (>100 ha) and 24 patches in small remnants (0.5?27.0 ha). Most of the small remnants were grazed by livestock and had lost much or all of the shrub understorey. The Galah Cacatua roseicapilla and Port Lincoln Ringnecked Parrot Platycercus zonarius were found in all patches, but the remaining large species of birds (Australian Raven Corvus coronoides,Pied Butcherbird Cracticus nigroregularis, Crested Pigeon Ocyphaps lophotes, and Yellow-throated Miner Manorina flavigula) were found more frequently in patches in small remnants. Conversely, with the exception of the Striated Pardalote Pardalotus striatus, small passerine species were found less frequently in patches in small remnants. Remnant size was significantly negatively correlated with frequency of occurrence of six of the eight common large species, indicating that these species concentrated in patches in small remnants, and significantly positively correlated with frequency of occurrence of two of four small passerine species. Having taken out the effect of remnant area, a stepwise regression procedure was used to see whether other biogeographic attributes of the remnants or habitat structure in the patches influenced the frequency of occurrence of individual species and species richness. As area of native vegetation within a 5 km radius increased so did the frequency of occurrence of the Galah and Port Lincoln Parrot, indicating that local numbers of the species affects their presence. Of the large birds only the Yellowthroated Miner was influenced by patch structural attributes whereas all species of small passerines showed responses to various structural attributes of the patches. Frequency of occurrence of the Striated Pardalote and the number of species of small passerines in a patch decreased with increasing distance to the nearest native vegatation. Overall frequency of occurence of small passerines increased with the number of linear strips of native vegetation linked to a remnant. In this study a majority of the small remnants were too small to support resident birds. The Gimlet patches, if used, would be part of a home range. Loss of the shrub understorey through grazing and loss of canopy cover through tree deaths had a significant impact on numbers of species of small passerines using the Gimlet patches. The conservation value of the patches in small remnants would be enhanced by increasing remnant size and by the linking of remnants to nearby native vegetation.


1984 ◽  
Vol 41 (4) ◽  
pp. 613-637 ◽  
Author(s):  
K. Patalas ◽  
A. Salki

Planktonic crustaceans in Southern Indian Lake were surveyed in 1972 before impoundment, during 1975 when water levels rose above the recorded high level, and then annually from 1977 to 1980 after full impoundment and diversion. Synoptic data were collected in each of these years in midsummer during July or August from a set of 53 stations covering all regions of the lake. Vertical hauls were made at each station using twin nets of 77-μm mesh and 25-cm mouth diameter. In 1972, the crustacean plankton fauna of Southern Indian Lake was composed mainly of 15 copepod and 15 cladoceran species. At least 25 of these species were truly pelagic, while 5 were littoral. Cyclopoids comprised 46% of total crustacean abundance, calanoids 33%, and cladocerans 21%. Dominant species within these three groups were Cyclops bicuspidatus thomasi (37.6% of total abundance), Diaptomus ashlandi (20.1%), and Chydorus sphaericus (8.9%). Total abundance averaged 76 individuals (ind)∙L−1, comparable to more southerly waters such as Lake Ontario (80 ind∙L−1) and Lake Winnipeg (53–108 ind∙L−1) (K. Patalas. 1975. Int. Ver. Limnol. Verh. 19: 504–511). Throughout the lake, total crustacean abundances varied from 10 ind∙L−1 near the Churchill River inflow to between 100 and 200 ind∙L−1 in a few well protected areas. From 50 to 100 ind∙L−1 occurred within the main body of Southern Indian Lake. In 1975, an unusually high water year, lake mean plankton abundance was 61 ind∙L−1. Following diversion in 1976, no dramatic changes in species composition were observed. However, the mean abundance of crustaceans decreased to 40–46 ind∙L−1 during the period 1977–80. Regional zooplankton responses were varied. No significant changes occurred in areas adjacent to the Churchill River inflow, with pre- and post-diversion densities being 35 and 36 ind∙L−1, respectively. In the main water bodies north of the diversion route, abundances declined by 60% and biomass by 50%. A 2–3 °C drop in northern basin water temperatures, related to diversion, reduced growth rates by approximately 20% and resulted in a 60% decline in crustacean production. Not all groups of crustaceans responded similarily to impoundment and diversion. Lakewide average numbers of cladocerans declined from 16 to 4 ind∙L−1 and the area of their distribution was reduced particularly in northern regions of the lake following impoundment. Cyclopoids declined from 35 to 16 ind∙L−1 but showed no change in their distribution. These reductions were related to decreased water temperatures, lower midsummer chlorophyll a concentrations, and decreased water transparencies. The mean abundance of calanoids as a group did not change, but the abundance and distribution of individual species were variably altered. Smaller calanoid species showed either no change or a decrease in their numbers and distribution. Larger species, e.g. Limnocalanus macrurus, Senecella calanoides, and Diaptomus sicilis, were significantly more abundant and widespread following diversion. Similar increases in Mysis relicta were also observed. These large species, preferred food items for both whitefish and cisco, are cold stenotherms, inhabiting deeper water layers. Their increased abundance is likely associated with decreased water transparency offering better protection against predatory fish, decreased water temperature creating more favorable conditions, and increased water depth enlarging the volume of deeper waters suitable for these species.


