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1.
Br J Anaesth ; 124(5): 553-561, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139135

RESUMO

BACKGROUND: Residual neuromuscular block has been associated with postoperative pulmonary complications. We hypothesised that sugammadex reduces postoperative pulmonary complications in patients aged ≥70 yr having surgery ≥3 h, compared with neostigmine. METHODS: Patients were enrolled in an open-label, assessor-blinded, randomised, controlled trial. At surgical closure, subjects were equally randomised to receive sugammadex 2 mg kg-1 or neostigmine 0.07 mg kg-1 (maximum 5 mg) for rocuronium reversal. The primary endpoint was incidence of postoperative pulmonary complications. Secondary endpoints included residual paralysis (train-of-four ratio <0.9 in the PACU) and Phase 1 recovery (time to attain pain control and stable respiratory, haemodynamic, and neurological status). The analysis was by intention-to-treat. RESULTS: Of the 200 subjects randomised, 98 received sugammadex and 99 received neostigmine. There was no significant difference in the primary endpoint of postoperative pulmonary complications despite a signal towards reduced incidence for sugammadex (33% vs 40%; odds ratio [OR]=0.74; 95% confidence interval [CI]=[0.40, 1.37]; P=0.30) compared with neostigmine. Sugammadex decreased residual neuromuscular block (10% vs 49%; OR=0.11, 95% CI=[0.04, 0.25]; P<0.001). Phase 1 recovery time was comparable between sugammadex (97.3 min [standard deviation, sd=54.3]) and neostigmine (110.0 min [sd=62.0]), difference -12.7 min (95% CI, [-29.2, 3.9], P=0.13). In an exploratory analysis, there were fewer 30 day hospital readmissions in the sugammadex group compared with the neostigmine group (5% vs 15%; OR=0.30, 95% CI=[0.08, 0.91]; P=0.03). CONCLUSIONS: In older adults undergoing prolonged surgery, sugammadex was associated with a 40% reduction in residual neuromuscular block, a 10% reduction in 30 day hospital readmission rate, but no difference in the occurrence of postoperative pulmonary complications. Based on this exploratory study, larger studies should determine whether sugammadex may reduce postoperative pulmonary complications and 30 day hospital readmissions. CLINICAL TRIAL REGISTRATION: NCT02861131.


Assuntos
Recuperação Demorada da Anestesia/prevenção & controle , Pneumopatias/prevenção & controle , Neostigmina/farmacologia , Complicações Pós-Operatórias/prevenção & controle , Sugammadex/farmacologia , Idoso , Idoso de 80 Anos ou mais , Inibidores da Colinesterase/farmacologia , Método Duplo-Cego , Feminino , Humanos , Período Intraoperatório , Pneumopatias/etiologia , Masculino , Bloqueio Neuromuscular , Junção Neuromuscular/efeitos dos fármacos , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Readmissão do Paciente/estatística & dados numéricos , Rocurônio/antagonistas & inibidores
2.
Br J Anaesth ; 124(2): 164-172, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31780139

RESUMO

BACKGROUND: For some laparoscopic procedures, deep neuromuscular block has been shown to facilitate lower insufflation pressures and lower patient pain scores, and enhance postoperative recovery. We investigated the impact of deep neuromuscular block and its reversal on postoperative shoulder pain and outcomes after robotic prostate surgery. METHODS: Elderly men undergoing robotic prostatectomy were randomised to deep neuromuscular block (target post-tetanic twitch of 1-2 at the facial nerve) with sugammadex reversal or moderate neuromuscular block (target 1-2 train-of-four ratio) with neostigmine reversal. The primary endpoint was postoperative shoulder pain. The secondary endpoints included intraoperative insufflation pressure, surgical rating score, incidence of residual neuromuscular block, and postoperative recovery. RESULTS: A total of 50 subjects for each treatment arm were included in the analysis. The degree of neuromuscular block had no effect on the incidence of shoulder pain (deep block group 12% vs moderate block group 10%; P=1.0) or average insufflation pressure (median [inter-quartile range]) (13.3 [12.5-13.6] mm Hg vs 13.3 [11.7-14] mm Hg, P=0.86). After surgery, the deep block group had a higher normalised train-of-four ratio (0.98 [0.79-1.11] vs 0.85 [0.74-1.00]; P=0.008). The presence of postoperative shoulder pain was associated with higher BMI (31.8 [28-33.9] kg m-2vs 28 [24.8-31.1] kg m-2; P=0.036) and longer insufflation time (186 [156-257] min vs 154 [126-198] min; P=0.028). CONCLUSIONS: The use of deep neuromuscular block during surgery does not decrease postoperative shoulder pain or enhance recovery after robotic prostatectomy. CLINICAL TRIAL REGISTRATION: NCT03210376.


