scholarly journals A COMPARISON OF THE RESPONSES OF THE TENUISSIMUS MUSCLE TO NEUROMUSCULAR BLOCKING DRUGS IN VIVO AND IN VITRO

1962 ◽  
Vol 18 (1) ◽  
pp. 204-216 ◽  
Author(s):  
JENNIFER MACLAGAN
Keyword(s):  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Drugs

Cholinesterase Inhibition by Potato Glycoalkaloids Slows Mivacurium Metabolism

2000 ◽  
Vol 93 (2) ◽  
pp. 510-519 ◽  
Author(s):  
Daniel S. McGehee ◽  
Matthew D. Krasowski ◽  
Dennis L. Fung ◽  
Barry Wilson ◽  
Gerald A. Gronert ◽  
...  
Keyword(s):  
Cholinesterase Inhibitors ◽  
Neuromuscular Blocking ◽  
Dietary Factors ◽  
Serum Cholinesterase ◽  
Cholinesterase Inhibition ◽  
Duration Of Action ◽  
Neuromuscular Blocking Drugs ◽  
Enzyme Systems

Background The duration of action for many pharmaceutical agents is dependent on their breakdown by endogenous hydrolytic enzymes. Dietary factors that interact with these enzyme systems may alter drug efficacy and time course. Cholinesterases such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyze and inactivate several anesthetic drugs, including cocaine, heroin, esmolol, local ester anesthetics, and neuromuscular blocking drugs. Natural glycoalkaloid toxins produced by plants of the family Solanaceae, which includes potatoes and tomatoes, inhibit both AChE and BuChE. Here the authors assess the extent to which two solanaceous glycoalkaloids (SGAs), alpha-solanine and alpha-chaconine, can alter the effects of neuromuscular blocking drugs and cholinesterase inhibitors in vivo and in vitro. Methods Inhibition of purified human AChE and BuChE by SGAs, neuromuscular blocking drugs, and cholinesterase inhibitors was assessed by an in vitro colorimetric cholinesterase assay. In vivo experiments were carried out using anesthetized rabbits to test whether SGAs affect recovery from mivacurium-induced paralysis. Results SGAs inhibited human BuChE at concentrations similar to those found in serum of individuals who have eaten a standard serving of potatoes. Coapplication of SGAs (30-100 nm) with neuromuscular blocking drugs and cholinesterase inhibitors produced additive cholinesterase inhibition. SGA administration to anesthetized rabbits inhibited serum cholinesterase activity and mivacurium hydrolysis. In addition, SGA prolonged the time needed for recovery from mivacurium-induced paralysis (149 +/- 12% of control; n = 12). Conclusions These findings support the hypothesis that inhibition of endogenous enzyme systems by dietary factors can influence anesthetic drug metabolism and duration of action. Diet may contribute to the wide variation in recovery time from neuromuscular blockade seen in normal, healthy individuals.

scholarly journals On the relationship between inhibition and receptor occupancy by nondepolarizing neuromuscular blocking drugs

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Hikaru Hoshino ◽  
Eiko Furutani
Keyword(s):  
Receptor Binding ◽  
Receptor Occupancy ◽  
Neuromuscular Blocking ◽  
In Vitro Experiments ◽  
Binding Model ◽  
Neuromuscular Blocking Drugs ◽  
The Relationship ◽  
Nondepolarizing Neuromuscular Blocking Drugs

Abstract Background Nondepolarizing neuromuscular blocking drugs (NDNBs) are clinically used to produce muscle relaxation during general anesthesia. To better understand clinical properties of NDNBs, comparative in vitro pharmacologic studies have been performed. In these studies, a receptor binding model, which relies on the assumption that the inhibition, i.e., the effect of an NDNB, is proportional to the receptor occupancy by the drug, has been effectively used to describe obtained experimental data. However, it has not been studied in literature under which conditions the above assumption can be justified nor the assumption still holds in vivo. The purpose of this study is to explore the in vivo relationship between the inhibition and the receptor occupancy by an NDNB and to draw implications on how in vitro experimental results can be used to discuss the in vivo properties of NDNBs. Methods An ordinary differential equation model is employed to simulate physiologic processes of the activation of receptors by acetylcholine (ACh) as well as inhibition by an NDNB. With this model, the degree of inhibition is quantified by the fractional amount of receptors that are not activated by ACh due to the presence of an NDNB. The results are visualized by plotting the fractional amounts of the activated receptors as a function of the receptor occupancy. Results Numerical investigations reflecting in vivo conditions show that the degree of inhibition is not proportional to the receptor occupancy, i.e., there is a nonlinear relationship between the inhibition and the receptor occupancy. However, under a setting of high concentration of ACh reflecting a typical situation of in vitro experiments, the relationship between the inhibition and the receptor occupancy becomes linear, suggesting the validity of the receptor binding model. Also, it is found that the extent of nonlinearity depends on the selectivity of NDNBs for the two binding sites of the receptors. Conclusions While the receptor binding model may be effective for estimating affinity of an NDNB through in vitro experiments, these models do not directly describe in vivo properties of NDNBs, because the nonlinearity between the inhibition and the receptor occupancy causes the modulation of the resultant concentration-effect relationships of NDNBs.

