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PubMedDate not supplied

Enhancement of analgesic effect of intrathecal neostigmine and clonidine on bupivacaine spinal anesthesia.

BACKGROUND AND OBJECTIVES: Intrathecal administration of neostigmine has been shown to produce analgesia in both animals and humans. The concurrent administration of intrathecal neostigmine and clonidine has been reported to produce no neurotoxicity in sheep. The purpose of the present study was to evaluate the efficacy and safety of the combining intrathecal neostigmine and clonidine for the relief of pain in patients after cesarean delivery. METHODS: After giving their consents, 80 parturients who were scheduled for cesarean delivery during spinal anesthesia were enrolled by a double-blind randomized design into four groups: bupivacaine group (n = 20) received intrathecal (i.t.) 10 mg bupivacaine; bupivacaine + neostigmine group (n = 19) received i.t. 10 mg bupivacaine + 50 microg neostigmine; bupivacaine + clonidine group (n = 20) received i.t. 10 mg bupivacaine + 150 microg clonidine; and bupivacaine + both (n = 21) received i.t. 10 mg bupivacaine + 50 microg neostigmine + 150 microg clonidine. The maximum spread of anesthesia, duration of analgesia and motor block, vital signs, and incidence of adverse effects were recorded for 14 hours postinjection. Fifty milligrams intramuscular meperidine was given as a rescue analgesic whenever patient's pain score was greater than 5/10 by the visual analog scale. RESULTS: The demographic data were similar for all four groups. Bupivacaine + both group had a significantly higher maximum spread of anesthesia of 23.3 +/- 2.9 segments than bupivacaine group of 20.5 +/- 2.9 segment. Bupivacaine + both group showed a later onset of postsurgical pain of 6.5 +/- 1.5 hours as compared to bupivacaine group of 1.3 +/- 0.6 hours. The pain score in bupivacaine + both group was significantly lower than that of bupivacaine group during the first 10 hours. The 24-hour meperidine consumption also was lower in bupivacaine + both group than that of bupivacaine group. However, motor block was significantly prolonged from 3.5 +/- 1.1 hours in bupivacaine group to 7.1 +/- 1.6 hours in bupivacaine + both group. In addition, other side effects such as nausea and vomiting and dizziness were significantly increased in bupivacaine + both group. CONCLUSION: Our study showed that the combination of 150 microg i.t. clonidine and 50 microg neostigmine provided longer postsurgical analgesia than with either drug used alone. However, this combination also produced significantly more adverse effects of prolonged motor block and nausea and vomiting. A further study combining the two study drugs but using a lower dose of i.t. neostigmine (e.g., 25 microg) is recommended.

Analgesics, Non-Narcotic↗
PubMed1999

Analgesic and adverse effects of a low dose of intrathecally administered hyperbaric neostigmine alone or combined with morphine in patients submitted to spinal anaesthesia: pilot studies.

We report the analgesic and adverse effects of intrathecally administered hyperbaric neostigmine, alone or combined with morphine, in two patients suffering from severe lower limb ischaemic pain (group 1), five patients undergoing Caesarean section (group 2) and 19 patients scheduled for orthopaedic surgery (group 3) under spinal anaesthesia. These patients were enrolled in three pilot studies undertaken before the initiation of the planned controlled studies. Hyperbaric neostigmine (50 micrograms in glucose 8%) produced analgesia lasting more than 6 h in patients of group 1, but the effect was accompanied by episodes of vomiting. A lower dose of hyperbaric neostigmine (25 micrograms), alone (two patients) or combined with morphine (50 micrograms) (one patient) produced no discernible analgesic effect but was followed by severe nausea and vomiting within 15 min of intrathecal injection in patients of group 2. Two patients who received hyperbaric morphine (100 micrograms) had analgesia for more than 24 h and exhibited mild pruritus. In patients of group 3, hyperbaric neostigmine alone (25 micrograms) produced analgesia of shorter duration than neostigmine (25 micrograms) plus morphine (50 micrograms) or morphine (100 micrograms). Neostigmine alone or combined with morphine was associated with adverse events, mainly nausea and vomiting that lasted up to 9-12 in some patients. Other adverse events observed included anxiety, somnolence and involuntary defaecation. Most patients who received the combination of neostigmine and morphine exhibited more severe nausea, vomiting and somnolence. The low clinical efficacy of intrathecally administered neostigmine alone or in combination with morphine impairs the design of a double-blind protocol and might restrict the clinical usefulness of the drug combination.