Assuntos
Inibidores da Colinesterase/farmacologia , Neostigmina/farmacologia , Bloqueio Neuromuscular , Prostatectomia , Procedimentos Cirúrgicos Robóticos , Dor de Ombro/prevenção & controle , Sugammadex/farmacologia , Idoso , Humanos , Masculino
3.
J Med Life ; 12(3): 260-265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31666828

RESUMO

Lower back pain is one of the leading causes of disability in the world. The aim of this study was to evaluate the effect of supplementation of dexmedetomidine and neostigmine with lidocaine 1.5% and triamcinolone for epidural block in increasing the duration of analgesia among patients suffering from chronic low back pain. In this double-blind, randomized clinical trial, 33 patients with chronic low back pain were included in three groups of 11 patients for epidural blockage. Triamcinolone (40 mg/ml) was added to lidocaine 1.5% solution (2 cc/segment) for all three groups. In group N, neostigmine was used at a dose of 1 mg (mg), followed by group D (dexmedetomidine 35 µg [0.5 µg/kg]), and grou [ND (neostigmine 0.5 mg, and 35 µg dexmedetomidine, all of which were added to the triamcinolone and lidocaine solution in each group. Medications were injected into the epidural space using an interlaminar approach. Subsequently, scores of pain and duration of analgesia were recorded in questionnaires and analysed using SPSS version 23. One month after the injections, pain scores recorded in the N group were 7.6±1.4, followed by 5.88±1.2 in group D and 5.42 ±1.1 in group ND. Therefore, the pain scores were significantly higher in the neostigmine group than the other two groups (p = 0.02), but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine. Three months after the injections, there was a significant difference in pain scores between the two groups (P = 0.01). Both neostigmine and dexmedetomidine were capable of reducing the pain of patients with chronic low back pain after epidural block. However, neostigmine's impact is lower compared to dexmedetomidine. The combination of the two drugs also reduced the pain scores of the patients after the intervention.


Assuntos
Analgesia Epidural , Dor Crônica/tratamento farmacológico , Dexmedetomidina/uso terapêutico , Lidocaína/uso terapêutico , Dor Lombar/tratamento farmacológico , Neostigmina/uso terapêutico , Triancinolona/uso terapêutico , Adulto , Pressão Sanguínea/efeitos dos fármacos , Dor Crônica/fisiopatologia , Dexmedetomidina/farmacologia , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Lidocaína/farmacologia , Dor Lombar/fisiopatologia , Masculino , Neostigmina/farmacologia , Oxigênio/metabolismo , Manejo da Dor , Triancinolona/farmacologia
4.
Niger J Clin Pract ; 22(5): 609-615, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31089014

RESUMO

Objective: The effect of sugammadex on consciousness is not yet fully understood. This prospective, randomized, double-blind, multicenter study was performed to compare the effects of intravenous (IV) sugammadex and neostigmine + atropine reversals on time-to-consciousness during intraoperative wake-up tests in patients undergoing spinal surgery. Subjects and Methods: A total of 66 American Society of Anesthesiologists I-II patients aged 10-25 years undergoing spinal surgery were recruited. In all patients, bispectral index (BIS), motor-evoked potential (MEP), somatosensory-evoked potentials (SSEP), and train-of-four (TOF) scores were monitored. Patients received the same total IV anesthesia protocol with a propofol-remifentanil mixture. Patients were randomly allocated into two groups. During wake-up test, when the TOF count reached 2 (T2), either sugammadex 2 mg.kg-1 in group S or neostigmine 0.04 mg.kg-1 + atropine 0.01 mg.kg-1 in group N were administered. BIS90, SSEP90, MEP90 was recorded when TOF ratio reached 90, whereas time-to-consciousness (Timecons) was recorded when the patient responded to verbal commands. Results: BIS90 (77.4 ± 4.7, 74.8 ± 3.7), SSEP90(36 ± 9.9, 29.7 ± 8.5), and MEP90 (465.3 ± 34.8, 431.3 ± 28.2) values were significantly greater in group S than in group N (P < 0.05 for each variables). Timecons was significantly shorter with sugammadex than with the neostigmine + atropine combination (P < 0.05). Conclusion: Using IV sugammadex 2 mg.kg-1 reversal provides faster responses to verbal commands than neostigmine-atropine combination during the intraoperative wake-up test in patients undergoing spinal surgery because the time to consciousness was significantly shorter. This difference was thought to be related with faster return of neuromuscular transmission because the TOF ratio was >0.9 well before return of consciousness in both groups.