On the Relationship between Inhibition and Receptor Occupancy by Nondepolarizing Neuromuscular Blocking Drugs

2021 ◽  
Author(s):  
Hikaru Hoshino ◽  
Eiko Furutani
Keyword(s):  
Receptor Binding ◽  
Receptor Occupancy ◽  
Neuromuscular Blocking ◽  
In Vitro Experiments ◽  
Binding Model ◽  
Neuromuscular Blocking Drugs ◽  
The Relationship ◽  
Nondepolarizing Neuromuscular Blocking Drugs

Abstract Background: Nondepolarizing neuromuscular blocking drugs (NDNBs) are clinically used to produce muscle relaxation during general anesthesia. To better understand clinical properties of NDNBs, comparative in vitro pharmacologic studies have been performed. In these studies, a receptor binding model, which relies on the assumption that the inhibition, i.e., the e ect of an NDNB, is proportional to the receptor occupancy by the drug, has been effectively used to describe obtained experimental data. However, it has not been studied in literature under which conditions the above assumption can be justified nor the assumption still holds in vivo. The purpose of this study is to explore the in vivo relationship between the inhibition and the receptor occupancy by an NDNB and to draw implications on how in vitro experimental results can be used to discuss the in vivo properties of NDNBs. Methods: An ordinary di erential equation model is employed to simulate physiologic processes of the activation of receptors by acetylcholine (ACh) as well as inhibition by an NDNB. With this model, the degree of inhibition is quantified by the fractional amount of receptors that are not activated by ACh due to the presence of an NDNB. The results are visualized by plotting the fractional amounts of the activated receptors as a function of the receptor occupancy. Results: Numerical investigations reflecting in vivo conditions show that the degree of inhibition is not proportional to the receptor occupancy, i.e., there is a nonlinear relationship between the inhibition and the receptor occupancy. However, under a setting of high concentration of ACh reflecting a typical situation of in vitro experiments, the relationship between the inhibition and the receptor occupancy becomes linear, suggesting the validity of the receptor binding model. Also, it is found that the extent of nonlinearity depends on the selectivity of NDNBs for the two binding sites of the receptors. Conclusions: While the receptor binding model may be effective for estimating affinity of an NDNB through in vitro experiments, these models do not directly describe in vivo properties of NDNBs, because the nonlinearity between the inhibition and the receptor occupancy causes the modulation of the resultant concentration-effect relationships of NDNBs.

Preclinical Pharmacology of CW002

2016 ◽  
Vol 125 (4) ◽  
pp. 732-743 ◽  
Author(s):  
Hiroshi Sunaga ◽  
John J. Savarese ◽  
Jeff D. McGilvra ◽  
Paul M. Heerdt ◽  
Matthew R. Belmont ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Blocking Agent ◽  
Neuromuscular Blocking ◽  
Safety And Efficacy ◽  
Circulatory Effects ◽  
Autonomic Changes ◽  
Train Of Four

Abstract Background CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by l-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous l-cysteine.1 Further, Institutional Animal Care and Use Committee–approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described. Methods Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by l-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 × ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated. Results ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; l-cysteine readily antagonized block in monkeys: 5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 × ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 × ED95. Conclusions The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by l-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy.

scholarly journals Evaluation of the antimicrobial effects of atracurium, rocuronium and mivacurium. Antimicrobial effects of muscle relaxants

2010 ◽  
Vol 1 (1) ◽  
pp. 2 ◽  
Author(s):  
Volkan Hanci ◽  
Fusun Cömert ◽  
Hilal Ayoğlu ◽  
Canan Kulah ◽  
Serhan Yurtlu ◽  
...  
Keyword(s):  
Intensive Care ◽  
Antibacterial Effect ◽  
Neuromuscular Blocking ◽  
Antibacterial Effects ◽  
Minimum Concentration ◽  
Neuromuscular Blocking Drugs ◽  
Antimicrobial Effects ◽  
Anaesthetic Agents ◽  
Broth Microdilution Method