Analgesia, Obstetrical↗
PubMedDate not supplied

Postoperative analgesia by intraarticular clonidine and neostigmine in patients undergoing knee arthroscopy.

BACKGROUND AND OBJECTIVE: Clonidine and neostigmine have a central mechanism of analgesic action and are synergistic when given intrathecally. Both drugs also have a peripheral analgesic effect. The purpose of this study was to compare the analgesic effect of intraarticular clonidine and neostigmine, used separately and in combination, in patients undergoing knee arthroscopy. METHODS: Eighty-four American Society of Anesthesiologists (ASA) I and II patients scheduled for meniscus repair under arthroscopy were allocated randomly in 6 groups to receive in a double-blind manner at the end of surgery 150 microg of intraarticular clonidine with subcutaneous saline, 500 microg of intraarticular neostigmine with subcutaneous saline, an intraarticular combination of 150 microg of clonidine and 500 microg of neostigmine with subcutaneous saline, 150 microg of intraarticular clonidine with 500 microg of subcutaneous neostigmine, 500 microg of intraarticular neostigmine with 150 microg of subcutaneous clonidine, or intraarticular and subcutaneous isotonic saline. Postoperative pain scores were measured on a visual analog scale (VAS) at rest and on mobilization. Paracetamol (1 g) was given as a rescue medication when pain score was greater than 40. RESULTS: VAS scores at rest and on mobilization were lower in the first 5 groups compared with the intraarticular saline group (P <.05), but no significant difference was documented between the treated groups. The time to the first paracetamol administration was shorter in the saline group compared with the other groups, and the paracetamol demand was also higher in this group. Forty-five percent of the patients who had received clonidine had at least 1 episode of hypotension versus 4% of those who did not (P <.01). The incidence of bradycardia was 20% and 0%, respectively (P =.01). The incidence of nausea was not statistically different in patients who did and did not receive neostigmine (43% v. 36%, respectively). CONCLUSION: Intraarticular administration of 150 microg of clonidine, 500 microg of neostigmine, or both produce postoperative analgesia, and the combination is not more effective.

Adult↗
PubMed2001

Neostigmine increases postoperative colonic motility in patients undergoing colorectal surgery.

BACKGROUND: Gastrointestinal motility is frequently impaired after abdominal surgery. We investigated the effects of neostigmine on colonic motility in patients after colorectal surgery and in healthy volunteers. METHODS: Colonic motility was recorded by a manometry/barostat system in 12 patients after left colonic or rectal resection during baseline and after the intravenous administration of increasing doses of neostigmine on postoperative days 1, 2, and 3. In addition, colonic motility was recorded in 7 healthy volunteers. RESULTS: Neostigmine increased the colonic motility index. This increase was from 135 +/- 28 mm Hg/min at baseline to 574 +/- 219 mm Hg/min after administration of 5 microg/kg neostigmine on day 3 after surgery (mean +/- SEM, P <.05). In healthy volunteers, neostigmine at a dose of 5 microg/kg increased the colonic motility index from 184 +/- 73 to 446 +/- 114 mm Hg/min (P <.05). Barostat bag volumes decreased dose-dependently after neostigmine administration in patients as well as in volunteers, indicating an increase in colonic tone. CONCLUSIONS: Colonic motility and tone increased after neostigmine administration at a dose of 5 microg/kg in postoperative patients and in healthy volunteers. Neostigmine can be used to stimulate colonic motility after colorectal surgery and has a similar effect postoperatively as in healthy volunteers.

Adult↗
PubMed2000

Degradation kinetics of neostigmine in solution.

The degradation kinetics of neostigmine were studied in aqueous solutions with varied pH from 1.5 to 9.9 under accelerated storage conditions. The stability of neostigmine in solutions containing propylene glycol or polyethylene glycol 400 was also investigated. The reaction order of neostigmine in these aqueous and solvent systems followed pseudo-first-order degradation kinetics. The degradation rates of neostigmine under various buffer concentrations within the investigated pH range were obtained. They indicated that the degradation was independent of the species of buffering agent. Maximum stability of neostigmine was determined at pH 5.0 buffer species conditions. The activation energy could be estimated from the Arrhenius plot as 15.72 kcal/mole. The half-life of 883.7 days was estimated at room temperature in 0.1 M, pH 4.9 acetate buffer solution (mu = 0.5). Ultraviolet (UV) irradiation at 254 nm of the neostigmine solutions in pH 4.9 acetate buffer showed an accelerated degradation in comparison with light-protected samples. Incorporation of propylene glycol into the neostigmine solution at pH 4.9 enhanced the stability; however, an adverse effect on the stability of neostigmine was noted when a polyethylene glycol 400 solvent system was used.