Assuntos
Atropina/farmacologia , Inibidores da Colinesterase/farmacologia , Estado de Consciência/efeitos dos fármacos , Neostigmina/farmacologia , Parassimpatolíticos/farmacologia , Sugammadex/farmacologia , Administração Intravenosa , Adolescente , Adulto , Analgésicos Opioides , Anestesia Geral , Anestésicos Intravenosos , Atropina/administração & dosagem , Criança , Inibidores da Colinesterase/administração & dosagem , Monitores de Consciência , Método Duplo-Cego , Potencial Evocado Motor , Potenciais Somatossensoriais Evocados , Feminino , Humanos , Masculino , Neostigmina/administração & dosagem , Monitoração Neuromuscular , Parassimpatolíticos/administração & dosagem , Propofol , Estudos Prospectivos , Remifentanil , Sugammadex/administração & dosagem , Fatores de Tempo , Adulto Jovem
5.
Anesthesiology ; 131(3): 467-476, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31045894

RESUMO

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: The ventilatory response to hypoxia is a critical reflex that is impaired by neuromuscular blocking drugs. However, the degree to which this reflex is restored after reversal of blockade is unknown. WHAT THIS ARTICLE TELLS US THAT IS NEW: Despite full reversal of neuromuscular blockade at the thumb using different drug classes, this hypoxic chemoreflex is not fully restored. BACKGROUND: The ventilatory response to hypoxia is a life-saving chemoreflex originating at the carotid bodies that is impaired by nondepolarizing neuromuscular blocking agents. This study evaluated the effect of three strategies for reversal of a partial neuromuscular block on ventilatory control in 34 healthy male volunteers on the chemoreflex. The hypothesis was that the hypoxic ventilatory response is fully restored following the return to a train-of-four ratio of 1. METHODS: In this single-center, experimental, randomized, controlled trial, ventilatory responses to 5-min hypoxia (oxygen saturation, 80 ± 2%) and ventilation at hyperoxic isohypercapnia (end-tidal carbon dioxide concentration, 55 mmHg) were obtained at baseline, during rocuronium-induced partial neuromuscular block (train-of-four ratio of 0.7 measured at the adductor pollicis muscle by electromyography), and following reversal until the train-of-four ratio reached unity with placebo (n = 12), 1 mg neostigmine/0.5 mg atropine (n = 11), or 2 mg/kg sugammadex (n = 11). RESULTS: This study confirmed that low-dose rocuronium reduced the ventilatory response to hypoxia from 0.55 ± 0.22 (baseline) to 0.31 ± 0.21 l · min · % (train-of-four ratio, 0.7; P < 0.001). Following full reversal as measured at the thumb, there was persistent residual blunting of the hypoxic ventilatory response (0.45 ± 0.16 l · min · %; train-of-four ratio, 1.0; P < 0.001). Treatment effect was not significant (analysis of covariance, P = 0.299) with chemoreflex impairment in 5 (45%) subjects following sugammadex reversal, in 7 subjects (64%) following neostigmine reversal, and in 10 subjects (83%) after spontaneous reversal to a train-of-four ratio of 1. CONCLUSIONS: Despite full reversal of partial neuromuscular block at the thumb, impairment of the peripheral chemoreflex may persist at train-of-four ratios greater than 0.9 following reversal with neostigmine and sugammadex or spontaneous recovery of the neuromuscular block.


Assuntos
Hipóxia/fisiopatologia , Neostigmina/farmacologia , Bloqueio Neuromuscular/métodos , Respiração/efeitos dos fármacos , Rocurônio/antagonistas & inibidores , Sugammadex/farmacologia , Adolescente , Adulto , Período de Recuperação da Anestesia , Inibidores da Colinesterase/farmacologia , Método Duplo-Cego , Eletromiografia , Voluntários Saudáveis , Humanos , Masculino , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Adulto Jovem
6.
Int Urol Nephrol ; 51(1): 73-78, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30478812

RESUMO

OBJECTIVES: Pregnancy is associated with many functional changes of the urinary bladder. It was reported that most of healthy women complain from urinary symptoms during pregnancy. The parasympathetic system is mainly mediating bladder emptying. The aim of the study is to investigate the cholinergic effect and the role of acetylcholinesterase in the bladder during pregnancy. METHODS: Sixteen rats were used in the present study as control group (non-pregnant) and pregnant group (18-20 days pregnant). Isolated urinary smooth muscle strips were suspended in organ baths filled with Krebs' solution for isometric tension recording. RESULTS: Electric field stimulation (EFS), (0.1-40 Hz), of the control and pregnant bladder preparations produced frequency-dependent contractions. Atropine (1 µM) inhibited EFS-induced contractions in the two groups by 65% and 50% respectively indicating the response of cholinergic innervation. Neostigmine significantly enhanced EFS responses, confirming its selectivity for inhibiting acetylcholinesterase which is responsible for termination of acetylcholine. Concentration-response curves for acetylcholine were reduced in pregnant group than control. Concentration-response curves for ATP were increased in pregnant group than control. Neostigmine augmented concentration-response curves for acetylcholine in control and pregnant groups. The effect of neostigmine on acetylcholine contractile responses in pregnancy group was higher than in control. CONCLUSIONS: Urinary bladder dysfunction during pregnancy might be due to augmentation of acetylcholinesterase effect. This will lead to the decrease in response to cholinergic stimuli. New pharmaceutical drugs specifically affecting the enzyme in the bladder can help in avoiding the unpleasant urinary symptoms during pregnancy.


