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1.
Anesthesiology ; 91(1): 119-26, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10422936

RESUMEN

BACKGROUND: The authors examined the plasma concentrations of the isomers of mivacurium and its pharmacodynamics during spontaeous and neostigmine-facilitated recovery after a mivacurium infusion. METHODS: Sixteen patients receiving nitrous oxide-opioid anesthesia received 0.25 mg/kg mivacurium. Patient response to neuromuscular stimulation was determined using a mechanomyograph Once T1 had recovered to 25% of its baseline height, a mivacurium infusion was begun and adjusted to maintain 95-99% neuromuscular block. The infusion was discontinued after 90 min and muscle strength allowed to recover either spontaneously or after neostigmine/glycopyrrolate (0.05/0.01 mg/kg). Plasma concentrations of the isomers of mivacurium after discontinuation of the infusion were determined using an HPLC assay. Differences between the groups were determined using a one-way analysis of variance with a Bonferroni-corrected t test or Student t test as appropriate. P < or = 0.05 was considered significant. RESULTS: Differences in the times for recovery to a train-of-four ratio of 70% did not achieve statistical significance (mean+/-SD, 13.3+/-6.0 vs. 16.3+/-2.5 min for the neostigmine and spontaneous groups, respectively). Plasma cholinesterase activity decreased significantly from baseline values after administration of neostigmine (5.88+/-0.21 vs. 0.43+/-0.04 U/ml plasma). Plasma concentrations of the trans-trans isomer were significantly greater in the neostigmine group than in the spontaneous recovery group 5, 6, 8, and 10 min after discontinuation of the infusion. Differences in the plasma concentration of the cis-trans isomer did not achieve statistical significance. CONCLUSIONS: Although administration of neostigmine decreased plasma cholinesterase activity and caused the trans-trans isomer to remain in the plasma at higher concentration, it did not delay recovery from mivacurium-induced block.


Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Isoquinolinas/farmacología , Neostigmina/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacología , Adulto , Humanos , Isoquinolinas/sangre , Masculino , Persona de Mediana Edad , Mivacurio , Unión Neuromuscular/efectos de los fármacos , Estereoisomerismo , Factores de Tiempo
2.
Anesth Analg ; 88(3): 648-53, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10072021

RESUMEN

UNLABELLED: The hypothesis of this study was that, in a given patient, recovery from a tracheal intubating dose of mivacurium would indicate the time course of spontaneous recovery after discontinuation of an infusion of mivacurium. Thirty-eight male patients consented to participate in the study. After induction of anesthesia and endotracheal intubation, the ulnar nerve was stimulated with train-of-four (TOF) stimuli at 12-s intervals. Patients received 0.3 mg/kg mivacurium in two evenly divided doses of 0.15 mg/kg each, separated by 30 s. Complete ablation of TOF responses occurred in most patients. Once the first twitch in the TOF (T ) had recovered to 25% of its baseline height, a mivacurium infusion was begun to maintain 95% suppression of T1. As surgery was nearing completion, the infusion was discontinued, and neuromuscular function was allowed to recover spontaneously. Data were analyzed for recovery intervals after the administration of the initial doses of mivacurium and after discontinuation of the infusion. Analysis of variance was used to determine the strength of correlation between the time from administration of the initial 0.3 mg/kg dose to 5% recovery of T1 and the times to recovery of TOF ratios of 70% and 90%. The 25%-75% recovery interval after discontinuation of the infusion ranged from 2.8 to 11.3 min. The time interval after administration of mivacurium 0.3 mg/kg to 5% recovery of T1 correlated with both the time to recovery of a TOF ratio of 70% and 90%. Recovery to a TOF of 90% after discontinuation of the infusion required approximately the same amount of time as recovery to 5% T1 after the administration of 0.3 mg/kg mivacurium. Each patient's recovery of neuromuscular function after discontinuation of a mivacurium infusion was related to his recovery after the administration of 0.3 mg/kg mivacurium. Therefore, the need for pharmacologic antagonism of block can be anticipated well before the end of an anesthetic. IMPLICATIONS: Mivacurium (0.3 mg/kg) was administered to 38 patients. As they began to recover muscle strength, a mivacurium infusion was begun and later discontinued as surgery was nearing completion. Each patient's early recovery (administration to 5% recovery of T1) after the initial dose of mivacurium correlated well with more complete recovery of muscle strength after discontinuation of an infusion. This relationship enables early prediction of recovery speed after a mivacurium infusion.