Chromatography, High Pressure Liquid↗
PubMed1996

Dose-response relationships for neostigmine antagonism of rocuronium-induced neuromuscular block in children and adults.

Dose-response relationships for the antagonism of intermediate-acting neuromuscular blocking agents have not been evaluated previously in children. We have examined the dose-response relationships for neostigmine antagonism of 90% rocuronium-induced neuromuscular block in children and adults, during nitrous oxide-1 MAC of isoflurane anaesthesia. We studied 40 children, aged 2-10 yr, and 50 adults, aged 18-60 yr; all received a single bolus dose of rocuronium 0.6 mg kg-1 and accelerometry was used to monitor neuromuscular transmission. When the first twitch of the train-of-four (TOF) response (T1) recovered to 10% of its control (T0), one of five doses of neostigmine 0, 5, 10, 20 or 50 micrograms kg-1 was given by random allocation to each of the study groups (n = 8 children and n = 10 adults). Recovery of T1 and TOF ratio (T4/T1%) was recorded for 10 min after initial administration of neostigmine. Onset time of rocuronium-induced block was faster in children than in adults (mean 64.6 (95% confidence intervals 57.7-71.5) s vs 83.7 (70.7-96.6) s; P < 0.05). The time to 10% recovery of T1/T0 was shorter in children than in adults (25.4 (22.9-27.9) min vs 38.8 (36.1-41.4) min; P < 0.001). Spontaneous and antagonist-assisted recovery were more rapid in children than in adults. Adequate recovery (T4/T1 of 80%) occurred in children at 4, 5 and 8 min after neostigmine 50, 20 and 10 micrograms kg-1, respectively. Adequate recovery was not produced in adults by any dose of neostigmine within 10 min. The effective doses of neostigmine required to achieve a TOF ratio of 80% (ED80) after 10 min in children and adults were, respectively, 7.10 (5.2-9.8) micrograms kg-1 and 56.56 (45.5-71.9) micrograms kg-1 (P < 0.001). There was no advantage in administering doses of neostigmine greater than 20 micrograms kg-1 to antagonize 90% rocuronium-induced neuromuscular block in children. In contrast, it appeared prudent to use neostigmine 50 micrograms kg-1 or more for adequate antagonism of a similar degree of block in adults.

Adolescent↗
PubMed2003

Cross-tolerance between spinal neostigmine and morphine in the rat.

BACKGROUND: Direct or indirect acting cholinergic muscarinic agonists such as neostigmine, are potent antinociceptives when administered intrathecally (i.t.). This study examines whether spinal neostigmine tolerance and cross-tolerance to spinal morphine occurs. METHODS: Rats (32/group) were implanted with miniosmotic pumps delivering either i.t. saline 1 microl h(-1) (S), morphine 10 nmol microl(-1) h(-1) (M), or neostigmine 3 nmol microl(-1) h(-1) (N). Latencies (infrared thermal withdrawal rear paw) were measured daily for 6 days after which four animals from each group were given one i.t. challenge dose of morphine (m) 0.1, 1, 10, or 100 nmol, or neostigmine (n) 0.3, 3, 10, or 30 nmol. RESULTS: Neostigmine and morphine-infused animals both developed tolerance to spinal neostigmine, but neostigmine-infused animals showed no significant cross-tolerance to spinal morphine; mean ED(50) nmol (CI 95%) dose-response values were Sn 2.6 (1.9-3.5), Mn 15.6 (9.9-24.6)*, Nn 18.7 (11.7-29.8)*, Sm 0.7 (0.4-1.1), Nm 1.2 (0.8-2.0), Mm 152 (50-461)* (*significance vs saline infused control group). CONCLUSION: Thus, unidirectional cross-tolerance from morphine to neostigmine was evident. Previous studies suggest morphine has a cholinergic mechanism of action partially accounting for its antinociceptive effect, which may explain this observed unidirectional cross-tolerance.

