RESUMEN
Concordant results of functional magnetic resonance imaging (fMRI) and behavioral tests prove that some non-blood-brain barrier-penetrating drugs produce robust central nervous system (CNS) effects. The anticholinergic scopolamine interferes with learning when tested in rats, which coincides with a negative blood-oxygen-level-dependent (BOLD) change in the prefrontal cortex (PFC) as demonstrated by fMRI. The peripherally acting butylscopolamine also evokes a learning deficit in a water-labyrinth test and provokes a negative BOLD signal in the PFC. Donepezil-a highly CNS-penetrating cholinesterase inhibitor-prevents the negative BOLD and cognitive deficits regardless whether the provoking agent is scopolamine or butylscopolamine. Interestingly, the non-BBB-penetrating cholinesterase inhibitor neostigmine also prevents or substantially inhibits those cognitive and fMRI changes. Intact cerebral blood flow and optimal metabolism are crucial for the normal functioning of neurons and other cells in the brain. Drugs that are not BBB penetrating yet act on the CNS highlight the importance of unimpaired circulation, and point to the cerebral vasculature as a primary target for drug action in diseases where impaired circulation and consequently suboptimal energy metabolism are followed by upstream pathologic events.
Asunto(s)
Barrera Hematoencefálica , Inhibidores de la Colinesterasa/farmacología , Cognición/efectos de los fármacos , Imagen por Resonancia Magnética , Neostigmina/farmacología , Animales , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/metabolismo , Inhibidores de la Colinesterasa/farmacocinética , Neostigmina/farmacocinética , Radiografía , RatasRESUMEN
A simple, rapid and high sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of neostigmine in small-volume beagle dog plasma was developed to assess the plasma pharmacokinetics of neostigmine. After protein precipitation in a Sirocco 96-well filtration plate, the filtrate was directly injected into the LC-MS/MS system. The analytes were separated on a Hanbon Hedera CN column (100 × 4.6 mm, 5 µm) with a mobile phase composed of methanol-water (60:40, v/v) and the water containing 0.01% formic acid at a flow rate of 0.6mL/min, with a split ratio of 1:1 flowing 300 µL into the mass spectrometer. The run time was 3 min. Detection was accomplished by electrospray ionization source in multiple reactions monitoring mode with the precursor-to-product ion transitions m/z 223.0 â 72.0 and 306.0 â 140.0 for neostigmine and anisodamine (internal standard), respectively. The method was sensitive with a lower limit of quantitation of 0.1 ng/mL, and good linearity in the range 0.1-100ng/mL for neostigmine (r ≥ 0.998). All the validation data, such as accuracy, intra-run and inter-run precision, were within the required limits. The method was successfully applied to pharmacokinetic study of neostigmine methylsulfate injection in beagle dogs.
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Cromatografía Líquida de Alta Presión/métodos , Neostigmina/sangre , Neostigmina/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Perros , Estabilidad de Medicamentos , Modelos Lineales , Neostigmina/química , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To determine the correlation between in vitro release and in vivo absorption of sustained-releasing tablets of neostigmine bromide. METHODS: Water was used as dissolution medium to measured in vitro release of neostigmine bromide. After a single oral administration of 100 mg neostigmine bromide to rabbits, the plasma concentrations of neostigmine bromide in the rabbits were determined by HPLC. The compartment model and deconvolution method were employed to explain the in vitro-in vivo correlation. RESULTS: Using Y as cumulative in vitro release and Fa as percentage of absorption, the regression equation was established: Fa = 0.9298Y + 4.6074, r = 0.9961. The input function of R = 2.0163Y-11.242,r = 0.9270. CONCLUSION: The correlation between in vitro release and in vivo absorption of neostigmine bromide is good.
