Pancuronium Bromide for Chemical Immobilization of Adult Nile Crocodiles (Crocodylus niloticus): A Field Study.

(1) Background: Pancuronium bromide is a neuromuscular blocker used for immobilizing crocodiles that can be reversed with neostigmine. A recommended drug dose has only been established for saltwater crocodiles (Crocodylus porosus), mostly based on trials in juveniles and subadults. After trialing a dose recommendation in a small cohort of nine Nile crocodiles (Crocodylus niloticus), we developed and applied a new dose recommendation for large adult Nile crocodiles. (2) Methods: we trialed and adapted a pancuronium bromide (Pavulon 4 mg/2 mL) dose in Nile crocodiles originally established for saltwater crocodiles and applied the new dose for the immobilization of 32 Nile crocodiles destined for transport. Reversal was achieved with neostigmine (Stigmine 0.5 mg/mL). (3) Results: Nine crocodiles were included in the trial phase; the induction time was highly variable (average: 70 min; range: 20-143 min), and the recovery time was prolonged (average: 22 h; range: 50 min-5 days), especially in large animals after reversal with neostigmine. Based on these results, we established a dose-independent recommendation (3 mg pancuronium bromide and 2.5 mg neostigmine) for animals weighing ≥ 270 kg (TL ≥ ~3.8 m). When applied to 32 adult male crocodiles (BW range: 270-460 kg; TL range: 3.76-4.48 m), the shortest induction time was ~20 min and the longest ~45 min. (4) Conclusions: Pancuronium bromide and its antidote, neostigmine, are effective for the immobilization and reversal of adult male Nile crocodiles (TL ≥ 3.8 m or BW ≥ 270 kg) when given in a weight-independent fashion.

Predictive stability, novel HPLC-MS analysis and semi-automatic compounding process for the emergency implementation of a production line of pancuronium in injectable solution.

During the early months of the COVID-19 pandemic, the international medical product supply chain was tight, causing breaks in the availability of neuromuscular blocking agents essential for the treatment of patients in intensive care units. The present study describes the pharmaceutical development of an injectable 2 mg/mL solution of pancuronium bromide (PC) in a very short lapse of time. The sterile solution was compounded into a good manufacturing practice grade A clean room, filtered (0.2 µm) and filled into 10 mL type I glass, manually sealed with bromobutyl rubber stoppers. A novel HPLC-MS stability indicating method for pancuronium quantification and its degradation product was developed and validated. This fast, sensitive and straightforward method was used to study the stability of the formulation using a semi-predictive method, enabling a very fast attribution of a temporary shelf-life, which was confirmed by a classic prospective stability study. The production line and the analytical tools set-up were performed in six weeks and the semi-predictive stability study was conducted in 90 days, allowing us to predict a shelf life, which was successfully confirmed by prospective study. In conclusion, using innovative methods, we were able to rapidly overcome the shortage of a critical drug.

[Simultaneous determination of three quaternary ammonium muscle relaxants in blood by high performance liquid chromatography-tandem mass spectrometry].

Vecuronium, rocuronium, and pancuronium are widely used as non-depolarizing muscle relaxants. There have been occasional cases of allergic reactions and even death when using such muscle relaxants. Rapid determination of the concentration of these muscle relaxants in blood can provide valuable information for early clinical diagnosis. As quaternary ammonium compounds, these muscle relaxants are highly polar. Hence, they cannot be retained effectively on reversed-phase chromatographic columns with conventional mobile phases. These quaternary ammonium muscle relaxants are mainly separated by ion-pair chromatography. Using an ion-pairing reagent can help improve the retention capabilities of quaternary ammonium muscle relaxants. Nevertheless, the sensitivity of MS detection is significantly decreased because of ionic inhibition caused by the ion-pairing reagent in the mobile phase. Furthermore, ion-pairing reagents can pollute the MS system. A method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was established for the simultaneous determination of the three quaternary ammonium muscle relaxants in blood. The blood samples were diluted and subjected to high-speed centrifugation. The supernatant was purified on a Bond Elut AL-N solid phase extraction column and then filtered through a 0.45 µm microporous membrane. The quaternary ammonium muscle relaxants were separated on a ZIC-cHILIC analytical column (50 mm×2.1 mm, 3.0 µm) with gradient elution. Acetonitrile and 0.1% formic acid aqueous solution were used as mobile phases. The separated compounds were analyzed by tandem MS with an electrospray ionization (ESI) source in positive and multiple reaction monitoring (MRM) modes. The matrix effects of vecuronium, rocuronium, and pancuronium in blood were 88.1% to 95.4%. The calibration curves for vecuronium, rocuronium, and pancuronium showed good linear relationships in each range, and all correlation coefficients (R2) were > 0.996. The limits of detection of vecuronium, rocuronium, and pancuronium were 0.2-0.8 ng/mL, with the corresponding limits of quantification being 0.5-2.0 ng/mL. The recoveries of vecuronium, rocuronium, and pancuronium were 92.8% to 110.6%, with relative standard deviations (RSDs) of 3.2%-9.4%. This method is sensitive, accurate, and easy to operate, and it can be used to rapidly determine vecuronium, rocuronium, and pancuronium in blood.