Analgesics, Opioid↗
PubMed1997

Intrathecal neostigmine for post-cesarean section analgesia: dose response.

Intrathecal (IT) neostigmine produces analgesia in animals and humans and enhances systemic opioid analgesia. To examine the safety of IT neostigmine for eventual use in obstetrics, we studied 24 healthy, term pregnant patients scheduled to receive elective cesarean section using a combined spinal-epidural anesthetic. Using an open-label, dose-ranging design, patients received either IT placebo or neostigmine 10, 30, or 100 microg in a 1-mL solution of 5% glucose in normal saline followed in 15 min by 2% epidural lidocaine for cesarean section. Neostigmine did not affect fetal heart rate tracings or Apgar scores. The women received patient-controlled analgesia intravenous morphine postoperatively. Compared with the glucose control, neostigmine produced a dose-independent reduction in postoperative morphine use. Cumulative average 24-h morphine use was 82 +/- 7 mg for women receiving IT placebo and 50 +/- 8 mg for women receiving IT neostigmine (P < 0.003). Hourly morphine use was significantly reduced in the neostigmine groups for 10 h postoperatively. These data indicate that IT neostigmine can produce 10 h of post-cesarean section analgesia without adverse fetal effects and support cautious further prospective study.

Adult↗
PubMed2002

Intravenous regional anesthesia using prilocaine and neostigmine.

UNLABELLED: Neostigmine has been added to local anesthetics for central and peripheral nerve blocks resulting in prolonged, increased anesthesia and improved analgesia. We conducted this study to evaluate the effects of neostigmine when added to prilocaine for IV regional anesthesia (IVRA). Thirty patients undergoing hand surgery were randomly assigned to two groups to receive IVRA. The control group received 1 mL of saline plus 3 mg/kg of prilocaine diluted with saline to a total dose of 40 mL; the study group received 0.5 mg of neostigmine plus 3 mg/kg of prilocaine diluted with saline to a total dose of 40 mL. Sensory and motor block onset and recovery, anesthesia quality determined by an anesthesiologist, anesthesia quality determined by a surgeon, and dryness of the operative field were noted. Heart rate, mean arterial blood pressure, and oxygen saturation values were noted at 1, 5, 10, 20, and 40 min before surgery and after tourniquet release. Time to first analgesic requirement was also noted. Shortened sensory and motor block onset times, prolonged sensory and motor block recovery times, improved quality of anesthesia, and prolonged time to first analgesic requirement were found in the neostigmine group. We conclude that neostigmine as an adjunct to prilocaine improves quality of anesthesia and is beneficial in IVRA. IMPLICATIONS: Neostigmine has been added to local anesthetics for central and peripheral nerve blocks. This study was conducted to evaluate the effects of neostigmine when added to prilocaine for IV regional anesthesia (IVRA). Neostigmine as an adjunct to prilocaine improves quality of anesthesia and is beneficial in IVRA.

Adult↗
PubMed1981

Pharmacokinetics of edrophonium and neostigmine when antagonizing d-tubocurarine neuromuscular blockade in man.

The pharmacokinetics and effectiveness of edrophonium antagonism of d-tubocurarine neuromuscular blockade were compared with that of neostigmine in surgical patients anesthetized with halothane and nitrous oxide. After an intravenous (iv) injection of d-tubocurarine (0.3 mg/kg), the single twitch tension was allowed to return to five per cent of the control level. Edrophonium, 0.5 or 1.0 mg/kg (n = 12), or neostigmine, 0.07 mg/kg (n = 6), was then given iv in combination with atropine, 1.0 mg, as a 2-min controlled infusion. Train-of-four and single twitch tension were followed for 60 min in all patients. Twelve patients were monitored for 90 min, six patients for 120 min, four patients for 150 min, and two patients for 240 min. Blood was sampled intermittently for four hours and assayed for edrophonium or neostigmine using high-pressure liquid chromatography. Edrophonium was found to promptly antagonize the d-tubocurarine blockade. Twitch tension rapidly increased to a plateau (a rate of increase in twitch tension of less than 2 per cent of control per min) which was sustained in all cases. The mean time to plateau for edrophonium was 2.9 +/- 0.21 (+/-SE) min as compared to 6.1 +/- 0.75 min for neostigmine. Neuromuscular blockade did not reappear in any patient. The degree of antagonism of the neuromuscular blockade by neostigmine and edrophonium was not significantly different. Except for a longer distribution half-life, the pharmacokinetic variables for edrophonium did not differ significantly from those for neostigmine. The elimination half-lives of edrophonium and neostigmine were 110 +/- 34 min (mean +/- SD) and 77 +/- 47 min, respectively. The authors therefore conclude that edrophonium, 0.5-1.0 mg/kg, has pharmacokinetic variables comparable to neostigmine and produces prompt, sustained, and effective antagonism of d-tubocurarine neuromuscular blockade.