Asunto(s)
Neostigmina/farmacocinética , Administración Oral , Animales , Cromatografía Líquida de Alta Presión , Preparaciones de Acción Retardada/farmacocinética , Conejos , Solubilidad , ComprimidosRESUMEN
OBJECTIVE: To determine the response to neostigmine of the contractile activity of the jejunum and pelvic flexure and the effects of a continuous rate infusion (CRI) of neostigmine in horses. ANIMALS: 7 adult horses and tissue from 12 adult horses. PROCEDURES: A CRI of neostigmine (0.008 mg/kg/h) or placebo was administered to 6 horses in a crossover study design. Gastric emptying was evaluated by the acetaminophen test. The frequency of defecation and urination and the consistency and weight of feces were recorded throughout the experiment. The effect of neostigmine on smooth muscle contractile activity was evaluated in tissues from the jejunum and pelvic flexure. The effect of neostigmine and acetylcholine after incubation with muscarinic receptor antagonists (atropine and DAU 5884) and an acetylcholinesterase inhibitor (edrophonium) was also investigated in vitro. RESULTS: No difference was observed between neostigmine and placebo for time to reach peak plasma acetaminophen concentration and absorption rate constant. A CRI of neostigmine increased fecal production and frequency of urination. Neostigmine induced a dose-dependent increase of contractile amplitude in jejunum and pelvic flexure muscle strips. Incubation of muscle strips with atropine and DAU 5884 inhibited the response to acetylcholine and neostigmine. Incubation of smooth muscle strips from the jejunum with edrophonium increased the response to acetylcholine and had no effect on the response to neostigmine in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: A CRI of neostigmine increased fecal production and urination frequency in horses. A CRI of neostigmine did not decrease gastric emptying. Neostigmine stimulated contractile activity of jejunum and pelvic flexure smooth muscle strips in vitro.
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Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/farmacocinética , Motilidad Gastrointestinal/efectos de los fármacos , Caballos , Neostigmina/farmacología , Neostigmina/farmacocinética , Acetaminofén/farmacocinética , Acetilcolina/farmacología , Analgésicos no Narcóticos/farmacocinética , Animales , Agonistas Colinérgicos/farmacología , Femenino , MasculinoRESUMEN
No disponible
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Anciano , Humanos , Masculino , Neostigmina/farmacocinética , Neostigmina/uso terapéutico , Fármacos Neuromusculares/uso terapéutico , Bloqueantes Neuromusculares/metabolismo , Bloqueantes Neuromusculares/farmacocinética , Bloqueantes Neuromusculares/uso terapéutico , Monitoreo Intraoperatorio/instrumentación , Monitoreo de Drogas/normas , Monitoreo de Drogas , 34628 , Monitoreo Neuromuscular , Monitorización NeurofisiológicaRESUMEN
OBJECTIVE: To study the pharmacokinetics and relative bioavailability of neostigmine bromide conventional tablets and sustained-release tablets in rabbits. METHODS: Six healthy rabbits were randomly divided into two groups for a cross self-contrast trial. RP-HPLC was used to detect plasma concentrations of neostigmine bromide. The pharmacokinetic parameters were calculated with the aid of DAS 2.0 software. RESULTS: The main pharmacokinetics parameters of the sustained-release tablets and conventional tablets were as follows, respectively: T(max)(3.67 +/- 1.51) hand (1.58 +/- 0.38) h; C(max) (5.04 +/- 1.19) mg/L and (4.56 +/- 1.70) mg/L; AUC(0 --> infinity) (32.82 +/- 9.88) mg/L x h and (29.84 +/- 14.27) mg/L x h. The relative bioavailability of the neostigmine bromide sustained-release tablets was 115.4%. CONCLUSION: The pharmacokinetics of neostigmine bromide accords with two compartments model, showing constant plasma concentration and relatively high bioavailability.