Association between levobupivacaine and pancuronium. Interference in neuromuscular transmission and blockade in rats

ABSTRACT PURPOSE: To evaluate the effects of levobupivacaine on neuromuscular transmission and neuromuscular blockade produced by pancuronium in vitro. METHODS: Thirty rats were distributed into groups (n = 5) according to the drug used alone or in combination: Group I - levobupivacaine (5 µg.mL-1); Group II - pancuronium (2 µg.mL-1); Group III - pancuronium (2 µg.mL-1) + levobupivacaine (5µg.mL-1). The following parameters were evaluated: 1) amplitude of diaphragmatic response to indirect stimulation, before and 60 minutes after the addition of levobupivacaine and pancuronium alone, and after the addition of levobupivacaine combined with pancuronium; 2) membrane potentials (MP) and miniature endplate potentials (MEPP). RESULTS: Levobupivacaine alone did not alter the amplitude of muscle response and MP. In preparations previoulsy exposed to levobupivacaine, the block with pancuronium was significantly denser (90.2 ± 15.2%), showing a significant difference (p=0.031) in comparison to the block produced by pancuronium alone (48.9% ± 9.8%). There was a decrease in the frequency and amplitude of MEPPs. CONCLUSION: Levobupivacaine potentiated the neuromuscular blockade produced by pancuronium, confirming a presynaptic action by a decrease in miniature endplate potentials.

Pancuronium enhances isoflurane anesthesia in rats via inhibition of cerebral nicotinic acetylcholine receptors.

PURPOSE: This study was conducted to elucidate the mechanism of enhancement of volatile anesthetics by neuromuscular blocking agents in rats and to consider the relevance of this enhancement to clinical anesthesia. METHODS: Male Sprague-Dawley rats were used. After confirming a movement in response to tail clamping under 1.1 % isoflurane anesthesia, response was determined when the tail clamp was applied at several points after microinjection of pancuronium into the lateral ventricle. Arousal responses to microinjection of nicotine into the lateral ventricle were assessed with or without pretreatment with intraventricular pancuronium. The intravenous 50 % effective dose (ED50) and 95 % effective dose (ED95) for neuromuscular blockade with pancuronium administered in a cumulative fashion at 1.1 % isoflurane were calculated. RESULTS: Intraventricular pancuronium dose-dependently reduced the response to tail clamping, and the dose required to show immobilization of 50 % of rats (intraventricular ED50) was 1.62 µg/kg. Pretreatment with pancuronium at 6 µg/kg significantly reduced the effect of awakening by nicotine under isoflurane anesthesia (P = 0.044). The intravenous ED50 and ED95 for neuromuscular blockade were 63 µg/kg (90 % confidence interval [CI] 52-75 µg/kg) and 133 µg/kg (90 % CI 109-158 µg/kg), respectively. The ratio of intraventricular ED50 to intravenous ED50 was 0.026. CONCLUSION: Pancuronium microinjection into the lateral ventricle dose-dependently enhances the depth of isoflurane anesthesia, which might be caused by inhibition of neuronal nicotinic acetylcholine receptor transmission in the cerebrum. Intravenous injection of pancuronium at high doses might increase the cerebrospinal concentration to a level at which an effect can be observed.

Lethal drugs in capital punishment in USA: History, present, and future perspectives.

Lethal injection is the preferred method for the execution of condemned prisoners in the United States. A recent decision of The European Union to prohibit the export of drugs used in capital punishment to the USA along with domestic firms ceasing to manufacture these drugs has resulted in a drug shortage and a search for alternative drugs and new drug combinations that have not been previously validated for inducing death. As a consequence, some of the executions did not proceed as expected and sparked public debate regarding whether recent executions by lethal injection serve the purpose of avoiding "cruel and unusual punishment" in executions. Moreover, a cottage industry comprised of compounding pharmacies as emerged as a source of drug combinations used in capital punishment. Although there is a growing trend toward the abolishment of capital punishment in United States, the controversy concerning the efficacy of drug and involvement of health care professionals in the execution procedure is far from over.

Downregulation of nicotinic and muscarinic receptor function in rats after subchronic exposure to diazinon.