Assuntos
Acetilcolinesterase/metabolismo , Atropina/farmacologia , Neostigmina/farmacologia , Complicações na Gravidez , Doenças da Bexiga Urinária , Bexiga Urinária , Animais , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Feminino , Parassimpatolíticos/farmacologia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/metabolismo , Complicações na Gravidez/fisiopatologia , Ratos , Receptores Muscarínicos/metabolismo , Resultado do Tratamento , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Doenças da Bexiga Urinária/diagnóstico , Doenças da Bexiga Urinária/tratamento farmacológico , Doenças da Bexiga Urinária/metabolismo , Doenças da Bexiga Urinária/fisiopatologia
7.
Pharmacology ; 103(1-2): 38-49, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30380560

RESUMO

BACKGROUND/AIMS: In this study, we evaluated the functional impact of facilitatory presynaptic adenosine A2A and muscarinic M1 receptors in the recovery of neuromuscular tetanic depression caused by the blockage of high-affinity choline transporter (HChT) by hemicholinium-3 (HC-3), a condition that mimics a myasthenia-like condition. METHODS: Rat diaphragm preparations were indirectly stimulated via the phrenic nerve trunk with 50-Hz frequency trains, each consisting of 500-750 supramaximal intensity pulses. The tension at the beginning (A) and at the end (B) of the tetanus was recorded and the ratio (R) B/A calculated. RESULTS: Activation of A2A and M1 receptors with CGS21680 (CGS; 2 nmol/L) and McN-A-343c (McN; 3 µmol/L) increased R values. Similar facilitatory effects were obtained with forskolin (FSK; 3 µmol/L) and phorbol 12-myristate 13-acetate (PMA; 10 µmol/L), which activate adenylate cyclase and protein kinase C respectively. HC-3 (4 µmol/L) decreased transmitter exocytosis measured by real-time videomicroscopy with the FM4-64 fluorescent dye and prevented the facilitation of neuromuscular transmission caused by CGS, McN, and FSK, with a minor effect on PMA. The acetylcholinesterase inhibitor, neostigmine (NEO; 0.5 µmol/L), also decreased transmitter exocytosis. The paradoxical neuromuscular tetanic fade caused by NEO (0.5 µmol/L) was also prevented by HC-3 (4 µmol/L) and might result from the rundown of the positive feedback mechanism operated by neuronal nicotinic receptors (blocked by hexamethonium, 120 µmol/L). CONCLUSION: Data suggest that the recovery of tetanic neuromuscular facilitation by adenosine A2A and M1 receptors is highly dependent on HChT activity and may be weakened in myasthenic patients when HChT is inoperative.


Assuntos
Proteínas de Membrana Transportadoras/fisiologia , Receptor A2A de Adenosina/fisiologia , Receptor Muscarínico M1/fisiologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/farmacologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Colforsina/farmacologia , Diafragma/efeitos dos fármacos , Diafragma/fisiologia , Hemicolínio 3/farmacologia , Neostigmina/farmacologia , Fenetilaminas/farmacologia , Nervo Frênico/efeitos dos fármacos , Nervo Frênico/fisiologia , Ratos , Ratos Wistar , Transmissão Sináptica , Tétano/tratamento farmacológico , Tétano/fisiopatologia , Acetato de Tetradecanoilforbol/farmacologia
8.
Bull Exp Biol Med ; 166(1): 50-53, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30450520

RESUMO

The effects of intramuscular administration of neostigmine and physostigmine on Na+,K+-ATPase activity in various cerebral subdivisions were examined in rats. In CNS and peripheral tissues, both agents rapidly and significantly reduced activity of cholinesterases by 30-50%. The development of intoxication did not change the marker indices of stress reaction. In the cerebral cortex, physostigmine increased Na+,K+-ATPase activity, whereas neostigmine suppressed it. In addition, neostigmine decreased activity of this enzyme in the cerebellum. In contrast, both agents produced no effects on Na+,K+-ATPase activity in the striatum. The data corroborate the view on functional interaction between Na+,K+-ATPase and nicotinic cholinoreceptors in rat cerebral cortex.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neostigmina/farmacologia , Fisostigmina/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Masculino , Ratos , Ratos Wistar
9.
JBI Database System Rev Implement Rep ; 16(10): 1922-1928, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30335038
10.
Comput Biol Chem ; 76: 310-317, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30142564