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Preparaciones de Acción Retardada/farmacocinética , Neostigmina/administración & dosificación , Neostigmina/farmacocinética , Animales , Disponibilidad Biológica , Preparaciones de Acción Retardada/metabolismo , Femenino , Masculino , Neostigmina/sangre , Conejos , Distribución Aleatoria , ComprimidosRESUMEN
No disponible
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Humanos , Inhibidores de la Colinesterasa/farmacocinética , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa , Neostigmina/farmacocinéticaRESUMEN
Cholinesterase blockers are widely used in various fields of clinical medicine. In anesthesiology they are used for the means of decurarisation, as well as for performance of central segmental blockades. In recent years, along with the most frequently used neostigmine again an opportunity arose to use the well-known galantamine. A brief overview of the pharmacological properties of galantamine is completed by the study of its efficacy and safety in 30 patients (first group) who underwent general anesthesia with total myoplegia at a range of abdominal surgeries. The comparison group (second group) included 30 patients who were applied neostigmine. The method of clinical functional evaluation, the accelerometry and frontal electromyography confirmed that galantamine although inferior to neostigmine in efficiency, has a higher safety threshold.
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Anestesiología/métodos , Inhibidores de la Colinesterasa/uso terapéutico , Galantamina/uso terapéutico , Relajación Muscular/efectos de los fármacos , Neostigmina/uso terapéutico , Bloqueo Neuromuscular/métodos , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Colinesterasa/efectos adversos , Inhibidores de la Colinesterasa/farmacocinética , Femenino , Galantamina/efectos adversos , Galantamina/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Neostigmina/efectos adversos , Neostigmina/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Morbid obesity alters drug dose requirement and time course of drug response. In addition, morbid obesity's impact on many organ systems decreases the margin of safety of anesthetic drugs. Consequently, incorrect dosing will increase the rate of perioperative complications. In this review, we will discuss factors that affect the pharmacokinetics and pharmacodynamics of anesthetic agents in the obese population, we specify certain dosing scalars, and we relate our current knowledge of obesity's effects on the clinical pharmacology of anesthetic drugs. RECENT FINDINGS: A morbidly obese individual's increased cardiac output requires administration of higher drug doses than would be required for a standard-size person to attain the same peak-plasma concentration. Lean body weight (LBW) is highly correlated with the increased cardiac output, more so than fat mass or other variables. For most drugs, clearance increases nonlinearly with total body weight but linearly with LBW. Morbid obesity has no clinically significant impact on the uptake of the inhalation anesthetics isoflurane, sevoflurane, and desflurane when used in routine clinical practice. Total body weight dosing of neuromuscular blocking agents will result in a prolonged effect. SUMMARY: For the induction dose of hypnotics and the initial dose of other drugs that have a fast onset of effect, cardiac output or LBW are relevant dosing scalars. For maintenance dosing, LBW seems to be a more appropriate dosing scalar than total body weight.
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Obesidad Mórbida/metabolismo , Atención Perioperativa , Farmacocinética , Farmacología , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacología , Anestésicos/farmacocinética , Anestésicos/farmacología , Anestésicos por Inhalación/farmacocinética , Anestésicos por Inhalación/farmacología , Animales , Índice de Masa Corporal , Peso Corporal/fisiología , Inhibidores de la Colinesterasa/farmacocinética , Inhibidores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Relajantes Musculares Centrales/farmacocinética , Relajantes Musculares Centrales/farmacología , Neostigmina/farmacocinética , Neostigmina/farmacología , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