Asunto(s)
Periodo de Recuperación de la Anestesia , Isoquinolinas/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacología , Adulto , Anestesia General , Humanos , Intubación Intratraqueal , Isoquinolinas/farmacocinética , Masculino , Persona de Mediana Edad , Mivacurio , Fármacos Neuromusculares no Despolarizantes/farmacocinética
4.
J Clin Anesth ; 9(4): 328-30, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9195358

RESUMEN

We describe a case of difficult intubation, possibly due to marked pseudocholinesterase hyperactivity that caused rapid inactivation of succinycholine. Possible causes of difficult intubation and pseudocholinesterase hyperactivity are discussed. Literature on genetic variants associated with markedly increased pseudocholinesterase activity are reviewed. It is concluded that pseudocholinesterase hyperactivity may be a rare cause of difficult intubation. We recommend that pseudocholinesterase activity should be determined in all patients who appear to be resistant to the action of normal doses of succinylcholine or mivacurium.


Asunto(s)
Butirilcolinesterasa/sangre , Intubación Intratraqueal , Fármacos Neuromusculares Despolarizantes , Succinilcolina , Adulto , Dilatación y Legrado Uterino , Resistencia a Medicamentos , Femenino , Humanos , Embarazo , Embarazo Ectópico/cirugía
5.
Anaesthesist ; 46(10): 840-9, 1997 Oct.
Artículo en Alemán | MEDLINE | ID: mdl-9424966

RESUMEN

The benzylisochinoline muscle relaxants have a highly selective affinity to the motor endplate which is associated with an absence of autonomic side effects such as ganglionic and vagus block. The requirement of only low clinical doses also reduces histamine liberation. Muscle relaxants with high neuromuscular blocking potency have a slow onset. Both atracurium and cisatracurium undergo Hofmann-Elimination in the plasma whereas mivacurium is hydrolyzed by pseudocholinesterase. The difference in kinetics between these pathways render atracurium and cisatracurium muscle relaxants of intermediate duration of action while mivacurium is short acting. Cisatracurium, one of the ten stereoisomeres of atracurium, is 3 to 4 times as potent as atracurium, does not release histamine, has no cardiovascular side effects and, due to the small clinical doses resulting from its high neuromuscular blocking potency, produces only negligible quantities of laudanosine. Its ED95 is 0.05 mg/kg. Good intubation conditions can be expected within 1.5 to 2 min following 3- to 4-times the ED95. Thereafter is takes about 65 min for T1 to recover to 25% of control. Maintenance doses of 0.02 to 0.04 mg/kg have a duration of action of 15 to 20 min. An infusion of cisatracurium of 1.0 to 2.0 mcg/kg/min, is adequate to maintain a 90 to 95% neuromuscular block. The time of recovery is largely independent on the total dose of cisatracurium administered by either repeated injection or infusion. Mivacurium is a racemate of 3 stereoisomeres of which the trans-trans- and the cis-trans-compound account for 95% of the neuromuscular blocking effect. In adults the ED95 is 0.08 mg/kg. The ensuing recovery of T1 to 25% of control is about 15 min. Rapid injection of 3xED95 may transiently lower the arterial blood pressure and may produce skin flushing in an incidence of 30 to 40%. Larger doses should be injected slowly with 30 to 60 s. The onset of mivacurium neuromuscular block following 3xED95 is relatively slow (2 min). Maintenance doses of 0.05 to 0.1 mg/kg have a duration of action of 5 to 10 min. A 95% neuromuscular block may be maintained by an infusion of 3 to 12 micrograms/kg/min. The time of recovery does not depend on the total cumulative dose given by either repeated injection or by infusion. The duration of mivacurium neuromuscular block may be drastically prolonged in the presence of low or atypical plasmacholinesterase. Both neostigmine and edrophonium are suitable reversal agents. None of the presently available benzylisochinoline muscle relaxants has the potential to completely replace succinylcholine.


