Drug and pro-drug substrates and pseudo-substrates of human butyrylcholinesterase.

Butyrylcholinesterase (BChE) is present in plasma and numerous cells and organs. Its physiological function(s) is(are) still unclear. However, this enzyme is of pharmacological and toxicological importance. It displays a broad specificity and is capable of hydrolyzing a wide range of substrates with turnovers differing by several orders of magnitude. Nowaday, these substrates include more than two dozen carboxyl-ester drugs, numerous acetylated prodrugs, and transition state analogues of acetylcholine. In addition, BChE displays a promiscuous hydrolytic activity toward amide bonds of arylacylamides, and slowly hydrolyzes carbamyl- and phosphoryl-esters. Certain pseudo-substrates like carbamates and organophosphates are major drugs of potential medical interest. The existence of a large genetic poly-allelism, affecting the catalytic properties of BChE is at the origin of clinical complications in the use of certain drugs catabolized by BChE. The number of drugs and prodrugs hydrolyzed by BChE is expected to increase in the future. However, very few quantitative data (Km, kcat) are available for most marketed drugs, and except for myorelaxants like succinylcholine and mivacurium, the impact of BChE genetic mutations on catalytic parameters has not been evaluated for most of these drugs.

Modulation of Cerebral Function by Muscle Afferent Activity, with Reference to Intravenous Succinylcholine.

Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a Defasciculating Dose of Pancuronium. By WL Lanier, PA Iaizzo, and JH Milde. Anesthesiology 1989; 71:87-95. Reprinted with permission. By the mid-1980s, it was widely assumed that if the depolarizing muscle relaxant, succinylcholine, given IV, produced increases in intracranial pressure, it did so because fasciculations produced increases in intrathoracic and central venous pressures that were transferred to the brain; however, there was no direct evidence that this was true. In contrast, we explored the possibility that the succinylcholine effect on the brain was explained by the afferentation theory of cerebral arousal, which predicts that agents or maneuvers that stimulate muscle stretch receptors will tend to stimulate the brain. Our research in tracheally intubated, lightly anesthetized dogs discovered that IV succinylcholine (which does not cross the blood-brain barrier) produced a doubling of cerebral blood flow that lasted for 30 min and corresponded to activation of the electroencephalogram and increases in intracranial pressure. Later, in our Classic Paper, we were able to assess simultaneously cerebral physiology and afferent nerve traffic emanating from muscle stretch receptors (primarily muscle spindles). We affirmed that the cerebral arousal response to succinylcholine was indeed driven by muscle afferent traffic and was independent of fasciculations or increases in intrathoracic or central venous pressures. Later research in complementary models demonstrated that endogenous movement (e.g., coughing, hiccups) produced a cerebral response very similar to IV succinylcholine, apparently as a result of the same muscle afferent mechanisms, independent of intrathoracic and central venous pressures. Thus, the importance of afferentation theory as a driver of the cerebral state of arousal and cerebral physiology during anesthesia was affirmed.

Change in jaw occlusive power by paralysis of masseter muscle with a neuromuscular blocker: Sion's masseter muscle paralysis.

STUDY OBJECTIVE: We aimed to determine whether jaw occlusive power decreases with the injection of neuromuscular blocking agents in masseter muscle - a method we named Sion's masseter muscle paralysis (SMP). METHODS: A randomized, placebo-controlled animal study was conducted in which researchers were blinded to group allocation. We used 12 male mongrel dogs aged 10-12 months and weighing 30-35 kg. Four groups were formed: a conventional dose (CD) group (0.004 mg/kg succinylcholine in 4 ml normal saline [NS]); a high dose (HD) group (0.04 mg/kg succinylcholine in 4 ml NS); a placebo group (4 ml NS); and no intervention group. To measure the jaw occlusive power, 1 kg weight was hung sequentially on a specifically designed device on the animal's lower jaw. At -4, -2, 0', +2, +4, +6, +8, +10, +20, and +30 min, we measured the jaw occlusive power, oxygen saturation (SpO2), and end-tidal carbon dioxide (ETCO2). RESULTS: After SMP, jaw occlusive power began to decline in CD and HD group. The arithmetical mean jaw occlusive power values at -4, -2, 0', +2, +4, +6, +8, and +10 min were 9.7, 9.7, 9.7, 8.7, 8.3, 7.3, 6.7, and 6.3 kgw in the CD group and 9.7, 9.3, 8.7, 8.0, 6.7, 5.0, 5.0, and 5.3 kgw in the HD group. No abnormalities in SpO2or ETCO2were detected. CONCLUSION: Jaw occlusive power was decreased after SMP with succinylcholine, without inducing respiratory complication.