RESUMO

Cholinesterases (ChEs) play a vital role in regulating cholinergic transmission. Inhibition of ChEs is thought to be an emerging and useful therapeutic target for neurodegenerative disorders through restoration of acetylcholine (ACh) levels in the brain (e.g. Alzheimer's disease). To increase the chemical diversity of cholinesterase inhibitors, a series of quinoline chalcones derivatives were tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) isoenzymes. All tested compounds (4a-1; 5a-s) exhibited inhibitory activities against AChE and BChE to a considerable extent. Molecular docking studies were performed by using homology models on both AChE and BChE isoenzymes with the aim of exploring probable binding modes of the most potent inhibitor. In order to evaluate drug likeness of newly tested molecules, we carried out in-silico ADME evaluation. All compounds displayed favourable ADME findings which predict good oral bioavailability of these derivatives. Due to an excellent ADME profile the tested compounds were predicted to be safer which can be considered as novel cholinesterase inhibitors.


Assuntos
Chalconas/química , Inibidores da Colinesterase/química , Quinolinas/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Chalconas/síntese química , Chalconas/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Donepezila , Ensaios Enzimáticos , Humanos , Indanos/farmacologia , Cinética , Ligantes , Simulação de Acoplamento Molecular , Neostigmina/farmacologia , Piperidinas/farmacologia , Ligação Proteica , Quinolinas/síntese química , Quinolinas/metabolismo , Relação Estrutura-Atividade
11.
Anaesthesia ; 73(9): 1067-1078, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29974459

RESUMO

Inappropriate dosing of neostigmine for antagonism of neuromuscular blockade has been associated with postoperative pulmonary complications. We evaluated the effects of a quality improvement initiative tailored to optimise the use of neostigmine in antagonising neuromuscular blockade on postoperative pulmonary complications, costs and duration of hospital stay. The quality improvement initiative consisted of: a reduction in available neostigmine aliquot sizes; a cognitive aid; an educational component; and a financial incentive for the intra-operative documentation of train-of-four measurement before administration of neostigmine. We conducted a pre-specified analysis of data obtained in our quality improvement study. Additional analyses were conducted in a propensity-matched cohort. An interrupted time series design was used to discriminate between the intervention and a counterfactual scenario. We analysed 12,025 consecutive surgical cases performed in 2015. Postoperative pulmonary complications occurred in 220 (7.5%) of 2937 cases pre-intervention and 568 (6.3%) of 9088 cases post-intervention. Adjusted regression analyses showed significantly a lower risk of postoperative pulmonary complications (OR 0.73 (95%CI 0.61-0.88); p = 0.001), lower costs (incidence rate ratio 0.95 (95%CI 0.93-0.97); p < 0.001) and shorter duration of hospital stay (incidence rate ratio 0.91 (95%CI 0.87-0.94); p < 0.001) after implementation of the quality improvement initiative. Analyses in a propensity-matched sample (n = 2936 per group) and interrupted time series analysis (n = 27,202 cases) confirmed the findings. Our data show that a local, multifaceted quality improvement initiative can enhance the quality of intra-operative neuromuscular blocking agent utilisation, thereby reducing the incidence of postoperative pulmonary complications.


Assuntos
Inibidores da Colinesterase/administração & dosagem , Pneumopatias/prevenção & controle , Neostigmina/administração & dosagem , Bloqueio Neuromuscular/métodos , Complicações Pós-Operatórias/prevenção & controle , Adulto , Idoso , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Feminino , Custos Hospitalares/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Pneumopatias/induzido quimicamente , Pneumopatias/epidemiologia , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Neostigmina/efeitos adversos , Neostigmina/farmacologia , Bloqueio Neuromuscular/economia , Junção Neuromuscular/efeitos dos fármacos , Assistência Perioperatória/métodos , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Melhoria de Qualidade/organização & administração , Adulto Jovem
13.
J Neurosci ; 38(21): 4943-4956, 2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29724797