Asunto(s)
Anestesia , Atracurio/análogos & derivados , Isoquinolinas , Fármacos Neuromusculares no Despolarizantes , Atracurio/efectos adversos , Atracurio/farmacocinética , Humanos , Mivacurio , Fármacos Neuromusculares no Despolarizantes/efectos adversos , Fármacos Neuromusculares no Despolarizantes/farmacocinética
6.
Anesthesiology ; 85(1): 169-77, 1996 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-8694363

RESUMEN

BACKGROUND: Atracurium has four chiral centers and the marketed product is a mixture of ten optical and geometric isomers. Six of the isomers were prepared and evaluated for neuromuscular blocking activity and autonomic effects in anesthetized cats. This study reports the comparative pharmacology of the six isomers and atracurium that led to the selection of one isomer, cisatracurium (Nimbex, 51W89) for clinical development. METHODS: Purpose bred cats, anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital sodium (7 mg/kg) administered intraperitoneally, were used in this study. Neuromuscular blocking effects were assessed from the effects on the tibialis anterior twitch evoked at 0.15 Hz. Inhibition of the autonomic nervous system was assessed from the effects on the nictitating membrane contraction, in response to preganglionic sympathetic nerve stimulation and the bradycardia/vasodepressor responses to vagal nerve stimulation. Cardiovascular effects and plasma histamine concentrations were determined after a bolus injection of cisatracurium or atracurium. RESULTS: Like atracurium, all six isomers produced dose-dependent neuromuscular block (NMB). The calculated ED95NMB values varied approximately tenfold (43 +/- 2 microgram/kg -488 +/- 56 microgram/kg. The "R-series" isomers were more potent than the corresponding "S-series" isomers. With the exception of the S,Trans-S', Trans isomers, the NMB effects, i.e., onset times (range 2.6 +/- 0.2 min to 4.7 +/- 0.3 min) and total durations (range 9.9 +/- 1.4 min to 14 +/- 0.9 min), of the other five isomers were very similar to that atracurium. The former isomers had relatively short duration of action. The 25-75% recovery times after cisatracurium at 1 x ED95 (4.4 +/- 0.4 min), 4 x ED95 (4.5 +/- 0.4 min), and continuous infusions lasting at least 60 min that maintained 95-99% NMB (4.8% +/- 0.4 min) indicated a noncumulative effect. The vagal ID50:NMB ED95 ratios for atracurium and the six isomers ranged from 2 to 27. The sympathetic ID25:NMB ED95 ranged from 2.7 to 60. Atracurium and all of the isomers, except cisatracurium, produced cardiovascular effects after intravenous bolus administration at large doses (700-4,800 micrograms/kg). In contrast to atracurium, there were no changes in plasma histamine concentrations associated with the administration of doses of cisatracurium equivalent to 60X the NMB ED95 (62 +/- 8 micrograms/kg). CONCLUSIONS: Cisatracurium has neuromuscular blocking effects identical to those of atracurium, is more potent, and does not produce cardiovascular effects or increase plasma histamine concentrations.


Asunto(s)
Atracurio/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacología , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Gatos , Relación Dosis-Respuesta a Droga , Edrofonio/farmacología , Histamina/sangre , Masculino , Neostigmina/farmacología , Estereoisomerismo
8.
J Orthop Res ; 14(2): 273-81, 1996 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8648506

