Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preliminary disposition studies of the investigational, long-acting muscle relaxant doxacurium chloride (Nuromax) have demonstrated dual elimination by renal and hepatobiliary pathways, as well as slow hydrolysis by plasma cholinesterase. The present study compares the kinetics and dynamics of doxacurium in eight ASA physical status I or II elderly patients (67-72 yr of age) and eight ASA I or II young patients (22-49 yr of age). After institutionally approved written informed consent, kinetic and dynamic measurements were made after a 25-micrograms/kg bolus injection of doxacurium during 1.25 MAC nitrous oxide/oxygen/isoflurane anesthesia. Maximum twitch depression was similar in older patients (96.4% +/- 1.3%) to that in the young patients (96.6% +/- 1.8%). The time to achieve this level of block was significantly longer in the elderly than in the young (11.2 +/- 1.1 min versus 7.7 +/- 1.0 min, respectively). Recovery times to twitch heights of 5% and 25% of control tended to be prolonged and were more variable in the elderly (82.6 +/- 17.2 and 97.1 +/- 20.1 min, respectively) than in the young (54.8 +/- 9 and 67.5 +/- 8.2 min, respectively). Elimination half-life (96 +/- 20 min) and clearance (2.47 +/- 0.69 mL.kg-1.min-1) in the elderly patients were not statistically different from values found in the younger group. Volume of distribution at steady state in the elderly (220 +/- 80.2 mL/kg) was significantly larger than in the young (150 +/- 40.0 mL/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia. 214 83

The present investigation reports the effect of chronic oral administration of mancozeb, a fungicide, on hepatic microsomal carboxylesterases/amidases or B-esterases responsible for hydrolytic metabolism of aspirin (acetylsalicylic acid or ASA) at pH 5.5 and 7.4, 2-acetylaminofluorene (AAF), acetanilide and p-nitrophenylacetate (NPA) and cholinesterase in rat. Oral administration of mancozeb (250 mg/kg/day) for 30 days caused significant stimulation of ASA esterase I (pH 5.5), ASA esterase II (pH 7.4), AAF N-deacetylase and acetanilide N-deacetylase in liver. However, the activities of NPA esterase and cholinesterase remained unaffected. Evaluation of induction kinetics demonstrated that the pattern and magnitude of responses of these microsomal hydrolases to mancozeb treatment for 7 days were comparable to those obtained after treatment for 30 days. The activities of hydrolases were not altered in animals killed 4 hr after an oral dose of mancozeb. Mancozeb did not affect these hydrolases in vitro.
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PMID:Effect of mancozeb on hydrolytic metabolism of xenobiotics. 227 66

Mivacurium chloride (BW B1090U), a bis-benzylisoquinolinium diester compound, was found to undergo hydrolysis in vitro by purified human plasma cholinesterase in a pH-stat titrator at 88% of the rate of succinylcholine at pH 7.4, 37 degrees C and 5 microM substrate concentration. In 72 consenting ASA Physical Status I-II patients receiving nitrous oxide/oxygen-narcotic-thiopental anesthesia, the neuromuscular blocking effect of mivacurium was assessed following bolus doses from 0.03 to 0.30 mg/kg, as well as during and following continuous infusions from 35 to 324 min in length. The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.08 mg/kg. At 0.1 mg/kg, 96% block developed, onset to maximum block required 3.8 +/- 0.5 min, and recovery to 95% twitch height occurred 24.5 +/- 1.6 (SE) min after injection. At 0.25 mg/kg, onset was 2.3 +/- 0.3 min; 95% recovery developed within 30.4 +/- 2.2 min, an increase in duration of action of only 24% versus 150% higher dosage. Comparative recovery indices from 5 to 95% or from 25 to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.3 mg/kg (range 12.9 to 14.7 and 6.6 to 7.2 min, respectively). In 38 patients who received mivacurium by continuous infusion (duration 88.1 +/- 7.1/47.1 min, SE/SD) for maintenance of 95 +/- 4% twitch inhibition, the mean 5-95% and 25-75% recovery indices after discontinuation of infusion were 14.4 +/- 0.6 and 6.5 +/- 0.3 min (P greater than 0.5 vs. all single bolus doses). The train-of-four (T4) ratio, within 2.6 +/- 0.5 min after 95% twitch recovery following bolus doses, averaged 79.5 +/- 1.8% (n = 32). Similarly, after discontinuation of infusions, the T4 ratio reached 73.4 +/- 1.9% within 3.4 +/- 1.9 min after 95% twitch recovery (n = 33). Antagonism of residual block was seldom indicated, but, to test ease of reversal, eight patients electively received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at 67 to 93 (76.6 +/- 3.5) % block. Twitch returned to 95% of control within 4.5 to 9.5 (6.3 +/- 0.5) min after neostigmine. Mivacurium may offer increased versatility in providing clinical muscle relaxation in a variety of situations. Further studies seem appropriate.
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PMID:The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). A short-acting nondepolarizing ester neuromuscular blocking drug. 296 39