Diazinon (DZN) is an organophosphate insecticide which exerts its effect through the inhibition of acetylcholinesterase enzyme (AChE). In this work, we studied the development of tolerance to subchronic p.o. administration of DZN in rats, under both in vivo and in vitro conditions. A group of 20 rats (2 groups, n = 10) was administered p.o. the 1/10 of established LD50 DZN (namely 55.87 mg/kg bw) for 28 days. On the 14th and 28th day of study with isolated diaphragm and ileum, we examined the downregulation of nicotinic and muscarinic receptor function through Electrical Field Stimulation (EFS). Maximum contractility of the diaphragm was recorded on the 14th day of the study (25% higher compared to the non-treated rats), while on the 28th day the contractions almost did not differ from the values found in non-treated rats. EFS of isolated ileum on the 14th day of study caused significantly higher contractions compared to the non-treated rats, but after 28 days, ileum contractions decreased approximately to the level of contractions in non-treated rats. On the 14th study day, we also recorded increased amplitude of spontaneous ileum contractions, compared to non-treated rats. The application of increasing ACh concentrations caused dose-dependent ileum contractions, without statistically significant differences of median effective concentration (EC50) values in non-treated and treated rats. Tolerance to subchronic DZN administration develops due to various adaptation mechanisms, including the most important one-downregulation of nicotinic and muscarinic receptor function.

Tugging force: A new objective index for evaluating acute changes in neuromuscular function in mice.

INTRODUCTION: Many agents, including muscle relaxants, influence neuromuscular function. Although in vitro and in situ measurement systems of skeletal muscular contractility have been developed and in use for years, no convenient device and parameter are available to examine the time course of the acute effects of such agents on neuromuscular function in conscious mice. METHODS: We created a two-compartment device consisting of a transparent, wide, acrylic chamber with a foot shock grid, and an attached, opaque narrow tunnel to measure neuromuscular performance. A mouse placed into the wide chamber, quickly enters the narrow tunnel. We attached a string to the tail of the mouse to measure the developed tugging force when the mouse entered the narrow tunnel. RESULTS: After administering the muscle relaxants suxamethonium, vecuronium, and pancuronium, the peak tugging force decreased maximally at 3 or 5 min after administration, and recovered within 20 min. These responses to the muscle relaxants were dose-dependent. DISCUSSION: Tugging force is an objective and reproducible parameter for examining the time course of an acute change in neuromuscular function.

Effect of ropivacaine combined with pancuronium on neuromuscular transmission and effectiveness of neostigmine and 4-aminopyridine for blockade reversal: experimental study / Efeito da associação ropivacaina-pancurônio na transmissão neuromuscular e eficácia da neostigmine e 4-aminopiridina na reversão do bloqueio: estudo experimental / Efecto de la asociación ropivacaína-pancuronio en la transmisión neuromuscular. Eficacia de la neostigmina y 4-aminopiridina en la reversión del bloqueo. Estudio experimental

BACKGROUND AND OBJECTIVES: The local anesthetic effects on neuromuscular junction and its influence on blockade produced by nondepolarizing neuromuscular blockers are still under-investigated; however, this interaction has been described in experimental studies and in humans. The aim of this study was to evaluate in vitro the interaction between ropivacaine and pancuronium, the influence on transmission and neuromuscular blockade, and the effectiveness of neostigmine and 4-aminopyridine to reverse the blockade. METHODS: Rats were divided into groups (n = 5) according to the study drug: ropivacaine (5 µg mL-1); pancuronium (2 µg mL-1); ropivacaine + pancuronium. Neostigmine and 4-aminopyridine were used at concentrations of 2 µg mL-1 and 20 µg mL-1, respectively. The effects of ropivacaine on membrane potential and miniature endplate potential, the amplitude of diaphragm responses before and 60 min after the addition of ropivacaine (degree of neuromuscular blockade with pancuronium and with the association of pancuronium-ropivacaine), and the effectiveness of neostigmine and 4-aminopyridine on neuromuscular block reversal were evaluated. RESULTS: Ropivacaine did not alter the amplitude of muscle response (the membrane potential), but decreased the frequency and amplitude of the miniature endplate potential. Pancuronium blockade was potentiated by ropivacaine, and partially and fully reversed by neostigmine and 4-aminopyridine, respectively. CONCLUSIONS: Ropivacaine increased the neuromuscular block produced by pancuronium. The complete antagonism with 4-aminopyridine suggests presynaptic action of ropivacaine. .