2000 ◽  
Vol 92 (6) ◽  
pp. 1581-1587 ◽  
Author(s):  
Doris Østergaard ◽  
Søren N. Rasmussen ◽  
Jørgen Viby-Mogensen ◽  
Niels A. Pedersen ◽  
Rikke Boysen

Background The short duration of action of mivacurium results from its rapid hydrolysis by plasma cholinesterase. Bambuterol, an oral bronchodilator, has an inhibiting effect on plasma cholinesterase. The purpose of this study was to evaluate the effect of bambuterol-induced low plasma cholinesterase activity on the pharmacokinetics and pharmacodynamics of mivacurium. Methods Fourteen patients received 20 mg bambuterol and 14 patients received placebo orally 2 h before induction of anesthesia. During anesthesia the neuromuscular block was monitored at the thumb using train-of-four nerve stimulation every 12 s and mechanomyography. The times to different levels of neuromuscular recovery after 0.2 mg/kg mivacurium were measured. The concentrations in venous blood of the three isomers and the metabolites of mivacurium were measured using high-performance liquid chromatography. Results Plasma cholinesterase activity was inhibited a median of 90% (range, 67-97%) after bambuterol. The time to first response to train-of-four nerve stimulation was 15 min (range, 9-21 min) and 59 min (range, 32-179 min) in patients receiving placebo and bambuterol, respectively. The estimated clearances of the isomers were significantly lower and the elimination half-lives of all three isomers significantly prolonged in patients receiving bambuterol. No difference was seen in elimination half-lives of the metabolites. The elimination rate constant from the effect compartment and the potency of mivacurium was not affected by bambuterol. Conclusion A 90% inhibition of plasma cholinesterase activity significantly reduced clearance of the isomers of mivacurium. Correspondingly, the duration of action of 0.2 mg/kg mivacurium was prolonged three- to fourfold, compared with patients not administered bambuterol.


2020 ◽  
Vol 47 (6) ◽  
pp. 583-596
Author(s):  
Agnieszka Bienert ◽  
Paweł Sobczyński ◽  
Katarzyna Młodawska ◽  
Roma Hartmann-Sobczyńska ◽  
Edmund Grześkowiak ◽  
...  

Abstract Cardiac output (CO) is expected to affect elimination and distribution of highly extracted and perfusion rate-limited drugs. This work was undertaken to quantify the effect of CO measured by the pulse pressure method on pharmacokinetics and pharmacodynamics of propofol and fentanyl administrated during total intravenous anesthesia (TIVA). The data were obtained from 22 ASA III patients undergoing abdominal aortic surgery. Propofol was administered via target-controlled infusion system (Diprifusor) and fentanyl was administered at a dose of 2–3 µg/kg each time analgesia appeared to be inadequate. Hemodynamic measurements as well as bispectral index were monitored and recorded throughout the surgery. Data analysis was performed by using a non-linear mixed-effect population modeling (NONMEM 7.4 software). Three compartment models that incorporated blood flows as parameters were used to describe propofol and fentanyl pharmacokinetics. The delay of the anesthetic effect, with respect to plasma concentrations, was described using a biophase (effect) compartment. The bispectral index was linked to the propofol and fentanyl effect site concentrations through a synergistic Emax model. An empirical linear model was used to describe CO changes observed during the surgery. Cardiac output was identified as an important predictor of propofol and fentanyl pharmacokinetics. Consequently, it affected the depth of anesthesia and the recovery time after propofol-fentanyl TIVA infusion cessation. The model predicted (not observed) CO values correlated best with measured responses. Patients‘ age was identified as a covariate affecting the rate of CO changes during the anesthesia leading to age-related difference in individual patient’s responses to both drugs.


2015 ◽  
Vol 5 (4) ◽  
pp. 2358-2365 ◽  
Author(s):  
Zhengzheng Yang ◽  
Jun Li ◽  
Hailong Zhang ◽  
Yi Yang ◽  
Maochu Gong ◽  
...  

Small platinum oxide particles are beneficial for forming Pt0active species under diesel exhaust conditions, hence showing better DOC reactivity.


Paleobiology ◽  
2020 ◽  
Vol 46 (4) ◽  
pp. 478-494
Author(s):  
Indrė Žliobaitė ◽  
Mikael Fortelius

AbstractThe Red Queen's hypothesis portrays evolution as a never-ending competition for expansive energy, where one species’ gain is another species’ loss. The Red Queen is neutral with respect to body size, implying that neither small nor large species have a universal competitive advantage. Here we ask whether, and if so how, the Red Queen's hypothesis really can accommodate differences in body size. The maximum population growth in ecology clearly depends on body size—the smaller the species, the shorter the generation length, and the faster it can expand given sufficient opportunity. On the other hand, large species are more efficient in energy use due to metabolic scaling and can maintain more biomass with the same energy. The advantage of shorter generation makes a wide range of body sizes competitive, yet large species do not take over. We analytically show that individuals consume energy and reproduce in physiological time, but need to compete for energy in real time. The Red Queen, through adaptive evolution of populations, balances the pressures of real and physiological time. Modeling competition for energy as a proportional prize contest from economics, we further show that Red Queen's zero-sum game can generate unimodal hat-like patterns of species rise and decline that can be neutral in relation to body size.