Surgical conditions with rocuronium versus suxamethonium in cesarean section: a randomized trial.

BACKGROUND: Onset times and conditions for intubation after rocuronium versus suxamethonium at cesarean section have been evaluated, but no study thus far has examined the influence of these neuromuscular blocking drugs on the surgical conditions or their effect on the duration of surgery and the ease of fetal delivery. We aimed to compare the surgical conditions for delivery in parturients who received deep neuromuscular block with rocuronium with those who had induction with suxamethonium. METHODS: Ninety patients undergoing cesarean section under general anesthesia were randomized to receive either rocuronium 0.6 mg/kg or suxamethonium 1 mg/kg for tracheal intubation and delivery. Times to delivery and the quality of surgical conditions, using a five-point Surgical Rating Scale for Delivery (SRSD) ranging from 1 (poor) to 5 (excellent), were evaluated. RESULTS: The median SRSD (range) was found to be significantly better in the rocuronium group [4 (3-5) points vs 3 (2-4) points with suxamethonium (P <0.001)]. Whereas the mean (SD) induction-to-intubation interval was longer with rocuronium [106 (34) s vs 68 (32) s with suxamethonium (95% CI of the difference 24 to 52 s, P <0.001)], the incision-to-delivery interval was shorter in the rocuronium group [147 (68) s vs 196 (51) s with suxamethonium (95% CI of the difference -75 to -24 s, P <0.001)]. The mean induction-to-delivery intervals were similar [268 (73) s vs 276 (63) s, respectively]. CONCLUSIONS: Whereas the induction-to-delivery intervals were comparable, we found rocuronium superior to suxamethonium in allowing better surgical conditions for fetal delivery, which enabled an easier delivery and a shorter incision-to-delivery interval.

A Chronology for the Identification and Disclosure of Adverse Effects of Succinylcholine.

BACKGROUND: New therapies are created to address specific problems and enjoy popularity as they enter widespread clinical use. Broader use can reveal unknown adverse effects and impact the life cycle significantly. Succinylcholine, a depolarizing neuromuscular blocker, was the product of decades of research surrounding the ancient compound, curare. It was introduced into practice in the 1950s by Burroughs Wellcome and Company (BW Co) and was welcomed due to its rapidly acting muscle relaxation effects. Global clinical use revealed adverse effects, both minor and major, in particular, hyperkalemia and malignant hyperthermia. We investigated when practitioners and the manufacturer became aware of these adverse effects, how information about these side effects was disseminated, and whether the manufacturer met the regulatory requirements of the time, specifically regarding the timely reporting of adverse effects. SOURCES: Primary literature search using online and archived documents was conducted at the Wood Library-Museum of Anesthesiology, Schaumburg, IL. We consulted documents submitted by BW Co to federal authorities, through the Freedom of Information Act (FOIA), Food and Drug Administration (FDA) reports, promotional advertisements, package inserts, published articles, and textbooks. RESULTS: Initial clinical testing in humans in 1952 found no adverse effects on cardiovascular or respiratory systems. Fasciculations and myalgia were early side effects described in case reports in 1952. Large-scale clinical trials in 1953 found abnormally long recovery times among some patients; the discovery of abnormal pseudocholinesterase enzyme activity was not fully demonstrated until the early 1960s. Bradycardia was first reported in 1957 in children, and in 1959 in adults. In 1960, animal studies reported a transient increase in plasma potassium; further experiments in 1969 clearly demonstrated succinylcholine-induced hyperkalemia in burn patients. Malignant hyperthermia was first described in 1966. Similar cases of elevated temperatures and muscle rigidity were described globally but the underlying mechanism was not elucidated until the 1990s. Standard anesthesia textbooks did not report major side effects of succinylcholine until 1960 and included newly documented side effects with each edition. BW Co's packaging contained warnings as early as the 1950s but were later updated in 1962 and beyond to reflect the newly discovered hyperkalemia and malignant hyperthermia. CONCLUSION: Particularly given the regulatory environment of the time, BW Co appropriately reported the adverse effects of succinylcholine after market entry; it updated promotional and packaging material in a timely manner to reflect newly discovered adverse effects. The toxicity, though alarming and put clinicians on alert, did not seem to heavily impact succinylcholine's use, given its various desirable properties. It is still a choice muscle relaxant used today, although there are efforts to develop superior agents to replace succinylcholine.

