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PubMed2002

Intrathecal administration of liposomal neostigmine prolongs analgesia in mice.

BACKGROUND: There is substantial evidence that cholinomimetic drugs increase pain threshold. However, the profound side effects of these agents have limited their clinical use either as analgesics or as analgesic adjuncts. A delivery system that would assure a slow and sustained drug release may be of value in ameliorating the problem of untoward effects. METHODS: The acetylcholinesterase inhibitor neostigmine was encapsulated into multilamellar lipid vesicles composed of phosphocholine and cholesterol. Three doses of plain or liposomal neostigmine were administered by the intrathecal route to mice (n=8-10/group), and analgesic duration was quantified by tail flick test. The doses were chosen based on preliminary experiments, which showed the maximum tolerated intrathecal doses of plain and liposomal neostigmine formulation were 0.625 microg and 80 microg, respectively. Two other doses for each formulation were then derived by 1:1 serial dilutions. Results were compared using survival analysis. RESULTS: The median antinociceptive duration for plain neostigmine was 0.33, 0.99 and 1.0 h for the 0.115, 0.312 and 0.625 microg doses, respectively. For the liposomal formulation, the median antinociceptive duration was 1.0, 1.5 and 6.0 h for the 20, 40 and 80 microg doses, respectively. CONCLUSIONS: Liposomal neostigmine provides prolonged spinal antinociception, and permits the safe administration of a relatively large dose, because drug is gradually released from the liposomal depot. This technology holds promise for the development of a clinically useful neostigmine formulation to provide spinal analgesia.

Analgesia, Epidural↗

PubMed1992

Effect of intraperitoneal neostigmine on peritoneal transport characteristics in CAPD.

Lymphatics have been suggested to play a major role in the absorption of dialysate, which consequently affects the adequacy of peritoneal dialysis. Neostigmine has been found to decrease lymphatic absorption in rats, presumably by causing constriction of the lymphatic stomata. We investigated the effect of neostigmine on seven continuous ambulatory peritoneal dialysis (CAPD) patients in a prospective study. We performed modified peritoneal equilibration tests both with and without intraperitoneal neostigmine in a random order. Radiolabeled albumin (0.8 mg) was added to 2 liters of dialysate +/- 2.0 mg neostigmine. We evaluated ultrafiltration and creatinine, phosphate, and urea clearances. The dialysate bag and the peritoneum were scanned at the initiation and conclusion of the four-hour dwell period. We found no change in ultrafiltration, residual volumes, creatinine, phosphate and urea clearances, or albumin recovered. Of the seven patients exposed to neostigmine, four had diarrhea, abdominal cramps, nausea, and vomiting. In conclusion, we found that 2 mg i.p. neostigmine did cause significant side-effects and did not alter transport characteristics in CAPD patients.

Adult↗

PubMed2001

Lack of peripheral analgesia mediated by intraplantar administration of neostigmine in carrageenan-injected rats.

BACKGROUND AND OBJECTIVE: The aim of the study was to test the peripheral analgesic action of neostigmine. Intraplantar administration of neostigmine was studied in carrageenan-injected rats. METHODS: After assessing baseline values (T0) for paw circumference and the paw withdrawal threshold on both hind paws, the right hind paw was injected with 0.2 mL of 1% carrageenan and the left hind paw with 0.2 mL of saline (0.9% NaCl). Two hours later (T1), both hindpaws were tested for inflammation (paw circumference) and for hyperalgesia (paw withdrawal threshold) and subsequently 20 microg of neostigmine was injected in the right hind paw. The paw withdrawal threshold was tested again 10 (T2), 20 (T3) and 60 min (T4) and paw circumference 60 min (T4) after neostigmine injection. RESULTS: Carrageenan injection in the right hindpaw was associated with a decrease in the paw withdrawal threshold reflecting mechanical hyperalgesia (P < 0.001) and an increase in paw circumference reflecting oedema (P < 0.001) in the right hind paw when compared with the left side from T1 to T4. Neostigmine had no effect on paw circumference and the paw withdrawal threshold at measuring points T2, T3 and T4 when compared with T1 in the right hindpaw. CONCLUSION: Our results support the lack of peripheral analgesic effect of neostigmine.