Some anaesthetic agents may be contaminated with microorganisms during the process of preparing an infusion. For this reason, it is important to understand the antimicrobial effects of various anaesthetic agents, which have been investigated to some degree in previous studies. However, studies specifically focusing on antibacterial effects of neuromuscular blocking drugs (anaesthetic agents) are very rare. Herein, we analysed the antimicrobial effects of atracurium, rocuronium, and mivacurium, on four different microorganisms. The in vitro antimicrobial activities of atracurium, rocuronium and mivacurium were investigated using the broth microdilution method. The pH of the test solutions was determined using a pH meter. The test microorganisms included Staphylococcus aureus ATCC 29213, Enterococcus fecalis ATCC 29212, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853. The pH of the test solutions ranged between 7.20 and 7.32. The minimum inhibitory concentrations of atracurium, rocuronium and mivacurium for S. auereus, E. fecalis, E. coli and P. Aeruginosa were all found to be 512 µg/mL. Atracurium, rocuronium and mivacurium inhibit the growth of common intensive care unit pathogens at the same concentration (512 µg.mL–1). Thus, the neuromuscular blocking drugs, atracurium, rocuronium and mivacurium should be administered at a minimum concentration of 512 µg/mL in intensive care units to achieve this antibacterial effect. In our opinion, when used systemically, atracurium, rocuronium and mivacurium do not cause a systemic antibacterial effect. However, their antibacterial effects may be advantageous for inhibiting the spread of bacterial contamination during the preparation of the infusion solutions.

Acyclic Cucurbit[n]uril-Type Molecular Containers Bind Neuromuscular Blocking Agents In Vitro and Reverse Neuromuscular Block In Vivo

2012 ◽  
Vol 124 (45) ◽  
pp. 11520-11524 ◽  
Author(s):  
Da Ma ◽  
Ben Zhang ◽  
Ulrike Hoffmann ◽  
Martina Grosse Sundrup ◽  
Matthias Eikermann ◽  
...  
Keyword(s):  
Neuromuscular Block ◽  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Agents ◽  
Blocking Agents

Acyclic Cucurbit[n]uril-Type Molecular Containers Bind Neuromuscular Blocking Agents In Vitro and Reverse Neuromuscular Block In Vivo

2012 ◽  
Vol 51 (45) ◽  
pp. 11358-11362 ◽  
Author(s):  
Da Ma ◽  
Ben Zhang ◽  
Ulrike Hoffmann ◽  
Martina Grosse Sundrup ◽  
Matthias Eikermann ◽  
...  
Keyword(s):  
Neuromuscular Block ◽  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Agents ◽  
Blocking Agents

scholarly journals Acyclic Cucurbit[n]uril-Type Containers as Receptors for Neuromuscular Blocking Agents

2019 ◽  
Vol 92 (2) ◽  
pp. 163-171
Author(s):  
David Shaya ◽  
Lyle Isaacs
Keyword(s):  
Water Solubility ◽  
Neuromuscular Block ◽  
Binding Constants ◽  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Agents ◽  
Optical Methods ◽  
Titration Calorimetry ◽  
Blocking Agents

Acyclic cucurbit[n]uril molecular containers 1 and 2C3 have previously been shown to strongly bind to the neuromuscular blocking agents rocuronium, vecuronium, pancuronium, and cisatracurium in vitro by optical methods and to reverse neuromuscular block in vivo in rats. In this paper we study the in vitro binding of a panel of acyclic CB[n]-type receptors toward the four neuromuscular blocking agents and acetylcholine to develop structure-binding affinity relationships. The selected variants include those with different aromatic sidewalls (e.g. 1Me4 with dimethyl o-xylylene walls; 3 with 1,8-linked naphthalene walls), with different glycoluril oligomer lengths (e.g. 4 and 5 based on glycoluril trimer), and with different linker lengths between aromatic wall and SO3- solubilizing group (e.g. 2C2–2C4). Based on the analysis of complexation induced changes in 1H NMR chemical shift we conclude that the hydrophobic regions of the guests bind in the hydrophobic cavity of the hosts with the cationic moieties of the guest binding at the ureidyl C=O portals by ion-dipole and ion-ion interactions. The thermodynamic parameters of binding were determined by direct and competition isothermal titration calorimetry experiments. We find that hosts 4 and 5 based on glycoluril trimer form significantly weaker complexes with the streroidal NMBAs than with the analogues hosts based on glycoluril tetramer (1 and 2C3). Similarly, hosts 1Me4 and 3 with different length and height aromatic walls do not exhibit the extreme binding constants displayed by 2C3 but rather behave similarly to 1. Finally, we find that hosts 2C2 and 2C4 bind only slightly more weakly to the NMBAs than 2C3, but retain the ability to discriminate against acetylcholine, and possess higher inherent water solubility than 2C3. Host 2C4, in particular, holds potential for future in vivo applications.

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