RESUMEN

Tenascin-C is an oligomeric glycoprotein of the extracellular matrix that is expressed in a variety of processes including development, tissue remodeling, wound healing, cell adhesion/antiadhesion, and cell/matrix interactions. Tenascin has recently been acknowledged as a component of the extracellular matrix of articular cartilage, but its function remains unclear. In this study, bovine articular chondrocytes were grown in alginate beads for 35 days to examine the kinetics of tenascin synthesis and incorporation into de novo extracellular matrix. During the culture period, 6 harvest days were established in which culture medium was recovered, alginate beads were dissociated with an EDTA solution, and chondrocytes were collected and lysed by sonication. Total DNA determination performed on the cell lysates demonstrated chondrocyte survival and proliferation. Western blotting performed on the medium, EDTA/alginate, and lysate samples demonstrated the production of both the 220 and 320 kDa tenascin size variants and their differential compartmentalization within the culture system. Tenascin was incorporated into the alginate bead matrix at a constant rate of 3.8 micrograms/day. The 320 kDa variant was produced in higher quantity, but the 220 kDa fragment was twice as likely to be incorporated into the de novo matrix. Methylene blue/acid fuchsin staining and tenascin immunohistochemistry demonstrated the incorporation of tenascin into a progressively expanding matrix surrounding the chondrocytes. The results suggest a role for tenascin in the assembly of the chondrocyte matrix and as a soluble mediator of chondrocytes with possible diverse functions for the tenascin size variants.


Asunto(s)
Cartílago Articular/citología , Matriz Extracelular/metabolismo , Tenascina/metabolismo , Animales , Western Blotting , Cartílago Articular/inmunología , Cartílago Articular/metabolismo , Bovinos , División Celular , Supervivencia Celular , Células Cultivadas , ADN/aislamiento & purificación , Inmunohistoquímica , Tenascina/biosíntesis
9.
Anesthesiology ; 84(2): 300-8, 1996 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-8602660

RESUMEN

BACKGROUND: Cisatracurium, one of the ten isomers in atracurium, is a nondepolarizing muscle relaxant with an intermediate duration of action. It is more potent and less likely to release histamine than atracurium. As one of the isomers composing atracurium, it presumably undergoes Hofmann elimination. This study was conducted to describe the pharmacokinetics of cisatracurium and its metabolites and to determine the dose proportionality of cisatracurium after administration of 2 or 4 times the ED(95). METHODS: Twenty ASA physical status 1 or 2 patients undergoing elective surgery under nitrous oxide/opioid/barbiturate anesthesia were studied. Patients received a single rapid intravenous bolus does of 0.1 or 0.2 mg x kg-1 (2 or 4 times the ED(95), respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio > or = 0.70 after cisatracurium-induced neuromuscular block. Plasma was extracted, acidified, and stored frozen before analysis for cisatracurium, laudanosine, the monoquaternary acid, and the monoquaternary alcohol metabolite. RESULTS: The clearances (5.28 +/- 1.23 vs. 4.66 +/- 0.67 ml x min(-1) x kg(-1) and terminal elimination half-lives (22.4 +/- 2.7 vs. 25.5 +/- 4.1 min) were not statistically different between patients receiving 0.1 mg x kg(-1) and 0.2 mg x kg(-1), respectively. Maximum concentration values for laudanosine averaged 38 +/- 21 and 103 +/- 34 ng x ml(-1) for patients receiving the 0.1 and 0.2 mg x kg(-1) doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101 +/- 27 and 253 +/- 51 ng x ml(-1), respectively. Monoquaternary acid was not quantified in any plasma sample. CONCLUSIONS: Cisatracurium undergoes Hofmann elimination to form laudanosine. The pharmacokinetics of cisatracurium are independent of dose after single intravenous doses of 0.1 and 0.2 mg x kg(-1).


Asunto(s)
Anestésicos por Inhalación , Anestésicos Intravenosos , Atracurio/farmacocinética , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Adulto , Anciano , Atracurio/administración & dosificación , Femenino , Fentanilo , Humanos , Isoquinolinas/farmacocinética , Masculino , Midazolam , Persona de Mediana Edad , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , Óxido Nitroso , Opio/farmacocinética , Estereoisomerismo , Tiopental
10.
J Pediatr Orthop ; 15(5): 682-90, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-7593586

RESUMEN

Epiphyseal replacement was performed via knee transplantation using donor tissue of different developmental times in a murine model. The performance of syngeneic donor tissue in a resection defect in 4-day-old mice of the same inbred strain was assessed over 2 weeks for cell viability, tritiated thymidine incorporation, and ability to attract a host blood supply, and at 2 months, with the existence of a joint and growth. Although there was variability within experimental groups, the syngeneic transplant was able to survive pending vascular invasion from the host. Growth occurred, although it never equaled normal growth. One possible approach to the difficult problem of joint reconstruction in the immature skeleton is to divide the endeavor into two parts: develop models of syngeneic joint transplantation in inbred strains of animals to assess the various problems that would occur were this tissue available and develop models of joint "synthesis" with autogeneic chondrocytes.