Doxacurium chloride (BW A938U) is a bis-quaternary benzylisoquinolinium diester nondepolarizing neuromuscular blocking compound that is minimally hydrolyzed by human plasma cholinesterase. The effect of bolus doses of doxacurium ranging from 10 to 80 micrograms/kg were studied in 81 consenting ASA physical status I and II patients anesthetized with nitrous oxide-oxygen-fentanyl-thiopental. The neuromuscular and cardiovascular effects of doxacurium were compared with those of eight patients receiving 100 micrograms/kg of pancuronium receiving identical anesthesia. The calculated ED95 for evoked twitch inhibition of the adductor pollicis at 0.15 Hz was 30 micrograms/kg. At 1.3 times the ED95 dose of doxacurium, recovery times to 5% and 25% of control twitch height were 59.2 +/- 4.1 (n = 23 of 26) and 75.7 +/- 5.6 (n = 23 of 26) min respectively. For pancuronium comparable recovery times were 81.7 +/- 10.3 (n = 8 of 8) and 83.0 +/- 8.4 (n = 5 of 8) min. Residual doxacurium blockade was readily antagonized by neostigmine. No dose-related effect on heart rate or mean arterial pressure was seen with doxacurium at doses up to and including 2.7 times the ED95 (80 micrograms/kg). Doxacurium administration did not result in any elevation of plasma histamine at doses up to and including 2.7 times the ED95. In this study doxacurium appears to be a long-acting nondepolarizing relaxant with readily reversible neuromuscular blocking effects and devoid of cardiovascular effects. This profile offers clinical advantages over current long-acting agents and further clinical trials seem appropriate.
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PMID:Clinical pharmacology of doxacurium chloride. A new long-acting nondepolarizing muscle relaxant. 297 33

Blood samples were drawn from 10 ASA physical status 1 and 2 patients before (baseline) and after the administration of cimetidine to determine the in vivo effect of cimetidine on plasma cholinesterase (PCHE) activity. The in vitro effects of cimetidine at different plasma concentrations were also studied using the same blood samples. PCHE activity in the baseline samples was 432 +/- 4.6 (mean +/- SEM) U/ml, the dibucaine number 82. Administration of oral cimetidine (300 mg) the night before and 2 hours before surgery, failed to have any effect on PCHE activity (no in vivo effect). Plasma cholinesterase activity in the presence of cimetidine in vitro at plasma concentrations of 1.5, 15, 150, and 1500 micrograms/ml was 428, 420, 397, and 177 U/ml, respectively. Thus, in vitro data showed that cimetidine at plasma concentrations (1.5 to 15 micrograms/ml) achieved with clinical doses also has no effect on PCHE activity.
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PMID:Cimetidine does not affect plasma cholinesterase activity. 333 48

The in vitro effect of procainamide on plasma cholinesterase (PCHE) activity in the plasma of ten normal ASA physical status I patients was studied using a kinetic method. The mean plasma cholinesterase activity without procainamide (control) was 0.90 +/- 0.09 units.ml-1. The dibucaine numbers of all the samples were in the normal range of 78 to 86, indicating normal genotypes. The mean plasma cholinesterase activity, in the presence of procainamide in concentrations of 5.0, 10.0, 20.0 and 40.0 micrograms.ml-1, was reduced to 0.73 +/- 0.04, 0.61 +/- 0.03, 0.45 +/- 0.02, and 0.36 +/- 0.01 units.ml-1, respectively. At therapeutic concentrations of 4 to 12 micrograms.ml-1, procainamide inhibited cholinesterase activity 15 to 30 per cent. The authors also showed that the concentration of procainamide required to inhibit 50 per cent of plasma cholinesterase activity was 20 micrograms.ml-1 (I50). The authors conclude that procainamide when tested in vitro had a statistically significant depressant effect on plasma cholinesterase activity at all the concentrations studied.
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PMID:The effect of procainamide on plasma cholinesterase activity. 367 82