RESUMO

Neuronal nicotinic acetylcholine receptors (nAChRs) are pentamers built from a variety of subunits. Some are homomeric assemblies of α subunits, others heteromeric assemblies of α and ß subunits which can adopt two stoichiometries (2α:3ß or 3α:2ß). There is evidence for the presence of heteromeric nAChRs with the two stoichiometries in the CNS, but it has not yet been possible to identify them at a given synapse. The 2α:3ß receptors are highly sensitive to agonists, whereas the 3α:2ß stoichiometric variants, initially described as low sensitivity receptors, are indeed activated by low and high concentrations of ACh. We have taken advantage of the discovery that two compounds (NS9283 and Zn) potentiate selectively the 3α:2ß nAChRs to establish (in mice of either sex) the presence of these variants at the motoneuron-Renshaw cell (MN-RC) synapse. NS9283 prolonged the decay of the two-component EPSC mediated by heteromeric nAChRs. NS9283 and Zn also prolonged spontaneous EPSCs involving heteromeric nAChRs, and one could rule out prolongations resulting from AChE inhibition by NS9283. These results establish the presence of 3α:2ß nAChRs at the MN-RC synapse. At the functional level, we had previously explained the duality of the EPSC by assuming that high ACh concentrations in the synaptic cleft account for the fast component and that spillover of ACh accounts for the slow component. The dual ACh sensitivity of 3α:2ß nAChRs now allows to attribute to these receptors both components of the EPSC.SIGNIFICANCE STATEMENT Heteromeric nicotinic receptors assemble α and ß subunits in pentameric structures, which can adopt two stoichiometries: 3α:2ß or 2α:3ß. Both stoichiometric variants are present in the CNS, but they have never been located and characterized functionally at the level of an identified synapse. Our data indicate that 3α:2ß receptors are present at the spinal cord synapses between motoneurons and Renshaw cells, where their dual mode of activation (by high concentrations of ACh for synaptic receptors, by low concentrations of ACh for extrasynaptic receptors) likely accounts for the biphasic character of the synaptic current. More generally, 3α:2ß nicotinic receptors appear unique by their capacity to operate both in the cleft of classical synapses and at extrasynaptic locations.


Assuntos
Receptores Nicotínicos/química , Células de Renshaw/química , Animais , Inibidores da Colinesterase/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neostigmina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Oxidiazóis/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/genética , Células de Renshaw/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Zinco/farmacologia
14.
Cell Physiol Biochem ; 46(6): 2412-2420, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29794481

RESUMO

BACKGROUND/AIMS: Ultrasound-guided supraclavicular brachial plexus block (BPB) has come into wider use as a regional anesthetic during upper limb operations. This study assessed the neurological and hemodynamic changes and gene expression after co-administration of midazolam or neostigmine with bupivacaine during supraclavicular BPB. METHODS: The study involved 90 adults divided into three groups: control (bupivacaine), midazolam (bupivacaine plus midazolam), and neostigmine (bupivacaine plus neostigmine). Blood samples were taken and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) mRNA levels were measured by real-time PCR, and oxidative stress markers were identified. In addition to the hemodynamic variables, the onset and duration of sensory and motor blockades, duration of analgesia, pain scores, time of first request for an analgesic, and amounts of analgesics ingested were evaluated. RESULTS: Compared with the control and neostigmine groups, the midazolam group experienced longer sensory and motor blockades, prolonged analgesia, lower pain scores at 12 h and 24 h, and lower need for postoperative analgesics. Moreover, the midazolam group exhibited lower oxidative stress markers with a higher fold change in IL-6 and TNF-α mRNA levels. CONCLUSION: Midazolam co-administered with bupivacaine provided better analgesic quality than did neostigmine with bupivacaine. This might be due to its superior antioxidant and anti-inflammatory effects.


Assuntos
Anestésicos Locais/administração & dosagem , Bloqueio do Plexo Braquial/métodos , Bupivacaína/administração & dosagem , Midazolam/administração & dosagem , Neostigmina/administração & dosagem , Adolescente , Adulto , Idoso , Anestésicos Locais/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bupivacaína/farmacologia , Método Duplo-Cego , Feminino , Expressão Gênica/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Malondialdeído/sangue , Midazolam/farmacologia , Pessoa de Meia-Idade , Neostigmina/farmacologia , Superóxido Dismutase/sangue , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ultrassonografia , Adulto Jovem
15.
J Biol Regul Homeost Agents ; 32(2): 295-298, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29685009

RESUMO

The development of ptosis as a consequence of pituitary tumor is an exceptionally rare occurrence. Here, we describe the case of sudden-onset unilateral ptosis induced by pituitary macroadenoma. The condition was characterized by false-positive Jolly and neostigmine tests. These findings mimic oculomotor nerve palsy and make the correct diagnostics rather challenging. The case points to the fact that patients with acquired ptosis need detailed neuroophthalmological examination.