Asunto(s)
Epífisis/trasplante , Articulación de la Rodilla/cirugía , Animales , Animales Recién Nacidos , Epífisis/crecimiento & desarrollo , Fémur/irrigación sanguínea , Fémur/crecimiento & desarrollo , Fémur/metabolismo , Ratones , Ratones Endogámicos C57BL , Tibia/irrigación sanguínea , Tibia/crecimiento & desarrollo , Tibia/metabolismo
11.
Anesthesiology ; 82(5): 1131-8, 1995 May.
Artículo en Inglés | MEDLINE | ID: mdl-7537945

RESUMEN

BACKGROUND: Atracurium consists of a mixture of ten stereoisomers. One of these isomers, 51W89, is a potent intermediate-acting nondepolarizing neuromuscular blocking agent. Its ED95 is 0.05 mg.kg-1 in patients receiving nitrous oxide/opioid anesthesia. In preclinical trials, 51W89 did not show evidence of histamine release in cats at doses up to 80 times the human ED95. This study was undertaken to determine the cardiovascular effects and histamine-releasing properties of 51W89 in patients undergoing elective surgical procedures. METHODS: Sixty patients, ASA physical status 1 or 2, anesthetized with nitrous oxide/fentanyl/thiopental were studied. Patients received either 2 times the ED95 of atracurium or 51W89 or 4 or 8 times the ED95 of 51W89 as a rapid intravenous bolus under stable anesthesia, before surgical stimulation. Blood pressure and heart rate were measured by oscillometry and the electrocardiogram in patients receiving 2 times the ED95 of 51W89 or atracurium and by an intraarterial catheter and a tachograph triggered by the arterial pulse waveform in patients receiving 4 or 8 times the ED95 of 51W89. Maximal blood pressure and heart rate changes during the 5 min after administration of the muscle relaxant were recorded. Venous blood samples were obtained before the administration of relaxant and at 2 and 5 min after the administration of relaxant for determination of plasma histamine concentrations by radioenzymatic assay. RESULTS: Maximal blood pressure and heart rate changes in all groups of patients receiving 51W89 were small and similar to those observed in patients receiving 2 times the ED95 of atracurium. The mean maximum percent changes (+/- SE) in heart rate and mean arterial pressure were -0.6 +/- 1.5 and 0.4 +/- 2.5, respectively, in the group receiving 2 times the ED95 atracurium; -1.3 +/- 3.3 and 2.3 +/- 4.4, respectively, in the group receiving 2 times the ED95 51W89; -2.6 +/- 1.0 and 2.6 +/- 1.5, respectively, in the group receiving 4 times the ED95 51W89; and -2.4 +/- 1.5 and -1.0 +/- 1.3, respectively, in the group receiving 8 times the ED95 51W89. No patient developed a decrease in blood pressure > or = 20% or an increase in heart rate > or = 20% that was attributable to muscle relaxant administration. There was no dose-related change in plasma histamine concentration associated with the administration of 51W89. One patient in the study developed transient facial flushing after the administration of atracurium. CONCLUSIONS: 51W89 is a benzylisoquinolinium-type, nondepolarizing muscle relaxant that does not affect plasma histamine concentrations. No cutaneous flushing or clinically important cardiovascular effects were noted after rapid injection of doses up to and including 8 times its ED95 (0.4 mg.kg-1) in healthy patients undergoing elective surgical procedures.


