The pharmacodynamics and pharmacokinetics of mivacurium in children

BACKGROUND: In children, onset time and duration of action of mivacurium are shorter than in adults. Some suggest that this is due to differences in plasma cholinesterase (pChe), whereas others indicate that there is no difference. The purpose of this study was to evaluate the pharmacodynamics and pharmacokinetics of mivacurium in phenotypically normal children aged 3-6 and 10-14 years old, respectively. METHODS: Ten children aged 3-6 years and 10 children aged 10-14 years were studied during halothane anaesthesia. Before induction of anaesthesia, a blood sample was drawn to measure the pChe activity and phenotype. The neuromuscular block was monitored at the thumb using train-of-four (TOF) nerve stimulation every 12 s and mechanomyography. The times to different levels of neuromuscular recovery following mivacurium 0.2 mg/kg were recorded. The concentrations in venous blood of the three isomers and the metabolites of mivacurium were measured. RESULTS: No statistically significant difference was found in pChe activity or in the pharmacodynamics of mivacurium. The onset time was 1.4 min (0.8-1.9) median (range) and 1.3 min (1.1-1.9) and the time to first response to TOF nerve stimulation was 9.6 min (6.5-12.6) and 10.5 min (7.0-14.0) in young and older children, respectively. The pharmacokinetic data were too sparse to allow analysis of the two age groups separately (8 and 8 patients), hence the data were pooled. The median clearances of the cis-cis, the cis-trans, and the trans-trans isomer were 5.5, 51.0 and 30.5 ml/kg/min, respectively. CONCLUSION: Our data indicate that there are no major differences in pharmacodynamics or pharmacokinetics of mivacurium between young (3-6 years) and older (10-14 years) children.     

Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients

BACKGROUND: Mivacurium is hydrolyzed by plasma cholinesterase, and is therefore less dependent on liver metabolism and renal elimination than other neuromuscular blocking drugs. This might favor the use of mivacurium in elderly patients. The purpose of this study was to compare the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium and their metabolites in young adult and elderly patients. METHODS: Sixty-four patients were included in a dose-response study, in which 32 young adults and 32 elderly patients received one of four doses of mivacurium. An additional bolus dose of mivacurium to a total of 0.1 mg/kg was given followed by a continuous infusion adjusted to maintain a 91-99% neuromuscular block. The times to maximum block and different levels of recovery were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Thirty-two patients were randomly selected for the pharmacokinetic study. Venous samples were taken for determination of the three mivacurium isomers and the metabolites. RESULTS: The estimated ED95 were 0.053 and 0.061 mg/kg in young adults and elderly patients, respectively (NS). The median infusion rate did not differ, but duration to a TOF ratio of 0.7 was significantly longer in elderly patients than in young adult patients (21.0 vs. 16.5 min). No statistically significant difference between the age groups in clearance and elimination half-life of the isomers was seen. The half-lives of the metabolites were significantly prolonged in the elderly patients. CONCLUSION: There were no significant differences in the potency or infusion requirements between the adult and elderly patients, but the rate of recovery was significantly, though only moderately prolonged, in the elderly patients. No significant difference in clearance was seen but the elimination half-lives of the metabolites was longer in the elderly patients.     

丁酰胆碱酯酶与腰椎退行性变的关系研究

目的研究血清丁酰胆碱酯酶与腰椎退行性变的相关性。方法在日立7170全自动生化分析仪上用速率法测定了42例未手术的腰椎退行性变患者和35例正常体检者的血清丁酰胆碱酯酶。对研究组随访,询问其疼痛感,在痛感明显时采血。其中28例在使用麻醉剂后再次采血测定血清丁酰胆碱酯酶。用配对t检验处理数据。结果42例未手术的腰椎退行性变患者的血清丁酰胆碱酯酶(16945;SD=1637)明显高于正常对照组(10831;SD=1096;P<0.001)。28例研究组病人在使用麻醉剂后血清丁酰胆碱酯酶明显下降(12742;1958,P<0.001)。结论血清丁酰胆碱酯酶测定或可用于腰椎退行性变的诊治。     