No disponible
Asunto(s)
Humanos , Endoscopía Gastrointestinal , Seudoobstrucción Colónica/cirugía , Descompresión Quirúrgica , Neostigmina/farmacocinéticaRESUMEN
OBJETIVOS: Comparar la evolución y la recuperación,tanto espontánea como tras reversión con neostigmina,del bloqueo neuromuscular (BNM) de rocuronio y cisatracuriodurante una anestesia intravenosa.MATERIAL Y MÉTODO: Pacientes ASA 1-2 fueron randomizadosde forma ciega para recibir una dosis única2ED95% de rocuronio o de cisatracurio durante una anestesiageneral intravenosa, y recibir neostigmina más atropinaa la recuperación de la primera respuesta del TOF(T1) del 5% o del 25%, o recibir placebo (suero fisiológico)a T1 25%. La monitorización del BNM se llevó a cabomediante aceleromiografía. La comparación entre gruposse realizó mediante las pruebas T student y ANOVA.RESULTADOS: Se incluyeron 60 pacientes en el estudio.Rocuronio presentó unos tiempos de instauración(1,04±0,32 vs 2,58±0,81 min) y duración Dosis-T1 5%(30±6,4 vs 38,1±9,7 min) significativamente inferiores acisatracurio. La duración total del bloqueo (Dosis-TOFratio 80%) también fue inferior para rocuroniocuando se usó reversión del BNM, pero no observamosdiferencias cuando no se utilizó reversión con neostigmina(62 ±18,9 min rocuronio vs 66,96±15,9 min cisatracurio).Para ambos fármacos, cuando no se utilizó reversióndel BNM, un alto porcentaje de pacientes mantuvoun TOFratio<80% a los 60 y 90 min de administrado elbloqueante (Rocuronio TOFratio<80%: 60% 60 min,20% 90 min; Cisatracurio TOFratio<80%: 80% 60 min,40% 90 min).CONCLUSIÓN: No revertir el BNM de rocuronio o cisatracurioen procesos anestésico-quirúrgicos inferiores a90 min puede llevarnos a un alto porcentaje de pacientescon BNM residual (TOFratio<80%) (AU)
OBJECTIVES: To compare the time-course of neuromuscular blockade with rocuronium or cisatracurium during intravenous anesthesia, in terms of both the time to spontaneous recovery or time to reversal after administration of neostigmine. MATERIAL AND METHODS: Patients classified as ASA 1-2 were randomized to receive blinded administration of a single injection of twice the 95% effective dose of rocuronium or cisatracurium for general anesthesia, and then neostigmine plus atropine at recovery of the first train-of-4 (TOF) twitch at 5% or 25% or normal saline solution as placebo at recovery of the first TOF twitch at 25%. The neuromuscular blockade was monitored by acceleromyography. Intergroup comparisons were carried out by Student t test and analysis of variance. RESULTS: Sixty patients were enrolled. Mean (SD) time to onset was faster with rocuronium at (1.04-0.32 minutes) compared with cisatracurium at (2.58-0.81 minutes) and duration was shorter: time to the first twich at 5% was 30 (6.4) minutes with rocuronium and 38.1 (9.7) minutes with cisatracurium. The total duration of blockade (time to the 80% TOF ratio) was also shorter with rocuronium when the neuromuscular blockade was reversed, but there were no differences in the time to block reversal when neostigmine was not used: 62 (18.9) minutes to recovery from the rocuronium blockade vs 66.96 (15.9) minutes to recover from a cisatracurium blockade. A high percentage of patients had less than an 80% TOF ratio at 60 and 90 minutes of administration of the neuromuscular blockerswhen reversal was not used (patients receiving rocuronium, 60% at 60 minutes, and 20% at 90 minutes; patients receiving cisatracurium, 80% at 60 minutes, and 40% at 90 minutes). CONCLUSION: Not antagonizing a rocuronium- or cisatracurium-induced neuromuscular blockade in surgical procedures lasting less than 90 minutes can lead to a high percentaje of residual blockade (TOF ratio <80%) (AU)
Asunto(s)
Humanos , Neostigmina/farmacocinética , Bloqueo Neuromuscular/métodos , Bloqueantes Neuromusculares/uso terapéutico , Monitoreo Intraoperatorio/métodos , Estudios ProspectivosRESUMEN