JUSTIFICATIVA E OBJETIVOS: Os efeitos dos anestésicos locais na junção neuromuscular e sua influência no bloqueio produzido por bloqueadores neuromusculares não-despolarizantes é ainda alvo de pouca investigação, no entanto esta interação tem sido descrita em trabalhos experimentais e em humanos. O objetivo deste estudo foi avaliar in vitro, a interação da ropivacaína com o pancurônio, a influência na transmissão e bloqueio neuromuscular e a efetividade da neostigmina e 4-aminopiridina na reversão do bloqueio. MÉTODO: Ratos foram distribuídos em grupos (n = 5) de acordo com o fármaco estudado: ropivacaína (5 µg mL-1); pancurônio (2 µg mL-1); ropivacaína + pancurônio. A neostigmina e a 4-aminopiridina foram usadas nas concentrações de 2 µg mL-1 e 20 µg.mL-1, respectivamente. Avaliou-se: 1) efeitos da ropivacaína sobre o potencial de membrana e potenciais de placa terminal em miniatura; 2) a amplitude das respostas do diafragma antes e 60 minutos após a adição da ropivacaína; o grau de bloqueio neuromuscular com o pancurônio e com a associação pancurônio - ropivacaína; 3) a efetividade da neostigmina e 4-aminopiridina na reversão do bloqueio neuromuscular. RESULTADOS: A ropivacaína não alterou a amplitude das respostas musculares, os potenciais de membrana, mas diminuiu a frequência e a amplitude dos potenciais de placa terminal em miniatura. O bloqueio produzido pelo pancurônio foi potencializado pela ropivacaína, e parcial e totalmente revertido pela neostigmina e 4-aminopiridina, respectivamente. CONCLUSÕES: A ropivacaína potencializou o bloqueio neuromuscular produzido pelo pancurônio. O antagonismo completo com a 4-aminopiridina sugere ação pré-sináptica da ropivacaína. .

JUSTIFICACIÓN Y OBJETIVOS: Los efectos de los anestésicos locales en la unión neuromuscular y su influencia en el bloqueo producido por bloqueantes neuromusculares no-despolarizantes todavía son poco investigados, sin embargo, esta interacción ha sido descrita en trabajos experimentales y en seres humanos. El objetivo de este estudio fue evaluar in vitro la interacción de la ropivacaína con el pancuronio, la influencia en la transmisión y bloqueo neuromuscular y la efectividad de la neostigmina y 4-aminopiridina en la reversión del bloqueo. MÉTODO: Unos ratones fueron distribuidos en grupos (n = 5) de acuerdo con el fármaco estudiado: ropivacaína (5 µg/ml-1); pancuronio (2 µg/ml-1); ropivacaína + pancuronio. La neostigmina y la 4-aminopiridina fueron usadas en concentraciones de 2 µg/ml-1 y 20 µg/ml-1, respectivamente. Evaluamos: 1) efectos de la ropivacaína sobre el potencial de membrana y potenciales de placa terminal en miniatura; 2) la amplitud de las respuestas del diafragma antes y 60 min después de la adición de la ropivacaína; el grado de bloqueo neuromuscular con el pancuronio y con la asociación pancuronio-ropivacaína; 3) la efectividad de la neostigmina y 4-aminopiridina en la reversión del bloqueo neuromuscular. RESULTADOS: La ropivacaína no alteró la amplitud de las respuestas musculares, los potenciales de membrana, pero disminuyó la frecuencia y la amplitud de los potenciales de placa terminal en miniatura. El bloqueo producido por el pancuronio fue potenciado por la ropivacaína, y parcial y totalmente revertido por la neostigmina y 4-aminopiridina, respectivamente. CONCLUSIONES: La ropivacaína potenció el bloqueo neuromuscular producido por el pancuronio. El antagonismo completo con la 4-aminopiridina muestra una acción presináptica de la ropivacaína. .

[Effect of ropivacaine combined with pancuronium on neuromuscular transmission and effectiveness of neostigmine and 4-aminopyridine for blockade reversal: experimental study]. / Efeito da associação ropivacaina-pancurônio na transmissão neuromuscular e eficácia da neostigmine e 4-aminopiridina na reversão do bloqueio: estudo experimental.

BACKGROUND AND OBJECTIVES: The local anesthetic effects on neuromuscular junction and its influence on blockade produced by nondepolarizing neuromuscular blockers are still under-investigated; however, this interaction has been described in experimental studies and in humans. The aim of this study was to evaluate in vitro the interaction between ropivacaine and pancuronium, the influence on transmission and neuromuscular blockade, and the effectiveness of neostigmine and 4-aminopyridine to reverse the blockade. METHODS: Rats were divided into groups (n=5) according to the study drug: ropivacaine (5µgmL(-1)); pancuronium (2µg.mL(-1)); ropivacaine+pancuronium. Neostigmine and 4-aminopyridine were used at concentrations of 2µgmL(-1) and 20µgmL(-1), respectively. The effects of ropivacaine on membrane potential and miniature end-plate potential, the amplitude of diaphragm responses before and 60minutes after the addition of ropivacaine (degree of neuromuscular blockade with pancuronium and with the association of pancuronium-ropivacaine), and the effectiveness of neostigmine and 4-aminopyridine on neuromuscular block reversal were evaluated. RESULTS: Ropivacaine did not alter the amplitude of muscle response (the membrane potential), but decreased the frequency and amplitude of the miniature end-plate potential. Pancuronium blockade was potentiated by ropivacaine, and partially and fully reversed by neostigmine and 4-aminopyridine, respectively. CONCLUSIONS: Ropivacaine increased the neuromuscular block produced by pancuronium. The complete antagonism with 4-aminopyridine suggests presynaptic action of ropivacaine.