Assuntos
Adenoma/complicações , Blefaroptose/etiologia , Doenças do Nervo Oculomotor/diagnóstico , Neoplasias Hipofisárias/complicações , Adenoma/diagnóstico , Adulto , Animais , Diagnóstico Diferencial , Reações Falso-Positivas , Humanos , Masculino , Miastenia Gravis/diagnóstico , Neostigmina/farmacologia , Parassimpatomiméticos/farmacologia , Neoplasias Hipofisárias/diagnóstico
17.
Minerva Anestesiol ; 84(8): 929-937, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29405667

RESUMO

BACKGROUND: This randomized controlled study compared the recovery times of sugammadex and neostigmine as antagonists of moderate rocuronium-induced neuromuscular block in patients with liver cirrhosis and controls undergoing liver resection. METHODS: The study enrolled 27 adult patients with Child class "A" liver cirrhosis and 28 patients with normal liver functions. Normal patients and patients with liver cirrhosis were randomized according to the type of antagonist (sugammadex 2 mg/kg or neostigmine 50 µg/kg). The primary outcome was the time from antagonist administration to a train-of-four (TOF) ratio of 0.9 using mechanosensor neuromuscular transmission module. The durations of the intubating and top-up doses of rocuronium, the length of stay in the post-anesthesia care unit (PACU), and the incidence of postoperative re-curarization were recorded. RESULTS: The durations of the intubating and top-up doses of rocuronium were prolonged in patients with liver cirrhosis than controls. The times to a TOF ratio of 0.9 were 3.1 (1.0) and 2.6 (1.0) min after sugammadex administration in patients with liver cirrhosis and controls, respectively, P=1.00. The corresponding times after neostigmine administration were longer than sugammadex 14.5 (3.6) and 15.7 (3.6) min, respectively, P<0.001. The duration of PACU stay was shorter with the use of sugammadex compared to neostigmine. We did not encounter postoperative re-curarization after sugammadex or neostigmine. CONCLUSIONS: Sugammadex rapidly antagonize moderate residual rocuronium-induced neuromuscular block in patients with Child class "A" liver cirrhosis undergoing liver resection. Sugammadex antagonism is associated with 80% reduction in the time to adequate neuromuscular recovery compared to neostigmine.


Assuntos
Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Hepatectomia , Cirrose Hepática/cirurgia , Neostigmina/farmacologia , Neostigmina/uso terapêutico , Bloqueio Neuromuscular/métodos , Fármacos Neuromusculares não Despolarizantes/farmacologia , Fármacos Neuromusculares não Despolarizantes/uso terapêutico , Rocurônio/antagonistas & inibidores , Rocurônio/uso terapêutico , Sugammadex/farmacologia , Sugammadex/uso terapêutico , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Talanta ; 180: 316-322, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29332816

RESUMO

The application of traditional ion-selective electrodes for comparative enzymatic analysis was demonstrated for the first time in this study. A kinetic-potentiometric method based on the monitoring of the concentration of the ionic substrate involved in the enzymatic reaction catalyzed by different cholinesterases is used for this purpose. A comparative study was performed comprising both enzymatic assays using different ionic substrates and the corresponding inhibited reactions in presence of neostigmine (a synthetic anticholinesterase). The developed approach is used to obtain valuable comparative results through calculation of kinetic parameters, such as Michaelis and inhibition constants. Interesting results were obtained for acetylcholinesterase and butyrylcholinesterase enzymes, which were selected as proof-of-concept: (i) the binding affinity that these enzymes have for their natural substrates showed to be higher (acetylcholine and butyrylcholine respectively) than for their corresponding thiol derivatives (acetylthiocholine and butyrylthiocholine), which are traditionally used in spectrophotometric enzymatic assays; (ii) as expected, the maximum hydrolysis rate found in the assays of each enzyme was independent of the substrate used; (iii) acetylcholinesterase enzyme inhibition due to neostigmine was found to be higher (higher inhibition constant). Advantageously, the use of ion-selective electrodes permits to perform cholinesterases' enzymatic assays using their natural substrates and under physiological conditions, unlike the traditional spectrophotometric methods used in routine enzymatic assays. Importantly, while well-known enzymes are use throughout this work, this approach can be extended to other types of enzymatic assays as a tangible alternative to traditional spectrophotometric methods.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Ensaios Enzimáticos/instrumentação , Neostigmina/farmacologia , Potenciometria/instrumentação , Animais , Electrophorus , Cavalos , Eletrodos Íon-Seletivos , Especificidade por Substrato
19.
Anaesthesia ; 73(3): 340-347, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29214645