Objetivos. Comprobar la eficacia de dosis bajas deneostigmina en la reversión del bloqueo neuromuscularno despolarizante residual (BNM-R).Material y Métodos. Se realizó el trabajo con 119pacientes adultos, ASA I-III, anestesiados con tiopental,fentanilo, O2-N2O-isoflurano y atracurio (n=62) o vecuronio(n=57). Se monitorizó el BNM-R mediante registroelectromiográfico del adductor pollicis ante estímuloulnar tipo tren de cuatro (TOF), considerando recuperaciónespontánea un TOF-Ratio > 75%. En caso contrariose revertía el BNM-R en función del grado de bloqueo(0-1, 2, 3 ó 4 respuestas al TOF) con neostigmina (0,035;0,03; 0,025 ó 0,02 mg/kg) y atropina (0,0175; 0,015; 0,0125ó 0,01 mg/kg) respectivamente. Se registró el tiempo dedecurarización y los efectos secundarios.Resultados. Los grupos resultaron demográficamentehomogéneos, con TOF-Ratio>75% el 25,8 (atracurio)y 21,1% (vecuronio), mostrando el resto 0-1 respuestasal TOF (11,3 y 19,2%), 2 (6,5 y 11,5%), 3 (4,8 y7,6%) ó 4 respuestas (51,6 y 50%) respectivamente,decurarizándose en 10,5±7 (atracurio) y 10,3±6,4 min(vecuronio). Hubo predominio de efectos secundariosen el grupo del atracurio (p=0,027) a expensas de sialorrea,naúseas y vómitos. No se registró ningún casode recurarización.Conclusiones. La reversión del BNM-R con dosisbajas de neostigmina y atropina ajustadas al grado debloqueo es efectiva incluso en bloqueos profundos yreduce el riesgo de efectos secundarios de estos fármacos
Objectives. To assess the effectiveness of low doses of neostigmine in the reversion of residual nonpolarising neuromuscular blockade (RNMB). Material and methods. The work involved one hundred and nineteen adult patients, ASA I-III, anaesthetised with fentanyl, thiopental, O2-N2O-isoflurane and atracurium (n=62) or vecuronium (n=57). RNMB was monitored with continuous electromyography of adductor pollicis with TOF stimulation. When TOF-Ratio (TR) 75% and secondary effects. Results. Both groups were homogeneous. Twentyfive point eight percent (25.8%) (group A) and 21.1% (group V) presented TR>75% at the end of surgery, while 11.3% and 19.2% showed TR 75% in 10.5±7 (group A) and 10.3±6.4 min. (group V). A predominance of secondary effects in the atracurium group was observed (p=0.027), basically due to excessive salivation, nausea and vomiting. There were no cases of RNMB. Conclusions. The reversion of the residual neuromuscular blockade of atracurium or vecuronium with low doses of neostigmine and atropine adjusted to the degree of RNMB is effective even in deep blockades, reducing the risk of secondary effects
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Humanos , Bloqueo Neuromuscular , Atracurio/farmacocinética , Bromuro de Vecuronio/farmacocinética , Neostigmina/farmacocinética , Complicaciones PosoperatoriasRESUMEN
BACKGROUND: The pharmacokinetics, maximum effect, and time course of action of neostigmine were studied in seven human volunteers. METHODS: Each volunteer was studied twice, during both normothermia and hypothermia. Anesthesia was induced with 30 microg/kg alfentanil and 3 mg/kg propofol, and was maintained with 60-70% nitrous oxide and 0.7-0.9% isoflurane. The mechanical response of the adductor pollicis to train-of-four stimulation of the ulnar nerve was recorded, and central body temperature maintained stable at either less than 34.5 degrees C or greater than 36.5 degrees C by surface cooling or warming. Before neostigmine administration, a stable 5% twitch height was obtained by an infusion of vecuronium, and the infusion rate remained unchanged thereafter. Neostigmine, 70 microg/kg, was then infused over 2 min, and blood samples for estimation of neostigmine concentrations were collected at intervals for 240 min. RESULTS: With hypothermia, the central volume of distribution of neostigmine decreased by 38%, and onset time of maximum effect increased (4.6 vs. 5.6 min). Hypothermia did not change the clearance (696 ml/min), maximum effect, or duration of action of neostigmine. CONCLUSIONS: The efficacy of neostigmine as an antagonist of vecuronium-induced neuromuscular block is not altered by mild hypothermia.