Effect of 50% enantiomeric excess bupivacaine mixture combined with pancuronium on neuromuscular transmission in rat phrenic nerve-diaphragm preparation; a pilot study.

BACKGROUND AND AIMS: Local anaesthetics are drugs that are widely used in clinical practice. However, the effects of these drugs on the neuromuscular junction and their influence on the blockade produced by non-depolarising neuromuscular blocking drugs are still under investigation. The aim of this study was to evaluate, in vitro, the influence of a 50% enantiomeric excess bupivacaine mixture on neuromuscular transmission and neuromuscular block produced by pancuronium. METHODS: Rats were distributed into three groups (n = 5) according to the drug studied namely, 50% enantiomeric excess bupivacaine mixture (5 µg/mL); pancuronium (2 µg/mL); 50% enantiomeric excess bupivacaine mixture + pancuronium. The following parameters were evaluated: (1) Effects of a 50% enantiomeric excess bupivacaine mixture on membrane potential (MP) and miniature endplate potentials (MEPPs); (2) amplitude of diaphragmatic response before and 60 min after the addition of a 50% enantiomeric excess bupivacaine mixture; the degree of neuromuscular block with pancuronium and pancuronium combined with a 50% enantiomeric excess bupivacaine mixture. RESULTS: A 50% enantiomeric excess bupivacaine mixture did not alter the amplitude of muscle response (MP) but decreased the frequency and amplitude of MEPP. The block produced by pancuronium was potentiated by a 50% enantiomeric excess bupivacaine mixture. CONCLUSION: A 50% enantiomeric excess bupivacaine mixture used alone did not affect neuromuscular transmission, but potentiated the neuromuscular block produced by pancuronium. No action was shown on the muscle fibre, and alterations on MEPPs demonstrated a presynaptic action.

Haemodynamic differences between pancuronium and vecuronium in an experimental pig model.

OBJECTIVE: To compare baseline cardiovascular function in anesthetised pigs using either pancuronium or vecuronium as a neuromuscular blocker. STUDY DESIGN: Retrospective, non-randomized comparison. ANIMALS: Norwegian Land Race pigs (Sus scrofa domesticus) weighing mean 42 ± SD 3 kg. METHODS: One hundred and sixteen animals from four different research protocols premedicated with identical doses of ketamine, diazepam, atropine and isoflurane, and anaesthetised with pentobarbital, fentanyl, midazolam and N(2)O were arranged into three uniform groups with respect to neuromuscular blocking agent: pancuronium bolus of 0.063 mg kg(-1) followed by 0.14 mg kg(-1) hour(-1) (n = 54), low-dose vecuronium 0.4 mg kg(-1) /0.2 mg kg(-1) hour(-1) (n = 29) and high-dose vecuronium 0.6 mg kg(-1) /0.3 mg kg(-1) hour(-1) (n = 33). RESULTS: The majority of cardiovascular parameters demonstrated no significant differences between groups. For heart rate, there was an overall group difference, p = 0.036. Dromotropy was low in the pancuronium group, with an increased normalised PR-interval compared to the high-dose vecuronium group, median 0.200 interquartile range (0.190, 0.215) versus 0.182 (0.166, 0.199), p < 0.05. Left ventricular compliance was increased in pancuronium-treated animals, demonstrated as a reduction in the nonlinear end-diastolic pressure volume relationship ß compared to both vecuronium groups, 0.021 (0.016, 0.025) versus 0.031 (0.025, 0.046) and 0.031 (0.022, 0.048), p < 0.05. The linear end-diastolic pressure volume relationship EDPVR(lin) was reduced as well in the pancuronium group, compared to the low-dose vecuronium group, 0.131 (0.116, 0.169) versus 0.181 (0.148, 0.247), p < 0.05. CONCLUSIONS: There are only minor haemodynamic differences when using pancuronium compared to vecuronium in the fentanyl-pentobarbital-midazolam-N(2)O anesthetised domestic pigs. Furthermore, increasing doses of vecuronium have minimal haemodynamic effects. CLINICAL RELEVANCE: Experimental studies in pigs using either pancuronium or vecuronium as a neuromuscular blocking agent are comparable with regard to cardiac and haemodynamic performance.

The effect of defasciculating doses of pancuronium and atracurium on succinylcholine neuromuscular blockade.