Adult↗
PubMed1986

Recovery times following edrophonium and neostigmine reversal of pancuronium, atracurium, and vecuronium steady-state infusions.

The ability of edrophonium and neostigmine to antagonize nondepolarizing neuromuscular blockade produced by steady-state infusions of atracurium, pancuronium, and vecuronium was studied in 71 adult patients anesthetized with nitrous oxide and halothane. Infusion rates of blocking drugs were adjusted so that single twitch depression as measured by the evoked integrated EMG of the hypothenar muscles was kept at 10% of control. Two minutes after the termination of the infusion either edrophonium (0.75 mg/kg) or neostigmine (0.05 mg/kg) was administered. Single twitch depression and train-of-four (T4/T1) fade was recorded during the recovery period. T4/T1 fade ratios observed at 20 min postreversal were 0.80 (atracurium-edrophonium); 0.76 (vecuronium-edrophonium); 0.44 (pancuronium-edrophonium); 0.95 (atracurium-neostigmine); 0.89 (vecuronium-neostigmine); and 0.68 (pancuronium-neostigmine). Under conditions of this study neostigmine produced more rapid and complete recovery than did edrophonium. Although edrophonium produced adequate antagonism of atracurium if 20-30 min were allowed to elapse, edrophonium reversal of pancuronium was rarely acceptable even at 30 min. Increasing the dose of edrophonium to 1.0 mg/kg produced single twitch values of 0.90 at 5 min postreversal but did not increase the rate of recovery of the train-of-four fade ratio. Neostigmine reversal of pancuronium, on the other hand, generally produced T4/T1 ratios of greater than 0.70 in 20-30 min. Although the pattern of recovery seen after reversal of vecuronium was in general quite similar to that seen after atracurium, two patients in the vecuronium-edrophonium group showed delayed recovery and also failed to respond significantly to subsequent doses of neostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

Atracurium↗
PubMed1993

Dose-response relationships for edrophonium and neostigmine antagonism of rocuronium bromide (ORG 9426)-induced neuromuscular blockade.

BACKGROUND: Rocuronium bromide (ORG 9426) is a new nondepolarizing muscle relaxant with a rapid onset but an intermediate duration of action. The dose-response relationships for neostigmine and edrophonium were studied during antagonism of neuromuscular block induced by rocuronium bromide. METHODS: Sixty-four ASA physical status 1 or 2 adults were given 0.6 mg/kg rocuronium bromide during thiopental-fentanyl-nitrous oxide-isoflurane anesthesia. Train-of-four (TOF) stimulation was applied to the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height reached 10% of its initial control value, edrophonium (0.1, 0.2, 0.4, or 1 mg/kg) or neostigmine (0.005, 0.01, 0.02, or 0.05 mg/kg) was administered by random allocation. Neuromuscular function in another eight subjects was allowed to recover spontaneously. Assisted recovery was defined as actual recovery minus mean spontaneous recovery in patients who were not given antagonists. RESULTS: The dose-response curves for neostigmine- and edrophonium-assisted antagonism of rocuronium bromide neuromuscular blockade for the single twitch and TOF ratio were not parallel. The doses of neostigmine required to achieve 50% and 80% recovery (ED50 and ED80, respectively) of the first twitch after 10 min were 0.017 (0.001) and 0.033 (0.001) mg/kg (mean (standard error of estimate for the mean)), respectively. Corresponding ED50 and ED80 values for edrophonium were 0.161 (0.001) and 0.690 (0.001) mg/kg, respectively. These values corresponded to neostigmine:edrophonium potency ratios of 9.5 (0.56) and 21 (0.67) for first twitch ED50 and ED80 height, respectively. The calculated doses producing ED50 of the TOF ratio at 10 min were 0.017 (0.001) and 0.469 (0.001) mg/kg for neostigmine and edrophonium, respectively. These values corresponded to a potency ratio of 27.5 (1.66). CONCLUSIONS: Under the conditions described in this study, if reversal was attempted at 10% first twitch recovery, edrophonium was less capable than neostigmine of reversing fade (potency ratio of 19.2 and 27.5 at 5 and 10 min, respectively) than first twitch (potency ratio of 6.7 and 9.5 at 5 and 10 min, respectively) during antagonism of rocuronium bromide-induced blockade. Edrophonium was found to be less effective than neostigmine at reversing rocuronium bromide-induced TOF fade.