Butyrylcholinesterase deficiency and its clinical importance in anaesthesia: a systematic review.

Butyrylcholinesterase deficiency prolongs the effects of the drugs it degrades; succinylcholine and mivacurium. Existing literature on butyrylcholinesterase deficiency is dominated by genetic and biochemical studies. We searched MEDLINE, Embase, Web of Science and Biosis to systematically review the causes and clinical consequences of butyrylcholinesterase deficiency. We considered outcomes clinically relevant if neuromuscular blockade, induced by succinylcholine or mivacurium, was assessed using clinical criteria or neuromuscular monitoring. We included 66 studies: 25 randomised controlled trials; 13 clinically controlled trials; 26 prospective observational studies; 1 retrospective study; and 1 qualitative study. Data heterogeneity precluded quantitative synthesis. Studies described genetic, physiological, acquired or pharmacologically induced causes of butyrylcholinesterase deficiency. The prolongation of neuromuscular blockade by butyrylcholinesterase deficiency was most pronounced with homozygosity of a genetic variant, but other more common factors included increasing age, pregnancy, severe liver disease, burn injuries and drug interactions.

Succinylcholine and Intracranial Pressure.

Intracranial and Hemodynamic Changes after Succinylcholine Administration in Cats. By Cottrell JE, Hartung J, Giffin JP, and Shwiry B. Anesthesia & Analgesia 1983; 62:1006-9. Reprinted with permission.Bolus injections of succinylcholine (1.5 mg/kg) significantly increased intracranial pressure (ICP) in cats under normal conditions from control levels of 8 +/- 1 mmHg to 16 +/- 3 mmHg (+/- SEM, P less than 0.01), and in the presence of artificially increased ICP from control levels of 27 +/- 1 mmHg to 47 +/- 4 mmHg (P less than 0.01). These approximately 100% increases in ICP were accompanied by a transitory decrease in mean arterial pressure (approximately 10 s), followed by a 15 to 20% increase (P less than 0.05). Pulmonary arterial pressure increased 20 to 30% (P less than 0.05). These results, when considered in conjunction with results previously obtained in humans, suggest that succinylcholine may be contraindicated in neurosurgical patients.

Duración del bloqueo neuromuscular con succinilcolina y su relación con niveles de colinesterasa plasmática en pacientes sépticos: Hospital Central Universitario Dr. Antonio María Pineda / Neuromuscular blockade duration with succinylcholine and its correlation with levels of plasma cholinesterase in septic patients: Hospital Central Universitario Dr. Antonio María Pineda

La succinilcolina es un fármaco neuromuscular despolarizante generalmente utilizado en el contexto de protocolo de intubación de secuencia rápida indicada en pacientes en los cuales es necesario asegurar la vía aérea en menos de sesenta segundos. Se realizó un estudio descriptivo transversal con el objetivo de determinar la duración del bloqueo neuromuscular con succinilcolina y los niveles de colinesterasa plasmática en pacientes sépticos intervenidos en el Hospital Central Universitario Dr. Antonio María Pineda. Se incluyeron 30 pacientes con sepsis con un promedio de edad de 49,6 ± 17,4 años y predominio del sexo masculino (70%); la principal indicación de cirugía abdominal fue obstrucción intestinal (36,6%) y peritonitis secundaria (23,3%). Los valores de colinesterasa plasmática se registraron disminuidos en 42,8% de los hombres y 33,3% de las mujeres encontrándose valores promedios de 5554,1 ± 1220,5 U/L y 4770,1 ± 1627,4 U/L, respectivamente. La duración del bloqueo neuromuscular fue mayor de 14 minutos en 66,6% de las mujeres; el promedio de duración fue de 14,4 ± 5,1 min (mujeres) y 9,4 ± 4,3 min en hombres. Hubo una pobre correlación entre los niveles de colinesterasa plasmática y la duración así como el tiempo de recuperación del bloqueo neuromuscular. En conclusión, el bloqueo neuromuscular prolongado debido a la baja actividad de la colinesterasa después de la administración de succinilcolina se presenta en menos de la mitad de los pacientes sépticos estudiados(AU)