BACKGROUND: A defasciculating dose of non-depolarizing muscle relaxant administered prior succinylcholine decrease its side effects including fasciculations and postoperative myalgias; however it is believed that the dosage of succinylcholine should be increased when such a pre-treatment is used. OBJECTIVES: We hypothesized that a defasciculating dose of pancuronium as a pre-treatment could prolong its duration of effect. PATIENTS AND METHODS: Forty patients scheduled for elective orthopaedic surgery were consecutively assigned into 5 groups, a first group without pre-treatment (succinylcholine 1 mg/kg) and 4 subsequent groups of pretreatment with atracurium 0.05 mg/kg + succinylcholine 1 or 1.5 mg/kg and pancuronium 7.5 µg /kg + succinylcholine 1 and 1.5 mg/kg. The muscle relaxant effect of succinylcholine was assessed with a force transducer using train of four stimulations every 12 seconds. Kruskall Wallis Anova test was used to compare results. RESULTS: The duration of succinylcholine induced paralysis (1 and 1.5 mg/kg) was significantly prolonged with pre-treatment with pancuronium but succinylcholine 1mg/kg did not reached maximum blockade after pre-treatment with atracurium. After pancuronium, full recovery after succinylcholine 1.5 and 1 mg/kg occurred respectively after 18 and 15 minutes. P < 0.05 vs. 12 minutes for succinylcholine 1mg/kg alone. CONCLUSIONS: This study highlights potentiation effect of a defasciculating dose of pancuronium on succinylcholine paralysis suggesting the lack of justification to increase succinylcholine dosage.

Study on neuromuscular blockade action of verapamil in albino rats.

BACKGROUND: Calcium Channel Blockers (CCBs) are now widely employed in the treatment of cardiovascular diseases and peri operative hypertension. It has been reported that calcium channel blockers inhibit neuromuscular transmission. They have been shown to increase the neuromuscular blockade produced by neuromuscular blocking agents in in-vitro muscle nerve preparations. The present study is undertaken to demonstrate the effect of calcium channel blocker, verapamil on neuromuscular transmission in albino rats. OBJECTIVES: To study the neuromuscular blockade action of verapamil in albino rats. METHODS: Twenty four albino rats of either sex weigh 150-250gms are selected and are randomly divided into 4 equal groups. The experimental rats are divided into four groups of 6 rats each and they are given the following treatment. Group 1(Control) - Normal saline (1ml/ kg), Group 2 (Standard) - Pancuronium (0.04 mg/kg) Group 3-Verapamil (2.5mg/kg), Group 4-given Verapamil (10mg/kg). The time of onset of hind limb paralysis and total duration of recovery are noted using inclined screen method. RESULTS: Analysis of the results of group 3 that was received 2.5mg/kg of Verapamil, there was no onset of paralysis, in group 4 that received injection Verapamil 10mg/kg, showed neuromuscular blockade activity. The mean onset of hind limb paralysis was delayed compared to standard group and the mean duration of hind limb paralysis was shorter than standard group. It was statistically significant (P≤ 0.05). INTERPRETATION AND CONCLUSION: It is generally held that external calcium is not necessary for the contraction of mammalian skeletal muscle, the demonstration of inward calcium currents that can be abolished by CCBs in these muscles prompted to re-examine the effect of Verapamil on the neuromuscular transmission. The present study allows us to determine the neuromuscular blockade activity of Verapamil.

Cellular exposure to muscle relaxants and propofol could lead to genomic instability in vitro.

Anesthesia is widely used in several medical settings and accepted as safe. However, there is some evidence that anesthetic agents can induce genomic changes leading to neural degeneration or apoptosis. Although chromosomal changes have not been observed in vivo, this is most likely due to DNA repair mechanisms, apoptosis, or cellular senescence. Potential chromosomal alterations after exposure to common anesthetic agents may be relevant in patients with genomic instability syndromes or with aggressive treatment of malignancies. In this study, the P388 murine B cells were cultured in vitro, and spectral karyotyping (SKY) was utilized to uncover genome-wide changes. Clinically relevant doses of cisatracurium and propofol increased structural and numerical chromosomal instability. These results may be relevant in patients with underlying chromosomal instability syndromes or concurrently being exposed to chemotherapeutic agents. Future studies may include utilization of stimulated peripheral blood lymphocytes to further confirm the significance of these results.

Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity.

1. Pancuronium, cisatracurium and vecuronium are antinicotinic agents that, in contrast with d-tubocurarine and hexamethonium, exhibit anticholinesterase activity. Pancuronium-, cisatracurium- and vecuronium-induced fade results from blockade of facilitatory nicotinic receptors on motor nerves, but fade produced by such agents also depends on the presynaptic activation of inhibitory muscarinic M2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A1 receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A2A receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM241385, an antagonist of presynaptic facilitatory A2A receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve-diaphragm (PND) preparation. 2. The muscles were stimulated indirectly at 75±3Hz to induce a sustained tetanizing muscular contraction. The lowest concentration at which each antinicotinic agent produced fade without modifying initial tetanic tension (presynaptic action) was determined. 3. d-Tubocurarine-induced fade occurred only at 55 nmol/L, a concentration that also reduced maximal tetanic tension (post-synaptic action). At 10 nmol/L, ZM 241385 alone did not produce fade, but it did attenuate pancuronium (0.32 µmol/L)-, cisatracurium (0.32 µmol/L)- and vecuronium (0.36 µmol/L)-induced fade. 4. The fade induced by the 'pure' antinicotinic agents d-tubocurarine (55 nmol/L) and hexamethonium (413 µmol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A2A receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity.