Asunto(s)
Atracurio/farmacología , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Liberación de Histamina/efectos de los fármacos , Adulto , Anciano , Anestesia , Relación Dosis-Respuesta a Droga , Fentanilo/administración & dosificación , Humanos , Persona de Mediana Edad , Óxido Nitroso/administración & dosificación , Estereoisomerismo , Tiopental/administración & dosificación
12.
Anesthesiology ; 82(5): 1139-45, 1995 May.
Artículo en Inglés | MEDLINE | ID: mdl-7741288

RESUMEN

BACKGROUND: Atracurium is a mixture of ten stereoisomers. 51W89, one of these isomers, is a potent nondepolarizing intermediate-duration neuromuscular blocking agent. Preclinical studies have shown 51W89 to be significantly more potent than atracurium but with a similar neuromuscular blocking profile. This study was undertaken to establish the neuromuscular blocking potency and pharmacodynamics of 51W89 in patients undergoing elective surgical procedures. METHODS: Ninety-nine ASA physical status 1 or 2 patients undergoing elective surgical procedures under nitrous oxide/opioid/barbiturate anesthesia were studied. The neuromuscular blocking effect of 51W89 was assessed after administration of bolus doses from 0.015 to 0.4 mg/kg, as well as during and after continuous infusions from 11 to 249 min in length. RESULTS: The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.048 mg/kg. At 0.10 mg/kg, maximum block developed within 5.2 +/- 0.3 min, and recovery to 95% twitch height occurred 64.4 +/- 3.9 min after injection. At 0.4 mg/kg, onset was 1.9 +/- 0.1 min, and 95% recovery developed within 121.0 +/- 5.9 min. Comparative recovery indexes from 5% to 95% or from 25% to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.4 mg/kg (means ranged from 29.6 to 32.3 min and from 12.6 to 14.3 min, respectively). The average infusion rate necessary to maintain approximately 95% twitch suppression was 1.35 micrograms/kg/min. Recovery indexes from infusions were 5-95% 33.2 +/- 1.8 min and 25-75% 15.0 +/- 0.6 min, not differing significantly from recovery indexes from single bolus doses. Twenty-five patients received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at twitch height recovery of between 6% and 21%. Antagonism to 95% control twitch height developed within 6.8 +/- 0.3 min, and the neostigmine-accelerated 25-75% recovery index was 2.8 +/- 0.2 min. CONCLUSIONS: 51W89 is a potent nondepolarizing neuromuscular blocking agent that shows noncumulative intermediate-duration neuromuscular blocking pharmacodynamics.


Asunto(s)
Atracurio/farmacología , Unión Neuromuscular/efectos de los fármacos , Adulto , Anestesia , Barbitúricos/administración & dosificación , Relación Dosis-Respuesta a Droga , Humanos , Narcóticos/administración & dosificación , Neostigmina/farmacología , Óxido Nitroso/administración & dosificación , Estereoisomerismo
13.
Artículo en Inglés | MEDLINE | ID: mdl-8533538

RESUMEN

Mivacurium is a benzylisoquinolinium diester. The drug is a nondepolarizing relaxant which is hydrolysed by plasma cholinesterase at 70-88% of the rate of suxamethonium. Enzymatic hydrolysis gives the drug its short duration of action. The length of paralysis is about 2-2.5 times that of suxamethonium and one-half to one-third that of the intermediate-acting nondepolarizers. The development of mivacurium represents a collaboration between industrial pharmacologists and chemists at Burroughs Wellcome Co. (USA) and investigators at the Massachusetts General Hospital, Boston, MA, USA.


Asunto(s)
Isoquinolinas/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacología , Colinesterasas/sangre , Diseño de Fármacos , Industria Farmacéutica , Semivida , Hospitales Generales , Humanos , Hidrólisis , Isoquinolinas/antagonistas & inhibidores , Isoquinolinas/farmacocinética , Mivacurio , Fármacos Neuromusculares no Despolarizantes/antagonistas & inhibidores , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Succinilcolina/farmacocinética
14.
Artículo en Inglés | MEDLINE | ID: mdl-8533554

RESUMEN

The benzylisoquinolinium relaxants currently include the intermediate-acting agent, atracurium, and the short-acting agent, mivacurium. This class of relaxants has always retained the distinct advantages of rapid degradation, enzymatic metabolism, or both in the plasma, resulting in short half-lives and fast, complete recovery, unrelated to dose or duration of administration. Any improvements in this class of relaxants must focus on retaining this property at the same time as decreasing or eliminating histamine release, which has always been the major disadvantage of the benzylisoquinoliniums. The introduction of 51W89, an isomer of atracurium, may represent an advance in the development of this class of relaxants.