Adult↗
PubMed1995

Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs.

BACKGROUND: The spinal delivery of the cholinesterase inhibitor neostigmine yields analgesia in rats and augments the analgesic effects of alpha 2 agonists in sheep. To assess its activity in humans, preclinical toxicology studies to define its safety were required in two species. METHODS: Rats with chronic intrathecal catheters received daily injections of saline (vehicle) or 5 micrograms/10 microliters or 10 micrograms/10 microliters neostigmine HCl (n = 6/group) for 4 days and were observed for general behavior and nociception (52.5 degrees C hot plate). On day 6, rats were anesthetized and submitted to whole body perfusion/fixation. For dog studies, male beagles were prepared following rigid aseptic precautions with catheters passed from the cisterna magna to the lumbar intrathecal space. Catheters were connected to an external vest-mounted pump. Based on preliminary studies, ten implanted dogs were randomly assigned to receive infusions of neostigmine for 28 days (4 mg/4 ml/day; n = 6) or saline (4 ml/day; n = 4). At 28 days, dogs were anesthetized, cisternal cerebrospinal fluid was obtained, and dogs were submitted to perfusion-fixation. Rat and dog spinal cords were embedded, sectioned, stained, and assessed by the pathologist without knowledge of treatment. RESULTS: In rats, neostigmine produced a dose-dependent increase in hot plate latency, and no tolerance was observed. Mild tremor was observed but was not debilitating. Histopathology revealed a mild fibrotic reaction to the catheter with mixed signs of moderate, acute, and chronic inflammation with no differences between saline or drug groups. In dogs, neostigmine had no effect on blood pressure or on the skin twitch response but produced bradycardia and an increase in muscle tone. At sacrifice, cerebrospinal fluid protein, specific gravity, and glucose were elevated in both saline and neostigmine groups. Histopathology displayed a local reaction to the spinal catheter and a mixed acute and chronic inflammatory reaction. No group differences were observed. These results suggest that, at the neostigmine concentration of 1 mg/ml in the rat and dog and in doses up to 4 mg/day in the dog, there is no evidence of spinal tissue toxicity that can be attributed to the drug. This result, observed in two species, suggests that intrathecal neostigmine given in this manner is without distinguishable toxicity in these two models.

Animals↗
PubMed1996

Pseudocholinesterase-mediated hydrolysis is superior to neostigmine for reversal of mivacurium-induced paralysis in vitro.

BACKGROUND: The metabolic hydrolysis of mivacurium (and succinylcholine) is markedly impaired in the presence of hereditary or acquired defects of pseudocholinesterase. Clinical reports are conflicting as to the utility of anticholinesterases, in the reversal of mivacurium paralysis. In the current study, the role of exogenous cholinesterases and/or of anticholinesterase, neostigmine, in the reversal of deep mivacurium-induced paralysis, was studied. The rat phrenic-diaphragm preparation, in a fixed volume of Krebs solution, was chosen to eliminate the confounding effects on the dissipation of neuromuscular effects caused by hydrolysis, elimination, and redistribution of the drug. METHODS: In the phrenic-diaphragm preparation, mivacurium was administered to obtain >90% single twitch inhibition. Single twitch responses (0.1 Hz) were monitored for 60 min, after which the response to train-of-four stimulation was tested. The reversal of mivacurium by 0.5, 1.0, or 2.0 units/ml of (true) acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase and by neostigmine, 0.1, 1.0, or 10.0 micrograms/ml tested. The efficacy of human plasma cholinesterase, 1 unit/ml in combination with each of the above neostigmine concentrations, also was examined. The reversal of succinylcholine-induced paralysis by the acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase (1 unit/ml) alone and in the presence of neostigmine (10.0 micrograms/ml) was additionally tested as a positive control. A train-of-four ratio > 0.75 was considered adequate reversal. RESULTS: Acetylcholinesterase was a poor hydrolyzer of mivacurium, as bioassayed by reversal of paralysis. Bovine pseudocholinesterase in concentrations of 0.5 and 1.0 units/ml did not effectively reverse single twitch and train-of-four responses by 60 min, but bovine pseudocholinesterase (2 units/ml) and all concentrations of human plasma cholinesterase did. Neostigmine alone, tested at all concentrations, was an incomplete reversal drug. Clinical or therapeutic concentrations (0.1 and 1.0 micrograms/ml) of neostigmine did not, but pharmacologic concentrations (10 micrograms/ml) interfere with the efficacy of human plasma cholinesterase (1 unit/ml). Bovine pseudocholinesterase and human plasma cholinesterase equally reversed the effects of succinylcholine but acetylcholinesterase did not, whereas the addition of 10 micrograms/ml neostigmine to the enzymes inhibited the reversal of succinylcholine. CONCLUSIONS: Human plasma cholinesterase will reverse mivacurium more effectively than bovine pseudocholinesterase, but both will effectively reverse succinylcholine. Acetylcholinesterase has no effects on either relaxant. The anticholinesterase neostigmine was an incomplete reversal drug. Pharmacologic concentrations of anticholinesterases do, while clinical or therapeutic concentrations do not, completely inhibit the metabolic activity of pseudocholinesterases.