Succinylcholine is a depolarizing neuromuscular drug generally used in the context of rapid sequence intubation indicated in patients in whom it is necessary to secure the airway in less than sixty seconds. A descriptive cross-sectional study was conducted in order to determine the duration of neuromuscular blockade with succinylcholine and plasma cholinesterase levels in septic patients admitted at Hospital Central Universitario Dr. Antonio Maria Pineda. A sample of 30 patients with sepsis were studied, with a mean age of 49.6 ± 17.4 years, predominantly male (70%). The main indication for abdominal surgery was intestinal obstruction (36.6%) and secondary peritonitis (23.3%). Diminished values of plasma cholinesterase were recorded in 42.8% of men and 33.3% of women; mean plasma levels were 5554.1 ± 1220.5 U/L and 4770.1 ± 1627.4 U/L, respectively. Duration of neuromuscular blockade was longer in women (66.6%) with an average duration of 14.4 ± 5.1 min and 9.4 ± 4.3 min for men. A poor correlation between cholinesterase plasmatic levels and duration as well as time of recovery of neuromuscular blockage was found. Prolonged neuromuscular blockade is due to low cholinesterase activity after administration of succinylcholine and occurs in less than half of septic patients studied(AU)

Perioperative Gabapentin Improves Patient-Centered Outcomes After Inguinal Hernia Repair.

INTRODUCTION: Over 5,300 inguinal hernia repairs (IHR) were performed in the Military Health System in 2015. Chronic pain can be a debilitating complication, occurring in up to 34% of patients after IHR and impacts mission readiness. Gabapentin has been shown to be effective for postoperative analgesia in a variety of operations. We evaluated the effect of a short course of perioperative gabapentin on chronic pain after IHR. METHODS: This was a double-blinded, randomized study involving male patients ≥18 years old with an initial inguinal hernia and no history of chronic pain or psychiatric disorder. Patients chose laparoscopic or open surgery and were then randomized to receive gabapentin 300 mg before surgery, then three times daily for 6 doses or placebo. There were 50 patients randomized to both the gabapentin and placebo groups for a total of 100 patients. Main outcomes were pain and health status, assessed with a visual analogue scale (VAS) and the Short Form-12v2 (SF-12v2). Assessments were performed preoperatively and 1, 6, 12, and 24 months postoperatively. Analysis of variance was used to compare groups. RESULTS: From the initial 100 patients, 19 withdrew or were excluded. Thus, 81 patients remained, 40 receiving gabapentin and 41 placebo. Throughout the 24-month follow-up, there was no difference in VAS pain scores between the gabapentin and placebo groups (p = 0.867). Beyond 1 month of follow-up, SF-12v2 physical component score (PCS) scores were improved in the gabapentin group (p = 0.039). When comparing open to laparoscopic groups, SF-12v2 PCS scores were improved in the laparoscopic group (p = 0.046) and SF-12v2 mental component summary scores were improved in the open group (p = 0.041). CONCLUSIONS: Perioperative gabapentin was not effective in decreasing chronic pain after IHR; however, patient perception of physical health, as measured by SF-12v2, did improve.

A study of intubating conditions: Sevoflurane versus propofol-suxamethonium in children.

BACKGROUND: Endotracheal intubation is an integral part of general anaesthesia in children, and the choice of induction agents and technique may affect the ease of intubation and thus the outcome of paediatric patients. We compared the ease of endotracheal intubation following sevoflurane and propofol-suxamethonium induction using Helbo-Hansen score. PATIENTS AND METHODS: A prospective, randomized double-blinded comparative study conducted on sixty-six children (two groups of 33 each) between the ages of 3-10 years undergoing different elective surgeries. Group I received intravenous propofol and intravenous suxamethonium while Group II had inhalational induction with sevoflurane in 60% nitrous oxide and oxygen. Data including intubating conditions, time to tracheal intubation and haemodynamic changes were analysed using SPSS version 18, with statistical significance set at P < 0.05. RESULTS: Using the Helbo-Hansen intubation score, the study reveals that 28 patients (85%) scored 4, 5 (15.2%) scored 5 and no patient scored 6 in Group I whereas 15 (45.5%) scored 4, 16 (48.5%) scored 5 and 2 (6.1%) scored 6 in Group II with P = 0.002. The mean time taken from induction to laryngoscopy was 91.27 ± 29.96 s in Group I and 219.09 ± 63.88 s in Group II (with P < 0.0001); mean time taken from laryngoscopy to completion of intubation was 29.03 ± 10.61 s and 28.09 ± 9.48 s which was not statistically significant with P = 0.71. CONCLUSION: Sevoflurane provides clinically acceptable intubating conditions and can be a suitable alternative to propofol-suxamethonium for endotracheal intubation in children. We recommend the use of sevoflurane to facilitate intubation in elective procedures in children.