Asunto(s)
Predicción , Isoquinolinas , Fármacos Neuromusculares no Despolarizantes , Periodo de Recuperación de la Anestesia , Atracurio/administración & dosificación , Atracurio/farmacocinética , Diseño de Fármacos , Hipersensibilidad a las Drogas/etiología , Semivida , Liberación de Histamina , Humanos , Isomerismo , Isoquinolinas/administración & dosificación , Isoquinolinas/efectos adversos , Isoquinolinas/clasificación , Isoquinolinas/farmacocinética , Mivacurio , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , Fármacos Neuromusculares no Despolarizantes/efectos adversos , Fármacos Neuromusculares no Despolarizantes/clasificación , Fármacos Neuromusculares no Despolarizantes/farmacocinética
17.
Anesthesiology ; 80(6): 1296-302, 1994 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-8010476

RESUMEN

BACKGROUND: Mivacurium consists of a mixture of three stereoisomers: cis-trans (34-40%), trans-trans (52-60%), and cis-cis (4-8%). These isomers differ in potency (the trans-trans and the cis-trans isomers are equipotent and the cis-cis isomer is 1/13th as potent a neuromuscular blocking agent) and in rates of in vitro hydrolysis (in vitro half-lives are less than 2 min for the cis-trans and trans-trans isomers and 276 min for the cis-cis isomer). The current study was undertaken to determine the pharmacokinetic profile of the individual stereoisomers of mivacurium, to evaluate the dose-proportionality of the more potent trans-trans and cis-trans isomers, and to evaluate the pharmacodynamics of mivacurium in healthy adult patients receiving a consecutive two-step infusion of mivacurium. METHODS: Eighteen ASA physical status 1 or 2 adult male patients undergoing elective surgery under nitrous oxide/oxygen/fentanyl anesthesia were studied. Neuromuscular function was monitored using a mechanomyograph at a frequency of 0.15 Hz. An infusion of mivacurium was begun at 5 micrograms.kg-1.min-1. Sixty minutes later, the infusion rate was doubled to 10 micrograms.kg-1.min-1, and, 60 min after that, the infusion was discontinued. All patients were allowed to recover spontaneously from mivacurium-induced neuromuscular block. Venous blood samples were drawn for the determination of the plasma concentrations of each isomer of mivacurium by a stereospecific high performance liquid chromatographic method. Pharmacokinetic parameters were determined using noncompartmental analysis. RESULTS: During the 5-micrograms.kg-1.min-1 infusion, patients developed 83.2 +/- 13.6% neuromuscular block. Increasing the infusion to 10 micrograms.kg-1.min-1 increased the depth of block to 99.0 +/- 2.0%. After discontinuation of the infusion, patients returned to 25% of their baseline muscle strength in 9.3 +/- 3.7 min and had 25-75% and 5-95% recovery indexes of 7.2 +/- 1.8 and 16.8 +/- 3.7 min, respectively. The volumes of distribution (V beta) of the cis-trans, trans-trans, and cis-cis isomers were 0.29 +/- 0.24, 0.15 +/- 0.05, and 0.34 +/- 0.08 l/kg, respectively. During the 5-micrograms.kg-1.min-1 infusion, the steady-state clearances of the potent cis-trans and trans-trans isomers were 106 +/- 67 and 63 +/- 34 ml.min-1.kg-1, respectively; the clearance of the less potent cis-cis isomer was 4.6 +/- 1.1 ml.min-1.kg-1. The elimination half-lives of the cis-trans and trans-trans isomers were 1.8 +/- 1.1 and 1.9 +/- 0.7 min, respectively, and that of the cis-cis isomer was 52.9 +/- 19.8 min. Clearance of the cis-trans and trans-trans isomers did not vary with infusion rate. CONCLUSIONS: The short elimination half-lives and high metabolic clearances of the potent cis-trans and trans-trans isomers are consistent with the short duration of action of mivacurium. The cis-cis isomer does not appear to produce significant neuromuscular block as evident by the return of twitch height to baseline despite persistent cis-cis isomer concentrations.