Asunto(s)
Hipotermia Inducida , Neostigmina/farmacología , Fármacos Neuromusculares no Despolarizantes/antagonistas & inhibidores , Parasimpaticomiméticos/farmacología , Bromuro de Vecuronio/antagonistas & inhibidores , Adulto , Anestesia , Femenino , Humanos , Masculino , Neostigmina/farmacocinéticaRESUMEN
The degradation kinetics of neostigmine were studied in aqueous solutions with varied pH from 1.5 to 9.9 under accelerated storage conditions. The stability of neostigmine in solutions containing propylene glycol or polyethylene glycol 400 was also investigated. The reaction order of neostigmine in these aqueous and solvent systems followed pseudo-first-order degradation kinetics. The degradation rates of neostigmine under various buffer concentrations within the investigated pH range were obtained. They indicated that the degradation was independent of the species of buffering agent. Maximum stability of neostigmine was determined at pH 5.0 buffer species conditions. The activation energy could be estimated from the Arrhenius plot as 15.72 kcal/mole. The half-life of 883.7 days was estimated at room temperature in 0.1 M, pH 4.9 acetate buffer solution (mu = 0.5). Ultraviolet (UV) irradiation at 254 nm of the neostigmine solutions in pH 4.9 acetate buffer showed an accelerated degradation in comparison with light-protected samples. Incorporation of propylene glycol into the neostigmine solution at pH 4.9 enhanced the stability; however, an adverse effect on the stability of neostigmine was noted when a polyethylene glycol 400 solvent system was used.
Asunto(s)
Neostigmina/farmacocinética , Parasimpaticomiméticos/farmacocinética , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Semivida , Concentración de Iones de Hidrógeno , SolucionesRESUMEN
BACKGROUND: This study defines the cerebrospinal fluid (CSF) pharmacokinetics of neostigmine after intrathecal injection in humans and its effect on CSF acetylcholine, and it correlates physiologic effects with neostigmine dose and CSF acetylcholine concentrations. METHODS: The CSF was sampled via an indwelling spinal catheter in 12 volunteers receiving intrathecal neostigmine (50-750 microg) and analyzed for neostigmine and acetylcholine. Pharmacokinetic and pharmacodynamic analyses were performed with NONMEM. Effect-site models linked the time course of the neostigmine concentration with the time course of analgesia. RESULTS: Acetylcholine concentrations increased from <20 pmol/ml at baseline to >100 pmol/ml within 15 min of neostigmine injection. The pharmacokinetics of intrathecal neostigmine were best described by a triexponential function with an absorption phase. Individual predicted concentrations varied 100-fold. Post hoc Bayesian estimates described the observed neostigmine concentrations with a median error of 22% and did not show systematic model misspecification. Individual estimates of effect site concentration producing a 50% maximal effect for foot visual analog scale analgesia correlated with the magnitude of individual CSF neostigmine concentrations. CONCLUSIONS: Intrathecal neostigmine concentrations can be well described by a triexponential disposition function, but the intersubject variability is large. The correlation between intersubject variability in concentration and intersubject variability in 50% maximal effect for foot analgesia suggests that both are offset by a common scalar, possibly the distance from the site of injection to the sampling and effect sites. These data provide the basis for the hypothesis of "observation at a distance" to describe the pharmacodynamics of intrathecally administered drugs.