Animals↗
PubMed1998

Effects of intrathecal neostigmine, bupivacaine, and their combination on sympathetic nerve activity in rats.

BACKGROUND: Intrathecal injection of local anesthetic agents is associated frequently with hypotension. Conversely, intrathecal administration of neostigmine increases blood pressure by enhancing the accumulation of acetylcholine in the spinal cord. The current study examined directly the interaction of intrathecal injection of bupivacaine and neostigmine on splanchnic sympathetic efferent nerve activity. METHODS: Experiments were performed in rats with intrathecal catheters implanted for the long-term. Rats were anesthetized with ketamine (40 mg/kg, intramuscularly) and alpha-chloralose (60 mg/kg, intraperitoneally). The skin incision sites were infiltrated with 1% lidocaine. Sympathetic efferent activity was recorded from the left greater splanchnic nerve. Sympathetic nerve activity was measured continuously before and after intrathecal injection of saline, 430 nmol (140 microg) of bupivacaine, 25 nmol (7.6 microg) of neostigmine, and a combination of bupivacaine and neostigmine all in volumes of 5 microl. Each group consisted of six animals. RESULTS: Compared with baseline nerve activity, intrathecal injection of neostigmine increased splanchnic sympathetic nerve activity significantly by (mean +/- SEM) 112 +/- 29% after an onset latency of 6.8 +/- 0.9 min. In contrast, bupivacaine decreased splanchnic nerve activity significantly (-65 +/- 13%) after a latency of 3.3 +/- 0.5 min after intrathecal administration. Similar to the effect of saline, intrathecal coadministration of bupivacaine and neostigmine did not alter the splanchnic sympathetic nerve activity significantly. CONCLUSIONS: The current study provides electrophysiologic evidence that intrathecal injection of neostigmine increases whereas bupivacaine decreases sympathetic nerve activity. Further, addition of neostigmine effectively counteracts the inhibitory effect of spinal bupivacaine on the sympathetic nerve activity.

Anesthetics, Local↗
PubMed1999

Dose-response effects of spinal neostigmine added to bupivacaine spinal anesthesia in volunteers.

BACKGROUND: Intrathecal adjuncts often are used to enhance small-dose spinal bupivacaine for ambulatory anesthesia. Neostigmine is a novel spinal analgesic that could be a useful adjunct, but no data exist to assess the effects of neostigmine on small-dose bupivacaine spinal anesthesia. METHODS: Eighteen volunteers received two bupivacaine spinal anesthetics (7.5 mg) in a randomized, double-blinded, crossover design. Dextrose, 5% (1 ml), was added to one spinal infusion and 6.25, 12.5, or 50 microg neostigmine in dextrose, 5%, was added to the other spinal. Sensory block was assessed with pinprick; by the duration of tolerance to electric stimulation equivalent to surgical incision at the pubis, knee, and ankle; and by the duration of tolerance to thigh tourniquet. Motor block at the quadriceps was assessed with surface electromyography. Side effects (nausea, vomiting, pruritus, and sedation) were noted. Hemodynamic and respiratory parameters were recorded every 5 min. Dose-response relations were assessed with analysis of variance, paired t tests, or Spearman rank correlation. RESULTS: The addition of 50 microg neostigmine significantly increased the duration of sensory and motor block and the time until discharge criteria were achieved. The addition of neostigmine produced dose-dependent nausea (33-67%) and vomiting (17-50%). Neostigmine at these doses had no effect on hemodynamic or respiratory parameters. CONCLUSIONS: The addition of 50 microg neostigmine prolonged the duration of sensory and motor block. However, high incidences of side effects and delayed recovery from anesthesia with the addition of 6.25 to 50 microg neostigmine may limit the clinical use of these doses for outpatient spinal anesthesia.