This study was designed to compare the effectiveness of antagonism of mivacurium blockade with either neostigmine, edrophonium, or spontaneous recovery. Thirty ASA physical status I or II patients provided informed consent and were randomized to one of the following groups: Group 1, placebo saline; Group 2, edrophonium (1 mg/kg); and Group 3, neostigmine (70 micrograms/kg) (n = 10/group). All studied patients had anesthesia induced with propofol and maintained with propofol/N2O/fentanyl. Mivacurium bolus of 0.2 mg/kg was used for endotracheal intubation and an infusion titrated to maintain deep levels of block (T1% = 1%-5%) (T1% = first response/control response x 100). The antagonist was injected at a deep level of the block (T1% = 1%-8%) and neuromuscular (NM) recovery was evaluated by train-of-four twitches (TOF). T1% was used during maintenance, whereas both T1% and TOF% (fourth response/first response x 100) were used during recovery. Investigators were blinded to the antagonist used. Plasma cholinesterase activity was measured prior to antagonist administration (0 min), as well as 15, 30, and 60 min after. Plasma cholinesterase activity was decreased to 29% of control at 15 min and remained at approximately 60% of the control after neostigmine administration. Edrophonium did not affect plasma cholinesterase activity. Clinically adequate spontaneous recovery (TOF% > or = 70%) of the mivacurium block with placebo required 15-18 min. On average, clinically adequate antagonism of mivacurium by edrophonium was 50% faster than placebo and 30%-40% faster than with neostigmine. In summary, the speed of antagonism with edrophonium is faster than with neostigmine when antagonizing deep mivacurium NM block.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antagonism of mivacurium neuromuscular block: neostigmine versus edrophonium. 748 38

Duration of neuromuscular block may be prolonged by H1/H2 antagonists. This study was designed to determine the influence of H1/H2 antagonist treatment on onset, duration and recovery after mivacurium chloride (MIV), a new nondepolarizing neuromuscular blocking agent with a relatively short duration of action, which is metabolized by human plasma cholinesterase (PChE). METHODS. After approval from the hospital ethical committee and written informed consent, 48 ASA I-II patients of either sex (ages 18-65 years, weight 45-100 kg) were included in this double blind study and randomly allocated to four groups of 12 each: group A, 0.105 mg/kg MIV (1.5 x ED95) and H1/H2 antagonist; group B, 0.105 mg/kg MIV and placebo; group C, 0.21 mg/kg MIV (3 x ED95) and H1/H2 antagonist; Group D 0.21 mg/kg MIV and placebo. Premedication consisted of 2 mg lormetazepam p.o., 300 mg ranitidine and 0.1 mg/kg dimetindene, or placebo p.o. Anaesthesia was induced with thiopentone (5-7 mg/kg) and maintained with N2O/O2 at a 65/35 ratio, enflurane (0.8-1.5%) and supplements of fentanyl. The ulnar nerve was stimulated with supramaximal 2 Hz train-of-four (TOF) every 10 s. Neuromuscular twitch response was recorded with EMG. Onset time (time from end of injection to maximal or total block), maximal block (%), T125 (time from end of injection to 25% recovery) were recorded after each dose, and recovery index (T1 from 25% to 75% recovery) and TOF70 (time from end of injection to TOF ratio of 70%), after the last dose. RESULTS. The four groups did not differ with respect to age, weight or height. There was no difference in the pharmacodynamics of mivacurium between the groups receiving H1/H2 antagonists and those receiving placebo. Following 1.5 x ED95 the onset was at 3.7 +/- 1.2 (H1/H2) and 3.8 +/- 0.9 min (placebo), respectively. Clinical duration (T125) was 13.1 +/- 3.4 and 12.8 +/- 3.4 min. 3 x ED95 led to a significant faster onset and longer duration (P < or = 0.05). Onset was at 1.9 +/- 0.7 (H1/H2) and 2.1 +/- 0.5 min (placebo), respectively, and clinical duration 19.1 +/- 6.1 and 19.3 +/- 3.8 min. Duration of repetitive doses (10.1 +/- 5.3 min), recovery index (6.8 +/- 2.9 min) and interval from last dose to spontaneous recovery (22.4 +/- 7.0 min) did not differ between groups. Three patients in group D (placebo and 0.21 mg/kg MIV) had haemodynamic changes of over 20% from baseline. Flush and erythema were significantly less pronounced after H1/H2 premedication than after placebo (4 vs 12 pts). CONCLUSIONS. Our results suggest that time of onset and clinical duration of effects of MIV are not altered by dimetindene and ranitidine. The duration depends more heavily on the dose of MIV. The recovery of neuromuscular function, once it has begun, is prolonged neither by MIV nor by H1/H2 antagonists. As MIV is mainly broken down by PChE, it is evident that its duration of action is more prolonged by atypical PChE activity than by interaction with other drugs. Oral H1/H2 premedication may diminish haemodynamic side-effects and clinical signs of histamine release.
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PMID:[Pharmacodynamics and clinical adverse effects of mivacurium. The effect of oral premedication with H1/H2 antagonists]. 810 16