Analgesics↗

PubMed1987

Neostigmine in the antagonism of the action of atracurium.

Antagonism of atracurium-induced neuromuscular blockade with neostigmine (one or two doses of 2.5 mg) was compared, using electromyography, with spontaneous recovery. Two levels of blockade were studied, one in which the initial response of the train-of-four has reached 10% of control and the other 50% of control. Adequate recovery was considered to be present when the ratio of the fourth response to the first (train-of-four ratio) had reached 70%. Neostigmine always accelerated recovery and "neostigmine block" was not detected. This acceleration of recovery after neostigmine was most marked with the greater degree of blockade, but two doses of neostigmine were no more effective than one. Spontaneous recovery to the train-of-four ratio of 70% was slow, in the order of 1 h after an initial dose of 0.5 mg kg-1 and 45 min after incremental doses of 0.2 mg kg-1. It is concluded that antagonism of atracurium with one dose of neostigmine is usually desirable, that two doses are unnecessary, and that spontaneous recovery is slower than is generally realized.

Atracurium↗

PubMed1989

Antagonism of moderate degrees of vecuronium-induced neuromuscular block by small doses of neostigmine.

We have studied the influence of a reduced dose of neostigmine on recovery from vecuronium-induced neuromuscular block in 26 adult patients, using electromyographic responses to train-of-four (TOF) stimulation. Neostigmine 10, 20 or 40 micrograms kg-1 was administered when the first response had recovered spontaneously to 5-10% or 40-50% of control. Antagonism was accepted as adequate when the first response reached 90% of control and the TOF ratio reached 0.7. At both degrees of spontaneous recovery, neostigmine 40 micrograms kg-1 evoked the most rapid antagonism. Clinical recovery was satisfactory with no differences between groups. Block produced by neostigmine was not observed. The pattern of recovery of the single response and the TOF ratio was not altered by neostigmine in the range of doses studied. We suggest that the dose of neostigmine should not be reduced below 40 micrograms kg-1 even when all responses of the TOF are present.

Adult↗

PubMed1993

Prejunctional action of neostigmine on mouse neuromuscular preparations.

We have studied the effects of neostigmine on the mouse diaphragm and triangularis sterni isolated nerve-muscle preparations. Mechanical responses of the muscle, end-plate potentials and miniature end-plate potentials, and extracellularly recorded nerve ending currents were recorded. In the mouse diaphragm nerve-muscle preparations, neostigmine 1 mumol litre-1 continued to produce some antagonism of tubocurarine-induced block after cholinesterase had been inactivated completely by diisopropyl fluorophosphate 22 mumol litre-1. In the mouse triangularis sterni preparation, neostigmine 0.1-1 mumol litre-1 increased the quantal content of the end-plate potential in a concentration-dependent manner. This effect appeared to be sufficient to account for the cholinesterase-independent antagonistic action to tubocurarine under the conditions of the experiments. Neostigmine 1-100 mumol litre-1 depressed the amplitude of the K+ currents of the perineural waveforms in a concentration-dependent manner, and this may account for its ability to increase the quantal content of the end-plate potential. Although inhibition of acetyl-cholinesterase is the main mechanism of action of neostigmine, the drug also exerts an additional direct action on motor nerve endings to block the delayed rectifier K+ channels and enhance transmitter release. This effect occurred at clinically relevant concentrations of neostigmine. Physostigmine and pyridostigmine did not possess this additional action.

Animals↗

PubMed1996

The effects of intrathecal neostigmine on somatic and visceral pain: improvement by association with a peripheral anticholinergic.