Determination of cholinesterase and acetylcholinesterase in amniotic fluid

The determination of acetylcholinesterase (AChE) has been shown to be as specific as alphafetoprotein (AFP) for the prenatal detection of open neural tube defects although AFP remains the method of choice. This paper describes a semi-automated technique for the analysis of acetylcholinesterase in amniotic fluid that: A) reduces the cost of the procedure; B) allows for a larger number of samples to be run at a time; and C) provides for more accurate and reproducible procedures and results. Six fetuses with neural tube defects (2 with gastroschisis and 3 where one twin was dead) were detected and found to have elevated AChE, TChE and 2 bands by electrophoresis. Quality control procedures using both pure enzyme and amniotic fluid with low and high levels of the enzyme are described. The analysis of 340 amniotic fluids of normal pregnancies indicates that the normal value for AChE is 5.17 +/- 2.63 mU/ml (97% confidence interval for the mean 4.84-5.49 mU/ml. A group of 27 abnormal pregnancies provides evidence that fetal vomiting and regurgitation, fetal demise, multiple cysts syndrome, idiopathic IUGR, arthrogryposis multiplex, hydrocephaly (stenosis of aqueductus), trisomy 21, trisomy 18, hydronephrosis, pyloric stenosis, heart malformation, ectopia cordis and multiple gestation produce elevated levels of pseudocholinesterase (PChE) in amniotic fluid. The use of pseudocholinesterase levels in amniotic fluid for prenatal diagnosis is proposed and discussed in view of its elevated levels in abnormal pregnancies where AChE is normal. The normal values for PChE are 23.86 mU/ml (mean) and 5.83 for standard deviation. Electrophoretic analysis was performed on all samples with values higher than one standard deviation above the mean.(ABSTRACT TRUNCATED AT 250 WORDS)     

The recovery of plasma cholinesterase and erythrocyte acetylcholinesterase activity in workers after over-exposure to dichlorvos

Plasma cholinesterase and erythrocyte acetylcholinesterase activities have a long history of use in monitoring both workers at risk of organophosphorus pesticide (OP) exposure and in investigating accidental exposures to OPs. On account of wide inter-individual variation, the establishment of unexposed, baseline enzyme activities is necessary for accurate interpretation. This paper describes the rate of recovery of the two enzymes' activity after substantial over-exposure of eight subjects to the OP dichlorvos. Plasma cholinesterase activity, immediately after exposure, was substantially more inhibited than erythrocyte acetylcholinesterase activity. The plasma enzyme activity showed an exponential pattern of recovery with a half-life of around 12 days, so recovery was essentially complete after about 50 days. This reported half-life of recovery is consistent with the reported de novo synthesis rate of plasma cholinesterase. The mean recovery of erythrocyte acetylcholinesterase activity appeared linear over time, attaining unexposed activity after about 82 days, which is somewhat shorter than the life-span of erythrocytes. These indicate the sort of time period, after an OP incident, before a valid unexposed level can be established in an individual; and substantiate the guidance given in the Health & Safety Executive's document MS17 on a minimum period of 60 days without exposure in order to establish pre-exposure baseline levels.     

Delayed Life-Threatening Reaction to Anthrax Vaccine

Background: Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Due to the current world threat of unpredictable biological terrorism, the Department of Defense has mandated the systematic vaccination of all US military personnel against this warfare agent. Many may experience a mild flu-like illness and soreness at the injection site, but systemic reactions are rare. Case Report: We report a delayed and potentially serious life-threatening adverse reaction to anthrax vaccine. A previously healthy 34-year-old male was transported to the emergency department with dyspnea, diaphoresis, pallor, and urticarial wheals on his face, arms, and torso after the administration of the third dose of anthrax vaccine. All symptoms resolved after pharmacological intervention and the patient was discharged. Pharmaco-epidemiological data indicate that 30% of anthrax vaccine recipients experience mild local reactions. With large numbers of military personnel being vaccinated, emergency physicians may encounter more vaccine-related adverse reactions.     

Influence of plasma cholinesterase activity on recovery from mivacurium-induced neuromuscular blockade in phenotypically normal patients

The significance of plasma cholinesterase (pChe) activity for the duration of action of mivacurium in phenotypically normal patients was evaluated in 35 patients during neurolept anaesthesia. The response to train-of-four nerve stimulation was recorded using a Myograph 2000. Ten patients with normal pChe (Group I) and five patients with decreased pChe activity (Group 2) were given a small test dose of mivacurium 0.03 mg kg-1. Mivacurium 0.1 mg kg-1 was administered following spontaneous recovery from the first dose. The mean suppression of the height of the first (T1) of the train-of-four responses following mivacurium 0.03 mg kg-1 patients with normal and decreased enzyme activity was 40% and 56%, respectively, and the mean T1 suppression after mivacurium 0.1 mg kg-1 was 100% in both groups. The times to different levels of twitch height recovery following the 0.1 mg kg-1 dose did not differ between the two groups of patients. Another 20 patients with normal or decreased pChe activity (Group 3) were given mivacurium 0.2 mg kg-1. In this group the time to maximum block was 1.4 min (1.0-4.0) mean (range) and the time to reappearance of the T1 response was 15.0 min (7.4-22.7) (range). An inverse relationship was found between the patients' pChe activity and the time to first response. It is concluded that mivacurium is short-acting in patients with normal pChe phenotype and normal to low-normal pChe activity. No patient with very low pChe activity was included in the study. A prolonged response to mivacurium may, however, be expected in these patients.     