RESUMO

Sugammadex more rapidly and reliably reverses rocuronium-induced neuromuscular block compared with neostigmine, but it is not known if subsequent patient outcomes, including nausea, vomiting and other aspects of recovery are modified. In this study, we compared the recovery characteristics of sugammadex and neostigmine/glycopyrrolate following reversal of neuromuscular block. This was a single-centre, randomised, blinded, parallel-group clinical trial in women undergoing elective day-surgical laparoscopic gynaecological surgery, with a standardised general anaesthesia regimen that included rocuronium. Neuromuscular block was reversed with either sugammadex 2 mg.kg-1 or neostigmine 40 µg.kg-1 and glycopyrrolate 400 µg. The primary outcome was the incidence of nausea and vomiting during the first six postoperative hours. Secondary outcomes included other measures of postoperative recovery such as patient symptoms and recovery scores. Three-hundred and four women were analysed by intention-to-treat (sugammadex n = 151, neostigmine n = 153), which included four major protocol violations. There was no significant difference between sugammadex and neostigmine groups in the incidence of early nausea and vomiting (49.0% vs. 51.0%, respectively; OR 0.92, 95%CI 0.59-1.45; p = 0.731). Double vision (11.5% vs. 20.0%; p = 0.044) and dry mouth (71.6% vs. 85.5%; p = 0.003) were less common after sugammadex. Sedation scores at 2 h were also lower after sugammadex (median (IQR [range]) 0 (0-3 [0-10]) vs. 2 (0-4.[0-10]); p = 0.021). Twenty-four-hour recovery scores were not significantly different between groups. Reversal with sugammadex in this patient population did not reduce postoperative nausea or vomiting compared with neostigmine/glycopyrrolate.


Assuntos
Glicopirrolato/farmacologia , Neostigmina/farmacologia , Bloqueio Neuromuscular , Sugammadex/farmacologia , Adulto , Período de Recuperação da Anestesia , Feminino , Humanos , Náusea e Vômito Pós-Operatórios/prevenção & controle
20.
J Physiol ; 595(24): 7495-7508, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29023733

RESUMO

KEY POINTS: A tonically active, muscarinic cholinergic inhibition of rostral raphe pallidus (rRPa) neurons influences thermogenesis of brown adipose tissue (BAT) independent of ambient temperature conditions. The tonically active cholinergic input to rRPa originates caudal to the hypothalamus. Muscarinic acetylcholine receptor (mAChR) activation in rRPa contributes to the inhibition of BAT sympathetic nerve activity (SNA) evoked by activation of neurons in the rostral ventrolateral medulla (RVLM). The RVLM is not the sole source of the muscarinic cholinergic input to rRPa. Activation of GABA receptors in rRPa does not mediate the cholinergic inhibition of BAT SNA. ABSTRACT: We sought to determine if body temperature and energy expenditure are influenced by a cholinergic input to neurons in the rostral raphe pallidus (rRPa), the site of sympathetic premotor neurons controlling thermogenesis of brown adipose tissue (BAT). Nanoinjections of the muscarinic acetylcholine receptor (mAChR) agonist, oxotremorine, or the cholinesterase inhibitor, neostigmine (NEOS), in the rRPa of anaesthetized rats decreased cold-evoked BAT sympathetic nerve activity (SNA, nadirs: -72 and -95%), BAT temperature (Tbat, -0.5 and -0.6°C), expired CO2 (Exp. CO2 , -0.3 and -0.5%) and heart rate (HR, -22 and -41 bpm). NEOS into rRPa reversed the increase in BAT SNA evoked by blockade of GABA receptors in rRPa. Nanoinjections of the mAChR antagonist, scopolamine (SCOP), in the rRPa of warm rats increased BAT SNA (peak: +1087%), Tbat (+1.8°C), Exp. CO2 (+0.7%), core temperature (Tcore, +0.5°C) and HR (+54 bpm). SCOP nanoinjections in rRPa produced similar activations of BAT during cold exposure, following a brain transection caudal to the hypothalamus, and during the blockade of glutamate receptors in rRPa. We conclude that a tonically active cholinergic input to the rRPa inhibits BAT SNA via activation of local mAChR. The inhibition of BAT SNA mediated by mAChR in rRPa does not depend on activation of GABA receptors in rRPa. The increase in BAT SNA following mAChR blockade in rRPa does not depend on the activity of neurons in the hypothalamus or on glutamate receptor activation in rRPa.


Assuntos
Tecido Adiposo Marrom/inervação , Inibição Neural , Núcleo Pálido da Rafe/fisiologia , Receptores Muscarínicos/metabolismo , Sistema Nervoso Simpático/fisiologia , Tecido Adiposo Marrom/fisiologia , Animais , Inibidores da Colinesterase/farmacologia , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Neostigmina/farmacologia , Oxotremorina/farmacologia , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo
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