This study was designed to qualitatively evaluate the analgesic actions of intrathecal neostigmine alone and with intravenous (IV) N-butyl-scopolamine on somatic and visceral pain. Twenty-seven patients scheduled for both tubal ligation and vaginoplasty were divided into three groups. Patients received a standard anesthetic with thiopental, atracurium, and N2O/O2/enflurane. N-butyl-scopolamine, 20 mg, or saline was administered as a 2-mL IV bolus 20 min before the end of the surgical procedure. The control group (CG) received spinal and IV saline; the neostigmine group (NG), spinal neostigmine and IV saline; and the neostigmine-N-butyl-scopolamine group (NSG), spinal neostigmine and IV N-butyl-scopolamine. Postoperatively, patients assessed their pain on a 10-cm visual analog scale (VAS). The CG had both visceral and somatic pain at the first 30-min assessment, and all patients requested morphine. Patients from the NG had only visceral pain from the first assessment; however, they had lower VAS scores (P = 0.026) and requested less morphine (P = 0.037). Patients from the NSG were pain free during all assessment times (P < 0.0001). Neostigmine was more effective for somatic pain than visceral pain. N-butyl-scopolamine administration acted peripherally as an effective complement for treatment of visceral pain, reflecting an association between central cholinergic effects and peripheral anticholinergic effects in the treatment of visceral postoperative pain.

Adult↗

PubMed1996

Dose-response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty.

This study was designed to examine postoperative analgesia with intrathecal neostigmine in a randomized, blinded trial with morphine as the active control in patients undergoing anterior and posterior vaginoplasty. A secondary aim was to provide preliminary data on the interaction between these two drugs. The incidence of adverse effects was also assessed. Forty-eight patients were divided into eight groups (50 micrograms, 100 micrograms, and 200 micrograms morphine [M]; saline; 50 micrograms, 100 micrograms, and 200 micrograms neostigmine [N]; and 50 micrograms morphine + 50 micrograms neostigmine). Anesthesia was provided with a balanced technique. All patients stayed 24 h in the recovery room where adequacy of postoperative analgesia and side effects were assessed. Increasing doses of intrathecal morphine (50 micrograms, 100 micrograms, and 200 micrograms) and intrathecal neostigmine (50 micrograms, 100 micrograms, and 200 micrograms) showed a dose-dependent pattern of analgesia (P < 0.001). The M50 + N50 combination resulted in a better analgesic effect with fewer side effects than M50, N50, and control groups. These preliminary data suggest that spinal neostigmine produces analgesia for vaginoplasty surgery similar in duration to spinal morphine and that the combination of morphine and neostigmine may allow a reduction in the dose of each component for postoperative analgesia.

Adult↗

PubMed1996

Spinal neostigmine diminishes, but does not abolish, hypotension from spinal bupivacaine in sheep.

Spinal neostigmine causes analgesia in animals and humans and abolishes hypotension from spinal bupivacaine in rats. Since drug distribution and action can vary with the size of the spinal cord, we tested the effects of the maximum tolerated dose of spinal neostigmine alone and with bupivacaine in conscious sheep. Neostigmine alone increased arterial blood pressure by 10%, with a statistically significant increase beginning 30 min after injection. Compared with spinal bupivacaine alone, addition of neostigmine resulted in hypotension of slower onset (15 vs 5 min), shorter duration (45 vs 105 min), and smaller magnitude (-18% +/- 3% vs -37% +/- 6%). Addition of neostigmine did not affect height of sensory block from spinal bupivacaine. These data agree with preliminary clinical reports that spinal neostigmine diminishes, but does not abolish, hypotension from spinal bupivacaine in humans.

Analgesia↗

PubMed2001

Neostigmine combined with bupivacaine, clonidine, and sufentanil for spinal labor analgesia.