Investigation of the cardiac effects of pancuronium, rocuronium, vecuronium, and mivacurium on the isolated rat atrium.

BACKGROUND: Pancuronium, vecuronium, rocuronium, and mivacurium are nondepolarizing neuromuscular blocking agents that affect the cardiovascular system with different potencies. Their cardiovascular effects are clinically significant in the anesthetic management of patients, particularly those undergoing cardiac surgery. OBJECTIVE: We aimed to compare the cardiac effects of these compounds, such as heart rate and developed force, in one species under identical experimental conditions in isolated rat atria. METHODS: The left or right atria of rats were removed and suspended in organ baths. Pancuronium, vecuronium, rocuronium, or mivacurium were added cumulatively (10(-9)-10(-5) M) in the presence and absence of the nonselective ß-blocker propranolol (10(-8) M) and the noradrenaline reuptake inhibitor desipramine (10(-7) M), and heart rate changes were recorded in spontaneously beating right atria. Left atrial preparations were stimulated by electrical field stimulation using a bipolar platinum electrode, and the effects of cumulative concentrations of these nondepolarizing neuromuscular blocking agents on the developed force in the presence and absence of propranolol (10(-8) M) and desipramine (10(-7) M) were recorded. RESULTS: Pancuronium increased heart rate in a dose-dependent manner compared with the control group (P < 0.027). Vecuronium, rocuronium, and mivacurium also increased heart rate in a dose-dependent manner, but the changes were not statistically significant. Although propranolol decreased the pancuronium heart rate effect (P < 0.05), it did not change the heart rate effects with vecuronium, rocuronium, or mivacurium. Desipramine did not change the heart rate effects of vecuronium, rocuronium, mivacurium, or pancuronium. All 4 drugs increased developed force in a dose-dependent manner; the increases were significant at 10(-5) M concentration for pancuronium and at 10(-6) and 10(-5) M concentrations for vecuronium, rocuronium, and mivacurium (P < 0.038). These increases in developed force were abolished with the addition of propranolol. Desipramine did not change the developed force effects of any of the 4 drugs. CONCLUSIONS: The heart rate effect of pancuronium and developed force effects of pancuronium, vecuronium, rocuronium, and mivacurium may occur via direct stimulation of ß receptors. Although our investigation was an in vitro study, the effects found may be important especially under pathologic conditions, such as hypertension, in which patients usually use ß-blocking agents, which cause ß receptor upregulation.

Anestesia peribulbar com ropivacaína como alternativa ao bloqueio neuromuscular para facectomia em cães / Peribulbar anesthesia with ropivacaine as an alternative to neuromuscular blocking agents for cataract surgery in dogs

Desenvolveu-se uma técnica de bloqueio peribulbar comparando-a à técnica de anestesia oftálmica com bloqueio neuromuscular parcial em cães submetidos à facectomia extracapsular. Doze cães, de diferentes raças, foram alocados em dois grupos (G1 e G2) e anestesiados com acepromazina (0,05mg/kg, IV) e propofol (5mg/kg, IV) e mantidos com isofluorano sob ventilação espontânea. Os cães do G1 receberam o bloqueio peribulbar com ropivacaína 0,75 por cento, e os do G2 o bloqueio neuromuscular parcial com brometo de pancurônio (0,01mg/kg, IV). Utilizaram-se, como parâmetros comparativos, escores de posicionamento do globo ocular, controle do reflexo oculocardíaco e pressão intraocular (mmHg). Foi possível propor uma técnica eficaz para cães baseando-se na técnica de bloqueio peribulbar posterior realizada no homem. Em ambos os grupos, o globo ocular permaneceu centralizado. Não ocorreram alterações eletrocardiográficas atribuídas ao reflexo oculocardíaco. Houve redução significativa da pressão intraocular em G1 após o bloqueio (10,7±0,6 e 14,7±0,6). Conclui-se que o bloqueio peribulbar proporcionou condições cirúrgicas apropriadas para a realização da facectomia, com a vantagem de promover bloqueio sensitivo do olho.