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Inhibidores de la Colinesterasa/líquido cefalorraquídeo , Inhibidores de la Colinesterasa/farmacocinética , Neostigmina/líquido cefalorraquídeo , Neostigmina/farmacocinética , Acetilcolina/líquido cefalorraquídeo , Adulto , Algoritmos , Teorema de Bayes , Inhibidores de la Colinesterasa/administración & dosificación , Femenino , Semivida , Humanos , Inyecciones Espinales , Masculino , Neostigmina/administración & dosificación , Dimensión del DolorRESUMEN
The muscarinic receptor antagonist scopolamine produces a transient memory deficit in healthy humans. This deficit has been offered as a model of the cholinergic deficit of Alzheimer's disease (AD). However, we have previously shown that scopolamine produces a deficit of cortical perfusion maximal in the frontal lobe, dissimilar to the parietal cortex deficit characteristic of AD. The current experiment was aimed at replicating and extending this observation by critically testing the central cholinergic origin of both cognitive and perfusion deficits. Nine healthy subjects participated in regional cerebral blood flow (rCBF) measurements at baseline, after scopolamine (7.2 micrograms/kg i.v.), and after both physostigmine (22 micrograms/kg i.v.) and neostigmine (7 or 11 micrograms/kg i.v.). rCBF was quantified by the xenon 133 inhalation method. As expected, scopolamine reduced cortical perfusion, mainly in the frontal cortex, and produced a memory deficit. Physostigmine, but not neostigmine, reversed all three variables partially or completely. These results support the hypothesis that all three consequences of scopolamine, namely, reduction of mean flow, frontal deficit, and memory impairment, are cholinergically mediated. Furthermore, because neostigmine poorly crosses the blood-brain barrier, these findings confirm that the effect is centrally mediated and cannot be explained by peripheral effects. However, they also confirm the frontal cortex locus of action for both scopolamine and its reversal by physostigmine and therefore suggest a major dissimilarity to the characteristic rCBF appearance of AD. This study extends our previous preliminary findings with tacrine and strengthens the suggestion that only nicotinic receptors are associated with the characteristic parietal deficit of AD.
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Acetilcolina/fisiología , Amnesia/tratamiento farmacológico , Circulación Cerebrovascular/efectos de los fármacos , Lóbulo Frontal/irrigación sanguínea , Antagonistas Muscarínicos/efectos adversos , Parasimpaticomiméticos/uso terapéutico , Fisostigmina/uso terapéutico , Escopolamina/efectos adversos , Adulto , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Amnesia/inducido químicamente , Amnesia/diagnóstico por imagen , Barrera Hematoencefálica , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Recuerdo Mental/efectos de los fármacos , Neostigmina/farmacocinética , Neostigmina/farmacología , Parasimpaticomiméticos/farmacología , Fisostigmina/farmacología , Cintigrafía , Receptores Muscarínicos/efectos de los fármacos , Receptores Muscarínicos/fisiología , Escopolamina/antagonistas & inhibidores , Radioisótopos de XenónRESUMEN
Pharmacological profiles of four cholinesterase (ChE) inhibitors: edrophonium, pyridostigmine, neostigmine, and ambenonium after to administration to rats were analyzed. A pharmacodynamic model was developed by considering acetylcholinesterase (AChE) inhibition, direct antagonism to the nicotinic receptor, and desensitization of the nicotinic receptor. Pharmacokinetics of these drugs are dose-independent and have similar volumes of distribution at steady state (0.4-0.6 L/kg various doses). The t1/2 increases in the order of neostigmine, edrophonium, pyridostigmine, and ambenonium. Inhibitory constants of ChE inhibitors to bovine erythrocyte AChE determined in vitro were 2019, 276, 26, and 3.7 nM for edrophonium, pyridostigmine, neostigmine, and ambenonium, respectively. The effect of ChE inhibitor was monitored as the increase of developed tension of triceps muscle induced by sciatic nerve stimulation. The maximum value of contractile tension after i.v. administration decreased at high doses of each drug and the dose-response curves were biphasic. Time courses of plasma concentration and contractile muscle tension were modeled to estimate the association/dissociation rate constants to AChE and the nicotinic receptor, desensitization rate constant of receptor and the dissociation constant of acetylcholine (ACh) to nicotinic receptor/basal acetylcholine level ratio (Kd/ACh0). The estimated Kd/ACh0 values were not dependent on the drug. A significant correlation between inhibitory constants of ChE inhibitors to AChE estimated by in vivo pharmacodynamic analysis and those determined by an in vitro enzyme kinetic study was shown, while the relationship between dissociation constants to nicotinic receptor estimated by in vivo pharmacodynamic analysis and those measured by an in vitro binding study was not clear. Other process such as desensitisization induced by endogenous ACh diffusion rate of drugs into the synaptic cleft, action of presynaptic receptors, etc., might contribute to the dose-effect relationship of ChE inhibitors.