Mivacurium is a new non-depolarizing muscle relaxant consisting of three stereoisomers. The two active isomers (cis-trans and trans-trans) undergo rapid metabolism by plasma cholinesterase (t1/2 beta < 2 min). Due to its rapid elimination, the need for reversal of mivacurium-induced neuromuscular block is controversial, and to date there have been no studies evaluating reversal of deep blocks. The object of the current investigation was to establish the lowest effective dose of edrophonium required to reverse deep mivacurium-induced neuromuscular block. One hundred ASA Class I and II patients undergoing outpatient surgery in two teaching institutions were studied in this randomized, placebo-controlled double-blind trial. Under balanced propofol/nitrous oxide/alfentanil anaesthesia, a continuous infusion of mivacurium was adjusted to maintain between 5-10% of control T1 amplitude. Upon completion of surgery, neuromuscular block was reversed by injecting normal saline (Group PLAC), edrophonium 0.125 mg.kg-1 (Group EDR-1), 0.25 mg.kg-1 (Group EDR-2), or 0.50 mg.kg-1 (Group EDR-3), in addition to a corresponding dose of atropine. Spontaneous recovery, from a T1 response of < 10% to a TOF ratio > or = 0.7, required 13.5 +/- 2.6 min (PLAC Group). In comparison, patients in the EDR-1 group required 9.2 +/- 2.6 min (P < 0.01). Higher doses of edrophonium conferred no advantage. Four patients (4%) had not achieved a TOF ratio of > or = 70%, 20 min after reversal, and required additional edrophonium. Two patients (PLAC group), had dibucaine numbers and cholinesterase levels consistent with an EUEA genotype, whereas the two patients with delayed recovery in the EDR-1 group had characteristics of a normal genotype. We conclude that a very low dose of edrophonium (0.125 mg.kg-1) hastens reversal of deep mivacurium-induced neuromuscular block by approximately four minutes, and that edrophonium doses exceeding 0.125 mg.kg-1 provide no additional benefit. Heterozygous patients with atypical plasma cholinesterase levels, as well as certain individuals with normal dibucaine numbers and plasma cholinesterase activity, are at risk for prolonged neuromuscular block, but the block is easily reversed with edrophonium.
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PMID:Edrophonium requirements for reversal of deep neuromuscular block following infusion of mivacurium. 859 May 11

Mivacurium, a new short acting non depolarizing neuromuscular blocker, is metabolized, as suxamethonium, by plasma cholinesterase. Therefore its duration of action is increased in patients with reduced plasma cholinesterase activity. We report a case of prolonged neuromuscular block after an i.v. bolus of mivacurium (0.20 mg.kg-1) in a 69 year-old ASA II woman with an unrecognized cholinesterase deficiency undergoing a lumbar sympathectomy for arteriopathy of the lower limbs. The duration of the block was 6 h and plasma cholinesterase concentrations were very low (540 and 610 UI.L-1), as well as the dibucaine number (16%), which suggests an homozygous enzymatic deficiency. Mechanical ventilation and sedation were continued until spontaneous return of full neuromuscular function.
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PMID:[Prolonged neuromuscular block after mivacurium injection]. 874 74


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