A peribulbar block technique was developed and its clinical efficacy was compared with neuromuscular blockade in dogs undergoing cataract surgery. Twelve dogs of different breeds were randomly and equally allocated in two groups. After given acepromazine (0.05mg/kg, IV), anesthesia was induced with propofol (5mg/kg, IV) and maintained with isoflurane in oxygen during spontaneous breathing. A peribulbar block with 0.75 percent ropivacaine was performed in G1 dogs while partial neuromuscular blockade with pancuronium (0.01mg/kg IV) was provided in G2 dogs. Globe position scores, oculocardiac reflex, and intra-ocular pressure (mmHg) were evaluated at pre-defined intervals during surgery. Peribulbar blocks were successful performed according to posterior peribulbar block described in humans. In both groups, the globe was centralized and globe position scores did not differ between groups. The intra-ocular pressure was significantly lower in G1 after the block (10.7±0.6 vs 14.7±0.6). There were no electrocardiographycal changes attributed to the oculocardiac reflex. In conclusion, satisfactory surgical conditions were provided by the peribulbar block. This technique can be used as an alternative to the use of neuromuscular blocking agents in dogs undergoing cataract surgery, with the advantage of providing analgesia of the eye.

Hemodynamic Effects of Vecuronium, Pancuronium and Rocuronium during O2-Midazolam-Fentanyl Anesthesia in Patients with Coronary Artery Disease or Valvular Heart Diseases / 대한마취과학회지

BACKGROUND: This study was designed to evaluate the hemodynamic effects of vecuronium, pancuronium and rocuronium in patients with coronary artery disease (CABG) or valvular heart disease (VHD). METHODS: With IRB approval, 121 patients (61 patients with CABG and 60 patients with VHD) were randomly divided into a vecuronium, pancuronium and rocuronium group, respectively. Midazolam and fentanyl were administered and then 3 times of ED95 of a muscle relaxant (vecuronium, 0.12 mg/kg; pancuronium, 0.12 mg/kg; or rocuronium, 0.9 mg/kg) was injected. Additional dose of fentanyl was given and the patient was intubated. Hemodynamic variables were measured before the induction of anesthesia, just prior and 1 min after the administration of the muscle relaxant, just before intubation, 5 and 10 min after intubation. RESULTS: The number of patients enrolled in the CABG-vecuronium, CABG-pancuronium, CABG- rocuronium, VHD-vecuronium, VHD-pancuronium, and VHD-rocuronium was 20, 20, 21, 19, 20, and 21 respectively. Each of 10, 4, 4, 5, 1, and 1, respectively, were treated for hypotension or bradycardia during the induction of anesthesia. The heart rate (HR) changed significantly only in the CABG- vecuronium group compared with the control value. All three muscle relaxants decreased mean systemic artery pressure (MAP) significantly in both CABG and VHD patients. The decrease in HR and MAP were significantly greater in CABG-vecuronium and VHD-vecuronium than in CABG-pancuronium and VHD-pancuronium, respectively. The decrease in HR was also greater in VHD-vecuronium than in VHD-rocuronium. Cardiac index (CI) decreased in CABG-vecuronium and all VHD patients. The decrease in CI was greater in CABG-vecuronium than in CABG-pancuronium but it was not significantly different among the three muscle relaxants in VHD patients. CONCLUSIONS: While pancuronium and rocuronium exerted minimal hemodynamic effects, vecuronium reduced HR and MAP more significantly than pancuronium in both CABG and VHD patients, and CI also decreased more significantly with vecuronium in CABG patients.

Does Perioperative Monitoring of the Train-of-Four Response Influence the Frequency of Postoperative Residual Curarization in Propofol Anesthesia? / 대한마취과학회지

BACKGROUND: Sometimes hypoxemia occurs in the postoperative recovery room because of postoperative residual curarization (PORC). Some reports show that postoperative residual curarization is common. PORC occurs after the use of the long-acting muscle relaxants. It has been recommended to use intermediate-acting muscle relaxants and a TOF monitor to decrease PORC. The purpose of this study was to examine whether the use of the TOF monitor during propofol anesthesia affects the incidence of postoperative residual curarization. METHODS: 38 ASA I or II patients were divided randomly into two groups of 19 each. They received propofol-fentanyl-nitrous oxide for anesthesia. Pancuronium (80 100 microgram/kg) was used to facilitate tracheal intubation and additional doses were used to maintain surgical relaxation. The requirement for incremental doses of pancuronium and adequacy of recovery following reversal were assessed, either with (control group:n = 19) or without (experimental group:n = 19) TOF monitoring. Fifteen minutes after the arrival at the recovery room, neuromuscular function was assessed clinically and by using TOF. RESULTS: There were no statistical differences in body weight, age, or duration of operation between the two groups. There was no statistical difference in the total dose of pancuronium and total dose of pancuronium relative to body weight and duration of operation. There were statistical differences in TOF ratio in the recovery room (0.73 vs. 0.86). The incidence of PORC was 47% in the control group and 5% in the experimental group. CONCLUSIONS: Though the monitoring of TOF did not effect the dose of muscle relaxant, it may have reduced the incidence of PORC. However, the PORC had no clinical significance because the mean TOF ratio in the two groups was over 0.7 and there were no clinical signs of residual muscle weakness.