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Inhibidores de la Colinesterasa/farmacocinética , Contracción Muscular/efectos de los fármacos , Miastenia Gravis/metabolismo , Cloruro de Ambenonio/farmacocinética , Cloruro de Ambenonio/farmacología , Animales , Bovinos , Inhibidores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Edrofonio/farmacocinética , Edrofonio/farmacología , Inyecciones Intravenosas , Masculino , Modelos Biológicos , Neostigmina/farmacocinética , Neostigmina/farmacología , Bromuro de Piridostigmina/farmacocinética , Bromuro de Piridostigmina/farmacología , Ratas , Ratas Wistar , Análisis de Regresión , Nervio Ciático/efectos de los fármacosAsunto(s)
Adyuvantes Anestésicos/efectos adversos , Anestesia General , Atropina/efectos adversos , Glicopirrolato/efectos adversos , Neostigmina/efectos adversos , Complicaciones del Embarazo/cirugía , Adyuvantes Anestésicos/farmacocinética , Adulto , Atropina/farmacocinética , Femenino , Corazón Fetal/efectos de los fármacos , Glicopirrolato/farmacocinética , Humanos , Intercambio Materno-Fetal , Neostigmina/farmacocinética , EmbarazoRESUMEN
Pharmacokinetics of a very short-acting, a short-acting and two long-acting cholinesterase (ChE) inhibitors, edrophonium, neostigmine, pyridostigmine and ambenonium, respectively, were compared to elucidate the major determinant of their pharmacokinetics. No dose-dependency in pharmacokinetic behavior was observed within the range of 2-10 mumol/kg for edrophonium, 0.5-2 mumol/kg for pyridostigmine, 0.1-0.5 mumol/kg for neostigmine and 0.3-3 mumol/kg for ambenonium, respectively. Neostigmine has the shortest elimination half-life, and edrophonium, pyridostigmine and ambenonium follow in that. Four ChE inhibitors have similar Vdss values within the range of 0.3-0.7 l/kg, which is similar to the muscle/plasma concentration ratio of these drugs. The liver or kidney to plasma concentration ratio of all ChE inhibitors at 20min after i.v. administration ranged from 5 to 15. Small distribution volumes estimated from the plasma concentration profiles may reflect the distribution to muscle and to the extracellular space of other organs/tissues, while the rapid disappearance of ChE inhibitors from plasma may reflect the concentrative uptake to the liver and kidney.
Asunto(s)
Inhibidores de la Colinesterasa/farmacocinética , Cloruro de Ambenonio/farmacocinética , Animales , Edrofonio/farmacocinética , Semivida , Masculino , Neostigmina/farmacocinética , Bromuro de Piridostigmina/farmacocinética , Ratas , Ratas WistarRESUMEN
The penetration of neostigmine across excised human skin mounted in flow-through diffusion cells, delivered from a 0.28 M aqueous solution, was below detection limits. The presence of either NaCl or LiCl in the donor solution caused significant fluxes of neostigmine, with permeability coefficients (Kp's) in the range of 10(-6) cm min-1. Paradoxically, low concentrations of NaCl or LiCl (0.25 and 0.5 M) were more effective in this respect than the 1 M solution, which was the least effective concentration in the range of 0.25-3 M. Thus, the dependence of the experimental Kp values on inorganic ion concentration followed a biphasic course, suggesting the participation of two distinctive mechanisms in the penetration-enhancement process. The early phase corresponding to 0.25 and 0.5 M NaCl or LiCl is being partly ascribed to a decrease in the viscosity of lamellar water caused by the influx of the respective hydrated ions, hydration of LiCl or NaCl being more extensive at low alkali halide concentration that at higher ones (reference cited). The late phase corresponding to 2 and 3 M LiCl and NaCl is partly ascribed to a Donnan-like effect whereby the presence of a large excess of poorly diffusible common ion (Na+ or Li+) enhances the partitioning into the skin of the more diffusible ion, in this case neostigmine cation. The presence of inorganic ions at different concentrations had no effect on the partial molal volume of neostigmine bromide (Vi infinity = 223.5 cm3 mol-1), which was practically the same for all concentrations of either LiCl and NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)