Adult↗
PubMed1996

Conditions to optimise the reversal action of neostigmine upon a vecuronium-induced neuromuscular block.

BACKGROUND: Since neostigmine was introduced for reversal of neuromuscular block, there has been controversy about the optimum dose for antagonizing neuromuscular block. The purpose of this study was to characterise recovery of neuromuscular transmission following a vecuronium-induced block 15 min after neostigmine administration using different stimulation patterns, and to determine the effects of different doses of neostigmine given at various pre-reversal twitch heights. METHODS: Adductor pollicis (AP) mechanical activity in response to low (0.1 and 2 Hz) and high (50 and 100 Hz) frequency stimulation, was recorded 15 min after 20, 40 and 80 micrograms/kg neostigmine, given to reverse a vecuronium-induced block at 10, 25 and 50% pre-reversal twitch height (TH). Fifty four ASA class I and II anaesthetised (methohexital, fentanyl, N2O/O2) young adult patients were studied and randomly allocated into 9 groups of 6 patients each. RESULTS: In contrast to twitch height (TH) and residual force after 50 Hz, 5 s tetanic stimulation (RF50Hz), the greater sensitivity of train-of-four (TOF) ratio and residual force after 100 Hz, 5 s tetanic stimulation (RF100Hz) points out the best reversal conditions (prereversal TH and the optimal neostigmine dose) (P < 0.001, two-way analysis of variance). The highest reversal scores (about 0.9 TOF ratio and RF100Hz) were obtained when 40 micrograms/kg of neostigmine was given at 25 and 50% TH. A 0.9 TOF ratio was also observed when 40 micrograms/kg of neostigmine was given at 10% TH, but, under these conditions, RF100Hz was only 0.6 (P < 0.05, Duncan test). CONCLUSION: To optimise the reversal action of neostigmine in order to obtain the highest neuromuscular transmission recovery (0.9 TOF ratio and RF100Hz) during a vecuronium-induced neuromuscular block, the 40 micrograms/kg dose has to be given at 25 to 50% recovery of TH.

Adolescent↗
PubMed1988

Effects of neostigmine and physostigmine on the acetylcholine receptor-ionophore complex in frog isolated sympathetic neurones.

1. The effects of neostigmine and physostigmine, reversible carbamate acetylcholinesterase (AChE)-inhibitors, on nicotinic acetylcholine-induced inward currents (IACh) were investigated in enzymatically isolated single sympathetic ganglion cells from the bullfrog. The 'concentration clamp' technique which combines intracellular perfusion with a rapid external solution change under single electrode voltage-clamp conditions was used. 2. Pretreatment with neostigmine and physostigmine did not enhance IACh at any concentrations, suggesting that AChE activity had already disappeared during the enzymatic treatment of the preparation. 3. Both neostigmine and physostigmine inhibited IACh in a dose-dependent manner with IC50 values of 7.0 x 10(-4) M and 1.1 x 10(-4) M, respectively. The blockade by neostigmine was competitive, while that by physostigmine was non-competitive. 4. The inhibition of IACh by neostigmine and physostigmine showed no apparent voltage dependency. 5. Neostigmine did not cause obvious changes of the kinetics of IACh. However, physostigmine reduced both the fast and slow time constants of inactivation of IACh, thus facilitating the rate of inactivation without affecting the activation kinetics of IACh. 6. These results suggest that neostigmine and physostigmine have different direct actions on the ACh receptor-ionophore complex. Neostigmine may act on the ACh-receptor (the binding site of ACh) while physostigmine may interact with the ACh-gated cation channels.

Animals↗