UNLABELLED: We previously found that spinal clonidine prolongs labor analgesia when combined with spinal bupivacaine and sufentanil. We sought to determine whether the addition of spinal neostigmine to these drugs would further enhance labor analgesia. By use of a combined spinal/epidural technique, 36 patients were randomized to receive a hyperbaric spinal injection of bupivacaine 2.5 mg plus clonidine 50 microg and sufentanil 10 microg with or without neostigmine 10 microg. Pain, maternal hemodynamics, fetal heart rate, nausea, pruritus, sedation, motor block, sensory levels to pinprick, and maternal oxygen saturation were assessed at regularly specified intervals after spinal injection until additional analgesia was requested. The duration of spinal analgesia was similar between groups (215 +/- 60 min in the Control group versus 205 +/- 62 min in the Neostigmine group). Likewise, pain scores, the duration of labor, Apgar scores, and side effects were similar between groups except that patients administered neostigmine experienced significantly more nausea and vomiting (53% vs 7%, P = 0.01). We conclude that spinal neostigmine 10 microg produces severe nausea and does not potentiate the duration of spinal analgesia in laboring women from spinal bupivacaine, clonidine, and sufentanil. IMPLICATIONS: Spinal neostigmine 10 microg as an adjunct to spinal bupivacaine, clonidine, and sufentanil produces severe nausea and fails to potentiate analgesia in laboring women.

Adjuvants, Anesthesia↗

PubMed1986

Neostigmine and edrophonium antagonism of varying intensity neuromuscular blockade induced by atracurium, pancuronium, or vecuronium.

To compare the time course of neostigmine and edrophonium antagonism of varying intensity neuromuscular blockade induced by atracurium, pancuronium, or vecuronium, the authors studied 98 patients anesthetized with nitrous oxide (60%) and halothane or enflurane. Neuromuscular blockade, as monitored by single stimulus-induced twitch tension (TT), was antagonized at varying degrees of spontaneous recovery (2-80% of control TT). Time to antagonism (time from injection of neostigmine or edrophonium to 90% recovery of control TT) was not different between edrophonium, 0.5 mg/kg, and neostigmine, 0.04 mg/kg, when spontaneous recovery had been allowed to occur to at least 11% of control TT prior to antagonist administration (P greater than 0.05). For profound neuromuscular blockade (TT less than or equal to 10% of control) induced by pancuronium or vecuronium, time (mean +/- SD) to antagonism with neostigmine, 0.04 mg/kg, was 7.0 +/- 2.2 min and 5.6 +/- 1.7 min, respectively, while the same for edrophonium, 0.5 mg/kg, was 20.0 +/- 8.0 min and 15.0 +/- 12.5 min, respectively (P less than 0.05). Time to antagonism of profound atracurium-induced neuromuscular blockade was 8.5 +/- 3.3 min for neostigmine, 0.04 mg/kg, and 9.8 +/- 7.0 min for edrophonium, 0.5 mg/kg, (P less than 0.05). For profound vecuronium-and pancuronium-induced neuromuscular blockade, time to antagonism by edrophonium, 1.0 mg/kg, was 4.6 +/- 3.0 min and 3.9 +/- 1.6 min respectively. The authors conclude that neostigmine, 0.04 mg/kg, antagonizes neuromuscular blockade within 12 min when TT is greater than 2% of control at time of reversal. When TT is greater than 10% of control, edrophonium, 0.5 mg/kg, produces similar time to antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1989

Dose-response relationships for edrophonium and neostigmine as antagonists of atracurium and vecuronium neuromuscular blockade.