1987 ◽  
Vol 111 ◽  
Author(s):  
N. Selamoglu ◽  
J. A. Mucha ◽  
D. L. Flamm ◽  
D. E. Ibbotson

AbstractThe copper catalyzed fluorination of silicon is first-order in [F2] and in [Cu]s until the coverage reaches ∼4 monolayers. Above ∼4 monolayers the reaction rate is zero order in copper, suggesting a limited number of catalytically active Cu/Si sites. Surface diffusion of copper leads to decrease in the etch rate as a function of time as well as feature size-dependent etch depths. The copper compounds CuF2, CuO, and copper silicides, Cu5 Si and Cu3 Si all catalyzed the F2-Si reaction which suggests that they are all converted to the same active species. The results can be explained by mechanisms involving copper fluorides or copper silicides as active intermediates.


Author(s):  
Ana Cristina Franzoi ◽  
Gledir T. Stein Martins ◽  
Sérgio Duvoisin Jr. ◽  
Bruno Szpoganicz

Kinetic studies of hydrolysis and deuteration of glycylglycine by dinuclear [BMXDCu 2]4+ complexes were following by NMR1H. Two parallel reactions were observed for the ternary system BMXD-Cu 2-Glycylglycine: peptide bond hydrolysis and NCH2 deuteration reactions. The reaction rates show the first-order behavior to the concentration of the ternary [BMXDCu2Glycylglycine] complex. The specific rate constants for the hydrolysis reaction are: KLCu2HGG4+ (L = BMXD and GG = glycylglycine) = 1,8 x 10-6 s-1; KLCu 2GG3+ = 2,3 x 10-6 s-1; KLCu2H-1GG2+, KLCu 2(OH)H-1GG+ and KLCu 2(OH) 2H-1GG = 0, and the specific deuteration rate constants for individual species are: KLCu 2HGG4+ = 3,9 x 10-6 s-1; KLCu 2GG3+ = 4,3 x 10-6 s-1; KLCu2H-1GG2+, KLCu2(OH)H-1GG+ and KLCu2(OH)2H-1GG = 0. The results show that the most active species toward hydrolysis and deuteration reactions are the protonated and non-protonated species, the former being the most reactive species. Semi-empirical calculations for energy minimization showed that the binuclear [BMXDCu 2]4+) complexes adopt the boat-type conformation, in order to accommodate the dipeptide glycylglycine.


1990 ◽  
Vol 267 (1) ◽  
pp. 197-202 ◽  
Author(s):  
M Potier ◽  
L Michaud ◽  
J Tranchemontagne ◽  
L Thauvette

Lysosomal neuraminidase (sialidase; EC 3.2.1.18) and beta-galactosidase (EC 3.2.1.23), together with a carboxypeptidase, the so-called ‘protective protein’, were co-purified from the human placenta by affinity chromatography on a concanavalin A-Sepharose column followed by a thiogalactoside-agarose affinity column for beta-galactosidase. Analysis of the purified material by gel-filtration h.p.l.c. revealed three distinct molecular forms, all with high beta-galactosidase specific activity, but only the largest one expressed neuraminidase activity. Rechromatography of each individual species separately indicated that all three are in fact part of an equilibrium system (the neuraminidase-beta-galactosidase-carboxypeptidase complex or NGC-complex) and that these species undergo slow conversion into one another through dissociation and association of protomeric components. Each species was sufficiently stable for the determination of their hydrodynamic properties by gel-filtration h.p.l.c. and sedimentation velocity. The largest species had an apparent sedimentation coefficient S20.w, of 18.8 S and a Stokes' radius of 8.5 nm, giving a molecular mass of 679 kDa and a fractional ratio, f/f min, of 1.47. The latter value indicates that the macromolecule is asymmetric or highly hydrated. This large species is composed of four types of polypeptide chains of molecular mass 66 kDa (neuraminidase), 63 kDa (beta-galactosidase), 32 kDa and 20 kDa (carboxypeptidase heterodimer). The 32 kDa and 20 kDa protomers are linked together by a disulphide bridge. Glycopeptidase F digestion of the NGC-complex transformed the diffuse 66-63 kDa band on the SDS gel into two close but sharp bands at 58 and 56 kDa. The two smaller species which were separated on the h.p.l.c. column correspond to tetrameric and dimeric forms of the 66-63 kDa protomers and express exclusively beta-galactosidase activity. Treatment of the NGC-complex with increasing concentrations of guanidinium hydrochloride up to 1.5 M also resulted in dissociation of the complex into the same smaller species mentioned above plus two protomers of molecular mass around 60 and 50 kDa. A model of the largest molecular species as a hexamer of the 66-63 kDa protomers associated to five carboxypeptidase heterodimers (32 kDa and 20 kDa) is proposed


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