Rocuronium versus suxamethonium for rapid sequence induction of general anaesthesia for caesarean section: influence on neonatal outcomes.

BACKGROUND: In a previous study we compared rocuronium and suxamethonium for rapid-sequence induction of general anaesthesia for caesarean section and found no difference in maternal outcome. There was however, a significant difference in Apgar scores. As this was a secondary outcome, we extended the study to explore this finding on a larger sample. METHODS: We included 488 parturients of whom 240 were women from the original study. Women were randomly assigned to receive either rocuronium 1mg/kg (ROC n=245) or suxamethonium 1mg/kg (SUX n=243) after propofol 2mg/kg. Anaesthesia was maintained with up to 50% nitrous oxide and up to one minimum alveolar concentration of sevoflurane until the umbilical cord was clamped. We compared neonatal outcome using Apgar scores and umbilical cord blood gases. RESULTS: Data were analysed for 525 newborns (ROC n=263vs. SUX n=262). There was a statistically significant difference in the proportion of Apgar scores <7 at 1min (ROC 17.5% vs. SUX 10.3%, P=0.023) but no difference at 5min (ROC 8% vs. SUX 4.2%, P=0.1) or 10min (ROC 3.0% vs. SUX 1.9%, P=0.58). There was no difference between groups in other measured outcomes. CONCLUSION: The use of rocuronium was associated with lower Apgar scores at 1min compared with suxamethonium. The clinical significance of this is unclear and warrants further investigation.

Suxamethonium induces a prompt increase in the bispectral index.

Upon inducting general anesthesia in the operating room, we have observed a prompt increase in the bispectral index (BIS) after the intravenous injection of suxamethonium. We hypothesized that the cause of this BIS increase is muscle hyperactivity owing to fasciculation. However, no reports have been published regarding this abrupt increase in the BIS upon the induction of general anesthesia by suxamethonium. To investigate the degree of change in the BIS in patients receiving anesthesia with suxamethonium, we performed a prospective observational study of 63 participants who underwent closed reduction for nasal bone fracture. Anesthesia was induced by the total intravenous administration of anesthetics and 1.5 mg kg of suxamethonium was injected intravenously upon achieving BIS between 45 and 55. Intubation was performed after fasciculation. Electromyograms and BIS values were recorded from the induction of suxamethonium until 15 minutes after intubation. The mean BIS values were 95.4, 48.5, and 69.3 before induction, before the intravenous injection of suxamethonium, and immediately after fasciculation, respectively. The BIS value immediately after fasciculation (69.3 ±â€Š10.6) was significantly higher than the cutoff BIS value of 60 (P < .001). Although fasciculation after the intravenous injection of suxamethonium resulted in the prompt increase of the BIS to values over 60, none of the participants was awake during surgery. In conclusion, the administration of suxamethonium resulted in the postfasciculation increase of the BIS to an average value of 69.3 without affecting the patient's state of consciousness.

Conditions of endotracheal intubation with and without muscle relaxant in children.

Aim To compare intubation conditions and hemodynamic response of two induction regimens, with or without muscle relaxant using a combination of either fentanyl and propofol or propofol and suxamethonium. Methods A total of 80 children aged 4-12 years were enrolled in a prospective randomized double-blinded study. Children were randomly allocated in two equal groups. In group F induction was done with fentanyl and propofol, while propofol and suxamethonium were used in group S. Intubation conditions were assessed using Copenhagen Consensus Score (CCS), based on ease of laryngoscopy, position of vocal cords, degree of coughing, jaw relaxation and limb movements. Systolic blood pressure (SBP),diastolic blood pressure (DBP), mean arterial pressure (MAP) and heart rate (HR) were observed at preinduction, postinduction and postintubation at 1, 3 and 5 minute. Results Clinically acceptable CCS was found in 95% of patients in group F versus 100% in group S. Intubation conditions wereexcellent in 85%, good in 10% and poor in 5% of patients in group F. In the group F, signifficantly lower SBP and MAP postinduction and postintubation at 1 and 3 minute, and lower DBP postinduction and postintubation at 1 minute (p<0.05) was found comparing to group S. In group S, significantly higher postinduction and postintubation HR at 1 minute was found comparing to group F (p<0.05). Conclusion Induction combination fentanyl-propofol provide acceptable intubation conditions comparable with suxamethonium in children. This induction regimen ensures better hemodynamic stability associated with endotracheal intubation. It could be recommended for intubation when muscle relaxants are not indicated.

Patients with prolonged effect of succinylcholine or mivacurium had novel mutations in the butyrylcholinesterase gene.