To determine the potencies of edrophonium and neostigmine as antagonists of nondepolarizing neuromuscular blockade produced by atracurium and vecuronium, dose-response curves were constructed for both antagonists when given at 10% spontaneous recovery of first twitch height. Ninety ASA physical status 1 and 2 adults were given either 0.4 mg/kg atracurium or 0.08 mg/kg vecuronium during thiopental-nitrous oxide-enflurane anesthesia. Train-of-four stimulation was applied to the ulnar nerve every 12 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 ten subjects was allowed to recover spontaneously. Assisted recovery was defined as actual recovery minus mean spontaneous recovery observed in patients who were not given antagonists. First twitch recovery was initially more rapid when vecuronium was antagonized compared with atracurium, but no difference was detected after 10 min. At 10 min the neostigmine ED80 was 0.022 +/- 0.003 (SEM) mg/kg after atracurium and 0.024 +/- 0.003 mg/kg after vecuronium. The edrophonium ED80 was 0.44 +/- 0.11 mg/kg with atracurium and 0.46 +/- 0.12 mg/kg with vecuronium, giving a neostigmine:edrophonium potency ratio of 20. Atracurium train-of-four fade could be antagonized more easily with edrophonium, whereas that of vecuronium was more easily antagonized by neostigmine. It is concluded that edrophonium and neostigmine are not equally effective against atracurium and vecuronium.

Atracurium↗

PubMed1996

Interaction between intrathecal neostigmine and epidural clonidine in human volunteers.

BACKGROUND: alpha 2-Adrenergic agonists are thought to produce analgesia, in part, by activating spinal acetylcholine release. The purpose of the current study was to examine the interaction between intrathecal neostigmine and epidural clonidine for analgesia and side effects in humans. METHODS: A total of 58 volunteers received an intrathecal injection of 5% dextrose in normal saline (D5NS) or neostigmine (50, 100, or 200 micrograms in D5NS), followed in 1 h by epidural saline or clonidine (computer-controlled infusion targeted to 50, 100, 200, or 400 ng/ml in cerebrospinal fluid) using an isobolographic design. Visual analog scale pain to a noxious cold stimulus, nausea, weakness, sedation, and other safety variables was measured before and at specified intervals after drug administration. RESULTS: The first 21 volunteers randomized to receive intrathecal hyperbaric neostigmine rather than D5NS received the drug while in the sitting position, and had none-to-minimal analgesia 1 h later. The remaining volunteers received the drug while in the lateral position, and demonstrated dose-dependent analgesia in the foot 1 h later. Epidural clonidine also caused dose-dependent analgesia. The combination of neostigmine and clonidine resulted in an additive enhancement for analgesia, but no enhancement of each drug's side effects, and a reduction in clonidine-induced hypotension. Neostigmine injected into subjects in the lateral position diminished clonidine-induced reductions in blood pressure and plasma norepinephrine. CONCLUSION: These results support enhancement of alpha 2-adrenergic analgesia by intrathecal neostigmine, but do not demonstrate synergy, as observed in animals. Lack of enhancement of side effects suggests this combination may be clinically useful.

Acetylcholine↗

PubMed2003

Pharmacologic interaction between cannabinoid and either clonidine or neostigmine in the rat formalin test.

BACKGROUND: Although spinal cannabinoid receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not been investigated at the spinal level. Spinal alpha 2 receptor agonist (clonidine) and cholinesterase inhibitor (neostigmine) are also active in the modulation of nociception. The authors examined the properties of drug interaction after coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of cannabinoid 1 and 2 receptors in cannabinoid-induced antinociception at the spinal level. METHODS: Catheters were inserted into the intrathecal space of male Sprague-Dawley rats, and 50 microl of 5% formalin solution was injected into the hind paw to evoke the pain. Isobolographic analysis was used for evaluation of pharmacologic interaction. RESULTS: Intrathecal 55,212-2, clonidine, and neostigmine dose-dependently suppressed the flinching observed during phase 1 and 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by cannabinoid 1 receptor antagonist (AM 251) but not by cannabinoid 2 receptor antagonist (AM 630). No antinociceptive effect was seen after intrathecal administration of cannabinoid 2 receptor agonist (JWH 133). CONCLUSIONS: Intrathecal 55,212-2, clonidine, and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.

Adrenergic alpha-Agonists↗

PubMed1981

Comparison of physostigmine and neostigmine for antagonism of neuromuscular block.