Studies on acetylcholinesterase and gamma-glutamyltranspeptidase in mouse brain in ammonia toxicity

Short- and long-term ammonia toxicity was induced in mice by intraperitoneal injection, respectively, of single and six doses of 0.6 mM ammonium acetate per 100 g of body weight. The animals were sacrificed half an hour after either the single injection or after the last injection of six doses. Under these experimental conditions the ammonia levels were found to be elevated twofold in cerebral cortex, brain stem, and basal ganglia after the administration of a single dose of ammonium acetate. A fourfold increase in the content of ammonia was observed in cerebral cortex, brain stem, and basal ganglia after six injections. An elevation in the activity of pseudocholinesterase (enzyme localized in brain capillaries and dial cells) in all the above four regions resulted as a short-term effect of ammonia toxicity. True acetylcholinesterase was found to be elevated in all the four regions in short-term and in long-term ammonia toxicity. Gamma-glutamyltranspeptidase (GGTP), another enzyme localized in cerebral capillaries and glial cells, was found to be depressed in all the regions of the brain in both short- and long-term ammonia toxicity. The implications of these results are discussed in relation to glial cell function.     

Differential response of neutral endopeptidase 24.11 (“enkephalinase”), and cholinergic and opioidergic markers to hypoglossal axotomy

Neutral endopeptidase 24.11 (NEP; “enkephalinase”) may inactivate a number of centrally active neuropeptides including the enkephalins and substance P. In most areas of the central nervous system, the cell types which express NEP activity are not known. The hypoglossal nucleus (N. XII) was selected as a model system to characterize the cytochemical localization of NEP. The effect of hypoglossal nerve axotomy upon the distribution of NEP activity in the hypoglossal nucleus was compared to the effect upon cholinergic markers, the muopiate receptor, and the enkephalins. By use of a fluorescence histochemical method, NEP was localized at all levels of N.XII to the soma and proximal processes of the majority of the apparent motor neurons in the nucleus. Fluorescent double-labeling studies revealed the presence of numerous enkephalinergic varicosities which localized to the neuropil surrounding NEP-stained motor neurons. To determine whether NEP was synthesized by these motor neurons, 18 rats received a unilateral transection of the hypoglossal nerve. A pronounced decrease in NEP staining in N.XII was observed on the operated side as early as 3 days following axotomy. This decrease persisted at all levels of the nucleus for about 5 weeks. By 7 weeks, the staining between the control and operated sides was indistinguishable. By contrast, there was no apparent change in the density or distribution of enkephalin-immunoreactive varicosities in five animals examined 6 to 32 days following axotomy. Radioligand binding of [³H]DAMGO to the μ-opiate receptor in N.XII was studied in 20 animals by quantitative autoradiography at 2, 6, and 11 days after axotomy. No significant changes in the level of radioligand binding to the μ-receptor were detected in response to axotomy. In contrast to the opiate system, the cholinergic enzymes choline acetyltransferase, acetylcholinesterase, and pseudocholinesterase showed a coordinate decrease in motor neuron-associated staining on the operated side of N.XII at 3 ,6 , and 11 days following axotomy which paralleled the decrease in NEP staining. By contrast, the lysosomal enzyme marker, acid phosphatase, showed a pronounced increase in staining on the operated side. The results of this study are consistent with the synthesis of NEP by cholinergic N.XII motor neurons and indicates that the enkephalins and NEP in N.XII are closely associated, but derive from separate neuronal populations. The widespread overlap in the distribution of NEP-stained motor neurons and enkephalinergic varicosities in N.XII provides additional anatomical support for a potential role for NEP in the inactivation of centrally active enkephalins. The apparently stable levels of the enkephalins and μ-opiate receptor after axotomy, in contrast to the coordinate decrease in cholinergic enzyme staining, suggest a differential regulation of the opiate and cholinergic systems in response to axotomy. © 1994 Wiley-Liss, Inc.     

Molecular forms of acetylcholinesterase in synaptic and extrasynaptic regions of avian tonic muscle

Molecular forms of acetylcholinesterase and pseudocholinesterase were analyzed directly in the micro-dissected individual endplates of a slow-tonic chicken muscle. The major form in the endplate is the L2(6.5 S) form, while the collagen-tailed H2c (20 S) form, normally considered to be the synaptic form, is a very minor component, in contrast to its predominance at the chicken fast-twitch fibre endplate. The same is true for pseudocholinesterase at these endplates. Outside the tonic fibre endplates the same forms occur as at the endplates, but at a very much lower concentration. The enzyme at the tonic fibre endplate cannot be attached to the basal lamina by a collagen tail, but appears to have a hydrophobic attachment. Acetylcholinesterase is functional at tonic fibre endplates, but the absence of the collagen-tailed form may account for the lower efficiency of the enzymic removal of acetylcholine there.