Asunto(s)
Isoquinolinas/farmacocinética , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Adulto , Fentanilo , Humanos , Isoquinolinas/sangre , Masculino , Persona de Mediana Edad , Mivacurio , Bloqueo Nervioso , Unión Neuromuscular/efectos de los fármacos , Fármacos Neuromusculares no Despolarizantes/sangre , Óxido Nitroso , Oxígeno , Estereoisomerismo
18.
J Clin Anesth ; 5(5): 399-403, 1993.
Artículo en Inglés | MEDLINE | ID: mdl-8217176

RESUMEN

STUDY OBJECTIVE: To determine whether treatment with ondansetron, a new antiemetic drug, affects nondepolarizing neuromuscular blockade. DESIGN: Randomized, double-blind, prospective study. SETTING: Operating room at a university medical center. PATIENTS: 30 ASA physical status I and II patients scheduled for elective surgery. INTERVENTIONS: After the induction of anesthesia with midazolam 2 to 4 mg/kg, sodium thiopental 6 to 8 mg/kg, and fentanyl 4 to 8 micrograms/kg, the ulnar nerve was stimulated at the wrist through subcutaneous needle electrodes at a frequency of 0.15 Hz. The response to stimulation was measured and recorded with a force-displacement transducer applied to the thumb. Patients were randomized to one of three treatment groups. A steady baseline to ulnar nerve stimulation with nitrous oxide-oxygen-opioid-thiopental anesthesia was established. The first study group (Group 1) received a placebo, the second group (Group 2) received 8 mg of ondansetron, and the third group (Group 3) received 16 mg of ondansetron as an intravenous infusion over 5 minutes. Patients were then given incremental doses of atracurium 0.05 mg/kg at 3-minute intervals to establish approximately 95% twitch inhibition so as to construct a dose-response curve. An atracurium infusion was then begun to maintain a constant degree of neuromuscular blockade. At the end of surgery, patients were allowed to recover spontaneously, or pharmacologic antagonism of residual neuromuscular blockade was achieved with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Mechanomyographic response to train-of-four stimuli (2 Hz for 2 seconds) every 20 seconds was monitored during the atracurium infusion and recovery from neuromuscular blockade. MEASUREMENTS AND MAIN RESULTS: Log dose-response curves were determined for the study groups and compared using analysis of variance (ANOVA). The 50%, 75%, and 95% effective doses (ED50, ED75, and ED95) were calculated from the equation describing the log dose-response. Maintenance infusion rates were determined, and the neostigmine-accelerated recovery index of 25% to 75% was measured for each group. The results were compared using ANOVA. There were no significant differences among the treatment groups with respect to maintenance infusion rate (7.8 +/- 1.8 micrograms/kg/min for Group 1, 7.7 +/- 2.5 micrograms/kg/min for Group 2, and 7.3 +/- 2.3 micrograms/kg/min for Group 3) or neostigmine-accelerated recovery interval of 25% to 75% (4.5 +/- 2.3 minutes, 4.4 +/- 3.1 minutes, 6.6 +/- 3.9 minutes in Groups 1, 2, and 3, respectively). The log dose-response data for Groups 1, 2, and 3 did not differ significantly (p = 0.068), and the calculated ED95 in each treatment group demonstrated no dose-related change (0.254 +/- 0.022, 0.279 +/- 0.033, and 0.240 +/- 0.022 for Groups 1, 2, and 3, respectively). CONCLUSIONS: Ondansetron is an antiemetic drug that can be used in the perioperative period without concern for potentiation of nondepolarizing neuromuscular blockade, change in atracurium maintenance dose, or change in rate of neostigmine-induced recovery from neuromuscular blockade with atracurium.


Asunto(s)
Atracurio/farmacología , Náusea/prevención & control , Unión Neuromuscular/efectos de los fármacos , Ondansetrón/uso terapéutico , Vómitos/prevención & control , Adulto , Método Doble Ciego , Interacciones Farmacológicas , Procedimientos Quirúrgicos Electivos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
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