INTRODUCTION: Mutations in the butyrylcholinesterase enzyme (BChE) can result in prolonged duration of action of the neuromuscular blocking agents, succinylcholine and mivacurium, as BChE hydrolyses these drugs. Hereditary low BChE activity can cause extensively prolonged apnoea during general anaesthesia when these drugs are used. The aim of this study was to describe novel mutations in the butyrylcholinesterase gene (BCHE) in patients who have experienced prolonged duration of action of mivacurium or succinylcholine. METHODS: The Danish Cholinesterase Research Unit registers patients with prolonged duration of action to succinylcholine and mivacurium. Patients were studied if they had equivocal phenotypes on the basis of BChE activity, biochemical inhibitor reactions and with pedigree if possible. Complete nucleotide sequencing was performed to describe the genotype and pedigree was used to separate the alleles. Multiple sequence alignment of BChE was performed for comparison with other species. RESULTS: Genotyping indicated seven novel mutations in the BCHE (I373T, G467S, W518R, L184S, V421A, M462I and R577H). CONCLUSION: We have found seven new variants of the BCHE, which seem to reduce the activity of BChE in patients undergoing anaesthesia involving succinylcholine or mivacurium.

BPC 157: The counteraction of succinylcholine, hyperkalemia, and arrhythmias.

After the demonstration of its life-saving effect in severe hyperkalemia and the recovery of skeletal muscle after injury, pentadecapeptide BPC 157 has been shown to attenuate the local paralytic effect induced by succinylcholine, in addition to systemic muscle disability (and consequent muscle damage). Hyperkalemia, arrhythmias and a rise in serum enzyme values, were counteracted in rats. Assessments were made at 3 and 30min and 1, 3, 5, and 7 days after succinylcholine administration (1.0mg/kg into the right anterior tibial muscle). BPC 157 (10µg/kg, 10ng/kg) (given intraperitoneally 30min before or immediately after succinylcholine or per-orally in drinking water through 24h until succinylcholine administration) mitigated both local and systemic disturbances. BPC 157 completely eliminated hyperkalemia and arrhythmias, markedly attenuated or erradicated behavioral agitation, muscle twitches, motionless resting and completely eliminated post-succinylcholine hyperalgesia. BPC 157 immediately eliminated leg contractures and counteracted both edema and the decrease in muscle fibers in the diaphragm and injected/non-injected anterior tibial muscles. Therefore, the depolarizing neuromuscular blocker effects of succinylcholine were successfully antagonized.

[Danish Cholinesterase Research Unit diagnoses patients with prolonged paralysis after succinylcholine and mivacurium]. / Dansk Kolinesterase Kartotek udreder patienter med forlænget paralyse efter suxamethon og mivacurium.

The Danish Cholinesterase Research Unit (DCRU) is a nationwide unit for patients carrying mutations in the butyrylcholinesterase enzyme (BChE). BChE hydrolyzes the neuromuscular blocking drugs succinylcholine and mivacurium. Patients with mutations in the butyrylcholinesterase gene are at risk of experiencing a prolonged effect of the drugs, such as weakness or paralysis for hours. In order to diagnose the referred patients correctly, DCRU combines results such as BChE activity, genotyping, pedigree and clinical reactions to succinylcholine or mivacurium.

Effects of skeletal muscle denervation on the potency of succinylcholine.

The aim of the present study was to investigate the time­dependent effects of denervation on the sensitivity of skeletal muscles to the relaxant succinylcholine (SuCh) and to assess the possible association of the de novo expression of γ­acetylcholine receptor (AChR). Innervated as well as denervated mouse muscle cells and human embryonic kidney (HEK293) cells expressing γ­AChR and ε­AChR were used in the present study. The effects of SuCh on the current of nicotinic (n)AChRs were examined using a whole­cell patch clamp technique. Compared with innervated skeletal muscle cells, the SuCh concentration producing 50% of the maximal response (EC50) were decreased by 20, 56, 73, 66, 60 and 62% (P<0.05), and current responses induced by 30 µM SuCh were increased by 1.9­, 4.6­, 9.4­, 7.1­, 5.2­ and 5.1­fold (P<0.05) at days 1, 4, 7, 14, 21 and 28 after denervation, respectively. However, SuCh was equipotent regarding γ­AChR and ε­AChR (P>0.05). These results indicated that short­term denervation led to a change in the sensitivity of muscle cells to SuCh, which, however, was unlikely to be associated with the de novo expression of γ­AChR.