The ability of physostigmine alone and in combination with neostigmine to reverse d-tubocurarine-induced neuromuscular block was evaluated in surgical patients. The relaxation was maintained at a level of 90% twitch suppression during balanced anesthesia, and antagonism was attempted with physostigmine 1.5 mg x 3; neostigmine 0.5 mg x 3; neostigmine 1.0 mg x 3; or with a combination of physostigmine 0.75 mg and neostigmine 0.5 mg x 3. The measured parameters included the twitch force or EMG amplitude of the adductor pollicis brevis muscle after supramaximal 0.1 Hz stimulation and fading of these responses after repetitive 2 and 50 Hz stimuli. Although the restitution rate of twitch height and EMG amplitude were essentially the same with both antagonists, there was a considerable time-lag in regeneration of the fades after repetitive stimuli with physostigmine as compared with the neostigmine group. The addition of physostigmine to a subeffective dose of neostigmine resulted in antagonism comparable to that seen in other groups. The clinical antagonism was satisfactory in all patients receiving physostigmine. The divergence of relaxation-indicating parameters (twitch responses and fades) after physostigmine suggests dissimilar modes of action of two antagonists at the neuromuscular junction.

Adult↗

PubMed1958

Comparison of the effects of eserine and neostigmine on the leech muscle preparation.

The relative potencies of eserine and neostigmine were determined on three preparations of cholinesterase. Eserine was found to be twice as potent as neostigmine on the pseudocholinesterase of horse plasma, half as potent on the true cholinesterase of cat central nervous system, but twelve times as potent on the true cholinesterase prepared from the leech body wall. On the leech preparation, about ten times smaller concentrations of eserine than of neostigmine were required to potentiate the acetylcholine response, but after removal of the anticholinesterase from the bath fluid, the potentiation persisted much longer after neostigmine than after eserine. The greater sensitivity of the leech muscle to eserine is fully accounted for by the fact that its cholinesterase is more sensitive to eserine than to neostigmine. The longer lasting potentiation after neostigmine on the other hand suggests that this anticholinesterase becomes more firmly attached to the cholinesterase receptors in this muscle than does eserine.

Acetylcholine↗

PubMed1962

A ganglion stimulating action of neostigmine.

The actions of neostigmine on transmission in the superior cervical ganglion have been investigated by means of the nictitating membrane preparation in the anaesthetized cat. Intravenous injections of neostigmine produced a rapid and often complete reversal of hexamethonium block, whereas eserine had no effect. This reversal by neostigmine was obtained regularly even after large doses of eserine or dyflos, but was sometimes brief. In ganglia perfused with heparinized plasma containing neostigmine (10(-8) to 10(-4)), there was no potentiation of the responses to maximal stimulation of the preganglionic nerve. Intra-arterial injections of neostigmine to both normal and preganglionically denervated ganglia produced first a potentiation of the responses to nicotine, then, with larger doses, a contraction of the nictitating membrane and, concurrently, a depression of the responses to nicotine. These results are consistent with the view that neostigmine exerts a direct stimulant action on the ganglion, which is distinct from its anticholinesterase action.

Animals↗

PubMed1986

The effect of chronic neostigmine treatment on channel properties at the rat skeletal neuromuscular junction.

We have studied the effects of chronic neostigmine treatment on single channel properties at the rat skeletal neuromuscular junction. Rats received 0.86 mg kg-1 neostigmine (s.c.) daily for 9-11 days. Microelectrode recordings were then made from the extensor digitorum longus muscle. The amplitude of miniature endplate potentials was significantly reduced in muscles from neostigmine-treated rats as compared with controls. Acetylcholine (2-5 microM) applied in the bath produced a depolarization and associated channel opening frequency (from voltage noise analysis) which were significantly reduced in neostigmine-treated muscles with respect to controls. The depolarization resulting from the opening of a single channel (from voltage noise analysis) and single channel open time and conductance (from current noise analysis) were not significantly changed by chronic neostigmine treatment. It is concluded that chronic neostigmine treatment causes an adaptive reduction in the number of functional acetylcholine receptors at the endplate without otherwise affecting single channel properties themselves.

Animals↗